Title of Invention	METHOD FOR SYNTHESIS OF ACYLOXYALKYL DERIVATIVES OF GABA ANALOGS
Abstract	1. A method of synthesizing a compound of Formula (I) comprising contacting a compound of Formula (II), a compound of Formula (III) and at least one equivalent of a metal salt or an organic base or a combination thereof wherein at a temperature between -25oc and 120oc wherein: X is F,Cl,Br or I; n is O or 1; R1 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R4 and R5 together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R6 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring; and R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl.

Title of Invention

METHOD FOR SYNTHESIS OF ACYLOXYALKYL DERIVATIVES OF GABA ANALOGS

Abstract

1. A method of synthesizing a compound of Formula (I) comprising contacting a compound of Formula (II), a compound of Formula (III) and at least one equivalent of a metal salt or an organic base or a combination thereof wherein at a temperature between -25oc and 120oc wherein: X is F,Cl,Br or I; n is O or 1; R1 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R4 and R5 together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R6 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring; and R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl.

Full Text	METHODS FOR SYNTHESIS OF ACYLOXYALKYL DERIVATIVES OF GABA ANALOGS Field Methods for synthesis of l-(acyloxy)-alkyl carbamates are provided. More particularly, the synthesis of prodrugs (i.e., 1-(acyloxy)-alkyl carbamates of GABA analogs) from 1-haloalkyl carbamates of GABA analogs are described. Also described are new 1-haloalkyl carbamates of GABA analogs. Background One solution to drug delivery and/or bioavailability issues in pharmaceutical development is converting known drugs to prodrugs. Typically, in a prodrug, a polar functional group (e.g., a carboxylic acid, an amino group, a hydroxyl group, etc.) is masked by a promoiety, which is labile under physiological conditions. Accordingly, prodrugs are usually transported through hydrophobic biological barriers such as membranes and typically possess superior physicochemical properties than the parent drug. Pharmacologically effective prodrugs are non-toxic and are preferably selectively cleaved at the locus of drug action. Ideally, cleavage of the promoiety occurs rapidly and quantitatively with the formation of non-toxic by-products (i.e., the hydrolyzed promoiety). The acyloxyalkoxycarbonyl functionality is an example of a promoiety that may be used to modulate the physiochemical properties of pharmaceuticals (Alexander, United • States Patent NO.,4,916,230 Alexander, United States Patent No, 5,733,9,07; Alexander et al, U.S. Patent No. 4,426,391). Typically, l-(acyloxy)-alkyl derivatives of a pharmaceutical possess superior bioavailability, may be less irritating to topical and gastric mucosal membranes and are usually more permeable through such membranes when compared to the parent drug. However, although l~(acyloxy)-alkyl ester derivatives of alcohols and l-(acyloxy)-alkyl carbamate derivatives of amines have been frequently used to mask these polar functional groups in pharmaceuticals, existing synthetic methods for preparing these desirable derivatives are inadequate. Methods disclosed in the art for synthesis of acyloxyalkyl esters and carbamates are typically multi-step routes that utilize unstable intermediates and/or toxic compounds or salts and accordingly are difficult to perform on large scale (Alexander, United States Patent No. 4,760,057; und, United States Patent No. 5,401,868; Alexander, United States Patent ISio. 4,/60,057; Saari et ah, European Patent 0416689B1). Accordingly, there is a need for a new synthesis of l-(acyloxy)-alkyl derivatives that proceeds rapidly and efficiently, which is amenable to scale-up and proceeds through readily accessible synthetic precursors. Summary A method for synthesizing l-(acyloxy)-alkyl derivatives from acyloxy derivatives, which typically proceeds in high yield, does not necessarily require the use of heavy metals and is readily amenable to_scale-up is provided herein. In a first aspect, a method of synthesizing a compound of Formula (I) is provided which comprises^ contacting a compound of Formula (II), a compound of Formula (III) and at least one equivalent of a metal salt wherein: X is F, C1, Br or I; n is O or 1; R1 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R4 and R5 together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R6 and R9 are independently selected from the group consisting of "hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring; and R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl. In a second aspect a method of synthesizing a compound of Formula (I) is provided which comprises contacting a compound of Formula (II), a compound of Formula (III) and at least one equivalent of an organic base, where X, n, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are as defined, supra. In a third aspect a compound of Formula (II) is provided, wherein: X is F,Cl,Br or I; n is O or 1; R2 and R3 are independently hydrogen, allcyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R4 and R5 together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R6 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring; and R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl. Detailed Description Definitions "Compounds" refers to compounds encompassed by structural formulae (I) - (VIII) disclosed herein and includes any specific compounds within these formulae whose structure is disclosed herein. Compounds may be identified either by their chemical structure and/or chemical name. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound. The compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. The compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds. The compounds described also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include, but are not limited to, 2H, 3H, 13C, 14C, 15N, 180,17O, etc. Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compounds maybe hydrated, solvated or N-oxides. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention. Further, it should be understood, when partial structures of the compounds are illustrated, that brackets indicate the point of attachment of the partial structure to the rest of the molecule. "1-Acyloxy-Alkyl Carbamate" refers to an N-1-acyloxy-alkoxycarbonyl derivative of a primary or secondary amine as encompassed by structural formulae (I), (V) and (VI) disclosed herein. "Alky!" by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), cycloprop-1-en-l-yl; cycloprop-2-en-l-yl, prop-1-yn-l-yl, prop-2-yn-l-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-l-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-l-yl, but-l-en-2-yl, 2-methyl-prop-1 -en- 1-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl, cyclobut-1-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-l,3-dien-l-yl, but- 1-yn- 1-yl, but-l-yn-3-yl, but-3-yn-l-yl, etc.; and the like. The term "alkyl" is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions "alkanyl," "alkenyl," and "alkynyl" are used. Preferably, an alkyl group comprises from 1 to 20 carbon atoms, more preferably, from 1 to 10 carbon atoms, most preferably, from 1 to 6 carbon atoms. "Alkanyl" by itself or as part of another substituent refers to a saturated branched, straight-chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl (Sec-butyl), 2-methyl-propan-l-yl (isobutyl), 2-methyl-propan-2-yl (/-butyl), cyclobutan-1-yl, etc.; and the like. "Alkenyl" by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-l-yl; cycloprop-2-en-l-yl; butenyls such as but-1-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl, cyclobut-1-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-l,3-dien-l-yl, etc.; and the like. "Alkynvl" by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1 -yn-1 -yl, prop-2-yn-1 -yl, etc.; butynyls such as but-1 -yn-1 -yl, but-1 -yn-3-yl, but-3-yn-l-yl, etc.; and the like. "Acyl" by itself or as part of another substituent refers to a radical -C(O)R30, where R30 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as defined herein. Representative examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like. "Alkoxy" by itself or as part of another substituent refers to a radical -OR31 where R31 represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like. "Alkoxvcarbonyl" by itself or as part of another substituent refers to a radical -OR32 where R32 represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl and the like. "Aryl" by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like. Preferably, an aryl group comprises from 6 to 20 carbon atoms, more preferably, from 6 to 12 carbon atoms. "Arylalkyl" by itself or as part of another substituent refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 2-phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2-naphthylethen-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl and/or arylalkynyl is used. Preferably, an arylalkyl group is (C6-C20) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C10) and the aryl moiety is (C6-C20), more preferably, an arylalkyl group is (C6-C20) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C8) and the aryl moiety is (C6-C12). "Aryldialkvlsilvl" by itself or as part of another substituent refers to the radical - SiR33R34R35 where one of R33, R34 or R35 is aryl as defined herein and the other two of R33, R34 or R35 are alkyl as defined herein. "Bridged cvcloalkyl" by itself or as part of another substituent refers to a radical selected from the group consisting of wherein: A is (CR38R39)b; R38 and R39 are independently selected from the group consisting of hydrogen and methyl; R and R37 are independently selected from the group consisting of hydrogen and methyl; b is an integer from 1 to 4; and c is an integer from 0 to 2. "Carbamoyl" by itself or as part of another substituent refers to the radical. -C(O)NR40R41 where R40 and R41 are independently hydrogen, alkyl, cycloalkyl or aryl as defined herein. "Cycloalkvl" by itself or as part of another substituent refers to a saturated or unsaturated cyclic alkyl radical. Where a specific level of saturation is intended, the nomenclature "cycloalkanyl" or "cycloalkenyl" is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like. Preferably, the cycloalkyl group is (C3-C10) cycloalkyl, more preferably (C3-C7) cycloalkyl. "Cycloheteroalkvl" by itself or as part of another substituent refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Where a specific level of saturation is intended, the nomenclature "cycloheteroalkanyl" or "cycloheteroalkenyl" is used. Typical cycloheteroalkyl groups include, but are not limited to, groups derived from epoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like. "GABA analog" refers to a compound, unless specified otherwise, as having the following structure: wherein: R6 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; R and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring. "1-Haloalkyl Carbamate" refers to an N-1-haloalkoxycarbonyl derivative of a primary or secondary amine as encompassed by structural formulae (II), (VII) and (VIII) disclosed herein. "Heteroalkyl, Heteroalkanvl, Heteroalkerivl and Heteroalkynyl" by themselves or as part of another substituent refer to alkyl, alkanyl, alkenyl and alkynyl groups, respectively, in which one or more of the carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatomic groups. Typical heteroatomic groups which can be included in these groups include, but are not limited to, -O-, -S-, -O-O-, -S-S-, -O-S-, -NR42R43, -=N-N=-, -N=N-, -N=N-NR44R45, -PR46-, -P(O)2-, -POR47-, -O-P(O)2-, -SO-, -SO2-, -SnR48R49- and the like, where R42, R43, R.44, R45, R46, R47, R48 and R49 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. "Heteroaryl" by itself or as part of another substituent refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, P-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofiiran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. Preferably, the heteroaryl group is from 5-20 membered heteroaryl, more preferably from 5-10 membered heteroaryl. Preferred heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine "Heteroarylalkyl" by itself or as part of another substituent refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylalkenyl and/or heterorylalkynyl is used. In preferred embodiments, the heteroarylalkyl group is a 6-30 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10 membered and the heteroaryl moiety is a 5-20-membered heteroaryl, more preferably, 6-20 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8 membered and the heteroaryl moiety is a 5-12-membered heteroaryl. "Parent Aromatic Ring System" refers to an unsaturated cyclic or polycyclic ring system having a conjugated n electron system. Specifically included within the definition of "parent aromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, &s-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like. "Parent Heteroaromatic Ring System" refers to a parent aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "parent heteroaromatic ring systems" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, arsindole, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Typical parent heteroaromatic ring systems include., but are not limited to, arsindole, carbazole, b-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. "Pharmaceutically acceptable salt" refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. "Prodrug" refers to a derivative of a drug molecule that requires a transformation within the body to release the active drug. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the parent drug. A hydroxyl containing drug may be converted to, for example, to a sulfonate, ester or carbonate prodrug, which may be hydrolyzed in vivo to provide the hydroxyl compound. An amino containing drug may be converted, for example, to a carbamate, amide, enamine, imine, N-phosphonyl, N-phosphoryl or N-sulfenyl prodrug, which may be hydrolyzed in vivo to provide the amino compound. A carboxylic acid drug may be converted to an ester (including silyl esters and thioesters), amide or hydrazide prodrug, which be hydrolyzed in vivo to provide the carboxylic acid compound. Prodrugs for drugs which have functional groups different than those listed above are well known to the skilled artisan. "Promoiety" refers to a form of protecting group that when used to mask a functional group within a drug molecule converts the drug into a prodrug. Typically, the promoiety will be attached to the drug via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo. "Protecting group" refers to a grouping of atoms that when attached to a reactive functional group in a molecule masks, reduces or prevents reactivity of the functional group. Examples of protecting groups can be found in Green et ah, "Protective Groups in Organic Chemistry", (Wiley, 2nd ed. 1991) and Harrison et ah, "Compendium of Synthetic Organic Methods", Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC") and the like. Representative hydroxy protecting groups include, but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers. "Substituted" refers to a group in which one or more hydrogen atoms are independently replaced with the same or different substituent(s). Typical substituents include, but are not limited to, -M, -R60, -O", =O, -OR60, -SR60, -S, =S, -NR60R61, =NR60, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2O; -S(O)2OH, -S(O)2R60, -OS(O2)O-OS(O)2R60, -P(O)(O)2, -P(O)(OR60)(O'), -OP(O)(OR60)(OR61), -C^R60, -C(S)R60, -C(O)OR60, -C(O)NR60R61,-C(O)O", -C(S)OR60, -NR62C(O)NR60R61, -NR62C(S)NR6OR61, -NR62C(NR63)NR60R6! and -C(NR62)NR60R61 where M is independently a halogen; R60, R61, R and R are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R60 and R61 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and R64 and R65 are independently hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R64 and R65 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably, substituents include -M, -R60, =O, -OR60, -SR60, -S", =S, -NR60R61, =NR60, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2R60, -OS(O2)O-OS(O)2R60, -P(O)(O-)2, -P(O)(OR60)(O-), -OP(O)(OR60)(OR6!), -C(O)R60, -C(S)R60, -C(O)OR60, C(O)NR60R61-C(pyyt -NR62C(O)NR60R61, more preferably, -M, -R60, =O, -OR60, -SR60, -NR60R61, -CF3, -CN, -NO2, -S(O)2R60, -P(O)(ORfi0)(O'), -OP(O)(OR60)(OR61), -C(O)R60, -C(O)OR60, -C(O)NR60R61,-C(O)O\ most preferably, -M, -R60, =O, -OR60, -SR60, -NR60R61, -CF3, -CN, -NO2, -S(O)2R60, -OP(O)(OR60)(OR61), -C(O)R60, -C(O)OR60 ,-C(O)O", where R60, R61 and R62 are as defined above. "Trialkylsilyl" by itself or as part of another substituent refers to a radical - SiR50R51R52 where R50, R51 and R52 are alkyl as defined herein. Reference will now be made in detail to preferred embodiments of the invention. While the invention will be described in conjunction with the preferred embodiments, it will be understood that it is not intended to limit the invention to those preferred embodiments. To the contrary, it is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims. Method of Synthesis of l-(Acyloxy)-Alkyl GABA Analogs Methods of synthesis of l-(acyloxy)-alkyl carbamates of GABA analogs from 1-haloalkylcarbamates of GAB A analogs are disclosed. Preferably, l-(acyloxy)-alkyl carbamates of GABA analogs are synthesized by reaction of a 1-haloalkyl carbamate of a GABA analog with a carboxylic acid in the presence of either a metal salt or an organic base, In one embodiment, the carboxylic acid also serves a solvent for the reaction. In a first aspect, a compound of Formula (I) is synthesized by a method comprising contacting a compound of Formula (II), a compound of Formula (III) and at least one equivalent of a metal salt wherein: X is F,Cl,Br or I; n is O or l; R1 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R4 and R5 together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R6 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring; and R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl. In a second aspect, a compound of Formula (I) is synthesized by a method comprising contacting a compound of Formula (II), a compound of Formula (III) and at least one equivalent of an organic base, wherein X, n, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are as defined, supra. Those of skill in the art will appreciate that many of the embodiments described, infra, are embodiments of both aspects, supra. In one embodiment, R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl or substituted heteroaryl. In another embodiment, R2 and R3 are independently hydrogen, alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl, or heteroaryl. In still another embodiment, R2 and R3 are independently hydrogen, alkanyl or substituted alkanyl. In still another embodiment, R2 and R3 are independently hydrogen or alkanyl. In still another embodiment, R1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl or substituted heteroaryl. In still another embodiment, R1 is alkyl or substituted alkyl. In still another embodiment, R1 is alkanyl or substituted alkanyl. hi still another embodiment, R1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl or substituted heteroaryl, and R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. In still another embodiment, R1 is alkyl, substituted alkyl, aryl, arylalkyl or heteroaryl and R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. In still another embodiment, R1 is alkanyl or substituted alkanyl and R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. In still another embodiment, R1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl or substituted cycloalkyl and R2 and R3 are independently hydrogen, alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl or heteroaryl. In still another embodiment, R1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl or substituted cycloalkyl and R2 and R3 are independently hydrogen, alkanyl or substituted alkanyl. In still another embodiment, R1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl or substituted cycloalkyl and R2 and R3 are independently alkanyl. In still another embodiment, R is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroaryl or substituted heteroaryl and R2 and R3 together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. In still another embodiment, R1 is alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R2 and R3 are independently hydrogen, alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl or heteroaryl. In still another embodiment, R1 is alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R2 and R3 are independently hydrogen, alkanyl or substituted alkanyl. hi still another embodiment, R1 is alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R2 and R3 are independently alkanyl. Br still another embodiment, R1 is alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R2 and R3 together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. hi still another embodiment, R1 is alkanyl or substituted alkanyl and R2 and R3 are independently hydrogen, alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl or heteroaryl. In still another embodiment, R1 is alkanyl or substituted alkanyl and R2 and R3 are independently hydrogen, alkanyl or substituted alkanyl. In still another embodiment, R1 is alkanyl or substituted alkanyl and R2 and R3 are independently alkanyl. hi still another embodiment, R1 is alkanyl or substituted alkanyl, and R2 and R3 together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl;, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl. In still another embodiment, R2 and R3 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl and R and R are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl and R2 and R3 together with the atom to which they are attached form a cyclobutyl, cyclopentyl or cyclohexyl ring. . In still another embodiment, R2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl or phenyl and R3 is hydrogen. In still another embodiment, R2 is methyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or cyclohexyloxycarbonyl and R3 is methyl. In still another embodiment, R1 is methyl, ethyl, «-propyl, isopropyl, H-butyl, isobutyl, sec-butyl, tert-butyl, 1,1-dimethoxyethyl or 1,1-diethoxyethyl. In still another embodiment, R2 is methyl, ethyl, //-propyl, isopropyl, 7i-butyl, isobutyl, sec-butyl or tert-butyl, and R3 is hydrogen, hi still another embodiment, Rl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1,1-dimethoxyethyl or 1,1-diethoxyethyl, R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and R3 is hydrogen. In still another embodiment, R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl. In still another embodiment, R10 is hydrogen. In still another embodiment, R10 is alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl or trialkylsilyl. hi still another embodiment, R10 is methyl, ethyl, ter/-butyl, allyl, benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl, -C(CH3)=CH2, -CH2C(O)N(CH3)2, where V is -O- or -CH2-. hi one embodiment, n is 0. In another embodiment, n is 1. hi one embodiment, R5 is selected from the group consisting of hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkyl and substituted heteroarylalkanyl. In another embodiment, R5 is selected from the group consisting of hydrogen, alkanyl and cycloalkanyl. In still another embodiment, R5 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl and cyclohexyl. In still another embodiment, R5 is selected from the group consisting of substituted alkanyl. In still another embodiment, R is selected from the group consisting of -CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, - CH2CH2SCH3, CH2SH, -CH2(CH2)3NH2 and -CH2CH2CH2NHC(NH)NH2. hi still another embodiment, R5 is selected from the group consisting of aryl, arylalkanyl, substituted arylalkanyl and heteroarylalkanyl. In still another embodiment, R5 is selected from the group consisting of phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 4-imidazolylmethyl and 3-indolylmethyl. hi still another embodiment, R4 and R5 together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring, In still another embodiment, R4 and R5 together with the atoms to which they are attached form an azetidine, pyrrolidine or piperidine ring. In one embodiment, R6 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and substituted cycloalkyl. In another embodiment, R6 and R9 are independently selected from the group consisting of hydrogen and alkanyl. In still another embodiment, R6 and R9 are both hydrogen. In one embodiment, R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl and substituted cycloheteroalkyl. In another embodiment, R7 and R8 are independently selected from the group consisting of hydrogen, alkanyl and substituted alkanyl. In still another embodiment, R7 is hydrogen and R8 is selected from the group consisting of C1-6 alkanyl. In still another embodiment, R7 and R8 together with the carbon atom to which they are attached are cycloalkanyl or substituted cycloalkanyl. In still another embodiment, R7 and R8 together with the carbon atom to which they are attached are selected from the group consisting of cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl and substituted cyclohexyl. In still another embodiment, R7 and R8 together with the carbon atom to which they are attached are cycloheteroalkyl or substituted cycloheteroalkyl. In still another embodiment, R7 and R8 together with the carbon atom to which they are attached are bridged cycloalkyl. In one embodiment, X is chloro, bromo or iodo. In another embodiment, X is chloro, and R2 and R3 are independently hydrogen or alkanyl. In still another embodiment, X is chloro, and R2 and R3 together with the atom to which they are attached form a cycloalkanyl ring. In still another embodiment, X is chloro, bromo or iodo, and R2 and R3 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl. In still another embodiment, X is chloro, bromo or iodo, and R2 and R3 together with the atom to which they are attached form a cyclobutyl, cyclopentyl or cyclohexyl ring, hi still another embodiment, X is chloro, bromo or iodo, R2 is methyl, ethyl, 72-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl or phenyl and R3 is hydrogen. In one embodiment, a compound of Formulae (I) or (II) is derived is derived from a GABA analog of Formula (IV): wherein the GABA analog of Formula (IV) is selected from the group consisting of: 1-Aminomethyl-l-cyclohexane acetic acid (i.e. gabapentin); l-Aminomethyl-l-(3-methylcyclohexane) acetic acid; l-Aminomethyl-l-(4-methylcyclohexane) acetic acid; l-Aminomethyl-l-(4-isopropylcyclohexane) acetic acid; l-Ammomemyl-l-(4-tert-butylcyclohexane) acetic acid; l-Aminomethyl-l-(3,3-dimethylcyclohexane) acetic acid; l-Aminomethyl-l-(3,3,5,5-tetramethylcyclohexane) acetic acid; 1-Aminomethyl-l-cyclopentane acetic acid; l-Aminomethyl-l-(3-methylcyclopentane) acetic acid; l-Aminomethyl-l-(3,4-dimethylcyclopentane) acetic acid; 7-Aminomethyl-bicyclo[2.2.1]hept-7-yl acetic acid; 9-Aminomethyl-bicyclo[3.3.1]non-9-yl acetic acid; 4-Aminomethyl-4-(tetrahydropyran-4-yl) acetic acid; 3-Aminomethyl-3-(tetrahydropyran-3-yl) acetic acid; 4-Aminomethyl-4-(tetrahydrothiopyran-4-yl) acetic acid; 3-Aminomethyl-3-(tetrahydrothiopyran-3-yl) acetic acid; (S)-3-Aminomethyl-5-methyl-hexanoic acid (i.e. pregabalin); 3-Aminomethyl-5-methyl-heptanoic acid; 3-Aminomethyl-5-methyl-octanoic acid; 3-Aminomethyl-5-methyl-nonanoic acid; 3-Aminomethyl-5-methyl-decanoic acid; 3 -Aminomethyl-5-cyclopropyl-hexanoic acid; 3-Aminomethyl-5-cyclobutyl-hexanoic acid; 3-Aminomethyl-5-cyclopentyl-hexanoic acid; 3-Aminomethyl-5-cyclohexyl-hexanoic acid; 3-Aminomethyl-5-phenyl-hexanoic acid; 3-Aminomethyl-5-phenyl-pentanoic acid; 3-Aminomethyl-4-cyclobutyl-butyric acid; 3 -Aminomethyl-4-cycIopentyl-butyric acid; 3-Aminomethyl-4-cyclohexyl-butyric acid; 3 -Ajtninomethyl-4-phenoxy-butyric acid; 3-Aminomethyl-5-phenoxy-hexanoic acid; and 3-Aminomethyl-5-benzylsulfanyl-pentanoic acid. In another embodiment, the compound of Formula (I) is a compound of Formulae (V)or(VI): The skilled artisan will appreciate that the embodiments, infra, refer to compounds of Formulae (V) and (VI) In one embodiment, n is 0. In another embodiment n is 1. In one embodiment, R5 is selected from the group consisting of hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkyl and substituted heteroarylalkanyl. hi another embodiment, R'1 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-bxAy\, cyclopentyl, cyclohexyl, -CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, - CH2CH2SGH3, CH2SH, -CH2(CH2)3NH2 and -CH2CH2CH2NHC(NH)NH2, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 4-imidazolylmethyl and 3-indolylmethyl. In still another embodiment, R and R5 together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. In still another embodiment, R4 and R5 together with the atoms to which they are attached form an azetidine, pyrrolidine or piperidine ring. In one embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .sec-butyl, /er/-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is hydrogen and R3 is hydrogen. In another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, /ert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is methyl and R3 is hydrogen. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is ethyl and R3 is hydrogen. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is propyl and R3 is hydrogen, hi still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is isopropyl and R3 is hydrogen. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is butyl and R3 is hydrogen. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is isobutyl and R3 is hydrogen. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is sec-butyl and R3 is hydrogen. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is tert-butyl and R3 is hydrogen. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is cyclohexyl and R3 is hydrogen. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .sec-butyl, tert-butyl, pentyl, isopentyl, .sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is phenyl and R3 is hydrogen. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .sec-butyl, tert-butyl, pentyl, isopentyl, .sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is methyl and R3 is methyl. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .sec-butyl, tert-butyl, pentyl, isopentyl, .sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is methoxycarbonyl and R3 is methyl. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .sec-butyl, tert-butyl, pentyl, isopentyl, .sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is ethoxycarbonyl and R3 is methyl. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is isopropoxycarbonyl and R3 is methyl. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, .sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R is cyclohexyloxycarbonyl and R is methyl. In still another embodiment, R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl and R2 and R3 together with the atom to which they are attached form a cyclohexyl ring. In one embodiment, R2 is methyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or cyclohexyloxycarbonyl and R3 is methyl. In another embodiment, R2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl and R3 is hydrogen. In one embodiment, R1 is methyl, ethyl, 71-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, /er/-butyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl or cyclohexyl, and R10 is hydrogen, allyl, benzyl or trimethylsilyl. In one embodiment, R1 is methyl, ethyl, w-propyl, isopropyl, H-butyl, isobutyl, .sec-butyl, tert-butyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl or cyclohexyl, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is hydrogen, methyl, ethyl, isopropyl, zz-butyl, isobutyl, sec-butyl or tert-butyl, and R3 is hydrogen. In another embodiment, R1 is ethyl or isopropyl, R10 is allyl, benzyl or trimethylsilyl, R2 is methyl, /z-propyl or isopropyl, and R3 is hydrogen. In still another embodiment, R1 is isopropyl, R10 is benzyl, R2 is methyl, and R3 is hydrogen. In still another embodiment, R1 is isopropyl, R10 is allyl, R2 is methyl, and R3 is hydrogen. In one embodiment, R1 is ethyl or isopropyl, R10 is allyl, benzyl or trimethylsilyl, R2 is methyl, ;?-propyl or isopropyl, R3 is hydrogen and X is chloro. In another embodiment, R1 is isopropyl, R10 is benzyl, R2 is methyl, R3 is hydrogen and X is chloro. In still another embodiment, R1 is isopropyl, R10 is allyl, R2 is methyl, R3 is hydrogen and X is chloro. In one embodiment, X is bromo or chloro. In another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is hydrogen and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is methyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is ethyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is propyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is isopropyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is butyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is isobutyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl,, R2 is sec-butyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is tert-butyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is cyclohexyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is phenyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is methyl and R3 is methyl. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R is methoxycarbonyl and R is methyl, hi still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is ethoxycarbonyl and R3 is methyl. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is isopropoxycarbonyl and R3 is methyl. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is cyclohexyloxycarbonyl and R3 is methyl. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl and R2 and R3 together with the atom to which they are attached form a cyclohexyl ring. In still another embodiment, X is chloro, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl and R3 is hydrogen. In still another embodiment, X is chloro., R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is methyl, «-propyl or isopropyl, and R3 is hydrogen. In still another embodiment, X is chloro, R10 is allyl, R2 is methyl, and R3 is hydrogen. In still another embodiment, X is chloro, R10 is benzyl, R2 is methyl, and R3 is hydrogen. In still another embodiment, X is chloro, R10 is trimethylsilyl, R2 is methyl, and R3 is hydrogen. Those of skill in the art will appreciate that the following embodiments, infra, refer to compounds of Formulae (I), (II) and (III). In one embodiment, the ratio of the compound of Formula (II) to the compound of Formula (III) is between about 1:1 and 1:20. In another embodiment, the ratio of the compound of Formula (II) to the compound of Formula (III) is between about 1:1 and 1:5. In still another embodiment, the ratio of the compound of Formula (II) to the compound of Formula (III) is about 1:1. In one embodiment, the compounds of Formulae (II) and (III) and the metal salt are contacted with a solvent. In another embodiment, the ratio of the compound of Formula (II) to the compound of Formula (III) is between about 1:1 and 1:20. hi still another embodiment, the ratio of the compound of Formula (II) to the compound of Formula (III) is between about 1:1 and 1:5. In still another embodiment, the ratio of the compound of Formula (II) to the compound of Foimula (III) is about 1:1. In one embodiment, the solvent is dichloromethane, dichloroethane, chloroform, toluene, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, pyridine, ethyl acetate, acetonitrile, acetone, 2-butanone, methyl tert-butyl ether, methanol, ethanol, isopropanol, tert-butanol, water, hexamethylphosphoramide or combinations thereof. In another embodiment, the metal is Ag, Hg, Na, K, Li, Cs, Ca, Mg or Zn. In one embodiment, the compounds of Formulae (II) and (III) and the organic base are contacted with a solvent, hi another embodiment, the ratio of the compound of Formula (II) to the compound of Formula (III) is between about 1:1 and 1:20. In still another embodiment, the ratio of the compound of Formula (II) to the compound of Formula (III) is between about 1:15 and 1:20. In still another embodiment, the ratio of the compound of Formula (II) to the compound of Formula (III) is about 1:10. Li still another embodiment, the ratio of the compound of Formula (II) to the compound of Formula (III) is between about 1:1 and 1:5. In still another embodiment, the ratio of the compound of Formula (II) to the compound of Formula (III) is about 1:1. In one embodiment, the solvent is dichloromethane, dichloroethane, chloroform, toluene, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, pyridine, ethyl acetate, acetonitrile, acetone, 2-butanone, methyl tert-butyl ether, methanol, ethanol, isopropanol, ter/-butanol, water, hexamethylphosphoramide or combinations thereof. In another embodiment, the organic base is triethylamine, tributylamine, diisopropylethylamine, dimethylisopropylamine, N-methyhnorpholine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, 1, 4-diazabicyclo[2.2.2]octane, 1, 8-diazabicyclo[5.4.0]undec-7-ene, 1, 5-diazabicyclo[4.3.0]undec-7-ene or combinations thereof. hi one embodiment, the compound of Formula (III) is a liquid under the conditions of said contacting, the compound of Formula (III) further serving as a solvent for the reaction with the compound of Formula (II). In another embodiment, the compound of Formula (III) is acetic acid, methoxyacetic acid, ethoxyacetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, 2-methylbutyric acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid or cyclohexanecarboxylic acid, hi still another embodiment, the compound of Formula (III) is isobutyric acid. In one embodiment, the compound of Formula (II), the compound of Formula (III) and the metal salt are contacted at a temperature between about -25 °C and about 120 °C. In another embodiment, the temperature is between about 0 °C and about 25 °C. In one embodiment, the compound of Formula (II), the compound of Formula (HI) and the organic base are contacted at a temperature between about -25 °C and about 120 °C. In another embodiment, the temperature is between about 0 °C and about 25 °C. In one embodiment, the compound of Formula (II), the compound of Formula (HI) and the organic base are contacted with a catalytic amount of an iodide salt. In still another embodiment, the iodide salt is sodium iodide, potassium iodide, tetramethylammonium iodide, tetraethylammonium iodide or tetrabutylammonium iodide. 1-HaloalkyI Carbamates of GABA Analogs Also disclosed herein are 1-haloalkyl carbamates of GABA analogs of Formula (II): R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R4 and R5 together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R6 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring; and R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl. Those of skill in the art will appreciate that the following embodiments, infra, refer to compounds of Formula (II). In one embodiment, R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl or substituted heteroaryl. In another embodiment, R2 and R3 are independently hydrogen, alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl or heteroaryl. In still another embodiment, R2 and R3 are independently hydrogen, alkanyl or substituted alkanyl. In still another embodiment, R2 and JR.3 are independently hydrogen or alkanyl. In still another embodiment, R2 and R3 together with the atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. In still another embodiment R and R together with the atom to which they are bonded form a cycloalkanyl ring. In one embodiment, X is chloro, bromo or iodo. In another embodiment, X is chloro. In one embodiment, X is chloro, bromo or iodo and R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkbxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. In another embodiment, X is chloro, bromo or iodo, and R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. In still another embodiment, X is chloro and R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. In still another embodiment, X is chloro, bromo or iodo, and R2 and R3 are independently hydrogen, alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl or heteroaryl. In still another embodiment, X is chloro, bromo or iodo, and R2 and R3 are independently hydrogen, alkanyl or substituted alkanyl. In still another embodiment, X is chloro, bromo or iodo, and R2 and R3 are independently alkanyl. In still another embodiment, X is chloro, bromo or iodo, and R2 and R3 together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. In still another embodiment, X is chloro, and R2 and R3 are independently hydrogen, alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl or heteroaryl. hi still another embodiment, X is chloro, and R and R are independently hydrogen, alkanyl or substituted alkanyl. In still another embodiment, X is chloro, and R2 and R3 are independently alkanyl. In still another embodiment, X is chloro, and R2 and R3 together with the atom to which they are attached form a cycloalkanyl ring. In one embodiment, R and R are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl. In another embodiment, X is chloro, bromo or iodo, and R2 and R3 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, fert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl. In still another embodiment, X is chloro, bromo or iodo, and R2 and R3 together with the atom to which they are attached form a cyclobutyl, cyclopentyl or cyclohexyl ring. In one embodiment, R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl or phenyl and R3 is hydrogen, hi another embodiment, R2 is methyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or cyclohexyloxycarbonyl and R3 is methyl. hi still another embodiment, X is chloro, bromo or iodo, R2 is methyl, ethyl, n-propyl, isopropyl, H-butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl or phenyl and R3 is hydrogen. hi one embodiment, R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl. hi another embodiment, R10 is hydrogen. In still another embodiment, R10 is alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl or trialkylsilyl. In still another embodiment, R10 is methyl, ethyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl, diphenyhnethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl, -C(CH3)=CH2, -CH2C(O)N(CH3)2, where V is -O- or -CH2-. hi still another embodiment, R10 is allyl. hi still another embodiment, R10 is benzyl. In still another embodiment, R10 is trimethylsilyl. In one embodiment, n is 0. hi another embodiment, n is 1. In one embodiment, R is hydrogen. In another embodiment, R5 is selected from the group consisting of hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkyl and substituted heteroarylalkanyl. In another embodiment, R5 is selected from the group consisting of hydrogen, alkanyl and cycloalkanyl. In still another embodiment, R5 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl and cyclohexyl. In still another embodiment, R5 is selected from the group consisting of substituted alkanyl. In still another embodiment, R5 is selected from the group consisting of -CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, - CH2CH2SCH3, CH2SH, -CH2(CH2)3NH2 and -CH2CH2CH2NHC(NH)NH2. In still another embodiment, R5 is selected from the group consisting of aryl, arylalkanyl, substituted arylalkanyl and heteroarylalkanyl. In still another embodiment, R5 is selected from the group consisting of phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 4-imidazolybnethyl and 3-indolylmethyl. In still another embodiment, R4 and R5 together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. In still another embodiment, R4 and R5 together with the atoms to which they are attached form an azetidine, pyrrolidine or piperidine ring. In one embodiment, R and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and substituted cycloalkyl. In another embodiment, R6 and R9 are independently selected from the group consisting of hydrogen and alkanyl. In still another embodiment, R6 and R9 are both hydrogen. "7 ft ' hi one embodiment, R and R are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl and substituted cycloheteroalkyl. hi another embodiment, R7 and R8 are independently selected from the group consisting of hydrogen, alkanyl and substituted alkanyl. In still another embodiment, R7 is hydrogen and R8 is selected from the group consisting of C1-6 alkanyl. hi still another embodiment, R7 and R8 together with the carbon atom to which they are attached are cycloalkanyl or substituted cycloalkanyl. hi still another embodiment, R7 and R8 together with the carbon atom to which they are attached are selected from the group consisting of cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl and substituted cyclohexyl. In still another embodiment, R and R together with the carbon atom to which they are attached are cycloheteroalkyl or substituted 1 ft cycloheteroalkyl. In still another embodiment, R and R together with the carbon atom to which they are attached are bridged cycloalkyl. In one embodiment, a compound of Formula (II) is derived from a GAB A analog of Formula (IVY. wherein the GAB A analog of Formula (TV) is selected from the group consistir 1-Aminomethyl-l-cyclohexane acetic acid {i.e., gabapentin); l-Aminomethyl-l-(3-methylcyclohexane) acetic acid; l-Aminomethyl-l-(4-methylcyclohexane) acetic acid; l-Aminomethyl-l-(4-isopropylcyclohexane) acetic acid; l-Aminomethyl-l-(4-tert-butylcyclohexane) acetic acid; l-Ammomethyl-l-(3,3-dimethylcyclohexane) acetic acid; 1-Aminomethyl-l-(3,3,5,5-tetrarnethylcyclohexane) acetic acid; 1-Aminomethyl-l-cyclopentane acetic acid; l-Aminomethyl-l-(3-methylcyclopentane) acetic acid; 1-Aminomethyl-l-(3,4-dimethylcyclopentane) acetic acid; 7-Aminomethyl-bicyclo[2.2.1]hept-7-yl acetic acid; 9-Aminomethyl-bicyclo[3.3.1]non-9-yl acetic acid; 4-Aminomethyl-4-(tetrahydropyran-4-yl) acetic acid; 3-Aminomethyl-3-(tetrahydropyran-3-yl) acetic acid; 4-Aminomethyl-4-(tetrahydrothiopyran-4-yl) acetic acid; 3-Aminomethyl-3-(tetrahydrothiopyran-3-yl) acetic acid; (S)-3-Aminomethyl-5-rnethyl-hexanoic acid (i.e., pregabalin); 3-Aminomethyl-5-methyl-heptanoic acid; 3-Aminomethyl-5-methyl-octanoicacid; 3-Aminomethyl-5-methyl-nonanoic acid; 3-Aminomethyl-5-methyl-decanoic acid; 3-Aminomethyl-5-cyclopropyl-hexanoic acid; 3-Aminomethyl-5-cyclobutyl-hexanoicacid; 3-Aminomethyl-5-cyclopentyl-hexanoic acid; 3-Ammomethyl-5-cyclohexyl-hexanoicacid; 3-Aminomethyl-5-phenyl-hexanoic acid; 3-Aminomethyl-5-phenyl-pentanoic acid; 3 -Aminomethyl-4-cyclobutyl-butyric acid; 3-AminomethyI-4-cyclopentyl-butyric acid; 3-Ammomethyl-4-cyclohexyl-butyricacid; 3-Aminomethyl-4-phenoxy-butyric acid; 3-Aminomethyl-5-phenoxy-hexanoic acid; and 3-Aminomethyl-5-benzylsulfanyI-pentanoic acid. In one embodiment, the compound of Formula (II) is a compound of Formulae (VII) or (VIII): Those of skill in the art will appreciate that the following embodiments, infra, refer to compounds of Formulae (VII) and (VIII). In one embodiment, n is 0. In another embodiment, n is 1. In one embodiment, R4 is hydrogen. In another embodiment, R5 is selected from the group consisting of hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkyl and substituted heteroarylalkanyl. In another embodiment, R5 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-bntyl, cyelopentyl, cyclohexyl, -CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, - CH2CH2SCH3, CH2SH, -CH2(CH2)3NH2 and -CH2CH2CH2NHC(NH)NH2, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 4-imidazolylmethyl and 3-indolylmethyl. In still another embodiment, R4 and R5 together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. In still another embodiment, R4 and R5 together with the atoms to which they are attached form an azetidine, pyrrolidine or piperidine ring. In one embodiment, X is cMoro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is hydrogen and R3 is hydrogen. In another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is methyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is ethyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is propyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is isopropyl and R3 is hydrogen. In-still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is butyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is isobutyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is sec-butyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is tert-butyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is cyclohexyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is phenyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is methyl and R3 is methyl. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is methoxycarbonyl and R3 is methyl. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is ethoxycarbonyl and R3 is methyl. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is isopropoxycarbonyl and R3 is methyl. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is cyclohexyloxycarbonyl and R3 is methyl. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, and R2 and R3 together with the atom to which they are attached form a cyclohexyl ring. In one embodiment, X is chloro, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl and R3 is hydrogen. In another embodiment, X is chloro, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is methyl, n-propyl br isopropyl, and R3 is hydrogen. In still another embodiment, X is chloro, R10 is allyl, R2 is methyl, and R3 is hydrogen. In still another embodiment, X is chloro, R10 is benzyl, R2 is methyl, and R3 is hydrogen. In still another embodiment, X is chloro, R10 is trimethylsilyl, R2 is methyl, and R3 is hydrogen. Synthesis of 1-HaloalkyI Carbamates and Conversion to 1-Acyloxy-AlkyI Carbamates The compounds and methods of the invention may be obtained and/or practiced according to the synthetic methods illustrated in Schemes 1-5. Numerous methods have been described in the art for the synthesis of GAB A analogs (i.e., compounds of formula (1), infra, where n = 0; see, e.g., Satzinger et al, United States Patent No. 4,024,175; Silverman et al, United States Patent No. 5,563,175; Horwell et al, United States Patent No. 6,020,370; Silverman et al, United States Patent No. 6,028,214; Horwell et al, United States Patent No. 6,103,932; Silverman et al, United States Patent No. 6,117,906; Silverman, International Publication No. WO 92/09560; Silverman etal, International Publication No. WO 93/23383; Horwell et al, International Publication No. WO 97/29101, Horwell et al, International Publication No. WO 97/33858; Horwell et al, International Publication No. WO 97/33859; Bryans et al, International Publication No. WO 98/17627; Guglietta et al, International Publication No. WO 99/08671; Bryans et al, International Publication No. WO 99/21824; Bryans et al, International Publication No. WO 99/31057; Belliotti et al, International Publication No. WO 99/31074; Bryans et al, International Publication No. WO 99/31075; Bryans et al, International Publication No. WO 99/61424; Bryans etal, International Publication No. WO 00/15611; Bryans, International Publication No. WO 00/31020; and Bryans et al, International Publication No. WO 00/50027). Other methods are known in the art for synthesizing GAB A analogs, which are readily accessible to the skilled artisan. Methods for synthesis of amino acid derivatives of GAB A analogs {i.e., compounds of formula (1), infra, where n = 1) are disclosed in Gallop et al, International Publication No. WO 02/100347). Accordingly, starting materials useful for preparing compounds and intermediates thereof, and/or practicing methods of the invention are commercially available or can be prepared by well-known synthetic methods. Other methods for synthesis of the prodrugs described herein are either described in the art or will be readily apparent to the skilled artisan in view of the references provided above and may be used to synthesize the compounds of the invention. Accordingly, the methods presented in the Schemes herein are illustrative rather than comprehensive. Intermediate (4) useful in the preparation of 1-haloalkyl carbamates of Formula (II) may be generated according to reactions detailed in Scheme 1. The amino group of (1) (a GAB A analog when n = 0, or an aminoacyl derivative of a GAB A analog when n = 1) is protected under standard conditions with a protecting group ("Pg") to afford compound (2). The carboxylic acid moiety in (2) is esterified to yield compound (3), either (i) via alkylation with RI0-Y, where Y is halide, O3SR' (R' is alkyl, substituted alkyl, aryl or substituted aryl), or other suitable leaving group), or (ii) via condensation with alcohol R10-OH under standard acylation conditions (e.g., in the presence of a coupling agent such as a carbodiimide, via an acyl halide, acid anhydride or other activated ester intermediate). Removal of the protecting group from (3) under standard deprotection conditions affords compound (4). Preferably, when n = 0, the protecting group Pg is removable under acidic conditions and compound (4) is isolated as a salt, which is stabilized towards lactam formation relative to the corresponding free base form. tert-Butoxycarbonyl (i.e., Boc) is one preferred protecting group, and may be removed with HC1 to afford (4) as a hydrochloride salt. In a preferred embodiment, where n is 0, the hydrochloride salt of (4) is prepared directly from (1) by treatment with an excess of thionyl chloride or hydrogen chloride gas and alcohol R10-OH (Scheme 2). Typical ratios of (1) to thionyl chloride from between 1:1 and 1:20, and ratios of (1) to alcohol from between 1:1 and 1:20 may be used. The reaction may be performed at temperatures between —20 °C and 25°C. Under conditions where the alcohol R10-OH is a liquid, the alcohol may be used as a solvent for the reaction. Alternatively, the reaction may be performed in the presence of a suitable solvent, such as, for example, dichloromethane, dichloroethane, chloroform, toluene, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, or pyridine. Preferred alcohols R10-OH for this reaction are arylalkyl, substituted arylalkyl and allylic alcohols. Allyl alcohol and benzyl alcohol are particularly preferred. In one embodiment, a compound of formula (II) is prepared by acylation of (4) with compound (5) (see Scheme 3), where X is halide and Z is a leaving group (e.g., halide, />-nitrophenolate, imidazolyl, etc.). Preferably, X is Cl or Br and Z is Cl. More preferably, X and Z are both Cl. The acylation reaction may be performed in the presence of a base, including inorganic and organic bases (e.g., tertiary amine bases, such as triethylamine, tributylamine, diisopropylethylamine, dimethylisopropylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, 1, 4-diazabicyclo[2.2.2]octane, 1, 8-diazabicyclo[5.4.0]undec-7-ene, 1, 5-diazabicyclo[4.3.0]undec-7-ene, etc.). Suitable solvents for this acylation include, but are not limited to, dichloromethane, dichloroethane, chloroform, toluene, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, pyridine, ethyl acetate, isopropyl acetate, acetonitrile, acetone, 2-butanone, methyl tert-bntyl ether, or combinations thereof. Alternatively, biphasic solvent mixtures comprising water and one or more of dichloromethane, dichloroethane, chloroform, toluene, ethyl acetate, isopropyl acetate or methyl ter-butyl ether, may be utilized. Typical temperatures for performing this reaction are between -20 °C and 50°C, more preferably, between -20 °C and 25°C. In another embodiment, a compound of formula (II), where R10 is trialkylsilyl or aryldialkylsilyl, may be prepared directly from compound (1) by silylation (e.g., using a silyl halide or silylamide reagent) and then acylation of the resulting intermediate with compound (5) (see Scheme 4). Suitable solvents for performing this reaction include, but are not limited to, dichloromethane, dichloroethane, chloroform, toluene, pyridine, and acetonitrile. Suitable bases for performing this reaction include, but are not limited to, triethylamine, tributylamine, diisopropylethylamine, dimethylisopropylamine, N-methylmorpholme, N-methylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyridine, 2,6-draiethylpyridine, 4-dimethylaminopyridine, 1, 4-diazabicyclo[2.2.2]octane, 1, 8-diazabicyclo[5.4.0]undec-7-ene or 1, 5-diazabicyclo[4.3.0]undec-7-ene. Typical temperatures for performing this reaction are between -78 °C and 50°C, more preferably, between -20 °C and 25°C. 1-Acyloxylalkyl carbamates of fonnula (I) are prepared from compounds of formula (II) by treatment with carboxylic acids of formula (III) in the presence of an organic or inorganic base, or other metal salt, as illustrated in Scheme 5. Preferred solvents, bases and other reaction conditions have been described in detail previously (see Section 4.2 above). In one embodiment, R10 is a carboxylic acid protecting group that can be removed under mild conditions to provide a compound of fonnula (I) where R10 is hydrogen. Carboxylic acid protecting groups removable via mild acidic hydrolysis, fluoride ion-promoted hydrolysis, catalytic hydrogenolysis, transfer hydrogenolysis, or other transition metal-mediated deprotection reactions are preferred. In one embodiment, R10 is trirnethylsilyl, allyl or benzyl. Examples The invention is further defined by reference to the following examples, which describe in detail the preparation of 1 -haloalkyl carbamates of GAB A analogs and illustrate methods of synthesizing l-(acyloxy)-alkyl, carbamates of GAB A analogues from 1-haloalkyl carbamates of GAB A analogs. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. Frnoc = 9-fluorenylmethyloxycarbonyl g = gram h = hour HPLC = high pressure liquid chromatography L = liter LC/MS =r liquid chromatography/mass spectroscopy M = molar min = minute mL = milliliter mmol = millimoles NHS = N-hydroxysuccinimide THF = tetrahydrofuran TFA = trifluoroacetic acid TLC = thin layer chromatography TMS = trimethylsilyl uL = microliter uM = micromolar v/v = volume to volume Example 1: Benzyl 1-AminomethvI-l-Cyclohexane Acetate Hydrochloride (6) A dry 500 mL, three-necked, round-bottomed flask was fitted with a magnetic stirring bar and a 60 mL pressure-equalizing addition runnel and flushed with nitrogen gas. The flask was charged with gabapentin (17.1 g, 0.1 mol) and benzyl alcohol (128 mL, 1.18 mol) and the mixture was cooled to 0°C with an ice-water bath. Thionyl chloride (51.8 mL, 77.25 g, 0.65 mol) was added dropwise to the stirred solution over a period of 1 h. The reaction was monitored by LC/MS, with product and unreacted gabapentin hydrochloride being observed. After stirring at room temperature for 3.5 days the reaction mixture contained residual gabapentin hydrochloride (by LC/MS). Additional thionyl chloride (20 mL, 30 g, 0.25 mol) was added at 0°C, and the reaction mixture allowed to stir at room temperature for another 12 h (LC/MS shows traces of residual gabapentin hydrochloride). A final portion of thionyl chloride (10 mL, 15 g, 0.12 mol) was added at 0°C and the reaction mixture allowed to stir at room temperature for 4 h (LC/MS showed no remaining gabapentin hydrochloride). The reaction mixture was then diluted with ethyl ether (200 mL) and cooled to 0° C while stirring. White crystalline solid formed, which was collected by filtration. The crude compound was recrystallized from a mixture of ethanol and ethyl ether (50 mL: 150 mL). Finally the white crystals were washed with 250 mL of ethyl acetate to give product (6) as a white solid (27 g, 91% yield). H NMR (CDC13, 400 MHz.): 8 1.43 - 1.52 (m, 10H), 2.64 (s, 2H), 3.08 (d, 2 H), 6.04 (br. s, 1H), 7.25 - 7.33 (m, 5H), 8.44 (br. s, 3H). MS (ESI) m/z 262.26 (M+H4). Example 2: l-[(tert-Butoxvcarbonvl)aminomethvIl-l-Cvciohexane Acetic Acid (7) Gabapenrin, (700 g , 4.09 mol) was slurried in water (2.7 L) with potassium carbonate (1.2 kg, 8.58 mol) and mechanically stirred under a nitrogen atmosphere. Di-tert-butyl dicarbonate (875 g, 4.00 mol) was dissolved in dioxane (4 L) and was added in large aliquots while maintaining the pH at 8 - 10, and if needed, adjusting the pH using additional potassium carbonate. The reaction was monitored by !H-NMR, noting the disappearance of the singlet resonance at 1.22 ppm for di-tert-butyl dicarbonate. After stirring overnight at ambient temperature the dioxane was removed in vacuo and the pH of the aqueous phase adjusted to between 3 and 4 using 10% sulfuric acid. The aqueous mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford compound (7) as a white powder (893 g, 80% yield). ]H NMR (CDCI3), 400 MHz): 5 1.24 - 1.50 (m, 10H), 2.30 (s, 2H), 3.15 (d, 2H), 5.02 (t, 1H). MS (ESI) m/z 294.18 (M+Na+). Melting point: 125 -130 °C. Example 3: Benzyl l-f(tert-Butoxvcarbonvl)aminomethvIl-l-Cvciohexane Acetate (8) In a 12 L, multi-neck, round bottom flask with a bottom valve, mechanical stirrer and nitrogen blanket, (7) (1098 g, 4.05 mol) and potassium carbonate (838 g, 6.075 mol) were added to N-methylpyrrolidinone (2 L) at room temperature. Benzyl bromide (457 mL, 3.84 mol) was added over one hour. The strongly exothermic reaction was maintained below 40 °C, and the resulting white suspension was stirred until judged complete by NMR, about 2 hours. Ice water (6 L) was carefully added to quench the reaction. Dichloromethane (3 L) was added, the organic phase separated and further extracted with water (2x2 L), 10% potassium carbonate (2x2 L), brine (2 L), then dried over sodium sulfate and concentrated in vacuo. The crude product (8) (1380 g., 94% yield) was carried to the next reaction without further purification. ]H NMR (CDC13, 400 MHz): 1.33 - 1.53 (m, 10H), 2.32 (s, 2H), 3.11 (d, 2H), 5.01 (br. t, 1H), 5.09 (s, 2H), 7.31 - 7.35 (m, 5H). MS (ESI) m/z 442.39 (M+Na4). Example 4: Benzyl 1-Aminomethyl-l-Cyclohexane Acetate Hydrochloride (6) Compound (8) from Example 3 above was added slowly with stirring and cooling to a 5 L, 3-neck, round bottom flask containing 4N HC1 in dioxane (2.5 L) over about a one hour period, the reaction mixture being maintained between 30 and 35 °C to keep the product from precipitating. The clear solution was divided into four aliquots, to each of which was added methyl-t-butyl ether (500 mL) to initiate crystallization of the product. Each batch fully solidified within 10 min. The solids were filtered, washed twice with ethyl acetate, then dried in a vacuum oven at 35 °C for 16 h to afford the product (6) as a white solid (936 g, 79% yield from (7)). JH NMR (CDC13,400 MHz.): 8 1.43 - 1.52 (m, 10H), 2.64 (s, 2H), 3.08 (d, 2 H), 6.04 (br. s, 1H), 7.25 - 7.33 (m, 5H), 8.44 (br. s, 3H). MS (ESI) m/z 262.26 (M+H"). Example 5: Benzyl l-{[(a-ChIoroethoxv)carbonyllaminomethyl)-l-Cvclohexane Acetate (9) In a 5-liter, 3-neck, round bottom flask, stirred mechanically and under nitrogen, was added dichloromethane (1.5 L), compound (6) (1.85 mol) and 1-chloroethyl chloroformate (258 g, 1.81 mol). The resulting solution was cooled to 15 °C and N-methylmorphoIine (396 mL, 3.60 mol) was added slowly, with cooling, over a one hour period. The resulting turbid solution was stirred for 30 min, after which 1H-NMR analysis showed the reaction to be complete. The reaction mixture was washed with water (2 x 2 L) and brine (1 L) and dried over sodium sulfate. Evaporation of the solvent afforded the title compound (9) as an orange oil (670 g, 98% yield). 1HNMR (CDC13,400MHz): 1.33 - 1.53 (m, 10H), 1.75 (d, 3H), 2.33 (s, 2H), 3.18 (d, 2 H), 5.09 (s, 2H), 5.58 (t, 1H), 6.53 (q, 1 H), 7.29-7.33 (m,5H). Example 6: Benzyl l-((a-Isobutanovloxyethoxy)carbonvH aminomethyl}-1-Cyclohexane Acetate (10) To a 10-L reactor equipped with a mechanical stirrer, cooling jackets and under nitrogen, was added isobutyric acid (1.35 L, 14.6 mol) via an addition funnel, followed by N-methylmorpholine (1.6 L, 14.6 mol). The resulting solution was cooled to 16 °C and a solution containing compound (9) (1237 g crude, 2.93 mol) dissolved in isobutyric acid (1.35 L 14.6 mol) was slowly added with stirring. After the addition was complete the resulting turbid solution was stirred for a total of 33 h, after which time 1H-NMR indicated less than 2% of starting material (9) remained. The crude reaction mixture was split in two equal batches, each of which was diluted with diethyl ether (6 L), washed with water (6 x 2L) in a centrifugal extractor to remove excess isobutyric acid, followed by washing with 10% potassium bicarbonate (4 x 2 L) and brine (2 x 2 L) before drying over anhydrous sodium sulfate. The combined organic extracts were concentrated to provide a dark orange oil (916 g). The crude oil (400 g) was loaded onto an 800 g Biotage™ silica gel chromatography column and eluted with 5% ethyl acetate in hexane (6 L), then with 7% ethyl acetate in hexane (12 L). The desired product elutes in the 7% fractions. The chromatographic purification was repeated with the remaining crude product to afford compound (10) as a thick colorless oil (822 g). !H NMR (CDC13,400 MHz): 8 1.5 (d, 6H), 1.24-1.53 (m, 13 H), 1.45 (d, 3H), 2.33 (s, 2H), 2.48-2.55 (m, 1H), 3.16 (d, 2H), 5.09 (s, 2H), 5.35 (t, 1H), 6.77 (q, 1H), 7.29 - 7.36 (m, 5H). MS (ESI) m/z 442.48 (M+Na4). Example 7: l-{[(a-Isobutanovloxvethoxv)carbonvnaminomethvl}-l-CvcIohexane Acetic Acid (11) Compound (10) (113 g) was dissolved in ethyl acetate (700 mL) and 10 g of 10% Pd-C was added. The reaction mixture was subjected to 50 psi of hydrogen gas in a Parr reactor for 40 min. Filtration through a sintered glass funnel and a hydrophobic membrane filtration cartridge (Millipore Opticap) removed the catalyst. The supernatant was concentrated to afford the product (11) as a white, crystalline solid (78 g, quantitative yield). Crystals formed in the freezer, then at room temperature over several days. 'H NMR (CDC13,400MHz): 1.15 (d, 6H)/1.40- 1.55 (m, 10H), 1.45 (d, 3H), 2.32 (s, 2H), 2.49 - 2.56 (m, 1H), 3.23 (d, 2H), 5.41 (t, 1H), 6.75 (q, 1H). MS(ESI) m/z 330.29 (M+H+). A portion of the product (25 g) was recrystallized by dissolution in 1 : 10 ethyl acetate : heptane (125 mL) at 60 °C, then slow cooling to 4°C. The white crystalline product (21 g) was isolated by filtration. Melting point: 63-64°C. Differential scanning calorimetry endotherm: 63 °C. Example 8: Sodium l-{-{\(a-Isobirtanoyloxvethoxy)carbonyll- aminomethyI}-l-Cyclohexane Acetate (12) Compound (11) (540 g, 1.64 mol) was dissolved in acetone (850 mL) and water (500 mL) in a 4 L beaker, equipped with overhead stirring, pH meter and addition funnel. Aqueous sodium carbonate (1.0 M) was added slowly in 50 mL aliquots. After addition of 0.49 eq. base (803 mL of sodium carbonate solution) the pH was 7.3. Acetone was removed in vacua at 25 °C and the pH re-checked to be —6.5. The remaining aqueous solution was divided into three 3-L flasks, shell frozen and lyophilized for two days. The resulting sodium salt (12) was scraped from the flasks as a hygroscopic solid and transferred quickly into bottles, which were immediately capped and transferred into a drying chamber at 14% relative humidity (RH). The remaining oily product in the flasks was dissolved in diethyl ether and concentrated in vacuo at 25 °C, then dried under high vacuum until a dry foam was produced. Example 9: Allyl l-Aminomethyl-l-Cydohexane Acetate Hydrochloride (13) A dry 500 mL, three-neck, round-bottomed flask was fitted with a magnetic stirring bar and a 100 mL pressure-equalizing addition funnel and flushed with nitrogen gas. The flask was charged with gabapentin (17.1 g, 0.1 mol) and allyl alcohol (100 mL, 1.46 mol) and the entire mixture was cooled to 0°C in an ice-water bath. Thionyl chloride (22.5 mL, 36 g, 0.3 mol) was added drop-wise over a period of 30 min to the stirred solution, and the reaction mixture allowed to stir for 16 h at room temperature. The mixture was then diluted with diethyl ether (200 mL) and cooled to 0°C while stirring. After several minutes white crystals formed, and were collected by filtration. The crude compound was recrystallized from a mixture of ethanol and diethyl ether (50 mL: 150 mL) to give the product (13) as a white solid (22 g, 88% yield), m.p: 138-142°C. 1H NMR (CD3OD, 400 MHz): 8 1.36-1.54 (m, 10H), 2.57 (s, 2H), 3.05 (s, 2H), 4.61 (d, 2H), 5.22 (dd, 1H), 5.33 (dd, 1H), 5.90-6.00 (m, 1H ). MS (ESI) m/z 212.0 (M+H+). Example 10: Allyl l-{[(a-Chloroethoxy)carbonyl1aminomethvI}-l-CycIohexane Acetate (14) To a solution of compound (13) (30 g, 0.121 mol) in dichloromethane (100 mL) was slowly added 1-chloroethyl chloroformate (13 mL, 16.9 g, 0.119 mol). The reaction mixture was cooled to 0°C and N-methylmorpholine (26.39 mL, 24.28 g, 0.24 mol) was slowly added over a period of 1 h while maintaining a temperature of less than 10°C. The resulting turbid solution was stirred for 30 min, and the reaction mixture was then diluted with diethyl ether (250 mL), washed with water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give the desired product (14) as light yellow viscous liquid (38 g, 99% yield). 1H NMR (CDCfe, 400 MHz): 5 1.35-1.58 (m, 10H), 1.78 (d, 3H), 2.32 (s, 2H), 3.22 (d, 2H), 4.57 (d, 2H), 5.25 (dd, 1H), 5.32 (dd, 1H), 5.52 (br. s, 1H), 5.90-5.94 (m, 1H), 6.54 (q, 1H). Example 11: Allyl 1-{[(a-Isobutanoyloxyethoxv)carbony!l aminomethyl}- 1-Cyclohexane Acetate (15) A solution of compound (14) (38 g, 0.12 mol) in isobutyric acid (55 mL, 52.5 g, 0.6 mol) was added to a mixture of isobutyric acid (55 mL, 52.5 g, 0.6 mol) in N-methylmorpholine (65 mL, 60 g, 0.59 mol) at 0°C over a period of 30 min. The resulting turbid solution was stirred for 16 h at room temperature. The reaction mixture was diluted with diethyl ether (500 mL) and washed with water (3 x 200 mL) followed by 10% potassium bicarbonate (4 x 200 mL) aid brine (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to yield a viscous liquid. This crude product was purified by column chromatography on silica gel, eluting with 7.5% ethyl acetate : hexane to give the desired compound (15) as a clear, viscous liquid (37 g, 84% yield).1H NMR (CDCfe, 400 MHz): 5 1.15 (d, 6H), 1.35-1.58 (m, 10H), 2.31 (s, 2H), 2.51 (m, 1H), 3.19 (d, 2H), 4.56 (d, 2H), 5.24 (dd, 1H), 5.32 (dd, 1H), 5.35 (br. s, 1H), 5.84-5.94 (m, 1H), 6.78 (q, 1H). MS (ESI) mh 392.24 (M+H4). Example 12: l-{[(a-IsobutanoyIoxyethoxy)carbonyIlaminomethvI?-l-Cyclohexane Acetic Acid (11) Method A: To a stirred suspension of ammonium formate (3.4 g, 54 mmol) in ethanol (34 mL), was added compound (15) (10 g, 27 mmol) together with 10% Pd/C (lg) under a nitrogen atmosphere. After one hour, the reaction mixture was filtered and the catalyst washed with ethanol (2x10 mL). The filtrates were combined and evaporated. The crude product was dissolved in diethyl ether (150 mL) and the organic phase was washed with 2N HC1 (100 mL), water (100 mL) and brine (100 mL). The ether layer was dried over anhydrous sodium sulfate and concentrated to give a viscous liquid that crystallized upon standing. The product was recrystallized using 1:10 ethyl acetate : heptane (100 mL) to give the product (11) as a white, crystalline solid (7.9 g, 88%)., m.p 63-64°C. Method B: To a stirred solution of compound (15) (1 g, 2.7 mmol) in acetonitrile (10 mL) under nitrogen was added (10 mg, 0.008 mmol) of tetrakis(triphenylphosphine) palladium (0) followed by morpholine (0.28 mL, 0.28 g, 3.2 mmol). After one hour, the solvent was removed in vacuo. The resulting oil was dissolved in diethyl ether (50 mL) and the organic phase was washed with 2N HC1 (20 mL), water (20 mL) and brine (20 mL). The ether layer was dried over anhydrous sodium sulfate and concentrated to give an oil, which was purified by column chrornatography on silica gel, eluting with 30% ethyl acetate : hexane. The desired product (11) was isolated as a white crystalline solid (0.75 g, 84% yield), m.p 63-64°C. Method C: To a stirred solution of compound (15) (1 g, 2.7 mmol) in dioxane (9 mL) was added ammonium formate (341 mg, 2.7 mmol) and palladium(H) acetate (12 mg) under a nitrogen atmosphere. The reaction mixture was heated to reflux for one hour and then concentrated in vacuo. The resulting oily residue was taken up in diethyl ether (50 mL), washed with 2N HC1 (20 mL), water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The crude compound was purified by column chromatography on silica gel, eluting with 30% ethyl acetate : hexane to give the desired product (11) as a colorless oil, which solidified on further standing at room temperature for 12 h (0.70 g, 78% yield), m.p. 62-64°C. Example 13: l-{[(a-Chloroethoxv)carbonvl]aminomethyl}-l-CvcIohexane Acetic Acid (16) via Trimethylsilyl l-([(a-ChIoroethory)carbonylIaininomethyU-l-CvcIohexane Acetate (17) In a 5-liter, 3-neck, round bottom flask containing dichloromethane (1.6 L) was added gabapentin (120.4 g, 0.704 mol) followed by triethylamine (294 mL, 2.11 mol). Chlorotrimethylsilane (178 mL, 1.40 mol) was slowly added while maintaining the reaction temperature below 15°C and the resulting suspension was stirred for 30 min. 1-Chloroethyl chloroformate (100 g, 0.704 mol) was then added slowly while maintaining the temperature below 15°C. After the addition was complete, additional triethylamine (88 mL, 0.63 mol) was added and the resulting suspension was stirred at room temperature for 30 min. The resulting silyl ester (17) was converted via acidic work-up to the corresponding acid (16) by washing the reaction mixture with water (2 x 1 L), followed by 1NHC1 (2 x 2 L) then brine (2 x 500 mL). After drying over anhydrous sodium sulfate and removal of the solvent in vaciio, the crude product (190 g) was obtained as an orange oil and used in Example 14 without further purification. 1H NMR (CDC13,400 MHz): § 1.41 - 1.57 (m, 10H), 1.78 (d, 3H), 2.33 (s, 2H), 3.27 (d, 2H), 5.42 (br. s, 1H), 6.55 (q, 1H). Example 14: l-{[(a-Isobtttanovloxvethoxv)carbonv}1aminomethyl}-l-CycIohexane Acetic Acid (11) To a 3-liter, 3-neck, round bottom flask was added isobutyric acid (254 g, 2.9 mol) followed by triethylamine (395 ml, 2.84 mol). The reaction mixture was cooled to room temperature and a solution of crude (16) from the above example (190 g, 0.69 mol) in dichloromethane (80 mL) was added in a controlled fashion to maintain the temperature below 30°C. The resulting pale yellow solution was stirred overnight. The reaction mixture was then diluted with one volume of dichloromethane and washed with water (6 x 500 mL), aqueous potassium bicarbonate (3 x 500 mL), and brine (2 x 500 mL). After drying over anhydrous sodium sulfate, removal of the solvent in vacuo afforded the crude product as a dark red oil (87 g). A portion (35 g) of this product was loaded onto an 800 g Biotage™ normal phase silica gel flash column and eluted with 40% diethyl ether in hexane (6 L), which after removal of the solvent in vacuo afforded product (11) as a colorless oil. This was repeated with a second 35 g portion of crude product yielding a further 13.5 g of (11). A sample of the product (25 g) was recrystallized by dissolution in heptane (325 mL) at 70 °C, then slow cooling to room temperature. The white crystalline product (11) (23 g) was isolated by filtration. Melting point: 63-64°C. Example 15: l-{{(a-ChIorobuto:xy)carbonvl1aminomethyl}-Cvdohexane Acetic Acid (18) via Trimethylsilyl l-{{(a-ChIorobutoxv)carbonvI}aminomethY])-l-CycIohexane Acetate (19) In a 5-liter, 3-neck, round bottom flask containing dichloromethane (1.6 L) was added gabapentin (113.5 g, 0.66 mol) followed by diisopropylethylamine (193.5 mL, 1.1 mol). Chlorotrimethylsilane (88.1 mL, 0.69 mol) was slowly added while maintaining the reaction temperature below 1 S°C and the resulting suspension was stirred for 30 min. 1-Chlorobutyl chloroformate (108 g, 0.63 mol) was then added slowly while maintaining the temperature below 15°C, and the resulting suspension was stirred at room temperature for 30 min. The resulting silyl ester (19) was converted via acidic work-up to the corresponding acid (18) by washing the reaction mixture with water (2x1 L), followed by IN HC1 (2 x 1 L) then brine (2 x 500 mL). After drying over anhydrous sodium sulfate and removal of the solvent in vacuo, the crude product (116 g, 60% yield) was obtained as an off-white solid and used in Example 16 without further purification. H NMR (CDCI3, 400 MHz): 5 0.93 (t, 3H), 1.28 - 1.62 (m, 12H), 1.92-2.06 (m, 2H), 2.35 (s, 2H), 3.28 (d, 2H), 5.44 (t, 1H), 6.45 (t, 1H). Example 16: l-{[{a-Propanoyloxvbutoxv)carbonvllaminomethyll-l-Cyclohexane Acetic Acid (20) To a 1-L, 3-neck, round bottom flask was added propionic acid (200 mL, 2.68 mol) followed by triethylamine (50.7 mL, 0.36 mol). The reaction mixture was cooled to room temperature and a solution of crude (18) from the above example (101 g, 0.33 mol) in dichloromethane (80 mL) was added in a controlled fashion to maintain the temperature below 30°C. The resulting pale yellow solution was stirred overnight. The reaction mixture was then diluted with one volume of dichloromethane and washed with water (6 x 250 mL), aqueous potassium bicarbonate (3 x 250 mL), and brine (2 x 250 mL). After drying over anhydrous sodium sulfate, removal of the solvent in vacuo afforded the crude product as a dark red oil (100 g). A portion (40 g) of this product was loaded onto an 800 g Biotage™ normal phase silica gel flash column and eluted with 20% diethyl ether in hexane (6 L), which after removal of the solvent in vacuo afforded product (20) as a colorless oil (15 g). 'H NMR (CDC13> 400MHz): 0.95 (t, 3H), 1.13 (t, 3H), 1.32-1.60 (m, 12H), 1.70-1.78 (m, 2H), 2.28 - 2.38 (m, 4H), 3.24 (d, 2H), 5.24 (t, 1H), 6.71 (t, 1H). MS(ESI) m/z 343.44 (M+H4). Example 17: l-{ [(a-ChIoroisobutoxv)carbonyllaminomethyI}-l-Cvclohexane Acetic Acid (21) via Trimethylsilyi l-(f(a-ChIoroisobutoxy)-carbonvnaminomethyI}- 1-Cyclohexane Acetate (22) To a mixture containing gabapentin (1.71 g, 10 mmol) and triethylamine (3.06 mL, 22 mmol) in dichloromethane (150 mL) was added chlorotrimethylsilane (1.4 mL, 11 mmol) and the resulting mixture was stirred until clear (about 20 min). A solution containing l-chloro-2-methylpropylchloroformate (1.27 mL, 11 mmol) in dichloromethane (10 mL) was then added at 0 °C and stirred at room temperature for 60 min. The resulting silyl ester (22) was converted via acidic work-up to the corresponding acid (21) by washing the reaction mixture with 10% citric acid (30 raL) and the organic layer separated. The aqueous layer was further extracted with ether (3 x 20 mL) and the combined organic phases were dried over MgSO4 and then concentrated in vaciio. Chromatography of the residue on silica gel, eluting with hexane: ethyl acetate (1:4) gave the title compound (21) (2.37g, 77%). 1H NMR (CDC13, 400 MHz): d 1.04 (d, J= 6.4 Hz, 3H), 1.06 (d, J= 6.4 Hz, 3H), 1.36-1.53 (m, 10H), 2.15 (m, 1H), 2.34 (s, 2H), 3.24 (m, 2H), 5.39 (t, 1H), 6.32 (d, J= 5.6 Hz), 1H). MS (ESI) m/z 306.34 (M+H). Example 18: l-{[(a-NicotinovIoxvisobutoxv)carbonvIlaminomethvl}-l-CycIohexane Acetic Acid (23) A mixture of (21) (268 mg, 0.88 mmol), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (158 mL, 1.01 mmol), and nicotinic acid (637 mg, 5.2 mmol) in acetone was stirred at room temperature for 48 h. After filtration, the filtrate was concentrated in vacuo and the resulting residue was purified by reverse phase preparative HPLC to afford the title compound (23) (50 mg, 14%). 1H NMR (CD3OD, 400 MHz): d 1.07 (d, 3H), 1.09 (d, 3H), 1.32-1.58 (m, 10H), 2.19 (m, 1H), 2.26 (s, 2H), 3.23 (m, 2H), 6.78 (d, 1H), 7.58 (m, 1H), 8.39 (d, 1H), 8.76 (d, 1H), 9.10 (s, 1H). MS (ESI) m/z 393.42 (M+H+). Example 19: Benzyl l-{f(a-ChIoroisobutoxy)carbonvllaminomethvi)-l-C'yclohexane Acetate (24) To a solution of (21) (1.02 g, 3.34 mmol) in dichloromethane was added 1,3-dicyclohexylcarbodiimide (758 mg, 3.67 mmol). After stirring at room temperature for 30 min, benzyl alcohol (380 mL, 3.67 mmol) and 4-(dimethylamino)pyridine (catalytic amount) were added. The resulting mixture was stirred at room temperature of 16 h. After filtration, the filtrate was washed with 10% citric acid, dried over Na2SO4, and concentrated. Chromatography of the residue on silica gel, eluting with 10% ethyl acetate/hexane, gave the title compound (24) (820 mg, 62%). 1H NMR (CDCI3, 400 MHz): d 1.03 (d, 3H), 1.05 (d, 3H), 1.36-1.53 (m, 10H), 2.13 (m, 1H), 2.35 (s, 2H), 3.22 (m, 2H), 5.11 (s, 2H), 5.49 (t, 1H), 6.32 (d, 1H), 7.34 (m, 5H). MS (ESI) m/z 396.24 (M+H1). Example 20: Cesium 2,2-Diethoxypropionate (25) To a stirred solution of pyruvic acid (14 mL, 0.2 mol) and triethylorthoformate (80 mL) at 10 °C was added concentrated sulfuric acid (1 mL). The resulting mixture was stirred at 5-10 °C for 1 h and then diluted with dichloromethane (200 mL). The organic solution was washed successively with water (3 x 80 mL) and saturated sodium chloride solution (80 mL) and then dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated to give a quantitative yield of 2,2-diethoxypropionic acid as an oil. 1H NMR (CDC13, 400 MHz): d 1.30 (t, 6H), 1.61 (s, 3H), 3.57 (q, 4H), 8.62 (s, 1H). The acid form was quantitatively converted to its cesium salt (25) by dissolving the acid in water (25 mL) followed by treatment with an equimolar quantity of cesium carbonate, and then lyophilization. 1H NMR (D2O, 400 MHz): d 0.98 (t, 6H), 1.28 (s, 3H), 3.22 (q, 2H), 3.47 (q, 2H). Example 21: Benzyl l-{[(a-2,2-Diethoxvpropanovloxvisobutoxv)carbonyll- aminomethyl}-Cyclohexane Acetate (26) A mixture of (24) (200mg, 0.51 mmol) and sodium iodide (114 mg, 0.76 mmol) in acetone was stirred at room temperature for 1 h. Cesium 2,2-diethoxypropionate (25) (300 mg, 1.02 mmol) and DMF (20 mL) were added and the resulting mixture was stirred at 40 °C for 18 h. After filtration, the filtrate was concentrated and the resulting residue was purified by silica gel flash column chromatography, eluting with 10% ethyl acetate/hexane to afford the title compound (26) (100 mg, 37% yield). MS (ESI) m/z 522.34 (M+H4). Example 22: l-{[(a-2,2-Diethoxvpropanoyloxvisobutoxv)carbonyI]- aminomethyl}-1-Cyclohexane Acetic Acid (27) A mixture of (26) (200 mg, 0.38 mmol) and 5% Pd-C (catalytic amount) was stirred under hydrogen at room temperature for 16 h. After filtration, the filtrate was concentrated and the resulting residue was purified by reverse phase preparative HPLC to afford the title compound (27) (98 mg, 60% yield). 1HNMR (CDC13, 400 MHz): d 0.97 (d, /6H), 1.19 (t, 3H), 1.21 (t, 3H), 1.32-1.58 (m, 10H), 1.51 (s, 3H), 2.06 (m, 1H), 2.30 (s, 2H), 3.23 (m, 2H), 3.46 (m, 2H), 3.56 (m, 2H), 5.30 (t, 1H), 6.59 (d, 1H). MS (ESI) m/z 432.24 (M+H). Example 23: l-{[(a-(2-Amino-2-methvIpropanoy])oxyisobutoxYVcarbonvI1aminomethyI}-l-CvcIohe xane Acetic Acid (28) Following the procedures of Examples 20-22, and substituting 2-amino-2-methylpropionic acid for 2,2-diethoxypropionic acid, provided the title compound (28). 1H NMR (CDC13,400 MHz): 5 0.97 (d, 6H), 1.44 (s, 3H), 1.45 (s 3H), 1.32-1.58 (m, 10H,), 2.05 (m, 1H), 2.30 (s, 2H), 3.23 (m, 2H), 5.50 (t, 1H), 6.58 (d, 1H). MS (ESI) m/z 373.48 (M+H+). Example 24: Methyl l-({(a-Chloroisobutoxy)carbonvnaminomethyl}-l-Cyclohexane Acetate (29) A mixture of (21) (1.0 g, 3.3 mmol), benzene (90 mL), and methanol (10 mL) was cooled to 0 °C. Trimethylsilyldiazomethane was added slowly at 0 °C until the yellow color persisted. The mixture was stirred at 0 °C for 30 min until the reaction was complete (monitored by TLC). After removing the solvent under reduced pressure, chromatography of the resulting residue on silica gel, eluting with 10% ethyl acetate/hexane gave the title compound (29) (760 mg, 72%). MS (ESI) m/z 320.24 (M+H4). Example 25: Methyl l-{[{a-Isobutanoyloxyisobutoxy)carbonvn- aminomethy]}-l-Cyclohexane Acetate (30) A mixture of (29) (760 mg, 2.38 mmol), silver carbonate (394 mg, 1.4 mmol), and isobutyric acid (442 mL, 4.76 mmol) in chloroform was stirred at room temperature for 24 h. Another batch of silver carbonate (394 mg, 1.4 mmol) and isobutyric acid (442 mL, 4.76 mmol) was added, and the resulting mixture was stirred for another 24 h. After filtration, the filtrate was concentrated and the resulting residue purified by silica gel flash column chromatography, eluting with 10% ethyl acetate/hexane, to afford the title compound (30) (560 mg, 63%). 1H NMR (CDC13, 400 MHz): d 0.94 (d, 3H), 0.96 (d, 3H), 1.15 (d, 3H), 1.17 (d, 3H), 1.32-1.58 (m, 10H), 2.01 (m, 1H), 2.19 (s, 2H), 2.55 (m, 1H), 3.18 (m, 2H), 3.67 (s, 3H), 5.33 (t, 1H), 6.56 (d, 1H). MS (ESI) m/z 372.38 (M+H4). Example 26: 3-{{(a-ChIoroethoxy)carbony}]aminomethyi}-5-Methvl-Hexanoic Acid (31) via Trimetthlsilyl 3-{[(a-Chloroethoxy)carbonyI]ammomethyl}-5-Methvl- Hexanoate (32) To a stirred suspension of pregabalin (270 mg, 1.38 mmol) in dichloromethane (5 mL) at -20 °C was added triethylamine (0.58 mL, 4.14 mmol) and a 1 M solution of chlorotrimethylsilane in dichloromethane (2.76 mL, 2.76 mmol). The resulting reaction mixture was allowed to warm to 0 °C, and stirred for 20 min. The solution was then cooled again to -20 °C and 1-chloroethyl chloroformate (0.151 mL, 1.38 mmol) added. The reaction mixture was stirred at 0 °C for an additional 30 min. The resulting silyl ester (32) was converted via acidic work-up to the corresponding acid (31) by quenching the reaction mixture with citric acid, diluting with dichloromethane, washing with water and brine; then drying over anhydrous Na2SO4. Filtration and evaporation afforded the title compound (31) (300 mg), which was used in the following example without further purification. Example 27: 3-{[(a-Isobutanoyloxyethoxy)carbonvIlaminomethyl}-5-Methvl-Hexanoic Acid (33) A solution of the above crude product (31) (320 mg) in dichloromethane (2 mL) was added to a mixture of isobutyric acid (1 mL) and N-methylmorpholine (0.5 mL) at 0 °C. The resulting mixture was stirred for 24 h at ambient temperature. The mixture was then diluted with dichloromethane, washed twice with water and brine, and dried over anhydrous Na2SO4. After filtration and removal of the solvent in vacuo, the crude product was purified by reverse phase preparative HPLC to afford the product (33) (70 mg, 16%) as a mixture of two diasteroisomers. 1H-NMR (CDC13, 400MHz): d 0.89 (m, 6H), 1.16 (m, 8H), 1.46 (d, 3H), 1.66 (m, 1H), 2.11-2.36 (m, 3H), 2.52 (m, 1H), 3.11 (m, 1H), 3.27 (m, 1H), 5.08 (t, 1H), 6.77 (m, 1H). MS (ESI) m/z 316.20 (M-HT). Example 28: 3-{[(a-Chloroisobutoxv)carbonvllaminomethvl}-5-Methyl-Hexanoic Acid (34) via Trimethylsily] 3-{{(a-Chloroisobutoxv)carbonyl}-anunomethyl)-5-MethvI- Hexanoate (35) To a stirred suspension of pregabalin (270 mg, 1.38 mmol) in dichloromethane (5 mL) at —20 °C was added triethylamine (0.58 mL, 4.14 mmol) and a 1 M solution of chlorotrimethylsilane in dichloromethane (2.76 mL, 2.76 mmol). The resulting reaction mixture was allowed to warm to 0 °C, and stirred for 20 min. The solution was then cooled again to -20 °C and l-chloro-2-methylpropyl chloroformate (0.201 mL, 1.38 mmol) added. The reaction mixture was stirred at 0 °C for an additional 30 min. The resulting silyl ester (35) was converted via acidic work-up to the corresponding acid (34) by quenching the reaction mixture with citric acid, diluting with dichloromethane, washing with water and brine, then drying over anhydrous Na2SO4. Filtration and evaporation afforded the title compound (34) (300 mg), which was used in the following example without further purification. Example 29: 3-{{(a-IsobutanoyIoxyisobutoxv)carbonvi\|aminomethyl}-5-MethyI- Hexanoic Acid (36) A solution of the above crude product (34) (300 mg) in dichloromethane (2 mL) was added to a mixture of isobutyric acid (1 mL) and N-methylmorpholine (0.5 mL) at 0 °C. The resulting mixture was stirred for 24 h at ambient temperature. The mixture was then diluted with dichloromethane, washed twice with water and brine, and dried over anhydrous Na2SO4. After filtration and removal of the solvent in vacuo, the crude product was purified by reverse phase preparative HPLC to afford the product (36) (27 mg, 6%) as a mixture of two diastereoisomers. 1H-NMR (CDCI3, 400MHz): 8 0.88 (m, 6H), 0.95 (d, 6H), 1.17 (m, 8H), 1.64 (m, 1H), 2.00-2.36 (m, 4H), 2.55 (m, 1H), 3.11 (m, 1H), 3.26 (m, 1H), 5.02 (br.s, 1H), 6.53 (m, 1H). MS (ESI) m/z 344.26 (M-HT). Example 30: 3-[(tcrt-Butoxycarbonyl)aminomethylI-5-MethyI-Hexanoic Acid (37) To a stirred suspension of pregabalin (950 mg, 4.85 mmol) and NaOH (452 mg, 11.32 mmol) in water (20 mL) was added a solution of di-tert-butyl dicarbonate (8.49 mmol) in dioxane (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 30 min. The solvent was removed in vacuo, and the residue was washed with diethyl ether to remove the excess of di-tert-butyl dicarbonate, then was acidified to pH 3 with citric acid. The resulting mixture was extracted with ethyl acetate (3 x 50 mL) and the combined organic fractions were washed with brine and dried over anhydrous Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (37) (1.24 g, 98%). 1H-NMR (CD3OD, 400 MHz): d 0.89 (2d, 6H), 1.17 (m, 2H), 1.44 (s, 9H), 1.65 (m, 2H), 2.08 (m, 1H), 2.31 (m, 2H), 3.06 (m, 1H)5 3.22 (m, 1H), 4.77 (br.s, 1H). MS (ESI) m/z 258.15 (M-H). Example 31: Benzyl 3-f(tert-Butoxycarbonvnaminomethvk}-5-Methyl-Hexanoate (38) To a stirred suspension of (37) (1.24 g, 4.78 mmol) and CS2CO3 (1.56 g, 4.78 mmol) in DMF (20 mL) was added benzyl bromide (0.56 mL, 4.68 mmol). The resulting mixture was stirred at ambient temperature until the reaction was complete (~2 h, as monitored by LC/MS). The mixture was poured into ice water and extracted with dichloromethane. The combined organic phase was washed with water and brine, then dried over anhydrous Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (38) (1.77 g, 100%), which was used without further purification in the following example. !H- NMR (CDCI3,400 MHz): 8 0.86 (2d, 6H), 1.13 (m, 2H), 1.42 (s, 9H), 1.62 (m, 1H), 2.31 (m, 2H), 3.00 (m, 1H), 3.18 (m, 1H), 4.75 (br.s, 1H), 5.10 (s, 2H), 7.33 (m, 5H). MS (ESI) m/z 372.30 (M+Na+). Example 32: Benzyl 3-AminomethyI-5-Methvl-Hexanoate Hydrochloride (39) A solution of (38) (1.77 g, 4.78 mmol) in 4M HC1 in dioxane (20 mL) was stirred at ambient temperature for 30 min. Removal of the solvent in vacuo afforded the title compound (39) as a white crystalline solid (1.4 g, 88%). 1H-NMR (CDC13,400 MHz): 5 0.85 (d, 6H)3 1.17 (m, 1H), 1.30 (m, 1H), 1.58 (m, 1H), 2.32 (m, 1H), 2.57 (m, 2H), 3.03 (m, 2H), 5.09 (s, 2H), 7.30 (m, 5H), 8.39 (br.s, 3H). MS (ESI) m/z 250.25 (M+H4). Example 33: Benzyl 3-{[(a-Chloroethoxy)carbonyI]aminomethvl)-5-Methvl- Hexanoate (40) To a stirred solution of (39) (428 mg, 1.51 mmol) in dichloromethane at 0 °C was added N-methylrnorpholine (0.33 mL, 3.02 mmol) and 1-chloroethyl chloroformate (0.164 mL, 1.51 mmol). The resulting solution was stirred at 0 °C until the reaction was complete (~30 min, as monitored by TLC) and then was diluted with dichloromethane, washed successively with cold 1NHC1 solution, water and brine, men dried over anhydrous Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (40) as a mixture of two diastereomers (530 mg, 100%), which was used without further purification in the following example. 1H-NMR (CDC13,400 MHz): 8 0.87 (m, 6H), 1.13 (m, 2H), 1.63 (m, 1H), 1.76 (m, 3H), 2.15 (m, 1H), 2.34 (m, 2H), 3.10 (m, 1H), 3.27 (m, 1H), 5.11 (br.s, 3H), 6.53 (q, 1H), 7.33 (m, 5H). Example 34: Benzyl 3-{f(a-Isobutanovloxyethoxy)carbonvllaminomethyIl-5-MethyI- Hexanoate (41) A solution of (40) (0.53 g, 1.50 mmol) in isobutyric acid (1 mL) was added to a mixture of isobutyric acid (0.96 mL, 10.8 mmol) and N-methylmorpholine (1.14 mL, 10.4 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with dichloromethane, washed successively with water, 10% aqueous NaHCO3 solution and brine, then dried over anhydrous Na2SO4- After filtration and removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel, eluting with 5% ethyl acetate in hexane to afford the title compound (41) as a mixture of two diastereomers (400 mg, 66%). 'H-NMR (CDCI3,400 MHz): 8 0.85 (m, 6H), 1.14 (m, 8H), 1.44 (m, 3H), 1.62 (m, 1H), 2.13 (m, 1H), 2.32 (m, 2H), 2.51 (m, 1H), 3.06 (m, 1H), 3.24 (m, 1H) 4.95 (m, 1H), 5.10 (s, 2H), 6.76 (q, 1H). Example 35: 3-{f(a-Isobutanoyloxyethoxv)carbonvl]aminomethvU-5-Methyl-Hexanoic Acid (33) A solution of (41) (270 mg, 0.663 mmol) in ethanol (20 mL) was stirred with 10% Pd on carbon (11 mg) in a 50 mL round-bottomed flask under an atmosphere of hydrogen gas (balloon). The reaction was judged complete in 30 min. (monitoring by TLC and LC/MS). The mixture was filtered through a pad of Celite, and the solvent removed in vacuo to afford the title compound (33) as a mixture of two diastereomers (177 mg, 84%). 'H-NMR (CDCI3, 400MHz): 8 0.89 (m, 6H), 1.16 (m, 8H), 1.46 (d, 3H), 1.66 (m, 1H), 2.11-2.36 (m, 3H), 2.52 (m, 1H), 3.11 (m, 1H), 3.27 (m, 1H), 5.08 (t, 1H), 6.77 (m, 1H). MS (ESI) in/z 316.20 (M-H"). Example 36: Benzyl 3-Wa-Chloroisobntoxv)carbonvHaminomethyl}-5-Methvl- Hexanoate(42) To a stirred solution of (39) (594 mg, 2.38 mmol) in dichloromethane at 0 °C was added N-methylmorpholine (0.523 mL, 4.77 mmol) and l-chloro-2-methylpropyl chloroformate (0.347 mL, 2.38 mmol). The resulting solution was stirred at 0 °C until the reaction was complete (~30 min, as monitored by TLC) and then was diluted with dichloromethane, washed successively with cold IN HC1 solution, water and brine, then dried over anhydrous Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (42) as a mixture of two diastereomers (840 mg, 92%), which was used en without further purification in the following example. 'H-NMR \|CDC13, 400MHz): 8 0.86 (2d, 6H), 1.02 (2d, 6H), 1.15 (m, 2H), 1.63 (m, 1H), 2.14 (m, 2Hft, 2.34 (m, 2H), 3.10 (m, 1H), 3.28 (m, 1H), 5.11 (br.s, 3H), 6.29 (d, 1H), 7.31 (m, 5H). Example 37: Benzyl 3-{ \(a-Isobutanoyloxyisobutoxy)carbon'yl}\|-aminometb.yl}]-5- Methyl-Hexanoate (43) A solution of (42) (840 mg, 2.19 mniol) in isobutyric acid (1 mL) was added to a mixture of isobutyric acid (1 mL, 10.95 mmol) and N-methylmoi pholine (1.2 mL, 10.95 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with dichloromethane (100 mL), washed successively with water, 10% aqueous NaHCO3 solution and brii e, then dried over anhydrous Na2SO4. After filtration and removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel, eluting with 5% e :hyl acetate in hexane to afford the title compound (43) as a mixture of two diastereomers (430 mg, 45%). 'H-NMR (CDC13, 400 MHz): d 0.85 (2d, 6H), 0.94 (d, 6H), 1.16 (m. 8H), .62 (m, 1H), 2.00 (m, 1H), 2.12 (m, 1H), 2.32 (m., 2H), 2.54 (m, 1H), 3.08 (m, 1H), 3.24 (m 1H), 4.94 (t, 1H), 5.10 (s, 2H), 6.55 (d, 1H), 7.33 (m, 5H). Example 38: 3-0(a-Isobutanoyloxyisobutoxv)carbonyllamin(\|methyU-5- Methyl-Hexanoic Acid (36) A solution of (43) (430 mg, 0.987 mmol) in ethanol (30 n L) was stirred with 10% Pd on carbon (50 mg) in a 100 mL round-bottomed flask under ai; atmosphere of hydrogen gas (balloon). The reaction was judged complete in 40 min. (moi itoring by TLC and LC/MS). The mixture was filtered through a pad of Celite, and tl e solvent removed in vacuo to afford the title compound (36) as a mixture of two diast 'H-NMR (CDCI3, 400MHz): 0.88 (m, 6H), 0.95 (d, 6H), 1.17 (m. 8H), 1.64 (m, 1H), 2.00- 2.36 (m, 4H), 2.55 (m, 1H), 3.11 (m, 1H), 3.26 (m, 1H), 5.02 (br.J, 1H), 6.53 (m, 1H). MS (ESI): m/z 344.26 (M-H). Finally, it should be noted that there are alternative ways present invention. Accordingly, the present embodiments are to t e considered as illustrative and not restrictive, and the invention is not to be limit herein, but may be modified within the scope and equivalents of t le appended claims. All publications and patents cited herein are incorporated by referenc : in their entirety. R1 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyi, substituted heteroalkyl, heteroatyl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cyeloalkyj, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted aikoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R4 and R5 together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R6 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring; and R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl. as claimed in 2. The method of Claim 1, wherein the compound of Formula (I) is derived from a GABA analog of Formula (IV): 1-Aminomethyl-l-cyclohexane acetic acid (i.e., gabapentin); l-Aminomethyl-l-(3-methylcyclohexane) acetic acid; l-Aminomethyl-l-(4-methylcyclohexane) acetic acid; l-Aminomethyl-l-(4-isopropylcyclohexane) acetic acid; l-Aminomethyl-l-(4-tert-butylcyclohexane) acetic acid; l-Aminomethyl-l-(3,3-dimethylcyclob.exane) acetic acid; l-Aminomethyl-l-(3,3,5,5-tetramethylcyclohexane) acetic acid; 1-Aminomethyl-l-cyclopentane acetic acid; l-Aminomethyl-l-(3-methylcyclopentane) acetic acid; l-Aminomethyl-l-(3,4-dimethylcyclopentane) acetic acid; 7-Aminomethyl-bicyclo[2.2.1]hept-7-yl acetic acid; 9-Aminomethyl-bicyclo[3.3.1]non-9-yl acetic acid; 4-Aminomethyl-4-(tetrahydropyran-4-yl) acetic acid; 3-Aminomethyl-3-(tetrahydropyran-3-yl) acetic acid; 4-Aminomethyl-4-(tetrahydrothiopyran-4-yl) acetic acid; 3-Aminometfayl-3-(tetrahydrothiopyran-3-yl) acetic acid; (S)-3-Aminomethyl-5-methyl-hexanoic acid (i.e. pregabalin); 3-Aminomethyl-5-methyl-heptanoic acid; 3-Aminomethyl-5-methyl-octanoic acid; 3-Aminomethyl-5-methyl-nonanoic acid; 3-Aminomethyl-5-methyl-decanoic acid; 3-Aminomethyl-5-cyclopropyl-hexanoic acid; 3-Aminomethyl-5-cyclobutyl-hexanoicacid; 3-Aminomethyl-5-cyclopentyl-hexanoic acid; 3-Aminomethyl-5-cyclohexyl-hexanoic acid; 3-Aminomethyl-5 -phenyl-hexanoic acid; 3-Aminomethyl-5-phenyl-pentanoic acid; 3-Aminomethyl-4-cyclobutyl-butyric acid; 3-Aminomethyl-4-cyclopentyl-butyricacid; 3-Aminomethyl-4-cyclohexyl-butyricacid; 3-Aminomethyl-4-phenoxy-butyric acid; 3-Aminomethyl-5-phenoxy-hexanoic acid; and 3-Aminomethyl-5-benzylsulfanyl-pentanoic acid. as claimed in 4. The method of Claim 3, wherein R1 is methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl or phenyl,-and R3 is hydrogen. as claimed in 5. The method el"Claim 3, wherein R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is methyl and R3 is methyl. as claimed in 6. The method ©f Claim 3, wherein R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or cyclohexyloxyearbonyl and R3 is methyl. as claimed in 7. The method of Claim 3, wherein, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dbnethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl and R2 and R3 together with the atom to which they are attached form a cyclohexyl ring. as claimed in 8. The method of Claim 3, wherein R2 is methyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or cyclohexyloxycarbonyl and R3 is methyl. as claimed in 9. The method of Claim 3, wherein R1 is methyl, ethyl, w-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, terf-butyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl or cyclohexyl and R10 is hydrogen, allyl, benzyl or trimethylsilyl. as claimed in 10. The method of Claim 3, wherein R is hydrogen, methyl, ethyl, «-propyl, isopropyl, w-butyl, isobutyl, sec-butyl or tert-butyl and R3 is hydrogen. as claimed in 11. The method of Claim 3, wherein R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, rert-butyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl or cyclohexyl, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is hydrogen, methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl and R3 is hydrogen. as claimed in 12. The method of Claim 3, wherein R1 is ethyl or isopropyl, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is methyl, «-propyl or isopropyl and R3 is hydrogen. as claimed in 13. The method of Claim 3, wherein R1 is isopropyl, R10 is benzyl, R2 is methyl and R3 is hydrogen. as claimed in 14. The method ofClaim 3, wherein R1 is ethyl or isopropyl, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is methyl, «-propyl or isopropyl, R3 is hydrogen and X is chloro. as claimed in 15. The method of-Claim 3, wherein R1 is isopropyl, R10 is benzyl, R2 is methyl, R3 is hydrogen and X is chloro. as claimed in 16. The method of Claim 1, wherein the ratio of the compound of Formula (II) to the compound of Formula (III) is between about 1:1 and about 1:20. as claimed in 17. The method of Claim 1 further comprising contacting the compound of Formula (II) and the compound of Formula (III) and at least one equivalent of a metal salt or an organic base or a combination thereof with an organic solvent. as claimed in 18. The method of Claim 17, wherein the solvent is dichloromethane, dichloroethane, chloroform, toluene, dimethylformamide, dimethylacetamide, N-methylpyrroIidinone, dimethyl sulfoxide, pyridine, ethyl acetate, acetonitrile, acetone, 2-butanone, methyl tert-butyl ether, methanol, ethanol, isopropanol, rert-butanol, water, hexamethylphosphoramide or combinations thereof. as claimed in 19. The method of Claim 1, wherein the metal salt is a Ag, Hg, Na, K, Li, Cs, Ca, Mg or Zn salt. as claimed in 20. The method of Claim 1, wherein the organic base is triethylamine, tributylamine, diisopropylethylamine, dimethylisopropylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, 1, 4-diazabicyclo[2.2.2]octane, 1, 8-diazabicyclo[5.4.0]undec-7-ene, 1, 5-diazabicyclo[4.3.0]undec-7-ene or combinations thereof. as claimed in 21. The method of Claim 1 wherein the compound of Formula (III) is a liquid. as claimed in 22. The method of Claim 21, wherein the compound of Formula (III) is acetic acid, methoxyacetic acid, ethoxyacetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, 2-methylbutyric acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid or cyclohexanecarboxylic acid. as claimed in 23. The method of Claim 22, wherein the compound of Formula (III) is isobutyric acid. as claimed in 24. The method of Claim 1, further comprising contacting the compound of Formula (II), the compound of Formula (III) and the metal salt or the organic base or a combination thereof at a temperature between about -25 °C and about 120 °C. as claimed in 25. The method of claim 24, wherein, the temperature is between about 0 °C and about 25 °C. as claimed in 26. The method of Claim 1 further comprising contacting the compound of Formula (II), the compound of Formula (III) and the metal salt or the organic base or a combination thereof with a catalytic amount of an iodide salt. as claimed in 27. The method of Claim 26, wherein the iodide salt is sodium iodide, potassium iodide, tetramethylammonium iodide, tetraethylammonium iodide or tetrabutylammonium iodide. R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R4 and R5 together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R6 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring; and R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl. wherein the GAB A analog of Formula (IV) is selected from the group consisting of: 1-Aininomethyl-l-cyclohexane acetic acid (i.e. gabapentin); I-Aminomethyl-l-(3-methylcyci tohexane) acetic acid; l-Aminomethyl-l-(4-methylcyclohexane) acetic acid; l-Aminomethyl-l-(4-isopropylcyclohexane) acetic acid; l-Aminomethyl-l-(4-ter/-butylcyclohexane) acetic acid; l-Aminomethyl-l-(3,3-dimethy]cyclohexane) acetic acid; l-Aminomethy1-1-(,3,3,5,5-tetramethylcyclohexane) acetic acid; 1-Aminomethyl-l-cyclopentane acetic acid; l-Aminomethyl-l-(3-methylcyclopentane) acetic acid; l-AminomethyI-l-(3,4-dimethylcyclopentane) acetic acid; 7-Aminomethyl-bicyclo[2.2.1]hept-7-yl acetic acid; 9-Aminomethyl-bicyclo[3.3.1]non-9-yI acetic acid; 4-Aminomethyl-4-(tetrahydropyran-4-yl) acetic acid; 3-Aminomethyl-3-(tetrahydropyran-3-yl) acetic acid; 4-Aminomethyl-4-(tetrahydrothiopyran-4-yl) acetic acid; 3-Aminomethyl-3-(tetrahydrothiopyran-3-yI) acetic acid; (S)-3-Aminomethyl-5-methyl-hexanoic acid (i.e., pregabalin); 3-Aminomethyl-5-methyl-heptanoic acid; 3-AminomethyI-5-methyl-octanoic acid; 3_AminomethyI-5-inethyl-nonanoic acid; 3-Aminomethyl-5-methyl-decanoic acid; 3 -Aminomethyl-5-cyclopropyl-hexanoic acid; 3-Aminomethyl-5-cyclobutyl-hexanoic acid; 3-Aminomethyl-5-cyclopentyl-hexanoicacid; 3-Aminomethyl-5-cyclohexyl-hexanoic acid; 3-Aminomethyl-5~phenyl-hexanoic acid; 3-Aminomethyl-5-phenyl-pentanoicacid; 3 -Aminomethyl-4-cyclobutyl-butyric acid; 3-Aminomethyl-4-cyclopentyl-butyric acid; 3-Aminomethyl-4-cycJohexyi-butyricacid; 3-Aminomethyl-4-phenoxy-butyric acid; 3-Aminomethyl-5-phenoxy-hexanoic acid; and and n is 0. as claimed in 31. The compound of Claim 30, wherein X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is hydrogen, methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl or phenyl and R3 is hydrogen. as claimed in 32. The compound of Claim 30, wherein X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is methyl and R3 is methyl. as claimed in 33. The compound of Claim 32, wherein X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or cyclohexyloxycarbonyl and R3 is methyl. as claimed in 34. The compound of Claim 30, wherein X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, and R2 and R3 together with the atom to which they are attached form a cyclohexyl ring. as claimed in 35. The compound of Claim 30, wherein X is chloro, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is hydrogen, methyl, ethyl, /z-propyl, isopropyl, /z-butyl, isobutyl, sec-butyl or tert-butyl and R3 is hydrogen. as claimed in 36. The compound of Claim 30, wherein X is chloro, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is methyl, n-propyl or isopropyl, and R3 is hydrogen. as claimed in 37. The compound ef Claim 30, wherein X is chloro, R10 is hydrogen, R2 is methyl, and R3 is hydrogen. as claimed in 38. The compound of Claim 30, wherein X is chloro, R10 is allyl, R2 is methyl, and R3 is hydrogen. as claimed in 39. The compound of Claim 30, wherein X is chloro, R10 is benzyl, R2 is methyl, and R3 is hydrogen. as claimed in 40. The compound of Claim 30, wherein X is chloro, R10 is trimethylsilyl, R2 is methyl, and R3 is hydrogen. 1. A method of synthesizing a compound of Formula (I) comprising contacting a compound of Formula (II), a compound of Formula (III) and at least one equivalent of a metal salt or an organic base or a combination thereof wherein at a temperature between -25oc and 120oc wherein: X is F,Cl,Br or I; n is O or 1; R1 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R4 and R5 together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R6 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring; and R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl.

Full Text

METHODS FOR SYNTHESIS OF ACYLOXYALKYL DERIVATIVES OF GABA
ANALOGS
Field
Methods for synthesis of l-(acyloxy)-alkyl carbamates are provided. More
particularly, the synthesis of prodrugs (i.e., 1-(acyloxy)-alkyl carbamates of GABA analogs)
from 1-haloalkyl carbamates of GABA analogs are described. Also described are new
1-haloalkyl carbamates of GABA analogs.
Background
One solution to drug delivery and/or bioavailability issues in pharmaceutical
development is converting known drugs to prodrugs. Typically, in a prodrug, a polar
functional group (e.g., a carboxylic acid, an amino group, a hydroxyl group, etc.) is masked
by a promoiety, which is labile under physiological conditions. Accordingly, prodrugs are
usually transported through hydrophobic biological barriers such as membranes and
typically possess superior physicochemical properties than the parent drug.
Pharmacologically effective prodrugs are non-toxic and are preferably selectively
cleaved at the locus of drug action. Ideally, cleavage of the promoiety occurs rapidly and
quantitatively with the formation of non-toxic by-products (i.e., the hydrolyzed promoiety).
The acyloxyalkoxycarbonyl functionality is an example of a promoiety that may be
used to modulate the physiochemical properties of pharmaceuticals (Alexander, United •
States Patent NO.,4,916,230 Alexander, United States Patent No, 5,733,9,07; Alexander et
al, U.S. Patent No. 4,426,391). Typically, l-(acyloxy)-alkyl derivatives of a
pharmaceutical possess superior bioavailability, may be less irritating to topical and gastric
mucosal membranes and are usually more permeable through such membranes when
compared to the parent drug.
However, although l~(acyloxy)-alkyl ester derivatives of alcohols and
l-(acyloxy)-alkyl carbamate derivatives of amines have been frequently used to mask these
polar functional groups in pharmaceuticals, existing synthetic methods for preparing these
desirable derivatives are inadequate. Methods disclosed in the art for synthesis of
acyloxyalkyl esters and carbamates are typically multi-step routes that utilize unstable
intermediates and/or toxic compounds or salts and accordingly are difficult to perform on
large scale (Alexander, United States Patent No. 4,760,057; und, United States Patent No.
5,401,868; Alexander, United States Patent ISio. 4,/60,057; Saari et ah, European Patent
0416689B1).
Accordingly, there is a need for a new synthesis of l-(acyloxy)-alkyl derivatives that
proceeds rapidly and efficiently, which is amenable to scale-up and proceeds through
readily accessible synthetic precursors.
Summary
A method for synthesizing l-(acyloxy)-alkyl derivatives from acyloxy derivatives,
which typically proceeds in high yield, does not necessarily require the use of heavy metals
and is readily amenable to_scale-up is provided herein.
In a first aspect, a method of synthesizing a compound of Formula (I) is provided
which comprises^
contacting a compound of Formula (II), a compound of Formula (III) and at least one
equivalent of a metal salt wherein:
X is F, C1, Br or I;
n is O or 1;
R1 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted
heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
R2 and R3 are independently hydrogen, alkyl, substituted alkyl,
alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded
form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl
ring;
R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl or substituted heteroarylalkyl;
R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,
substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted
heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl,
or optionally, R4 and R5 together with the atoms to which they are attached form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
R6 and R9 are independently selected from the group consisting of "hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;
R7 and R8 are independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and
substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which
they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl or bridged cycloalkyl ring; and
R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted
heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl.
In a second aspect a method of synthesizing a compound of Formula (I) is provided
which comprises
contacting a compound of Formula (II), a compound of Formula (III) and at least one
equivalent of an organic base, where X, n, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are as
defined, supra.
In a third aspect a compound of Formula (II) is provided,
wherein:
X is F,Cl,Br or I;
n is O or 1;
R2 and R3 are independently hydrogen, allcyl, substituted alkyl,
alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded
form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl
ring;
R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl or substituted heteroarylalkyl;
R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,
substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted
heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl,
or optionally, R4 and R5 together with the atoms to which they are attached form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
R6 and R9 are independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;
R7 and R8 are independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and
substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which
they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl or bridged cycloalkyl ring; and
R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted
heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl.
Detailed Description
Definitions
"Compounds" refers to compounds encompassed by structural formulae (I) - (VIII)
disclosed herein and includes any specific compounds within these formulae whose
structure is disclosed herein. Compounds may be identified either by their chemical
structure and/or chemical name. When the chemical structure and chemical name conflict,
the chemical structure is determinative of the identity of the compound. The compounds
described herein may contain one or more chiral centers and/or double bonds and therefore,
may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers),
enantiomers or diastereomers. Accordingly, the chemical structures depicted herein
encompass all possible enantiomers and stereoisomers of the illustrated compounds
including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure
or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric
and stereoisomeric mixtures can be resolved into their component enantiomers or
stereoisomers using separation techniques or chiral synthesis techniques well known to the
skilled artisan. The compounds may also exist in several tautomeric forms including the
enol form, the keto form and mixtures thereof. Accordingly, the chemical structures
depicted herein encompass all possible tautomeric forms of the illustrated compounds. The
compounds described also include isotopically labeled compounds where one or more
atoms have an atomic mass different from the atomic mass conventionally found in nature.
Examples of isotopes that may be incorporated into the compounds of the invention include,
but are not limited to, 2H, 3H, 13C, 14C, 15N, 180,17O, etc. Compounds may exist in
unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In
general, compounds maybe hydrated, solvated or N-oxides. Certain compounds may exist
in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for
the uses contemplated herein and are intended to be within the scope of the present
invention. Further, it should be understood, when partial structures of the compounds are
illustrated, that brackets indicate the point of attachment of the partial structure to the rest of
the molecule.
"1-Acyloxy-Alkyl Carbamate" refers to an N-1-acyloxy-alkoxycarbonyl derivative
of a primary or secondary amine as encompassed by structural formulae (I), (V) and (VI)
disclosed herein.
"Alky!" by itself or as part of another substituent refers to a saturated or unsaturated,
branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal
of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne.
Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl,
ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-l-yl,
prop-l-en-2-yl, prop-2-en-l-yl (allyl), cycloprop-1-en-l-yl; cycloprop-2-en-l-yl,
prop-1-yn-l-yl, prop-2-yn-l-yl, etc.; butyls such as butan-1-yl, butan-2-yl,
2-methyl-propan-l-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-l-yl, but-l-en-2-yl,
2-methyl-prop-1 -en- 1-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl,
buta-l,3-dien-2-yl, cyclobut-1-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-l,3-dien-l-yl,
but- 1-yn- 1-yl, but-l-yn-3-yl, but-3-yn-l-yl, etc.; and the like.
The term "alkyl" is specifically intended to include groups having any degree or
level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups
having one or more double carbon-carbon bonds, groups having one or more triple
carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon
bonds. Where a specific level of saturation is intended, the expressions "alkanyl,"
"alkenyl," and "alkynyl" are used. Preferably, an alkyl group comprises from 1 to 20
carbon atoms, more preferably, from 1 to 10 carbon atoms, most preferably, from 1 to 6
carbon atoms.
"Alkanyl" by itself or as part of another substituent refers to a saturated branched,
straight-chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a
single carbon atom of a parent alkane. Typical alkanyl groups include, but are not limited
to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl),
cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl (Sec-butyl),
2-methyl-propan-l-yl (isobutyl), 2-methyl-propan-2-yl (/-butyl), cyclobutan-1-yl, etc.; and
the like.
"Alkenyl" by itself or as part of another substituent refers to an unsaturated
branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double
bond derived by the removal of one hydrogen atom from a single carbon atom of a parent
alkene. The group may be in either the cis or trans conformation about the double bond(s).
Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as
prop-1-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-l-yl;
cycloprop-2-en-l-yl; butenyls such as but-1-en-l-yl, but-l-en-2-yl,
2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl,
buta-l,3-dien-2-yl, cyclobut-1-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-l,3-dien-l-yl, etc.;
and the like.
"Alkynvl" by itself or as part of another substituent refers to an unsaturated
branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond
derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as
prop-1 -yn-1 -yl, prop-2-yn-1 -yl, etc.; butynyls such as but-1 -yn-1 -yl, but-1 -yn-3-yl,
but-3-yn-l-yl, etc.; and the like.
"Acyl" by itself or as part of another substituent refers to a radical -C(O)R30, where
R30 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,
heteroarylalkyl as defined herein. Representative examples include, but are not limited to
formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl
and the like.
"Alkoxy" by itself or as part of another substituent refers to a radical -OR31 where
R31 represents an alkyl or cycloalkyl group as defined herein. Representative examples
include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the
like.
"Alkoxvcarbonyl" by itself or as part of another substituent refers to a radical -OR32
where R32 represents an alkyl or cycloalkyl group as defined herein. Representative
examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl and the like.
"Aryl" by itself or as part of another substituent refers to a monovalent aromatic
hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon
atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to,
groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene,
azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,
hexalene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene,
phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene
and the like. Preferably, an aryl group comprises from 6 to 20 carbon atoms, more
preferably, from 6 to 12 carbon atoms.
"Arylalkyl" by itself or as part of another substituent refers to an acyclic alkyl
radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or
sp3 carbon atom, is replaced with an aryl group. Typical arylalkyl groups include, but are
not limited to, benzyl, 2-phenylethan-l-yl, 2-phenylethen-l-yl, naphthylmethyl,
2-naphthylethan-l-yl, 2-naphthylethen-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and
the like. Where specific alkyl moieties are intended, the nomenclature arylalkanyl,
arylalkenyl and/or arylalkynyl is used. Preferably, an arylalkyl group is (C6-C20) arylalkyl,
e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C10) and the aryl
moiety is (C6-C20), more preferably, an arylalkyl group is (C6-C20) arylalkyl, e.g., the
alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C8) and the aryl moiety is
(C6-C12).
"Aryldialkvlsilvl" by itself or as part of another substituent refers to the radical -
SiR33R34R35 where one of R33, R34 or R35 is aryl as defined herein and the other two of R33,
R34 or R35 are alkyl as defined herein.
"Bridged cvcloalkyl" by itself or as part of another substituent refers to a radical
selected from the group consisting of
wherein:
A is (CR38R39)b;
R38 and R39 are independently selected from the group consisting of hydrogen and
methyl;
R and R37 are independently selected from the group consisting of hydrogen and
methyl;
b is an integer from 1 to 4; and
c is an integer from 0 to 2.
"Carbamoyl" by itself or as part of another substituent refers to the radical.
-C(O)NR40R41 where R40 and R41 are independently hydrogen, alkyl, cycloalkyl or aryl as
defined herein.
"Cycloalkvl" by itself or as part of another substituent refers to a saturated or
unsaturated cyclic alkyl radical. Where a specific level of saturation is intended, the
nomenclature "cycloalkanyl" or "cycloalkenyl" is used. Typical cycloalkyl groups include,
but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane,
cyclohexane and the like. Preferably, the cycloalkyl group is (C3-C10) cycloalkyl, more
preferably (C3-C7) cycloalkyl.
"Cycloheteroalkvl" by itself or as part of another substituent refers to a saturated or
unsaturated cyclic alkyl radical in which one or more carbon atoms (and any associated
hydrogen atoms) are independently replaced with the same or different heteroatom. Typical
heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc.
Where a specific level of saturation is intended, the nomenclature "cycloheteroalkanyl" or
"cycloheteroalkenyl" is used. Typical cycloheteroalkyl groups include, but are not limited
to, groups derived from epoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine,
piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like.
"GABA analog" refers to a compound, unless specified otherwise, as having the
following structure:
wherein:
R6 and R9 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;
R and R8 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and
substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which
they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl or bridged cycloalkyl ring.
"1-Haloalkyl Carbamate" refers to an N-1-haloalkoxycarbonyl derivative of a
primary or secondary amine as encompassed by structural formulae (II), (VII) and (VIII)
disclosed herein.
"Heteroalkyl, Heteroalkanvl, Heteroalkerivl and Heteroalkynyl" by themselves or as
part of another substituent refer to alkyl, alkanyl, alkenyl and alkynyl groups, respectively,
in which one or more of the carbon atoms (and any associated hydrogen atoms) are
independently replaced with the same or different heteroatomic groups. Typical
heteroatomic groups which can be included in these groups include, but are not limited to,
-O-, -S-, -O-O-, -S-S-, -O-S-, -NR42R43, -=N-N=-, -N=N-, -N=N-NR44R45, -PR46-, -P(O)2-,
-POR47-, -O-P(O)2-, -SO-, -SO2-, -SnR48R49- and the like, where R42, R43, R.44, R45, R46, R47,
R48 and R49 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted
heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.
"Heteroaryl" by itself or as part of another substituent refers to a monovalent
heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of
a parent heteroaromatic ring system. Typical heteroaryl groups include, but are not limited
to, groups derived from acridine, arsindole, carbazole, P-carboline, chromane, chromene,
cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofiiran,
isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,
oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine,
pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,
pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,
thiophene, triazole, xanthene, and the like. Preferably, the heteroaryl group is from 5-20
membered heteroaryl, more preferably from 5-10 membered heteroaryl. Preferred
heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran,
indole, pyridine, quinoline, imidazole, oxazole and pyrazine
"Heteroarylalkyl" by itself or as part of another substituent refers to an acyclic alkyl
radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or
sp3 carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are
intended, the nomenclature heteroarylalkanyl, heteroarylalkenyl and/or heterorylalkynyl is
used. In preferred embodiments, the heteroarylalkyl group is a 6-30 membered
heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10
membered and the heteroaryl moiety is a 5-20-membered heteroaryl, more preferably, 6-20
membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the
heteroarylalkyl is 1-8 membered and the heteroaryl moiety is a 5-12-membered heteroaryl.
"Parent Aromatic Ring System" refers to an unsaturated cyclic or polycyclic ring
system having a conjugated n electron system. Specifically included within the definition
of "parent aromatic ring system" are fused ring systems in which one or more of the rings
are aromatic and one or more of the rings are saturated or unsaturated, such as, for example,
fluorene, indane, indene, phenalene, etc. Typical parent aromatic ring systems include, but
are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,
benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene,
&s-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,
ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene,
phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene
and the like.
"Parent Heteroaromatic Ring System" refers to a parent aromatic ring system in
which one or more carbon atoms (and any associated hydrogen atoms) are independently
replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon
atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the
definition of "parent heteroaromatic ring systems" are fused ring systems in which one or
more of the rings are aromatic and one or more of the rings are saturated or unsaturated,
such as, for example, arsindole, benzodioxan, benzofuran, chromane, chromene, indole,
indoline, xanthene, etc. Typical parent heteroaromatic ring systems include., but are not
limited to, arsindole, carbazole, b-carboline, chromane, chromene, cinnoline, furan,
imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,
isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole,
perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine,
pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine,
quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,
triazole, xanthene, and the like.
"Pharmaceutically acceptable salt" refers to a salt of a compound, which possesses
the desired pharmacological activity of the parent compound. Such salts include: (1) acid
addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as
acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid,
pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,
2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid,
2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic
acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid,
glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the
like; or (2) salts formed when an acidic proton present in the parent compound is replaced
by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or
coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine,
N-methylglucamine and the like.
"Prodrug" refers to a derivative of a drug molecule that requires a transformation
within the body to release the active drug. Prodrugs are frequently, although not
necessarily, pharmacologically inactive until converted to the parent drug. A hydroxyl
containing drug may be converted to, for example, to a sulfonate, ester or carbonate
prodrug, which may be hydrolyzed in vivo to provide the hydroxyl compound. An amino
containing drug may be converted, for example, to a carbamate, amide, enamine, imine,
N-phosphonyl, N-phosphoryl or N-sulfenyl prodrug, which may be hydrolyzed in vivo to
provide the amino compound. A carboxylic acid drug may be converted to an ester
(including silyl esters and thioesters), amide or hydrazide prodrug, which be hydrolyzed in
vivo to provide the carboxylic acid compound. Prodrugs for drugs which have functional
groups different than those listed above are well known to the skilled artisan.
"Promoiety" refers to a form of protecting group that when used to mask a
functional group within a drug molecule converts the drug into a prodrug. Typically, the
promoiety will be attached to the drug via bond(s) that are cleaved by enzymatic or
non-enzymatic means in vivo.
"Protecting group" refers to a grouping of atoms that when attached to a reactive
functional group in a molecule masks, reduces or prevents reactivity of the functional group.
Examples of protecting groups can be found in Green et ah, "Protective Groups in Organic
Chemistry", (Wiley, 2nd ed. 1991) and Harrison et ah, "Compendium of Synthetic Organic
Methods", Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting
groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl,
benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"),
2-trimethylsilyl-ethanesulfonyl ("SES"), trityl and substituted trityl groups,
allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl
("NVOC") and the like. Representative hydroxy protecting groups include, but are not
limited to, those where the hydroxy group is either acylated or alkylated such as benzyl, and
trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl
ethers.
"Substituted" refers to a group in which one or more hydrogen atoms are
independently replaced with the same or different substituent(s). Typical substituents
include, but are not limited to, -M, -R60, -O", =O, -OR60, -SR60, -S*, =S, -NR60R61, =NR60,
-CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2O; -S(O)2OH, -S(O)2R60, -OS(O2)O-OS(O)2R60, -P(O)(O)2, -P(O)(OR60)(O'), -OP(O)(OR60)(OR61), -C^R60, -C(S)R60,
-C(O)OR60, -C(O)NR60R61,-C(O)O", -C(S)OR60, -NR62C(O)NR60R61, -NR62C(S)NR6OR61,
-NR62C(NR63)NR60R6! and -C(NR62)NR60R61 where M is independently a halogen; R60, R61,
R and R are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl,
substituted aryl, heteroaryl or substituted heteroaryl, or optionally R60 and R61 together with
the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted
cycloheteroalkyl ring; and R64 and R65 are independently hydrogen, alkyl, substituted alkyl,
aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl,
substituted aryl, heteroaryl or substituted heteroaryl, or optionally R64 and R65 together with
the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted
cycloheteroalkyl ring. Preferably, substituents include -M, -R60, =O, -OR60, -SR60, -S", =S,
-NR60R61, =NR60, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2R60, -OS(O2)O-OS(O)2R60, -P(O)(O-)2, -P(O)(OR60)(O-), -OP(O)(OR60)(OR6!), -C(O)R60, -C(S)R60,
-C(O)OR60, C(O)NR60R61-C(pyyt -NR62C(O)NR60R61, more preferably, -M, -R60, =O,
-OR60, -SR60, -NR60R61, -CF3, -CN, -NO2, -S(O)2R60, -P(O)(ORfi0)(O'),
-OP(O)(OR60)(OR61), -C(O)R60, -C(O)OR60, -C(O)NR60R61,-C(O)O\ most preferably, -M,
-R60, =O, -OR60, -SR60, -NR60R61, -CF3, -CN, -NO2, -S(O)2R60, -OP(O)(OR60)(OR61),
-C(O)R60, -C(O)OR60 ,-C(O)O", where R60, R61 and R62 are as defined above.
"Trialkylsilyl" by itself or as part of another substituent refers to a radical -
SiR50R51R52 where R50, R51 and R52 are alkyl as defined herein.
Reference will now be made in detail to preferred embodiments of the invention.
While the invention will be described in conjunction with the preferred embodiments, it will
be understood that it is not intended to limit the invention to those preferred embodiments.
To the contrary, it is intended to cover alternatives, modifications, and equivalents as may
be included within the spirit and scope of the invention as defined by the appended claims.
Method of Synthesis of l-(Acyloxy)-Alkyl GABA Analogs
Methods of synthesis of l-(acyloxy)-alkyl carbamates of GABA analogs from
1-haloalkylcarbamates of GAB A analogs are disclosed. Preferably, l-(acyloxy)-alkyl
carbamates of GABA analogs are synthesized by reaction of a 1-haloalkyl carbamate of a
GABA analog with a carboxylic acid in the presence of either a metal salt or an organic
base, In one embodiment, the carboxylic acid also serves a solvent for the reaction.
In a first aspect, a compound of Formula (I) is synthesized by a method comprising
contacting a compound of Formula (II), a compound of Formula (III) and at least one
equivalent of a metal salt wherein:
X is F,Cl,Br or I;
n is O or l;
R1 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted
heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
R2 and R3 are independently hydrogen, alkyl, substituted alkyl,
alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded
form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl
ring;
R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl or substituted heteroarylalkyl;
R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,
substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted
heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl,
or optionally, R4 and R5 together with the atoms to which they are attached form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
R6 and R9 are independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;
R7 and R8 are independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and
substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which
they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl or bridged cycloalkyl ring; and
R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted
heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl.
In a second aspect, a compound of Formula (I) is synthesized by a method
comprising contacting a compound of Formula (II), a compound of Formula (III) and at
least one equivalent of an organic base, wherein X, n, R1, R2, R3, R4, R5, R6, R7, R8, R9 and
R10 are as defined, supra.
Those of skill in the art will appreciate that many of the embodiments described,
infra, are embodiments of both aspects, supra.
In one embodiment, R2 and R3 are independently hydrogen, alkyl, substituted alkyl,
alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl
or substituted heteroaryl. In another embodiment, R2 and R3 are independently hydrogen,
alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl, or heteroaryl. In still another
embodiment, R2 and R3 are independently hydrogen, alkanyl or substituted alkanyl. In still
another embodiment, R2 and R3 are independently hydrogen or alkanyl.
In still another embodiment, R1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted
heteroalkyl, heteroaryl or substituted heteroaryl. In still another embodiment, R1 is alkyl or
substituted alkyl. In still another embodiment, R1 is alkanyl or substituted alkanyl.
hi still another embodiment, R1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted
heteroalkyl, heteroaryl or substituted heteroaryl, and R2 and R3 are independently hydrogen,
alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. In still another
embodiment, R1 is alkyl, substituted alkyl, aryl, arylalkyl or heteroaryl and R2 and R3 are
independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or
substituted heteroarylalkyl. In still another embodiment, R1 is alkanyl or substituted alkanyl
and R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl,
substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl or substituted heteroarylalkyl.
In still another embodiment, R1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, cycloalkyl or substituted cycloalkyl and R2 and R3 are
independently hydrogen, alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl or
heteroaryl. In still another embodiment, R1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, cycloalkyl or substituted cycloalkyl and R2 and R3 are
independently hydrogen, alkanyl or substituted alkanyl. In still another embodiment, R1 is
alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl or
substituted cycloalkyl and R2 and R3 are independently alkanyl.
In still another embodiment, R is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroaryl or substituted
heteroaryl and R2 and R3 together with the atom to which they are attached form a
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. In
still another embodiment, R1 is alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or
heteroaryl and R2 and R3 are independently hydrogen, alkyl, alkoxycarbonyl, aryl, arylalkyl,
carbamoyl, cycloalkyl or heteroaryl. In still another embodiment, R1 is alkyl, substituted
alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R2 and R3 are independently hydrogen,
alkanyl or substituted alkanyl. hi still another embodiment, R1 is alkyl, substituted alkyl,
aryl, arylalkyl, cycloalkyl or heteroaryl and R2 and R3 are independently alkanyl. Br still
another embodiment, R1 is alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl
and R2 and R3 together with the atom to which they are attached form a cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring.
hi still another embodiment, R1 is alkanyl or substituted alkanyl and R2 and R3 are
independently hydrogen, alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl or
heteroaryl. In still another embodiment, R1 is alkanyl or substituted alkanyl and R2 and R3
are independently hydrogen, alkanyl or substituted alkanyl. In still another embodiment, R1
is alkanyl or substituted alkanyl and R2 and R3 are independently alkanyl. hi still another
embodiment, R1 is alkanyl or substituted alkanyl, and R2 and R3 together with the atom to
which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or
substituted cycloheteroalkyl ring.
In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl;, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,
1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl,
phenethyl, styryl or 3-pyridyl.
In still another embodiment, R2 and R3 are independently hydrogen, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl,
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl,
phenyl, benzyl, phenethyl or 3-pyridyl.
In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,
1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl,
phenethyl, styryl or 3-pyridyl and R and R are independently hydrogen, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl,
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl,
phenyl, benzyl, phenethyl or 3-pyridyl. In still another embodiment, R1 is methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl,
neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl,
phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl and R2 and R3 together
with the atom to which they are attached form a cyclobutyl, cyclopentyl or cyclohexyl ring.
. In still another embodiment, R2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, cyclohexyl or phenyl and R3 is hydrogen. In still another embodiment,
R2 is methyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or
cyclohexyloxycarbonyl and R3 is methyl.
In still another embodiment, R1 is methyl, ethyl, «-propyl, isopropyl, H-butyl,
isobutyl, sec-butyl, tert-butyl, 1,1-dimethoxyethyl or 1,1-diethoxyethyl. In still another
embodiment, R2 is methyl, ethyl, //-propyl, isopropyl, 7i-butyl, isobutyl, sec-butyl or
tert-butyl, and R3 is hydrogen, hi still another embodiment, Rl is methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1,1-dimethoxyethyl or 1,1-diethoxyethyl,
R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and R3 is
hydrogen.
In still another embodiment, R10 is hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted
heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or
trialkylsilyl. In still another embodiment, R10 is hydrogen. In still another embodiment, R10
is alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, aryldialkylsilyl or trialkylsilyl. hi still another embodiment, R10 is
methyl, ethyl, ter/-butyl, allyl, benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylmethyl,
trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl,
-C(CH3)=CH2, -CH2C(O)N(CH3)2,
where V is -O- or -CH2-.
hi one embodiment, n is 0. In another embodiment, n is 1.
hi one embodiment, R5 is selected from the group consisting of hydrogen, alkanyl,
substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,
heteroarylalkyl and substituted heteroarylalkanyl. In another embodiment, R5 is selected
from the group consisting of hydrogen, alkanyl and cycloalkanyl. In still another
embodiment, R5 is selected from the group consisting of hydrogen, methyl, isopropyl,
isobutyl, sec-butyl, tert-butyl, cyclopentyl and cyclohexyl. In still another embodiment, R5
is selected from the group consisting of substituted alkanyl. In still another embodiment, R
is selected from the group consisting of -CH2OH, -CH(OH)CH3, -CH2CO2H,
-CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, - CH2CH2SCH3, CH2SH, -CH2(CH2)3NH2
and -CH2CH2CH2NHC(NH)NH2. hi still another embodiment, R5 is selected from the
group consisting of aryl, arylalkanyl, substituted arylalkanyl and heteroarylalkanyl. In still
another embodiment, R5 is selected from the group consisting of phenyl, benzyl,
4-hydroxybenzyl, 4-bromobenzyl, 4-imidazolylmethyl and 3-indolylmethyl.
hi still another embodiment, R4 and R5 together with the atoms to which they are
attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring, In still another
embodiment, R4 and R5 together with the atoms to which they are attached form an
azetidine, pyrrolidine or piperidine ring.
In one embodiment, R6 and R9 are independently selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and substituted
cycloalkyl. In another embodiment, R6 and R9 are independently selected from the group
consisting of hydrogen and alkanyl. In still another embodiment, R6 and R9 are both
hydrogen.
In one embodiment, R7 and R8 are independently selected from the group consisting
of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl
and substituted cycloheteroalkyl. In another embodiment, R7 and R8 are independently
selected from the group consisting of hydrogen, alkanyl and substituted alkanyl. In still
another embodiment, R7 is hydrogen and R8 is selected from the group consisting of C1-6
alkanyl.
In still another embodiment, R7 and R8 together with the carbon atom to which they
are attached are cycloalkanyl or substituted cycloalkanyl. In still another embodiment, R7
and R8 together with the carbon atom to which they are attached are selected from the group
consisting of cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl,
cyclohexyl and substituted cyclohexyl.
In still another embodiment, R7 and R8 together with the carbon atom to which they
are attached are cycloheteroalkyl or substituted cycloheteroalkyl. In still another
embodiment, R7 and R8 together with the carbon atom to which they are attached are
bridged cycloalkyl.
In one embodiment, X is chloro, bromo or iodo. In another embodiment, X is
chloro, and R2 and R3 are independently hydrogen or alkanyl. In still another embodiment,
X is chloro, and R2 and R3 together with the atom to which they are attached form a
cycloalkanyl ring. In still another embodiment, X is chloro, bromo or iodo, and R2 and R3
are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,
sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl,
phenethyl or 3-pyridyl. In still another embodiment, X is chloro, bromo or iodo, and R2 and
R3 together with the atom to which they are attached form a cyclobutyl, cyclopentyl or
cyclohexyl ring, hi still another embodiment, X is chloro, bromo or iodo, R2 is methyl,
ethyl, 72-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl or phenyl and
R3 is hydrogen.
In one embodiment, a compound of Formulae (I) or (II) is derived is derived from a
GABA analog of Formula (IV):
wherein the GABA analog of Formula (IV) is selected from the group consisting of:
1-Aminomethyl-l-cyclohexane acetic acid (i.e. gabapentin);
l-Aminomethyl-l-(3-methylcyclohexane) acetic acid;
l-Aminomethyl-l-(4-methylcyclohexane) acetic acid;
l-Aminomethyl-l-(4-isopropylcyclohexane) acetic acid;
l-Ammomemyl-l-(4-tert-butylcyclohexane) acetic acid;
l-Aminomethyl-l-(3,3-dimethylcyclohexane) acetic acid;
l-Aminomethyl-l-(3,3,5,5-tetramethylcyclohexane) acetic acid;
1-Aminomethyl-l-cyclopentane acetic acid;
l-Aminomethyl-l-(3-methylcyclopentane) acetic acid;
l-Aminomethyl-l-(3,4-dimethylcyclopentane) acetic acid;
7-Aminomethyl-bicyclo[2.2.1]hept-7-yl acetic acid;
9-Aminomethyl-bicyclo[3.3.1]non-9-yl acetic acid;
4-Aminomethyl-4-(tetrahydropyran-4-yl) acetic acid;
3-Aminomethyl-3-(tetrahydropyran-3-yl) acetic acid;
4-Aminomethyl-4-(tetrahydrothiopyran-4-yl) acetic acid;
3-Aminomethyl-3-(tetrahydrothiopyran-3-yl) acetic acid;
(S)-3-Aminomethyl-5-methyl-hexanoic acid (i.e. pregabalin);
3-Aminomethyl-5-methyl-heptanoic acid;
3-Aminomethyl-5-methyl-octanoic acid;
3-Aminomethyl-5-methyl-nonanoic acid;
3-Aminomethyl-5-methyl-decanoic acid;
3 -Aminomethyl-5-cyclopropyl-hexanoic acid;
3-Aminomethyl-5-cyclobutyl-hexanoic acid;
3-Aminomethyl-5-cyclopentyl-hexanoic acid;
3-Aminomethyl-5-cyclohexyl-hexanoic acid;
3-Aminomethyl-5-phenyl-hexanoic acid;
3-Aminomethyl-5-phenyl-pentanoic acid;
3-Aminomethyl-4-cyclobutyl-butyric acid;
3 -Aminomethyl-4-cycIopentyl-butyric acid;
3-Aminomethyl-4-cyclohexyl-butyric acid;
3 -Ajtninomethyl-4-phenoxy-butyric acid;
3-Aminomethyl-5-phenoxy-hexanoic acid; and
3-Aminomethyl-5-benzylsulfanyl-pentanoic acid.
In another embodiment, the compound of Formula (I) is a compound of Formulae
(V)or(VI):
The skilled artisan will appreciate that the embodiments, infra, refer to compounds
of Formulae (V) and (VI)
In one embodiment, n is 0. In another embodiment n is 1.
In one embodiment, R5 is selected from the group consisting of hydrogen, alkanyl,
substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,
heteroarylalkyl and substituted heteroarylalkanyl. hi another embodiment, R'1 is selected
from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-bxAy\,
cyclopentyl, cyclohexyl, -CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H,
-CH2CONH2, -CH2CH2CONH2, - CH2CH2SGH3, CH2SH, -CH2(CH2)3NH2 and
-CH2CH2CH2NHC(NH)NH2, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl,
4-imidazolylmethyl and 3-indolylmethyl.
In still another embodiment, R and R5 together with the atoms to which they are
attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. In still another
embodiment, R4 and R5 together with the atoms to which they are attached form an
azetidine, pyrrolidine or piperidine ring.
In one embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .sec-butyl,
/er/-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,
cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or
3-pyridyl, R2 is hydrogen and R3 is hydrogen. In another embodiment, R1 is methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, /ert-butyl, pentyl, isopentyl, sec-pentyl,
neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl,
phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is methyl and R3 is
hydrogen. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,
1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl,
phenethyl, styryl or 3-pyridyl, R2 is ethyl and R3 is hydrogen. In still another embodiment,
R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,
sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl,
cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is propyl
and R3 is hydrogen, hi still another embodiment, R1 is methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is isopropyl and R3 is
hydrogen. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,
1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl,
phenethyl, styryl or 3-pyridyl, R2 is butyl and R3 is hydrogen. In still another embodiment,
R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,
sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl,
cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is isobutyl
and R3 is hydrogen. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is sec-butyl and R3 is hydrogen.
In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,
1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl,
phenethyl, styryl or 3-pyridyl, R2 is tert-butyl and R3 is hydrogen. In still another
embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .sec-butyl, tert-butyl,
pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl,
cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl,
R2 is cyclohexyl and R3 is hydrogen. In still another embodiment, R1 is methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, .sec-butyl, tert-butyl, pentyl, isopentyl, .sec-pentyl,
neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl,
phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is phenyl and R3 is
hydrogen. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, .sec-butyl, tert-butyl, pentyl, isopentyl, .sec-pentyl, neopentyl, 1,1-dimethoxyethyl,
1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl,
phenethyl, styryl or 3-pyridyl, R2 is methyl and R3 is methyl. In still another embodiment,
R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .sec-butyl, tert-butyl, pentyl, isopentyl,
.sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl,
cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is
methoxycarbonyl and R3 is methyl. In still another embodiment, R1 is methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, .sec-butyl, tert-butyl, pentyl, isopentyl, .sec-pentyl,
neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl,
phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is ethoxycarbonyl and
R3 is methyl. In still another embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, .sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,
1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl,
phenethyl, styryl or 3-pyridyl, R2 is isopropoxycarbonyl and R3 is methyl. In still another
embodiment, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, isopentyl, .sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl,
cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl,
R is cyclohexyloxycarbonyl and R is methyl. In still another embodiment, R is methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl,
neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl,
phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl and R2 and R3 together
with the atom to which they are attached form a cyclohexyl ring.
In one embodiment, R2 is methyl, methoxycarbonyl, ethoxycarbonyl,
isopropoxycarbonyl or cyclohexyloxycarbonyl and R3 is methyl. In another embodiment,
R2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
and R3 is hydrogen.
In one embodiment, R1 is methyl, ethyl, 71-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, /er/-butyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl or
cyclohexyl, and R10 is hydrogen, allyl, benzyl or trimethylsilyl.
In one embodiment, R1 is methyl, ethyl, w-propyl, isopropyl, H-butyl, isobutyl,
.sec-butyl, tert-butyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl or
cyclohexyl, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is hydrogen, methyl, ethyl,
isopropyl, zz-butyl, isobutyl, sec-butyl or tert-butyl, and R3 is hydrogen. In another
embodiment, R1 is ethyl or isopropyl, R10 is allyl, benzyl or trimethylsilyl, R2 is methyl,
/z-propyl or isopropyl, and R3 is hydrogen. In still another embodiment, R1 is isopropyl, R10
is benzyl, R2 is methyl, and R3 is hydrogen. In still another embodiment, R1 is isopropyl,
R10 is allyl, R2 is methyl, and R3 is hydrogen.
In one embodiment, R1 is ethyl or isopropyl, R10 is allyl, benzyl or trimethylsilyl, R2
is methyl, ;?-propyl or isopropyl, R3 is hydrogen and X is chloro. In another embodiment,
R1 is isopropyl, R10 is benzyl, R2 is methyl, R3 is hydrogen and X is chloro. In still another
embodiment, R1 is isopropyl, R10 is allyl, R2 is methyl, R3 is hydrogen and X is chloro.
In one embodiment, X is bromo or chloro. In another embodiment, X is chloro,
bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is hydrogen and R3 is
hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl,
benzyl or trimethylsilyl, R2 is methyl and R3 is hydrogen. In still another embodiment, X is
chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is ethyl and R3 is
hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl,
benzyl or trimethylsilyl, R2 is propyl and R3 is hydrogen. In still another embodiment, X is
chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is isopropyl and
R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen,
allyl, benzyl or trimethylsilyl, R2 is butyl and R3 is hydrogen. In still another embodiment,
X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is isobutyl
and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is
hydrogen, allyl, benzyl or trimethylsilyl,, R2 is sec-butyl and R3 is hydrogen. In still another
embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2
is tert-butyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo,
R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is cyclohexyl and R3 is hydrogen. In still
another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or
trimethylsilyl, R2 is phenyl and R3 is hydrogen. In still another embodiment, X is chloro,
bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is methyl and R3 is
methyl. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl,
benzyl or trimethylsilyl, R is methoxycarbonyl and R is methyl, hi still another
embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2
is ethoxycarbonyl and R3 is methyl. In still another embodiment, X is chloro, bromo or
iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is isopropoxycarbonyl and R3 is
methyl. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl,
benzyl or trimethylsilyl, R2 is cyclohexyloxycarbonyl and R3 is methyl. In still another
embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl and
R2 and R3 together with the atom to which they are attached form a cyclohexyl ring. In still
another embodiment, X is chloro, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is
hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl and
R3 is hydrogen. In still another embodiment, X is chloro., R10 is hydrogen, allyl, benzyl or
trimethylsilyl, R2 is methyl, «-propyl or isopropyl, and R3 is hydrogen. In still another
embodiment, X is chloro, R10 is allyl, R2 is methyl, and R3 is hydrogen. In still another
embodiment, X is chloro, R10 is benzyl, R2 is methyl, and R3 is hydrogen. In still another
embodiment, X is chloro, R10 is trimethylsilyl, R2 is methyl, and R3 is hydrogen.
Those of skill in the art will appreciate that the following embodiments, infra, refer
to compounds of Formulae (I), (II) and (III). In one embodiment, the ratio of the
compound of Formula (II) to the compound of Formula (III) is between about 1:1 and 1:20.
In another embodiment, the ratio of the compound of Formula (II) to the compound of
Formula (III) is between about 1:1 and 1:5. In still another embodiment, the ratio of the
compound of Formula (II) to the compound of Formula (III) is about 1:1.
In one embodiment, the compounds of Formulae (II) and (III) and the metal salt are
contacted with a solvent. In another embodiment, the ratio of the compound of Formula (II)
to the compound of Formula (III) is between about 1:1 and 1:20. hi still another
embodiment, the ratio of the compound of Formula (II) to the compound of Formula (III) is
between about 1:1 and 1:5. In still another embodiment, the ratio of the compound of
Formula (II) to the compound of Foimula (III) is about 1:1. In one embodiment, the
solvent is dichloromethane, dichloroethane, chloroform, toluene, dimethylformamide,
dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, pyridine, ethyl acetate,
acetonitrile, acetone, 2-butanone, methyl tert-butyl ether, methanol, ethanol, isopropanol,
tert-butanol, water, hexamethylphosphoramide or combinations thereof. In another
embodiment, the metal is Ag, Hg, Na, K, Li, Cs, Ca, Mg or Zn.
In one embodiment, the compounds of Formulae (II) and (III) and the organic base
are contacted with a solvent, hi another embodiment, the ratio of the compound of Formula
(II) to the compound of Formula (III) is between about 1:1 and 1:20. In still another
embodiment, the ratio of the compound of Formula (II) to the compound of Formula (III) is
between about 1:15 and 1:20. In still another embodiment, the ratio of the compound of
Formula (II) to the compound of Formula (III) is about 1:10. Li still another embodiment,
the ratio of the compound of Formula (II) to the compound of Formula (III) is between
about 1:1 and 1:5. In still another embodiment, the ratio of the compound of Formula (II)
to the compound of Formula (III) is about 1:1. In one embodiment, the solvent is
dichloromethane, dichloroethane, chloroform, toluene, dimethylformamide,
dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, pyridine, ethyl acetate,
acetonitrile, acetone, 2-butanone, methyl tert-butyl ether, methanol, ethanol, isopropanol,
ter/-butanol, water, hexamethylphosphoramide or combinations thereof. In another
embodiment, the organic base is triethylamine, tributylamine, diisopropylethylamine,
dimethylisopropylamine, N-methyhnorpholine, N-methylpyrrolidine, N-methylpiperidine,
pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, 1,
4-diazabicyclo[2.2.2]octane, 1, 8-diazabicyclo[5.4.0]undec-7-ene, 1,
5-diazabicyclo[4.3.0]undec-7-ene or combinations thereof.
hi one embodiment, the compound of Formula (III) is a liquid under the conditions
of said contacting, the compound of Formula (III) further serving as a solvent for the
reaction with the compound of Formula (II). In another embodiment, the compound of
Formula (III) is acetic acid, methoxyacetic acid, ethoxyacetic acid, propionic acid, butyric
acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, 2-methylbutyric acid,
cyclobutanecarboxylic acid, cyclopentanecarboxylic acid or cyclohexanecarboxylic acid, hi
still another embodiment, the compound of Formula (III) is isobutyric acid.
In one embodiment, the compound of Formula (II), the compound of Formula (III)
and the metal salt are contacted at a temperature between about -25 °C and about 120 °C.
In another embodiment, the temperature is between about 0 °C and about 25 °C.
In one embodiment, the compound of Formula (II), the compound of Formula (HI)
and the organic base are contacted at a temperature between about -25 °C and about 120 °C.
In another embodiment, the temperature is between about 0 °C and about 25 °C.
In one embodiment, the compound of Formula (II), the compound of Formula (HI)
and the organic base are contacted with a catalytic amount of an iodide salt. In still another
embodiment, the iodide salt is sodium iodide, potassium iodide, tetramethylammonium
iodide, tetraethylammonium iodide or tetrabutylammonium iodide.
1-HaloalkyI Carbamates of GABA Analogs
Also disclosed herein are 1-haloalkyl carbamates of GABA analogs of Formula (II):
R2 and R3 are independently hydrogen, alkyl, substituted alkyl,
alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded
form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl
ring;
R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl or substituted heteroarylalkyl;
R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,
substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted
heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl,
or optionally, R4 and R5 together with the atoms to which they are attached form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
R6 and R9 are independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;
R7 and R8 are independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and
substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which
they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl or bridged cycloalkyl ring; and
R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted
heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl.
Those of skill in the art will appreciate that the following embodiments, infra, refer
to compounds of Formula (II). In one embodiment, R2 and R3 are independently hydrogen,
alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted
cycloalkyl, heteroaryl or substituted heteroaryl. In another embodiment, R2 and R3 are
independently hydrogen, alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl or
heteroaryl. In still another embodiment, R2 and R3 are independently hydrogen, alkanyl or
substituted alkanyl. In still another embodiment, R2 and JR.3 are independently hydrogen or
alkanyl. In still another embodiment, R2 and R3 together with the atom to which they are
bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted
cycloheteroalkyl ring. In still another embodiment R and R together with the atom to
which they are bonded form a cycloalkanyl ring.
In one embodiment, X is chloro, bromo or iodo. In another embodiment, X is
chloro.
In one embodiment, X is chloro, bromo or iodo and R2 and R3 are independently
hydrogen, alkyl, substituted alkyl, alkbxycarbonyl, substituted alkoxycarbonyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.
In another embodiment, X is chloro, bromo or iodo, and R2 and R3 are independently
hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.
In still another embodiment, X is chloro and R2 and R3 are independently hydrogen, alkyl,
substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.
In still another embodiment, X is chloro, bromo or iodo, and R2 and R3 are
independently hydrogen, alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl or
heteroaryl. In still another embodiment, X is chloro, bromo or iodo, and R2 and R3 are
independently hydrogen, alkanyl or substituted alkanyl. In still another embodiment, X is
chloro, bromo or iodo, and R2 and R3 are independently alkanyl. In still another
embodiment, X is chloro, bromo or iodo, and R2 and R3 together with the atom to which
they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted
cycloheteroalkyl ring.
In still another embodiment, X is chloro, and R2 and R3 are independently hydrogen,
alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl or heteroaryl. hi still another
embodiment, X is chloro, and R and R are independently hydrogen, alkanyl or substituted
alkanyl. In still another embodiment, X is chloro, and R2 and R3 are independently alkanyl.
In still another embodiment, X is chloro, and R2 and R3 together with the atom to which
they are attached form a cycloalkanyl ring.
In one embodiment, R and R are independently hydrogen, methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl,
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl,
phenyl, benzyl, phenethyl or 3-pyridyl.
In another embodiment, X is chloro, bromo or iodo, and R2 and R3 are independently
hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl,
cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,
fert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl. In
still another embodiment, X is chloro, bromo or iodo, and R2 and R3 together with the atom
to which they are attached form a cyclobutyl, cyclopentyl or cyclohexyl ring.
In one embodiment, R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, cyclohexyl or phenyl and R3 is hydrogen, hi another embodiment, R2
is methyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or
cyclohexyloxycarbonyl and R3 is methyl.
hi still another embodiment, X is chloro, bromo or iodo, R2 is methyl, ethyl,
n-propyl, isopropyl, H-butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl or phenyl and R3 is
hydrogen.
hi one embodiment, R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,
heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or
trialkylsilyl. hi another embodiment, R10 is hydrogen. In still another embodiment, R10 is
alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, aryldialkylsilyl or trialkylsilyl. In still another embodiment, R10 is
methyl, ethyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl, diphenyhnethyl, triphenylmethyl,
trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl,
-C(CH3)=CH2, -CH2C(O)N(CH3)2,
where V is -O- or -CH2-. hi still another embodiment, R10 is allyl. hi still another
embodiment, R10 is benzyl. In still another embodiment, R10 is trimethylsilyl.
In one embodiment, n is 0. hi another embodiment, n is 1.
In one embodiment, R is hydrogen. In another embodiment, R5 is selected from the
group consisting of hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl,
arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkyl and substituted
heteroarylalkanyl. In another embodiment, R5 is selected from the group consisting of
hydrogen, alkanyl and cycloalkanyl. In still another embodiment, R5 is selected from the
group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl
and cyclohexyl. In still another embodiment, R5 is selected from the group consisting of
substituted alkanyl. In still another embodiment, R5 is selected from the group consisting of
-CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, -
CH2CH2SCH3, CH2SH, -CH2(CH2)3NH2 and -CH2CH2CH2NHC(NH)NH2. In still another
embodiment, R5 is selected from the group consisting of aryl, arylalkanyl, substituted
arylalkanyl and heteroarylalkanyl. In still another embodiment, R5 is selected from the
group consisting of phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 4-imidazolybnethyl
and 3-indolylmethyl.
In still another embodiment, R4 and R5 together with the atoms to which they are
attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. In still another
embodiment, R4 and R5 together with the atoms to which they are attached form an
azetidine, pyrrolidine or piperidine ring.
In one embodiment, R and R9 are independently selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and substituted
cycloalkyl. In another embodiment, R6 and R9 are independently selected from the group
consisting of hydrogen and alkanyl. In still another embodiment, R6 and R9 are both
hydrogen.
"7 ft '
hi one embodiment, R and R are independently selected from the group consisting
of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl
and substituted cycloheteroalkyl. hi another embodiment, R7 and R8 are independently
selected from the group consisting of hydrogen, alkanyl and substituted alkanyl. In still
another embodiment, R7 is hydrogen and R8 is selected from the group consisting of C1-6
alkanyl.
hi still another embodiment, R7 and R8 together with the carbon atom to which they
are attached are cycloalkanyl or substituted cycloalkanyl. hi still another embodiment, R7
and R8 together with the carbon atom to which they are attached are selected from the group
consisting of cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl,

cyclohexyl and substituted cyclohexyl. In still another embodiment, R and R together
with the carbon atom to which they are attached are cycloheteroalkyl or substituted
1 ft
cycloheteroalkyl. In still another embodiment, R and R together with the carbon atom to
which they are attached are bridged cycloalkyl.
In one embodiment, a compound of Formula (II) is derived from a GAB A analog of
Formula (IVY.
wherein the GAB A analog of Formula (TV) is selected from the group consistir
1-Aminomethyl-l-cyclohexane acetic acid {i.e., gabapentin);
l-Aminomethyl-l-(3-methylcyclohexane) acetic acid;
l-Aminomethyl-l-(4-methylcyclohexane) acetic acid;
l-Aminomethyl-l-(4-isopropylcyclohexane) acetic acid;
l-Aminomethyl-l-(4-tert-butylcyclohexane) acetic acid;
l-Ammomethyl-l-(3,3-dimethylcyclohexane) acetic acid;
1-Aminomethyl-l-(3,3,5,5-tetrarnethylcyclohexane) acetic acid;
1-Aminomethyl-l-cyclopentane acetic acid;
l-Aminomethyl-l-(3-methylcyclopentane) acetic acid;
1-Aminomethyl-l-(3,4-dimethylcyclopentane) acetic acid;
7-Aminomethyl-bicyclo[2.2.1]hept-7-yl acetic acid;
9-Aminomethyl-bicyclo[3.3.1]non-9-yl acetic acid;
4-Aminomethyl-4-(tetrahydropyran-4-yl) acetic acid;
3-Aminomethyl-3-(tetrahydropyran-3-yl) acetic acid;
4-Aminomethyl-4-(tetrahydrothiopyran-4-yl) acetic acid;
3-Aminomethyl-3-(tetrahydrothiopyran-3-yl) acetic acid;
(S)-3-Aminomethyl-5-rnethyl-hexanoic acid (i.e., pregabalin);
3-Aminomethyl-5-methyl-heptanoic acid;
3-Aminomethyl-5-methyl-octanoicacid;
3-Aminomethyl-5-methyl-nonanoic acid;
3-Aminomethyl-5-methyl-decanoic acid;
3-Aminomethyl-5-cyclopropyl-hexanoic acid;
3-Aminomethyl-5-cyclobutyl-hexanoicacid;
3-Aminomethyl-5-cyclopentyl-hexanoic acid;
3-Ammomethyl-5-cyclohexyl-hexanoicacid;
3-Aminomethyl-5-phenyl-hexanoic acid;
3-Aminomethyl-5-phenyl-pentanoic acid;
3 -Aminomethyl-4-cyclobutyl-butyric acid;
3-AminomethyI-4-cyclopentyl-butyric acid;
3-Ammomethyl-4-cyclohexyl-butyricacid;
3-Aminomethyl-4-phenoxy-butyric acid;
3-Aminomethyl-5-phenoxy-hexanoic acid; and
3-Aminomethyl-5-benzylsulfanyI-pentanoic acid.
In one embodiment, the compound of Formula (II) is a compound of Formulae
(VII) or (VIII):
Those of skill in the art will appreciate that the following embodiments, infra, refer
to compounds of Formulae (VII) and (VIII).
In one embodiment, n is 0. In another embodiment, n is 1.
In one embodiment, R4 is hydrogen. In another embodiment, R5 is selected from the
group consisting of hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl,
arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkyl and substituted
heteroarylalkanyl. In another embodiment, R5 is selected from the group consisting of
hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-bntyl, cyelopentyl, cyclohexyl,
-CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, -
CH2CH2SCH3, CH2SH, -CH2(CH2)3NH2 and -CH2CH2CH2NHC(NH)NH2, phenyl, benzyl,
4-hydroxybenzyl, 4-bromobenzyl, 4-imidazolylmethyl and 3-indolylmethyl.
In still another embodiment, R4 and R5 together with the atoms to which they are
attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. In still another
embodiment, R4 and R5 together with the atoms to which they are attached form an
azetidine, pyrrolidine or piperidine ring.
In one embodiment, X is cMoro, bromo or iodo, R10 is hydrogen, allyl, benzyl or
trimethylsilyl, R2 is hydrogen and R3 is hydrogen. In another embodiment, X is chloro,
bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is methyl and R3 is
hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl,
benzyl or trimethylsilyl, R2 is ethyl and R3 is hydrogen. In still another embodiment, X is
chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is propyl and R3 is
hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl,
benzyl or trimethylsilyl, R2 is isopropyl and R3 is hydrogen. In-still another embodiment, X
is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is butyl and R3
is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl,
benzyl or trimethylsilyl, R2 is isobutyl and R3 is hydrogen. In still another embodiment, X
is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is sec-butyl and
R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen,
allyl, benzyl or trimethylsilyl, R2 is tert-butyl and R3 is hydrogen. In still another
embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2
is cyclohexyl and R3 is hydrogen. In still another embodiment, X is chloro, bromo or iodo,
R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is phenyl and R3 is hydrogen. In still
another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or
trimethylsilyl, R2 is methyl and R3 is methyl. In still another embodiment, X is chloro,
bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is methoxycarbonyl and
R3 is methyl. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen,
allyl, benzyl or trimethylsilyl, R2 is ethoxycarbonyl and R3 is methyl. In still another
embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2
is isopropoxycarbonyl and R3 is methyl. In still another embodiment, X is chloro, bromo or
iodo, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is cyclohexyloxycarbonyl and R3 is
methyl. In still another embodiment, X is chloro, bromo or iodo, R10 is hydrogen, allyl,
benzyl or trimethylsilyl, and R2 and R3 together with the atom to which they are attached
form a cyclohexyl ring.
In one embodiment, X is chloro, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2
is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl and
R3 is hydrogen. In another embodiment, X is chloro, R10 is hydrogen, allyl, benzyl or
trimethylsilyl, R2 is methyl, n-propyl br isopropyl, and R3 is hydrogen. In still another
embodiment, X is chloro, R10 is allyl, R2 is methyl, and R3 is hydrogen. In still another
embodiment, X is chloro, R10 is benzyl, R2 is methyl, and R3 is hydrogen. In still another
embodiment, X is chloro, R10 is trimethylsilyl, R2 is methyl, and R3 is hydrogen.
Synthesis of 1-HaloalkyI Carbamates and Conversion to 1-Acyloxy-AlkyI Carbamates
The compounds and methods of the invention may be obtained and/or practiced
according to the synthetic methods illustrated in Schemes 1-5. Numerous methods have
been described in the art for the synthesis of GAB A analogs (i.e., compounds of formula
(1), infra, where n = 0; see, e.g., Satzinger et al, United States Patent No. 4,024,175;
Silverman et al, United States Patent No. 5,563,175; Horwell et al, United States Patent
No. 6,020,370; Silverman et al, United States Patent No. 6,028,214; Horwell et al, United
States Patent No. 6,103,932; Silverman et al, United States Patent No. 6,117,906;
Silverman, International Publication No. WO 92/09560; Silverman etal, International
Publication No. WO 93/23383; Horwell et al, International Publication No. WO 97/29101,
Horwell et al, International Publication No. WO 97/33858; Horwell et al, International
Publication No. WO 97/33859; Bryans et al, International Publication No. WO 98/17627;
Guglietta et al, International Publication No. WO 99/08671; Bryans et al, International
Publication No. WO 99/21824; Bryans et al, International Publication No. WO 99/31057;
Belliotti et al, International Publication No. WO 99/31074; Bryans et al, International
Publication No. WO 99/31075; Bryans et al, International Publication No. WO 99/61424;
Bryans etal, International Publication No. WO 00/15611; Bryans, International Publication
No. WO 00/31020; and Bryans et al, International Publication No. WO 00/50027). Other
methods are known in the art for synthesizing GAB A analogs, which are readily accessible
to the skilled artisan. Methods for synthesis of amino acid derivatives of GAB A analogs
{i.e., compounds of formula (1), infra, where n = 1) are disclosed in Gallop et al,
International Publication No. WO 02/100347).
Accordingly, starting materials useful for preparing compounds and intermediates
thereof, and/or practicing methods of the invention are commercially available or can be
prepared by well-known synthetic methods. Other methods for synthesis of the prodrugs
described herein are either described in the art or will be readily apparent to the skilled
artisan in view of the references provided above and may be used to synthesize the
compounds of the invention. Accordingly, the methods presented in the Schemes herein are
illustrative rather than comprehensive.
Intermediate (4) useful in the preparation of 1-haloalkyl carbamates of Formula (II)
may be generated according to reactions detailed in Scheme 1.
The amino group of (1) (a GAB A analog when n = 0, or an aminoacyl derivative of
a GAB A analog when n = 1) is protected under standard conditions with a protecting group
("Pg") to afford compound (2). The carboxylic acid moiety in (2) is esterified to yield
compound (3), either (i) via alkylation with RI0-Y, where Y is halide, O3SR' (R' is alkyl,
substituted alkyl, aryl or substituted aryl), or other suitable leaving group), or (ii) via
condensation with alcohol R10-OH under standard acylation conditions (e.g., in the presence
of a coupling agent such as a carbodiimide, via an acyl halide, acid anhydride or other
activated ester intermediate). Removal of the protecting group from (3) under standard
deprotection conditions affords compound (4). Preferably, when n = 0, the protecting group
Pg is removable under acidic conditions and compound (4) is isolated as a salt, which is
stabilized towards lactam formation relative to the corresponding free base form.
tert-Butoxycarbonyl (i.e., Boc) is one preferred protecting group, and may be removed with
HC1 to afford (4) as a hydrochloride salt.
In a preferred embodiment, where n is 0, the hydrochloride salt of (4) is prepared
directly from (1) by treatment with an excess of thionyl chloride or hydrogen chloride gas
and alcohol R10-OH (Scheme 2). Typical ratios of (1) to thionyl chloride from between 1:1
and 1:20, and ratios of (1) to alcohol from between 1:1 and 1:20 may be used. The reaction
may be performed at temperatures between —20 °C and 25°C. Under conditions where the
alcohol R10-OH is a liquid, the alcohol may be used as a solvent for the reaction.
Alternatively, the reaction may be performed in the presence of a suitable solvent, such as,
for example, dichloromethane, dichloroethane, chloroform, toluene, dimethylformamide,
dimethylacetamide, N-methylpyrrolidinone, or pyridine. Preferred alcohols R10-OH for this
reaction are arylalkyl, substituted arylalkyl and allylic alcohols. Allyl alcohol and benzyl
alcohol are particularly preferred.
In one embodiment, a compound of formula (II) is prepared by acylation of (4) with
compound (5) (see Scheme 3), where X is halide and Z is a leaving group (e.g., halide,
/>-nitrophenolate, imidazolyl, etc.). Preferably, X is Cl or Br and Z is Cl. More preferably,
X and Z are both Cl. The acylation reaction may be performed in the presence of a base,
including inorganic and organic bases (e.g., tertiary amine bases, such as triethylamine,
tributylamine, diisopropylethylamine, dimethylisopropylamine, N-methylmorpholine,
N-methylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyridine,
2,6-dimethylpyridine, 4-dimethylaminopyridine, 1, 4-diazabicyclo[2.2.2]octane, 1,
8-diazabicyclo[5.4.0]undec-7-ene, 1, 5-diazabicyclo[4.3.0]undec-7-ene, etc.). Suitable
solvents for this acylation include, but are not limited to, dichloromethane, dichloroethane,
chloroform, toluene, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone,
dimethyl sulfoxide, pyridine, ethyl acetate, isopropyl acetate, acetonitrile, acetone,
2-butanone, methyl tert-bntyl ether, or combinations thereof. Alternatively, biphasic
solvent mixtures comprising water and one or more of dichloromethane, dichloroethane,
chloroform, toluene, ethyl acetate, isopropyl acetate or methyl ter*-butyl ether, may be
utilized. Typical temperatures for performing this reaction are between -20 °C and 50°C,
more preferably, between -20 °C and 25°C.
In another embodiment, a compound of formula (II), where R10 is trialkylsilyl or
aryldialkylsilyl, may be prepared directly from compound (1) by silylation (e.g., using a
silyl halide or silylamide reagent) and then acylation of the resulting intermediate with
compound (5) (see Scheme 4). Suitable solvents for performing this reaction include, but
are not limited to, dichloromethane, dichloroethane, chloroform, toluene, pyridine, and
acetonitrile. Suitable bases for performing this reaction include, but are not limited to,
triethylamine, tributylamine, diisopropylethylamine, dimethylisopropylamine,
N-methylmorpholme, N-methylpyrrolidine, N-methylpiperidine, pyridine,
2-methylpyridine, 2,6-draiethylpyridine, 4-dimethylaminopyridine, 1,
4-diazabicyclo[2.2.2]octane, 1, 8-diazabicyclo[5.4.0]undec-7-ene or 1,
5-diazabicyclo[4.3.0]undec-7-ene. Typical temperatures for performing this reaction are
between -78 °C and 50°C, more preferably, between -20 °C and 25°C.
1-Acyloxylalkyl carbamates of fonnula (I) are prepared from compounds of formula
(II) by treatment with carboxylic acids of formula (III) in the presence of an organic or
inorganic base, or other metal salt, as illustrated in Scheme 5. Preferred solvents, bases and
other reaction conditions have been described in detail previously (see Section 4.2 above).
In one embodiment, R10 is a carboxylic acid protecting group that can be removed
under mild conditions to provide a compound of fonnula (I) where R10 is hydrogen.
Carboxylic acid protecting groups removable via mild acidic hydrolysis, fluoride
ion-promoted hydrolysis, catalytic hydrogenolysis, transfer hydrogenolysis, or other
transition metal-mediated deprotection reactions are preferred. In one embodiment, R10 is
trirnethylsilyl, allyl or benzyl.
Examples
The invention is further defined by reference to the following examples, which
describe in detail the preparation of 1 -haloalkyl carbamates of GAB A analogs and illustrate
methods of synthesizing l-(acyloxy)-alkyl, carbamates of GAB A analogues from
1-haloalkyl carbamates of GAB A analogs. It will be apparent to those skilled in the art that
many modifications, both to materials and methods, may be practiced without departing
from the scope of the invention.
In the examples below, the following abbreviations have the following meanings. If
an abbreviation is not defined, it has its generally accepted meaning.
Frnoc = 9-fluorenylmethyloxycarbonyl
g = gram
h = hour
HPLC = high pressure liquid chromatography
L = liter
LC/MS =r liquid chromatography/mass spectroscopy
M = molar
min = minute
mL = milliliter
mmol = millimoles
NHS = N-hydroxysuccinimide
THF = tetrahydrofuran
TFA = trifluoroacetic acid
TLC = thin layer chromatography
TMS = trimethylsilyl
uL = microliter
uM = micromolar
v/v = volume to volume
Example 1: Benzyl 1-AminomethvI-l-Cyclohexane Acetate Hydrochloride (6)
A dry 500 mL, three-necked, round-bottomed flask was fitted with a magnetic
stirring bar and a 60 mL pressure-equalizing addition runnel and flushed with nitrogen gas.
The flask was charged with gabapentin (17.1 g, 0.1 mol) and benzyl alcohol (128 mL, 1.18
mol) and the mixture was cooled to 0°C with an ice-water bath. Thionyl chloride (51.8 mL,
77.25 g, 0.65 mol) was added dropwise to the stirred solution over a period of 1 h. The
reaction was monitored by LC/MS, with product and unreacted gabapentin hydrochloride
being observed. After stirring at room temperature for 3.5 days the reaction mixture
contained residual gabapentin hydrochloride (by LC/MS). Additional thionyl chloride (20
mL, 30 g, 0.25 mol) was added at 0°C, and the reaction mixture allowed to stir at room
temperature for another 12 h (LC/MS shows traces of residual gabapentin hydrochloride).
A final portion of thionyl chloride (10 mL, 15 g, 0.12 mol) was added at 0°C and the
reaction mixture allowed to stir at room temperature for 4 h (LC/MS showed no remaining
gabapentin hydrochloride). The reaction mixture was then diluted with ethyl ether (200
mL) and cooled to 0° C while stirring. White crystalline solid formed, which was collected
by filtration. The crude compound was recrystallized from a mixture of ethanol and ethyl
ether (50 mL: 150 mL). Finally the white crystals were washed with 250 mL of ethyl
acetate to give product (6) as a white solid (27 g, 91% yield). *H NMR (CDC13, 400 MHz.):
8 1.43 - 1.52 (m, 10H), 2.64 (s, 2H), 3.08 (d, 2 H), 6.04 (br. s, 1H), 7.25 - 7.33 (m, 5H),
8.44 (br. s, 3H). MS (ESI) m/z 262.26 (M+H4).
Example 2: l-[(tert-Butoxvcarbonvl)aminomethvIl-l-Cvciohexane Acetic Acid (7)
Gabapenrin, (700 g , 4.09 mol) was slurried in water (2.7 L) with potassium
carbonate (1.2 kg, 8.58 mol) and mechanically stirred under a nitrogen atmosphere.
Di-tert-butyl dicarbonate (875 g, 4.00 mol) was dissolved in dioxane (4 L) and was added in
large aliquots while maintaining the pH at 8 - 10, and if needed, adjusting the pH using
additional potassium carbonate. The reaction was monitored by !H-NMR, noting the
disappearance of the singlet resonance at 1.22 ppm for di-tert-butyl dicarbonate. After
stirring overnight at ambient temperature the dioxane was removed in vacuo and the pH of
the aqueous phase adjusted to between 3 and 4 using 10% sulfuric acid. The aqueous
mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried
over sodium sulfate and concentrated in vacuo to afford compound (7) as a white powder
(893 g, 80% yield). ]H NMR (CDCI3), 400 MHz): 5 1.24 - 1.50 (m, 10H), 2.30 (s, 2H),
3.15 (d, 2H), 5.02 (t, 1H). MS (ESI) m/z 294.18 (M+Na+). Melting point: 125 -130 °C.
Example 3: Benzyl l-f(tert-Butoxvcarbonvl)aminomethvIl-l-Cvciohexane Acetate (8)
In a 12 L, multi-neck, round bottom flask with a bottom valve, mechanical stirrer
and nitrogen blanket, (7) (1098 g, 4.05 mol) and potassium carbonate (838 g, 6.075 mol)
were added to N-methylpyrrolidinone (2 L) at room temperature. Benzyl bromide (457 mL,
3.84 mol) was added over one hour. The strongly exothermic reaction was maintained
below 40 °C, and the resulting white suspension was stirred until judged complete by NMR,
about 2 hours.
Ice water (6 L) was carefully added to quench the reaction. Dichloromethane (3 L)
was added, the organic phase separated and further extracted with water (2x2 L), 10%
potassium carbonate (2x2 L), brine (2 L), then dried over sodium sulfate and concentrated
in vacuo. The crude product (8) (1380 g., 94% yield) was carried to the next reaction
without further purification. ]H NMR (CDC13, 400 MHz): 1.33 - 1.53 (m, 10H), 2.32 (s,
2H), 3.11 (d, 2H), 5.01 (br. t, 1H), 5.09 (s, 2H), 7.31 - 7.35 (m, 5H). MS (ESI) m/z 442.39
(M+Na4).
Example 4: Benzyl 1-Aminomethyl-l-Cyclohexane Acetate Hydrochloride (6)
Compound (8) from Example 3 above was added slowly with stirring and cooling to
a 5 L, 3-neck, round bottom flask containing 4N HC1 in dioxane (2.5 L) over about a one
hour period, the reaction mixture being maintained between 30 and 35 °C to keep the
product from precipitating. The clear solution was divided into four aliquots, to each of
which was added methyl-t-butyl ether (500 mL) to initiate crystallization of the product.
Each batch fully solidified within 10 min. The solids were filtered, washed twice with ethyl
acetate, then dried in a vacuum oven at 35 °C for 16 h to afford the product (6) as a white
solid (936 g, 79% yield from (7)). JH NMR (CDC13,400 MHz.): 8 1.43 - 1.52 (m, 10H),
2.64 (s, 2H), 3.08 (d, 2 H), 6.04 (br. s, 1H), 7.25 - 7.33 (m, 5H), 8.44 (br. s, 3H). MS (ESI)
m/z 262.26 (M+H").
Example 5: Benzyl l-{[(a-ChIoroethoxv)carbonyllaminomethyl)-l-Cvclohexane
Acetate (9)
In a 5-liter, 3-neck, round bottom flask, stirred mechanically and under nitrogen,
was added dichloromethane (1.5 L), compound (6) (1.85 mol) and 1-chloroethyl
chloroformate (258 g, 1.81 mol). The resulting solution was cooled to 15 °C and
N-methylmorphoIine (396 mL, 3.60 mol) was added slowly, with cooling, over a one hour
period. The resulting turbid solution was stirred for 30 min, after which 1H-NMR analysis
showed the reaction to be complete. The reaction mixture was washed with water (2 x 2 L)
and brine (1 L) and dried over sodium sulfate. Evaporation of the solvent afforded the title
compound (9) as an orange oil (670 g, 98% yield). 1HNMR (CDC13,400MHz): 1.33 - 1.53
(m, 10H), 1.75 (d, 3H), 2.33 (s, 2H), 3.18 (d, 2 H), 5.09 (s, 2H), 5.58 (t, 1H), 6.53 (q, 1 H),
7.29-7.33 (m,5H).
Example 6: Benzyl l-((a-Isobutanovloxyethoxy)carbonvH
aminomethyl}-1-Cyclohexane Acetate (10)
To a 10-L reactor equipped with a mechanical stirrer, cooling jackets and under
nitrogen, was added isobutyric acid (1.35 L, 14.6 mol) via an addition funnel, followed by
N-methylmorpholine (1.6 L, 14.6 mol). The resulting solution was cooled to 16 °C and a
solution containing compound (9) (1237 g crude, 2.93 mol) dissolved in isobutyric acid
(1.35 L 14.6 mol) was slowly added with stirring. After the addition was complete the
resulting turbid solution was stirred for a total of 33 h, after which time 1H-NMR indicated
less than 2% of starting material (9) remained. The crude reaction mixture was split in two
equal batches, each of which was diluted with diethyl ether (6 L), washed with water (6 x
2L) in a centrifugal extractor to remove excess isobutyric acid, followed by washing with
10% potassium bicarbonate (4 x 2 L) and brine (2 x 2 L) before drying over anhydrous
sodium sulfate. The combined organic extracts were concentrated to provide a dark orange
oil (916 g). The crude oil (400 g) was loaded onto an 800 g Biotage™ silica gel
chromatography column and eluted with 5% ethyl acetate in hexane (6 L), then with 7%
ethyl acetate in hexane (12 L). The desired product elutes in the 7% fractions. The
chromatographic purification was repeated with the remaining crude product to afford
compound (10) as a thick colorless oil (822 g). !H NMR (CDC13,400 MHz): 8 1.5 (d, 6H),
1.24-1.53 (m, 13 H), 1.45 (d, 3H), 2.33 (s, 2H), 2.48-2.55 (m, 1H), 3.16 (d, 2H), 5.09 (s,
2H), 5.35 (t, 1H), 6.77 (q, 1H), 7.29 - 7.36 (m, 5H). MS (ESI) m/z 442.48 (M+Na4).
Example 7: l-{[(a-Isobutanovloxvethoxv)carbonvnaminomethvl}-l-CvcIohexane
Acetic Acid (11)
Compound (10) (113 g) was dissolved in ethyl acetate (700 mL) and 10 g of 10%
Pd-C was added. The reaction mixture was subjected to 50 psi of hydrogen gas in a Parr
reactor for 40 min. Filtration through a sintered glass funnel and a hydrophobic membrane
filtration cartridge (Millipore Opticap) removed the catalyst. The supernatant was
concentrated to afford the product (11) as a white, crystalline solid (78 g, quantitative yield).
Crystals formed in the freezer, then at room temperature over several days. 'H NMR
(CDC13,400MHz): 1.15 (d, 6H)/1.40- 1.55 (m, 10H), 1.45 (d, 3H), 2.32 (s, 2H), 2.49 -
2.56 (m, 1H), 3.23 (d, 2H), 5.41 (t, 1H), 6.75 (q, 1H). MS(ESI) m/z 330.29 (M+H+).
A portion of the product (25 g) was recrystallized by dissolution in 1 : 10 ethyl
acetate : heptane (125 mL) at 60 °C, then slow cooling to 4°C. The white crystalline product
(21 g) was isolated by filtration. Melting point: 63-64°C. Differential scanning calorimetry
endotherm: 63 °C.
Example 8: Sodium l-{-{\(a-Isobirtanoyloxvethoxy)carbonyll-
aminomethyI}-l-Cyclohexane Acetate (12)
Compound (11) (540 g, 1.64 mol) was dissolved in acetone (850 mL) and water
(500 mL) in a 4 L beaker, equipped with overhead stirring, pH meter and addition funnel.
Aqueous sodium carbonate (1.0 M) was added slowly in 50 mL aliquots. After addition of
0.49 eq. base (803 mL of sodium carbonate solution) the pH was 7.3. Acetone was
removed in vacua at 25 °C and the pH re-checked to be —6.5. The remaining aqueous
solution was divided into three 3-L flasks, shell frozen and lyophilized for two days. The
resulting sodium salt (12) was scraped from the flasks as a hygroscopic solid and transferred
quickly into bottles, which were immediately capped and transferred into a drying chamber
at 14% relative humidity (RH). The remaining oily product in the flasks was dissolved in
diethyl ether and concentrated in vacuo at 25 °C, then dried under high vacuum until a dry
foam was produced.
Example 9: Allyl l-Aminomethyl-l-Cydohexane Acetate Hydrochloride (13)
A dry 500 mL, three-neck, round-bottomed flask was fitted with a magnetic stirring
bar and a 100 mL pressure-equalizing addition funnel and flushed with nitrogen gas. The
flask was charged with gabapentin (17.1 g, 0.1 mol) and allyl alcohol (100 mL, 1.46 mol)
and the entire mixture was cooled to 0°C in an ice-water bath. Thionyl chloride (22.5 mL,
36 g, 0.3 mol) was added drop-wise over a period of 30 min to the stirred solution, and the
reaction mixture allowed to stir for 16 h at room temperature. The mixture was then diluted
with diethyl ether (200 mL) and cooled to 0°C while stirring. After several minutes white
crystals formed, and were collected by filtration. The crude compound was recrystallized
from a mixture of ethanol and diethyl ether (50 mL: 150 mL) to give the product (13) as a
white solid (22 g, 88% yield), m.p: 138-142°C. 1H NMR (CD3OD, 400 MHz): 8 1.36-1.54
(m, 10H), 2.57 (s, 2H), 3.05 (s, 2H), 4.61 (d, 2H), 5.22 (dd, 1H), 5.33 (dd, 1H), 5.90-6.00
(m, 1H ). MS (ESI) m/z 212.0 (M+H+).
Example 10: Allyl l-{[(a-Chloroethoxy)carbonyl1aminomethvI}-l-CycIohexane
Acetate (14)
To a solution of compound (13) (30 g, 0.121 mol) in dichloromethane (100 mL) was
slowly added 1-chloroethyl chloroformate (13 mL, 16.9 g, 0.119 mol). The reaction
mixture was cooled to 0°C and N-methylmorpholine (26.39 mL, 24.28 g, 0.24 mol) was
slowly added over a period of 1 h while maintaining a temperature of less than 10°C. The
resulting turbid solution was stirred for 30 min, and the reaction mixture was then diluted
with diethyl ether (250 mL), washed with water (100 mL) and brine (100 mL). The organic
phase was dried over anhydrous sodium sulfate and concentrated to give the desired product
(14) as light yellow viscous liquid (38 g, 99% yield). 1H NMR (CDCfe, 400 MHz): 5
1.35-1.58 (m, 10H), 1.78 (d, 3H), 2.32 (s, 2H), 3.22 (d, 2H), 4.57 (d, 2H), 5.25 (dd, 1H),
5.32 (dd, 1H), 5.52 (br. s, 1H), 5.90-5.94 (m, 1H), 6.54 (q, 1H).
Example 11: Allyl 1-{[(a-Isobutanoyloxyethoxv)carbony!l aminomethyl}-
1-Cyclohexane Acetate (15)
A solution of compound (14) (38 g, 0.12 mol) in isobutyric acid (55 mL, 52.5 g, 0.6
mol) was added to a mixture of isobutyric acid (55 mL, 52.5 g, 0.6 mol) in
N-methylmorpholine (65 mL, 60 g, 0.59 mol) at 0°C over a period of 30 min. The resulting
turbid solution was stirred for 16 h at room temperature. The reaction mixture was diluted
with diethyl ether (500 mL) and washed with water (3 x 200 mL) followed by 10%
potassium bicarbonate (4 x 200 mL) aid brine (200 mL). The organic phase was dried over
anhydrous sodium sulfate and concentrated to yield a viscous liquid. This crude product
was purified by column chromatography on silica gel, eluting with 7.5% ethyl acetate :
hexane to give the desired compound (15) as a clear, viscous liquid (37 g, 84% yield).1H
NMR (CDCfe, 400 MHz): 5 1.15 (d, 6H), 1.35-1.58 (m, 10H), 2.31 (s, 2H), 2.51 (m, 1H),
3.19 (d, 2H), 4.56 (d, 2H), 5.24 (dd, 1H), 5.32 (dd, 1H), 5.35 (br. s, 1H), 5.84-5.94 (m, 1H),
6.78 (q, 1H). MS (ESI) mh 392.24 (M+H4).
Example 12: l-{[(a-IsobutanoyIoxyethoxy)carbonyIlaminomethvI?-l-Cyclohexane
Acetic Acid (11)
Method A: To a stirred suspension of ammonium formate (3.4 g, 54 mmol) in
ethanol (34 mL), was added compound (15) (10 g, 27 mmol) together with 10% Pd/C (lg)
under a nitrogen atmosphere. After one hour, the reaction mixture was filtered and the
catalyst washed with ethanol (2x10 mL). The filtrates were combined and evaporated.
The crude product was dissolved in diethyl ether (150 mL) and the organic phase was
washed with 2N HC1 (100 mL), water (100 mL) and brine (100 mL). The ether layer was
dried over anhydrous sodium sulfate and concentrated to give a viscous liquid that
crystallized upon standing. The product was recrystallized using 1:10 ethyl acetate :
heptane (100 mL) to give the product (11) as a white, crystalline solid (7.9 g, 88%)., m.p
63-64°C.
Method B: To a stirred solution of compound (15) (1 g, 2.7 mmol) in acetonitrile
(10 mL) under nitrogen was added (10 mg, 0.008 mmol) of tetrakis(triphenylphosphine)
palladium (0) followed by morpholine (0.28 mL, 0.28 g, 3.2 mmol). After one hour, the
solvent was removed in vacuo. The resulting oil was dissolved in diethyl ether (50 mL) and
the organic phase was washed with 2N HC1 (20 mL), water (20 mL) and brine (20 mL).
The ether layer was dried over anhydrous sodium sulfate and concentrated to give an oil,
which was purified by column chrornatography on silica gel, eluting with 30% ethyl acetate
: hexane. The desired product (11) was isolated as a white crystalline solid (0.75 g, 84%
yield), m.p 63-64°C.
Method C: To a stirred solution of compound (15) (1 g, 2.7 mmol) in dioxane (9
mL) was added ammonium formate (341 mg, 2.7 mmol) and palladium(H) acetate (12 mg)
under a nitrogen atmosphere. The reaction mixture was heated to reflux for one hour and
then concentrated in vacuo. The resulting oily residue was taken up in diethyl ether (50
mL), washed with 2N HC1 (20 mL), water (20 mL) and brine (20 mL). The organic phase
was dried over anhydrous sodium sulfate and evaporated to dryness. The crude compound
was purified by column chromatography on silica gel, eluting with 30% ethyl acetate :
hexane to give the desired product (11) as a colorless oil, which solidified on further
standing at room temperature for 12 h (0.70 g, 78% yield), m.p. 62-64°C.
Example 13: l-{[(a-Chloroethoxv)carbonvl]aminomethyl}-l-CvcIohexane Acetic Acid
(16) via Trimethylsilyl l-([(a-ChIoroethory)carbonylIaininomethyU-l-CvcIohexane
Acetate (17)
In a 5-liter, 3-neck, round bottom flask containing dichloromethane (1.6 L) was
added gabapentin (120.4 g, 0.704 mol) followed by triethylamine (294 mL, 2.11 mol).
Chlorotrimethylsilane (178 mL, 1.40 mol) was slowly added while maintaining the reaction
temperature below 15°C and the resulting suspension was stirred for 30 min. 1-Chloroethyl
chloroformate (100 g, 0.704 mol) was then added slowly while maintaining the temperature
below 15°C. After the addition was complete, additional triethylamine (88 mL, 0.63 mol)
was added and the resulting suspension was stirred at room temperature for 30 min. The
resulting silyl ester (17) was converted via acidic work-up to the corresponding acid (16) by

washing the reaction mixture with water (2 x 1 L), followed by 1NHC1 (2 x 2 L) then brine
(2 x 500 mL). After drying over anhydrous sodium sulfate and removal of the solvent in
vaciio, the crude product (190 g) was obtained as an orange oil and used in Example 14
without further purification. 1H NMR (CDC13,400 MHz): § 1.41 - 1.57 (m, 10H), 1.78 (d,
3H), 2.33 (s, 2H), 3.27 (d, 2H), 5.42 (br. s, 1H), 6.55 (q, 1H).
Example 14: l-{[(a-Isobtttanovloxvethoxv)carbonv}1aminomethyl}-l-CycIohexane
Acetic Acid (11)
To a 3-liter, 3-neck, round bottom flask was added isobutyric acid (254 g, 2.9 mol)
followed by triethylamine (395 ml, 2.84 mol). The reaction mixture was cooled to room
temperature and a solution of crude (16) from the above example (190 g, 0.69 mol) in
dichloromethane (80 mL) was added in a controlled fashion to maintain the temperature
below 30°C. The resulting pale yellow solution was stirred overnight. The reaction mixture
was then diluted with one volume of dichloromethane and washed with water (6 x 500 mL),
aqueous potassium bicarbonate (3 x 500 mL), and brine (2 x 500 mL). After drying over
anhydrous sodium sulfate, removal of the solvent in vacuo afforded the crude product as a
dark red oil (87 g). A portion (35 g) of this product was loaded onto an 800 g Biotage™
normal phase silica gel flash column and eluted with 40% diethyl ether in hexane (6 L),
which after removal of the solvent in vacuo afforded product (11) as a colorless oil. This
was repeated with a second 35 g portion of crude product yielding a further 13.5 g of (11).
A sample of the product (25 g) was recrystallized by dissolution in heptane (325 mL) at 70
°C, then slow cooling to room temperature. The white crystalline product (11) (23 g) was
isolated by filtration. Melting point: 63-64°C.
Example 15: l-{{(a-ChIorobuto:xy)carbonvl1aminomethyl}-Cvdohexane Acetic Acid
(18) via Trimethylsilyl l-{{(a-ChIorobutoxv)carbonvI}aminomethY])-l-CycIohexane
Acetate (19)
In a 5-liter, 3-neck, round bottom flask containing dichloromethane (1.6 L) was
added gabapentin (113.5 g, 0.66 mol) followed by diisopropylethylamine (193.5 mL, 1.1
mol). Chlorotrimethylsilane (88.1 mL, 0.69 mol) was slowly added while maintaining the
reaction temperature below 1 S°C and the resulting suspension was stirred for 30 min.
1-Chlorobutyl chloroformate (108 g, 0.63 mol) was then added slowly while maintaining
the temperature below 15°C, and the resulting suspension was stirred at room temperature
for 30 min. The resulting silyl ester (19) was converted via acidic work-up to the
corresponding acid (18) by washing the reaction mixture with water (2x1 L), followed by
IN HC1 (2 x 1 L) then brine (2 x 500 mL). After drying over anhydrous sodium sulfate and
removal of the solvent in vacuo, the crude product (116 g, 60% yield) was obtained as an
off-white solid and used in Example 16 without further purification. *H NMR (CDCI3, 400
MHz): 5 0.93 (t, 3H), 1.28 - 1.62 (m, 12H), 1.92-2.06 (m, 2H), 2.35 (s, 2H), 3.28 (d, 2H),
5.44 (t, 1H), 6.45 (t, 1H).
Example 16: l-{[{a-Propanoyloxvbutoxv)carbonvllaminomethyll-l-Cyclohexane
Acetic Acid (20)
To a 1-L, 3-neck, round bottom flask was added propionic acid (200 mL, 2.68 mol)
followed by triethylamine (50.7 mL, 0.36 mol). The reaction mixture was cooled to room
temperature and a solution of crude (18) from the above example (101 g, 0.33 mol) in
dichloromethane (80 mL) was added in a controlled fashion to maintain the temperature
below 30°C. The resulting pale yellow solution was stirred overnight. The reaction mixture
was then diluted with one volume of dichloromethane and washed with water (6 x 250 mL),
aqueous potassium bicarbonate (3 x 250 mL), and brine (2 x 250 mL). After drying over
anhydrous sodium sulfate, removal of the solvent in vacuo afforded the crude product as a
dark red oil (100 g). A portion (40 g) of this product was loaded onto an 800 g Biotage™
normal phase silica gel flash column and eluted with 20% diethyl ether in hexane (6 L),
which after removal of the solvent in vacuo afforded product (20) as a colorless oil (15 g).
'H NMR (CDC13> 400MHz): 0.95 (t, 3H), 1.13 (t, 3H), 1.32-1.60 (m, 12H), 1.70-1.78 (m,
2H), 2.28 - 2.38 (m, 4H), 3.24 (d, 2H), 5.24 (t, 1H), 6.71 (t, 1H). MS(ESI) m/z 343.44
(M+H4).
Example 17: l-{ [(a-ChIoroisobutoxv)carbonyllaminomethyI}-l-Cvclohexane Acetic
Acid (21) via Trimethylsilyi l-(f(a-ChIoroisobutoxy)-carbonvnaminomethyI}-
1-Cyclohexane Acetate (22)
To a mixture containing gabapentin (1.71 g, 10 mmol) and triethylamine (3.06 mL,
22 mmol) in dichloromethane (150 mL) was added chlorotrimethylsilane (1.4 mL, 11
mmol) and the resulting mixture was stirred until clear (about 20 min). A solution
containing l-chloro-2-methylpropylchloroformate (1.27 mL, 11 mmol) in dichloromethane
(10 mL) was then added at 0 °C and stirred at room temperature for 60 min. The resulting
silyl ester (22) was converted via acidic work-up to the corresponding acid (21) by washing
the reaction mixture with 10% citric acid (30 raL) and the organic layer separated. The
aqueous layer was further extracted with ether (3 x 20 mL) and the combined organic
phases were dried over MgSO4 and then concentrated in vaciio. Chromatography of the
residue on silica gel, eluting with hexane: ethyl acetate (1:4) gave the title compound (21)
(2.37g, 77%). 1H NMR (CDC13, 400 MHz): d 1.04 (d, J= 6.4 Hz, 3H), 1.06 (d, J= 6.4 Hz,
3H), 1.36-1.53 (m, 10H), 2.15 (m, 1H), 2.34 (s, 2H), 3.24 (m, 2H), 5.39 (t, 1H), 6.32 (d, J=
5.6 Hz), 1H). MS (ESI) m/z 306.34 (M+H*).
Example 18: l-{[(a-NicotinovIoxvisobutoxv)carbonvIlaminomethvl}-l-CycIohexane
Acetic Acid (23)
A mixture of (21) (268 mg, 0.88 mmol), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
(158 mL, 1.01 mmol), and nicotinic acid (637 mg, 5.2 mmol) in acetone was stirred at room
temperature for 48 h. After filtration, the filtrate was concentrated in vacuo and the
resulting residue was purified by reverse phase preparative HPLC to afford the title
compound (23) (50 mg, 14%). 1H NMR (CD3OD, 400 MHz): d 1.07 (d, 3H), 1.09 (d, 3H),
1.32-1.58 (m, 10H), 2.19 (m, 1H), 2.26 (s, 2H), 3.23 (m, 2H), 6.78 (d, 1H), 7.58 (m, 1H),
8.39 (d, 1H), 8.76 (d, 1H), 9.10 (s, 1H). MS (ESI) m/z 393.42 (M+H+).
Example 19: Benzyl l-{f(a-ChIoroisobutoxy)carbonvllaminomethvi)-l-C'yclohexane
Acetate (24)
To a solution of (21) (1.02 g, 3.34 mmol) in dichloromethane was added
1,3-dicyclohexylcarbodiimide (758 mg, 3.67 mmol). After stirring at room temperature for
30 min, benzyl alcohol (380 mL, 3.67 mmol) and 4-(dimethylamino)pyridine (catalytic
amount) were added. The resulting mixture was stirred at room temperature of 16 h. After
filtration, the filtrate was washed with 10% citric acid, dried over Na2SO4, and concentrated.
Chromatography of the residue on silica gel, eluting with 10% ethyl acetate/hexane, gave
the title compound (24) (820 mg, 62%). 1H NMR (CDCI3, 400 MHz): d 1.03 (d, 3H), 1.05
(d, 3H), 1.36-1.53 (m, 10H), 2.13 (m, 1H), 2.35 (s, 2H), 3.22 (m, 2H), 5.11 (s, 2H), 5.49 (t,
1H), 6.32 (d, 1H), 7.34 (m, 5H). MS (ESI) m/z 396.24 (M+H1).
Example 20: Cesium 2,2-Diethoxypropionate (25)
To a stirred solution of pyruvic acid (14 mL, 0.2 mol) and triethylorthoformate (80
mL) at 10 °C was added concentrated sulfuric acid (1 mL). The resulting mixture was
stirred at 5-10 °C for 1 h and then diluted with dichloromethane (200 mL). The organic
solution was washed successively with water (3 x 80 mL) and saturated sodium chloride
solution (80 mL) and then dried over anhydrous sodium sulfate. The mixture was filtered
and then concentrated to give a quantitative yield of 2,2-diethoxypropionic acid as an oil.
1H NMR (CDC13, 400 MHz): d 1.30 (t, 6H), 1.61 (s, 3H), 3.57 (q, 4H), 8.62 (s, 1H). The
acid form was quantitatively converted to its cesium salt (25) by dissolving the acid in water
(25 mL) followed by treatment with an equimolar quantity of cesium carbonate, and then
lyophilization. 1H NMR (D2O, 400 MHz): d 0.98 (t, 6H), 1.28 (s, 3H), 3.22 (q, 2H), 3.47
(q, 2H).
Example 21: Benzyl l-{[(a-2,2-Diethoxvpropanovloxvisobutoxv)carbonyll-
aminomethyl}-Cyclohexane Acetate (26)
A mixture of (24) (200mg, 0.51 mmol) and sodium iodide (114 mg, 0.76 mmol) in
acetone was stirred at room temperature for 1 h. Cesium 2,2-diethoxypropionate (25) (300
mg, 1.02 mmol) and DMF (20 mL) were added and the resulting mixture was stirred at 40
°C for 18 h. After filtration, the filtrate was concentrated and the resulting residue was
purified by silica gel flash column chromatography, eluting with 10% ethyl acetate/hexane
to afford the title compound (26) (100 mg, 37% yield). MS (ESI) m/z 522.34 (M+H4).
Example 22: l-{[(a-2,2-Diethoxvpropanoyloxvisobutoxv)carbonyI]-
aminomethyl}-1-Cyclohexane Acetic Acid (27)
A mixture of (26) (200 mg, 0.38 mmol) and 5% Pd-C (catalytic amount) was stirred
under hydrogen at room temperature for 16 h. After filtration, the filtrate was concentrated
and the resulting residue was purified by reverse phase preparative HPLC to afford the title
compound (27) (98 mg, 60% yield). 1HNMR (CDC13, 400 MHz): d 0.97 (d, /6H), 1.19 (t,
3H), 1.21 (t, 3H), 1.32-1.58 (m, 10H), 1.51 (s, 3H), 2.06 (m, 1H), 2.30 (s, 2H), 3.23 (m,
2H), 3.46 (m, 2H), 3.56 (m, 2H), 5.30 (t, 1H), 6.59 (d, 1H). MS (ESI) m/z 432.24 (M+H*).
Example 23:
l-{[(a-(2-Amino-2-methvIpropanoy])oxyisobutoxYVcarbonvI1aminomethyI}-l-CvcIohe
xane Acetic Acid (28)
Following the procedures of Examples 20-22, and substituting
2-amino-2-methylpropionic acid for 2,2-diethoxypropionic acid, provided the title
compound (28). 1H NMR (CDC13,400 MHz): 5 0.97 (d, 6H), 1.44 (s, 3H), 1.45 (s 3H),
1.32-1.58 (m, 10H,), 2.05 (m, 1H), 2.30 (s, 2H), 3.23 (m, 2H), 5.50 (t, 1H), 6.58 (d, 1H).
MS (ESI) m/z 373.48 (M+H+).
Example 24: Methyl l-({(a-Chloroisobutoxy)carbonvnaminomethyl}-l-Cyclohexane
Acetate (29)
A mixture of (21) (1.0 g, 3.3 mmol), benzene (90 mL), and methanol (10 mL) was
cooled to 0 °C. Trimethylsilyldiazomethane was added slowly at 0 °C until the yellow color
persisted. The mixture was stirred at 0 °C for 30 min until the reaction was complete
(monitored by TLC). After removing the solvent under reduced pressure, chromatography
of the resulting residue on silica gel, eluting with 10% ethyl acetate/hexane gave the title
compound (29) (760 mg, 72%). MS (ESI) m/z 320.24 (M+H4).
Example 25: Methyl l-{[{a-Isobutanoyloxyisobutoxy)carbonvn-
aminomethy]}-l-Cyclohexane Acetate (30)
A mixture of (29) (760 mg, 2.38 mmol), silver carbonate (394 mg, 1.4 mmol), and
isobutyric acid (442 mL, 4.76 mmol) in chloroform was stirred at room temperature for 24 h.
Another batch of silver carbonate (394 mg, 1.4 mmol) and isobutyric acid (442 mL, 4.76
mmol) was added, and the resulting mixture was stirred for another 24 h. After filtration,
the filtrate was concentrated and the resulting residue purified by silica gel flash column
chromatography, eluting with 10% ethyl acetate/hexane, to afford the title compound (30)
(560 mg, 63%). 1H NMR (CDC13, 400 MHz): d 0.94 (d, 3H), 0.96 (d, 3H), 1.15 (d, 3H),
1.17 (d, 3H), 1.32-1.58 (m, 10H), 2.01 (m, 1H), 2.19 (s, 2H), 2.55 (m, 1H), 3.18 (m, 2H),
3.67 (s, 3H), 5.33 (t, 1H), 6.56 (d, 1H). MS (ESI) m/z 372.38 (M+H4).
Example 26: 3-{{(a-ChIoroethoxy)carbony}]aminomethyi}-5-Methvl-Hexanoic Acid
(31) via Trimetthlsilyl 3-{[(a-Chloroethoxy)carbonyI]ammomethyl}-5-Methvl-
Hexanoate (32)
To a stirred suspension of pregabalin (270 mg, 1.38 mmol) in dichloromethane (5 mL)
at -20 °C was added triethylamine (0.58 mL, 4.14 mmol) and a 1 M solution of
chlorotrimethylsilane in dichloromethane (2.76 mL, 2.76 mmol). The resulting reaction
mixture was allowed to warm to 0 °C, and stirred for 20 min. The solution was then cooled
again to -20 °C and 1-chloroethyl chloroformate (0.151 mL, 1.38 mmol) added. The
reaction mixture was stirred at 0 °C for an additional 30 min. The resulting silyl ester (32)
was converted via acidic work-up to the corresponding acid (31) by quenching the reaction
mixture with citric acid, diluting with dichloromethane, washing with water and brine; then
drying over anhydrous Na2SO4. Filtration and evaporation afforded the title compound (31)
(300 mg), which was used in the following example without further purification.
Example 27: 3-{[(a-Isobutanoyloxyethoxy)carbonvIlaminomethyl}-5-Methvl-Hexanoic
Acid (33)
A solution of the above crude product (31) (320 mg) in dichloromethane (2 mL) was
added to a mixture of isobutyric acid (1 mL) and N-methylmorpholine (0.5 mL) at 0 °C.
The resulting mixture was stirred for 24 h at ambient temperature. The mixture was then
diluted with dichloromethane, washed twice with water and brine, and dried over anhydrous
Na2SO4. After filtration and removal of the solvent in vacuo, the crude product was purified
by reverse phase preparative HPLC to afford the product (33) (70 mg, 16%) as a mixture of
two diasteroisomers. 1H-NMR (CDC13, 400MHz): d 0.89 (m, 6H), 1.16 (m, 8H), 1.46 (d,
3H), 1.66 (m, 1H), 2.11-2.36 (m, 3H), 2.52 (m, 1H), 3.11 (m, 1H), 3.27 (m, 1H), 5.08 (t,
1H), 6.77 (m, 1H). MS (ESI) m/z 316.20 (M-HT).
Example 28: 3-{[(a-Chloroisobutoxv)carbonvllaminomethvl}-5-Methyl-Hexanoic Acid
(34) via Trimethylsily] 3-{{(a-Chloroisobutoxv)carbonyl}-anunomethyl)-5-MethvI-
Hexanoate (35)
To a stirred suspension of pregabalin (270 mg, 1.38 mmol) in dichloromethane (5 mL)
at —20 °C was added triethylamine (0.58 mL, 4.14 mmol) and a 1 M solution of
chlorotrimethylsilane in dichloromethane (2.76 mL, 2.76 mmol). The resulting reaction
mixture was allowed to warm to 0 °C, and stirred for 20 min. The solution was then cooled

again to -20 °C and l-chloro-2-methylpropyl chloroformate (0.201 mL, 1.38 mmol) added.
The reaction mixture was stirred at 0 °C for an additional 30 min. The resulting silyl ester
(35) was converted via acidic work-up to the corresponding acid (34) by quenching the
reaction mixture with citric acid, diluting with dichloromethane, washing with water and
brine, then drying over anhydrous Na2SO4. Filtration and evaporation afforded the title
compound (34) (300 mg), which was used in the following example without further
purification.
Example 29: 3-{{(a-IsobutanoyIoxyisobutoxv)carbonvi|aminomethyl}-5-MethyI-
Hexanoic Acid (36)
A solution of the above crude product (34) (300 mg) in dichloromethane (2 mL) was
added to a mixture of isobutyric acid (1 mL) and N-methylmorpholine (0.5 mL) at 0 °C.
The resulting mixture was stirred for 24 h at ambient temperature. The mixture was then
diluted with dichloromethane, washed twice with water and brine, and dried over anhydrous
Na2SO4. After filtration and removal of the solvent in vacuo, the crude product was purified
by reverse phase preparative HPLC to afford the product (36) (27 mg, 6%) as a mixture of
two diastereoisomers. 1H-NMR (CDCI3, 400MHz): 8 0.88 (m, 6H), 0.95 (d, 6H), 1.17 (m,
8H), 1.64 (m, 1H), 2.00-2.36 (m, 4H), 2.55 (m, 1H), 3.11 (m, 1H), 3.26 (m, 1H), 5.02 (br.s,
1H), 6.53 (m, 1H). MS (ESI) m/z 344.26 (M-HT).
Example 30: 3-[(tcrt-Butoxycarbonyl)aminomethylI-5-MethyI-Hexanoic Acid (37)
To a stirred suspension of pregabalin (950 mg, 4.85 mmol) and NaOH (452 mg, 11.32
mmol) in water (20 mL) was added a solution of di-tert-butyl dicarbonate (8.49 mmol) in
dioxane (20 mL) at room temperature. The resulting mixture was stirred at room
temperature for 30 min. The solvent was removed in vacuo, and the residue was washed
with diethyl ether to remove the excess of di-tert-butyl dicarbonate, then was acidified to
pH 3 with citric acid. The resulting mixture was extracted with ethyl acetate (3 x 50 mL)
and the combined organic fractions were washed with brine and dried over anhydrous
Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (37)
(1.24 g, 98%). 1H-NMR (CD3OD, 400 MHz): d 0.89 (2d, 6H), 1.17 (m, 2H), 1.44 (s, 9H),
1.65 (m, 2H), 2.08 (m, 1H), 2.31 (m, 2H), 3.06 (m, 1H)5 3.22 (m, 1H), 4.77 (br.s, 1H). MS
(ESI) m/z 258.15 (M-H).
Example 31: Benzyl 3-f(tert-Butoxycarbonvnaminomethvk}-5-Methyl-Hexanoate (38)
To a stirred suspension of (37) (1.24 g, 4.78 mmol) and CS2CO3 (1.56 g, 4.78 mmol) in
DMF (20 mL) was added benzyl bromide (0.56 mL, 4.68 mmol). The resulting mixture
was stirred at ambient temperature until the reaction was complete (~2 h, as monitored by
LC/MS). The mixture was poured into ice water and extracted with dichloromethane. The
combined organic phase was washed with water and brine, then dried over anhydrous
Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (38)
(1.77 g, 100%), which was used without further purification in the following example. !H-
NMR (CDCI3,400 MHz): 8 0.86 (2d, 6H), 1.13 (m, 2H), 1.42 (s, 9H), 1.62 (m, 1H), 2.31
(m, 2H), 3.00 (m, 1H), 3.18 (m, 1H), 4.75 (br.s, 1H), 5.10 (s, 2H), 7.33 (m, 5H). MS (ESI)
m/z 372.30 (M+Na+).
Example 32: Benzyl 3-AminomethyI-5-Methvl-Hexanoate Hydrochloride (39)
A solution of (38) (1.77 g, 4.78 mmol) in 4M HC1 in dioxane (20 mL) was stirred at
ambient temperature for 30 min. Removal of the solvent in vacuo afforded the title
compound (39) as a white crystalline solid (1.4 g, 88%). 1H-NMR (CDC13,400 MHz):
5 0.85 (d, 6H)3 1.17 (m, 1H), 1.30 (m, 1H), 1.58 (m, 1H), 2.32 (m, 1H), 2.57 (m, 2H), 3.03
(m, 2H), 5.09 (s, 2H), 7.30 (m, 5H), 8.39 (br.s, 3H). MS (ESI) m/z 250.25 (M+H4).
Example 33: Benzyl 3-{[(a-Chloroethoxy)carbonyI]aminomethvl)-5-Methvl-
Hexanoate (40)
To a stirred solution of (39) (428 mg, 1.51 mmol) in dichloromethane at 0 °C was
added N-methylrnorpholine (0.33 mL, 3.02 mmol) and 1-chloroethyl chloroformate (0.164
mL, 1.51 mmol). The resulting solution was stirred at 0 °C until the reaction was complete
(~30 min, as monitored by TLC) and then was diluted with dichloromethane, washed
successively with cold 1NHC1 solution, water and brine, men dried over anhydrous
Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (40) as
a mixture of two diastereomers (530 mg, 100%), which was used without further
purification in the following example. 1H-NMR (CDC13,400 MHz): 8 0.87 (m, 6H), 1.13
(m, 2H), 1.63 (m, 1H), 1.76 (m, 3H), 2.15 (m, 1H), 2.34 (m, 2H), 3.10 (m, 1H), 3.27 (m,
1H), 5.11 (br.s, 3H), 6.53 (q, 1H), 7.33 (m, 5H).
Example 34: Benzyl 3-{f(a-Isobutanovloxyethoxy)carbonvllaminomethyIl-5-MethyI-
Hexanoate (41)
A solution of (40) (0.53 g, 1.50 mmol) in isobutyric acid (1 mL) was added to a
mixture of isobutyric acid (0.96 mL, 10.8 mmol) and N-methylmorpholine (1.14 mL, 10.4
mmol) at room temperature. The resulting reaction mixture was stirred at room temperature
for 48 h. The reaction mixture was diluted with dichloromethane, washed successively with
water, 10% aqueous NaHCO3 solution and brine, then dried over anhydrous Na2SO4- After
filtration and removal of the solvent in vacuo, the residue was purified by flash
chromatography on silica gel, eluting with 5% ethyl acetate in hexane to afford the title
compound (41) as a mixture of two diastereomers (400 mg, 66%). 'H-NMR (CDCI3,400
MHz): 8 0.85 (m, 6H), 1.14 (m, 8H), 1.44 (m, 3H), 1.62 (m, 1H), 2.13 (m, 1H), 2.32 (m,
2H), 2.51 (m, 1H), 3.06 (m, 1H), 3.24 (m, 1H) 4.95 (m, 1H), 5.10 (s, 2H), 6.76 (q, 1H).
Example 35: 3-{f(a-Isobutanoyloxyethoxv)carbonvl]aminomethvU-5-Methyl-Hexanoic
Acid (33)
A solution of (41) (270 mg, 0.663 mmol) in ethanol (20 mL) was stirred with 10% Pd
on carbon (11 mg) in a 50 mL round-bottomed flask under an atmosphere of hydrogen gas
(balloon). The reaction was judged complete in 30 min. (monitoring by TLC and LC/MS).
The mixture was filtered through a pad of Celite, and the solvent removed in vacuo to afford
the title compound (33) as a mixture of two diastereomers (177 mg, 84%). 'H-NMR
(CDCI3, 400MHz): 8 0.89 (m, 6H), 1.16 (m, 8H), 1.46 (d, 3H), 1.66 (m, 1H), 2.11-2.36 (m,
3H), 2.52 (m, 1H), 3.11 (m, 1H), 3.27 (m, 1H), 5.08 (t, 1H), 6.77 (m, 1H). MS (ESI) in/z
316.20 (M-H").
Example 36: Benzyl 3-Wa-Chloroisobntoxv)carbonvHaminomethyl}-5-Methvl-
Hexanoate(42)
To a stirred solution of (39) (594 mg, 2.38 mmol) in dichloromethane at 0 °C was
added N-methylmorpholine (0.523 mL, 4.77 mmol) and l-chloro-2-methylpropyl
chloroformate (0.347 mL, 2.38 mmol). The resulting solution was stirred at 0 °C until the
reaction was complete (~30 min, as monitored by TLC) and then was diluted with
dichloromethane, washed successively with cold IN HC1 solution, water and brine, then
dried over anhydrous Na2SO4. Filtration and removal of the solvent in vacuo afforded the
title compound (42) as a mixture of two diastereomers (840 mg, 92%), which was used
en
without further purification in the following example. 'H-NMR |CDC13, 400MHz): 8 0.86
(2d, 6H), 1.02 (2d, 6H), 1.15 (m, 2H), 1.63 (m, 1H), 2.14 (m, 2Hft, 2.34 (m, 2H), 3.10 (m,
1H), 3.28 (m, 1H), 5.11 (br.s, 3H), 6.29 (d, 1H), 7.31 (m, 5H).
Example 37: Benzyl 3-{ \(a-Isobutanoyloxyisobutoxy)carbon'yl}|-aminometb.yl}]-5-
Methyl-Hexanoate (43)
A solution of (42) (840 mg, 2.19 mniol) in isobutyric acid (1 mL) was added to a
mixture of isobutyric acid (1 mL, 10.95 mmol) and N-methylmoi pholine (1.2 mL, 10.95
mmol) at room temperature. The resulting reaction mixture was stirred at room temperature
for 48 h. The reaction mixture was diluted with dichloromethane (100 mL), washed
successively with water, 10% aqueous NaHCO3 solution and brii e, then dried over
anhydrous Na2SO4. After filtration and removal of the solvent in vacuo, the residue was
purified by flash chromatography on silica gel, eluting with 5% e :hyl acetate in hexane to
afford the title compound (43) as a mixture of two diastereomers (430 mg, 45%). 'H-NMR
(CDC13, 400 MHz): d 0.85 (2d, 6H), 0.94 (d, 6H), 1.16 (m. 8H), .62 (m, 1H), 2.00 (m, 1H),
2.12 (m, 1H), 2.32 (m., 2H), 2.54 (m, 1H), 3.08 (m, 1H), 3.24 (m 1H), 4.94 (t, 1H), 5.10 (s,
2H), 6.55 (d, 1H), 7.33 (m, 5H).
Example 38: 3-0(a-Isobutanoyloxyisobutoxv)carbonyllamin(|methyU-5-
Methyl-Hexanoic Acid (36)
A solution of (43) (430 mg, 0.987 mmol) in ethanol (30 n L) was stirred with 10%
Pd on carbon (50 mg) in a 100 mL round-bottomed flask under ai; atmosphere of hydrogen
gas (balloon). The reaction was judged complete in 40 min. (moi itoring by TLC and
LC/MS). The mixture was filtered through a pad of Celite, and tl e solvent removed in
vacuo to afford the title compound (36) as a mixture of two diast 'H-NMR (CDCI3, 400MHz): 0.88 (m, 6H), 0.95 (d, 6H), 1.17 (m. 8H), 1.64 (m, 1H), 2.00-
2.36 (m, 4H), 2.55 (m, 1H), 3.11 (m, 1H), 3.26 (m, 1H), 5.02 (br.J, 1H), 6.53 (m, 1H). MS
(ESI): m/z 344.26 (M-H).
Finally, it should be noted that there are alternative ways present invention. Accordingly, the present embodiments are to t e considered as
illustrative and not restrictive, and the invention is not to be limit herein, but may be modified within the scope and equivalents of t le appended claims. All
publications and patents cited herein are incorporated by referenc : in their entirety.
R1 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroalkyi, substituted heteroalkyl, heteroatyl, substituted
heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
R2 and R3 are independently hydrogen, alkyl, substituted alkyl,
alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded
form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl
ring;
R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cyeloalkyj, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl or substituted heteroarylalkyl;
R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted aikoxy, acyl,
substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted
heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl,
or optionally, R4 and R5 together with the atoms to which they are attached form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
R6 and R9 are independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;
R7 and R8 are independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and
substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which
they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl or bridged cycloalkyl ring; and
R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted
heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl.
as claimed in
2. The method of Claim 1, wherein the compound of Formula (I) is derived
from a GABA analog of Formula (IV):
1-Aminomethyl-l-cyclohexane acetic acid (i.e., gabapentin);
l-Aminomethyl-l-(3-methylcyclohexane) acetic acid;
l-Aminomethyl-l-(4-methylcyclohexane) acetic acid;
l-Aminomethyl-l-(4-isopropylcyclohexane) acetic acid;
l-Aminomethyl-l-(4-tert-butylcyclohexane) acetic acid;
l-Aminomethyl-l-(3,3-dimethylcyclob.exane) acetic acid;
l-Aminomethyl-l-(3,3,5,5-tetramethylcyclohexane) acetic acid;
1-Aminomethyl-l-cyclopentane acetic acid;
l-Aminomethyl-l-(3-methylcyclopentane) acetic acid;
l-Aminomethyl-l-(3,4-dimethylcyclopentane) acetic acid;
7-Aminomethyl-bicyclo[2.2.1]hept-7-yl acetic acid;
9-Aminomethyl-bicyclo[3.3.1]non-9-yl acetic acid;
4-Aminomethyl-4-(tetrahydropyran-4-yl) acetic acid;
3-Aminomethyl-3-(tetrahydropyran-3-yl) acetic acid;
4-Aminomethyl-4-(tetrahydrothiopyran-4-yl) acetic acid;
3-Aminometfayl-3-(tetrahydrothiopyran-3-yl) acetic acid;
(S)-3-Aminomethyl-5-methyl-hexanoic acid (i.e. pregabalin);
3-Aminomethyl-5-methyl-heptanoic acid;
3-Aminomethyl-5-methyl-octanoic acid;
3-Aminomethyl-5-methyl-nonanoic acid;
3-Aminomethyl-5-methyl-decanoic acid;
3-Aminomethyl-5-cyclopropyl-hexanoic acid;
3-Aminomethyl-5-cyclobutyl-hexanoicacid;
3-Aminomethyl-5-cyclopentyl-hexanoic acid;
3-Aminomethyl-5-cyclohexyl-hexanoic acid;
3-Aminomethyl-5 -phenyl-hexanoic acid;
3-Aminomethyl-5-phenyl-pentanoic acid;
3-Aminomethyl-4-cyclobutyl-butyric acid;
3-Aminomethyl-4-cyclopentyl-butyricacid;
3-Aminomethyl-4-cyclohexyl-butyricacid;
3-Aminomethyl-4-phenoxy-butyric acid;
3-Aminomethyl-5-phenoxy-hexanoic acid; and
3-Aminomethyl-5-benzylsulfanyl-pentanoic acid.
as claimed in
4. The method of Claim 3, wherein R1 is methyl, ethyl, propyl, isopropyl, n-
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R2 is hydrogen, methyl, ethyl,
propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl or phenyl,-and R3 is
hydrogen.
as claimed in
5. The method el"Claim 3, wherein R1 is methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,
1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl,
phenethyl, styryl or 3-pyridyl, R2 is methyl and R3 is methyl.
as claimed in
6. The method ©f Claim 3, wherein R1 is methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,
1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl,
phenethyl, styryl or 3-pyridyl, R2 is methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl
or cyclohexyloxyearbonyl and R3 is methyl.
as claimed in
7. The method of Claim 3, wherein, R1 is methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, .sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dbnethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl and R2 and R3 together with the
atom to which they are attached form a cyclohexyl ring.
as claimed in
8. The method of Claim 3, wherein R2 is methyl, methoxycarbonyl,
ethoxycarbonyl, isopropoxycarbonyl or cyclohexyloxycarbonyl and R3 is methyl.
as claimed in
9. The method of Claim 3, wherein R1 is methyl, ethyl, w-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, terf-butyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl,
cyclopentyl or cyclohexyl and R10 is hydrogen, allyl, benzyl or trimethylsilyl.
as claimed in
10. The method of Claim 3, wherein R is hydrogen, methyl, ethyl, «-propyl,
isopropyl, w-butyl, isobutyl, sec-butyl or tert-butyl and R3 is hydrogen.
as claimed in
11. The method of Claim 3, wherein R1 is methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, rert-butyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl,
cyclopentyl or cyclohexyl, R10 is hydrogen, allyl, benzyl or trimethylsilyl, R2 is hydrogen,
methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl and R3 is hydrogen.
as claimed in
12. The method of Claim 3, wherein R1 is ethyl or isopropyl, R10 is hydrogen,
allyl, benzyl or trimethylsilyl, R2 is methyl, «-propyl or isopropyl and R3 is hydrogen.
as claimed in
13. The method of Claim 3, wherein R1 is isopropyl, R10 is benzyl, R2 is methyl
and R3 is hydrogen.
as claimed in
14. The method ofClaim 3, wherein R1 is ethyl or isopropyl, R10 is hydrogen,
allyl, benzyl or trimethylsilyl, R2 is methyl, «-propyl or isopropyl, R3 is hydrogen and X is
chloro.
as claimed in
15. The method of-Claim 3, wherein R1 is isopropyl, R10 is benzyl, R2 is methyl,
R3 is hydrogen and X is chloro.
as claimed in
16. The method of Claim 1, wherein the ratio of the compound of Formula (II)
to the compound of Formula (III) is between about 1:1 and about 1:20.
as claimed in
17. The method of Claim 1 further comprising contacting the compound of
Formula (II) and the compound of Formula (III) and at least one equivalent of a metal salt
or an organic base or a combination thereof with an organic solvent.
as claimed in
18. The method of Claim 17, wherein the solvent is dichloromethane,
dichloroethane, chloroform, toluene, dimethylformamide, dimethylacetamide,
N-methylpyrroIidinone, dimethyl sulfoxide, pyridine, ethyl acetate, acetonitrile, acetone,
2-butanone, methyl tert-butyl ether, methanol, ethanol, isopropanol, rert-butanol, water,
hexamethylphosphoramide or combinations thereof.
as claimed in
19. The method of Claim 1, wherein the metal salt is a Ag, Hg, Na, K, Li, Cs,
Ca, Mg or Zn salt.
as claimed in
20. The method of Claim 1, wherein the organic base is triethylamine,
tributylamine, diisopropylethylamine, dimethylisopropylamine, N-methylmorpholine,
N-methylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyridine,
2,6-dimethylpyridine, 4-dimethylaminopyridine, 1, 4-diazabicyclo[2.2.2]octane, 1,
8-diazabicyclo[5.4.0]undec-7-ene, 1, 5-diazabicyclo[4.3.0]undec-7-ene or combinations
thereof.
as claimed in
21. The method of Claim 1 wherein the compound of Formula (III) is a liquid.
as claimed in
22. The method of Claim 21, wherein the compound of Formula (III) is acetic
acid, methoxyacetic acid, ethoxyacetic acid, propionic acid, butyric acid, isobutyric acid,
pivalic acid, valeric acid, isovaleric acid, 2-methylbutyric acid, cyclobutanecarboxylic acid,
cyclopentanecarboxylic acid or cyclohexanecarboxylic acid.
as claimed in
23. The method of Claim 22, wherein the compound of Formula (III) is
isobutyric acid.
as claimed in
24. The method of Claim 1, further comprising contacting the compound of
Formula (II), the compound of Formula (III) and the metal salt or the organic base or a
combination thereof at a temperature between about -25 °C and about 120 °C.
as claimed in
25. The method of claim 24, wherein, the temperature is between about 0 °C
and about 25 °C.
as claimed in
26. The method of Claim 1 further comprising contacting the compound of
Formula (II), the compound of Formula (III) and the metal salt or the organic base or a
combination thereof with a catalytic amount of an iodide salt.
as claimed in
27. The method of Claim 26, wherein the iodide salt is sodium iodide, potassium
iodide, tetramethylammonium iodide, tetraethylammonium iodide or tetrabutylammonium
iodide.
R2 and R3 are independently hydrogen, alkyl, substituted alkyl,
alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded
form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl
ring;
R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl or substituted heteroarylalkyl;
R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,
substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted
heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl,
or optionally, R4 and R5 together with the atoms to which they are attached form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
R6 and R9 are independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;
R7 and R8 are independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and
substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which
they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl or bridged cycloalkyl ring; and
R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted
heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl.
wherein the GAB A analog of Formula (IV) is selected from the group consisting of:
1-Aininomethyl-l-cyclohexane acetic acid (i.e. gabapentin);
I-Aminomethyl-l-(3-methylcyci tohexane) acetic acid;
l-Aminomethyl-l-(4-methylcyclohexane) acetic acid;
l-Aminomethyl-l-(4-isopropylcyclohexane) acetic acid;
l-Aminomethyl-l-(4-ter/-butylcyclohexane) acetic acid;
l-Aminomethyl-l-(3,3-dimethy]cyclohexane) acetic acid;
l-Aminomethy1-1-(,3,3,5,5-tetramethylcyclohexane) acetic acid;
1-Aminomethyl-l-cyclopentane acetic acid;
l-Aminomethyl-l-(3-methylcyclopentane) acetic acid;
l-AminomethyI-l-(3,4-dimethylcyclopentane) acetic acid;
7-Aminomethyl-bicyclo[2.2.1]hept-7-yl acetic acid;
9-Aminomethyl-bicyclo[3.3.1]non-9-yI acetic acid;
4-Aminomethyl-4-(tetrahydropyran-4-yl) acetic acid;
3-Aminomethyl-3-(tetrahydropyran-3-yl) acetic acid;
4-Aminomethyl-4-(tetrahydrothiopyran-4-yl) acetic acid;
3-Aminomethyl-3-(tetrahydrothiopyran-3-yI) acetic acid;
(S)-3-Aminomethyl-5-methyl-hexanoic acid (i.e., pregabalin);
3-Aminomethyl-5-methyl-heptanoic acid;
3-AminomethyI-5-methyl-octanoic acid;
3_AminomethyI-5-inethyl-nonanoic acid;
3-Aminomethyl-5-methyl-decanoic acid;
3 -Aminomethyl-5-cyclopropyl-hexanoic acid;
3-Aminomethyl-5-cyclobutyl-hexanoic acid;
3-Aminomethyl-5-cyclopentyl-hexanoicacid;
3-Aminomethyl-5-cyclohexyl-hexanoic acid;
3-Aminomethyl-5~phenyl-hexanoic acid;
3-Aminomethyl-5-phenyl-pentanoicacid;
3 -Aminomethyl-4-cyclobutyl-butyric acid;
3-Aminomethyl-4-cyclopentyl-butyric acid;
3-Aminomethyl-4-cycJohexyi-butyricacid;
3-Aminomethyl-4-phenoxy-butyric acid;
3-Aminomethyl-5-phenoxy-hexanoic acid; and
and n is 0.
as claimed in
31. The compound of Claim 30, wherein X is chloro, bromo or iodo, R10 is
hydrogen, allyl, benzyl or trimethylsilyl, R2 is hydrogen, methyl, ethyl, propyl, isopropyl, n-
butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl or phenyl and R3 is hydrogen.
as claimed in
32. The compound of Claim 30, wherein X is chloro, bromo or iodo, R10 is
hydrogen, allyl, benzyl or trimethylsilyl, R2 is methyl and R3 is methyl.
as claimed in
33. The compound of Claim 32, wherein X is chloro, bromo or iodo, R10 is
hydrogen, allyl, benzyl or trimethylsilyl, R2 is methoxycarbonyl, ethoxycarbonyl,
isopropoxycarbonyl or cyclohexyloxycarbonyl and R3 is methyl.
as claimed in
34. The compound of Claim 30, wherein X is chloro, bromo or iodo, R10 is
hydrogen, allyl, benzyl or trimethylsilyl, and R2 and R3 together with the atom to which
they are attached form a cyclohexyl ring.
as claimed in
35. The compound of Claim 30, wherein X is chloro, R10 is hydrogen, allyl,
benzyl or trimethylsilyl, R2 is hydrogen, methyl, ethyl, /z-propyl, isopropyl, /z-butyl,
isobutyl, sec-butyl or tert-butyl and R3 is hydrogen.
as claimed in
36. The compound of Claim 30, wherein X is chloro, R10 is hydrogen, allyl,
benzyl or trimethylsilyl, R2 is methyl, n-propyl or isopropyl, and R3 is hydrogen.
as claimed in
37. The compound ef Claim 30, wherein X is chloro, R10 is hydrogen, R2 is
methyl, and R3 is hydrogen.
as claimed in
38. The compound of Claim 30, wherein X is chloro, R10 is allyl, R2 is methyl,
and R3 is hydrogen.
as claimed in
39. The compound of Claim 30, wherein X is chloro, R10 is benzyl, R2 is methyl,
and R3 is hydrogen.
as claimed in
40. The compound of Claim 30, wherein X is chloro, R10 is trimethylsilyl, R2 is
methyl, and R3 is hydrogen.
1. A method of synthesizing a compound of Formula (I) comprising
contacting a compound of Formula (II), a compound of Formula (III) and at least one
equivalent of a metal salt or an organic base or a combination thereof wherein
at a temperature between -25oc and 120oc wherein:
X is F,Cl,Br or I;
n is O or 1;
R1 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted
heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
R2 and R3 are independently hydrogen, alkyl, substituted alkyl,
alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl, or optionally, R2 and R3 together with the atom to which they are bonded
form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl
ring;
R4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl or substituted heteroarylalkyl;
R5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,
substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted
heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl,
or optionally, R4 and R5 together with the atoms to which they are attached form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
R6 and R9 are independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;
R7 and R8 are independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and
substituted heteroarylalkyl, or optionally, R7 and R8 together with the carbon atom to which
they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl or bridged cycloalkyl ring; and
R10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted
heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl.

Documents:

1911-KOLNP-2004-FORM 27 1.1.pdf

1911-KOLNP-2004-FORM 27.pdf

1911-KOLNP-2004-FORM-27.pdf

1911-kolnp-2004-granted-abstract.pdf

1911-kolnp-2004-granted-claims.pdf

1911-kolnp-2004-granted-correspondence.pdf

1911-kolnp-2004-granted-description (complete).pdf

1911-kolnp-2004-granted-examination report.pdf

1911-kolnp-2004-granted-form 1.pdf

1911-kolnp-2004-granted-form 13.pdf

1911-kolnp-2004-granted-form 18.pdf

1911-kolnp-2004-granted-form 2.pdf

1911-kolnp-2004-granted-form 26.pdf

1911-kolnp-2004-granted-form 3.pdf

1911-kolnp-2004-granted-form 5.pdf

1911-kolnp-2004-granted-letter patent.pdf

1911-kolnp-2004-granted-reply to examination report.pdf

1911-kolnp-2004-granted-specification.pdf

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Patent Number

223050

Indian Patent Application Number

1911/KOLNP/2004

PG Journal Number

36/2008

Publication Date

05-Sep-2008

Grant Date

03-Sep-2008

Date of Filing

13-Dec-2004

Name of Patentee

XENOPORT INC.

Applicant Address

3410 CENTRAL EXPRESSWAY, SANTA CLARA, CA

Inventors:

#	Inventor's Name	Inventor's Address
1	RAILLARD, STEPHEN P.	964 TROPHY DRIVE MOUNTAIN VIEW, CALIFORNIA 94040
2	MANTHATI, SURESH KUMAR	175 CALVERT DRIVE, APT. D102 CUPERTINO, CALIFORNIA 95014
3	XIANG, JIA-NING	707 DE SOTO DRIVE PALO ALTO, CALIFORNIA 94303
4	GALLOP, MARK A.	511 ORANGE AVENUE LOS ALTOS, CALIFORNIA 94022
5	ZHOU, CINDY X.	1054 COLORADO AVENUE PALO ALTO, CALIFORNIA 94303
6	YAO, FENMEI	1920 CALIFORNIA ST. APT. 7 MOUNTAIN VIEW, CALIFORNIA 94040

PCT International Classification Number

C07C 205/00, 261/00

PCT International Application Number

PCT/US03/18495

PCT International Filing date

2003-06-11

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	10/171,485	2002-06-11	U.S.A.