Indian Patents. 231492:"ALPHA-AMINO ACID AMIDE COMPOUNDS AND PREPARATION THEREOF"

Title of Invention	"ALPHA-AMINO ACID AMIDE COMPOUNDS AND PREPARATION THEREOF"
Abstract	The present invention relates to substitute alpha amino acid amide compounds of formula I, wherein; R, R', R2 and Ri are such as herein described in the specification.

Full Text	The present inventions relates to alpha-amino acid amide compounds, process for the preparation thereof and its pharmaceutical composition The present invention relates to α-amino acid amides, processes for the preparation thereof and pharmaceutical compositions containing them. More precisely, the invention relates to serinamide, ylycinamide alaninamide and phenylala-uninamide derivatives of general formula (I): (Formula Removed) wherein: R is straight or branched alkyl; cycloalkylalkyl; arylaLkyl or phenylalkyl optionally substituted at the ring with alkyl, halogen or haloalkyl; fused or non-fused aryl optionally substituted with alkyl, alkoxy, halogen or haloalkyl; R' is hydrogen; alkyl; phenyl; phenylalkyl; R1 is optionally acylated C1 -C4 hydroxyalkyl or phenylalkyl; R2 is hydrogen; alkyl; phenyl; phenylalkyl; with the proviso thai when R is aryl, R, can be hydrogen or alkyl C1 -C4. An alkyl group if not otherwise specified is preferably a C1 -C10 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-hutyl, isobutyl, n-pentyl, n- hexyl, n-heptyl , n-oct.yl, n-nonyl, 2-ethylpentyl, 1- othylheptyl, 1-methyloctyl, 4-heptyl. A cycloalkylalkyl group is preferably a group having 1 to 3 carbon atoms in the alkyl moiety and 3 to 7 carbon atoms in the cycloalkyl moiety such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1 -(5-norbornylenyl)ethyl. An optionally substituted arylalkyl or phenylalkyl group is preferably 2-naphthalenylmethyl, benzyl, phoneLhyl, pheriylpropyl, phenylbutyl, 3-(4-methyl-phenyl)propyl, 3-(4-fluorophenyl)propy), 3-(4-chlorophenyljpropyl , 3-{4-trifluoromethylphenyl)propyl, 3-phenyl-l-methylpropyl, 2-phenyl-l-methylethyl, 3-phenyl-3-methyl-propyl, 1-phenylethyl. A fused or non-fused aryl group is preferably l,2,3,4-tetrahydro-2-naphthalenyl, 2-indanyl optionally substituted by one or more a.lkoxy, halogen or haloalkyl yiroups. An acylated C^-C^ hydroxyalkyl group is preferably acetoxyalkyl, propanoyloxyalkyl, , 2-methylpropanoyl-oxyalkyj, benzoyloxyalkyl group. A class of preferred compounds is that wherein: Rx is CH2OH; R is C3-C10 alkyl, C2-C4 phenylalkyl, l,2/3,4-tetrahydro-2-naphthalenyl or 2-indanyl optionally substituted with alkyl, alkoxy, halogen or haloalkyl; R1 is hydrogen or methyl and R2 is hydrogen or methyl. A particularly preferred sub-class is that wherein Rt is CH2OH; R is phenyl-(C2-C3)-alkyl or 1,2,3,4-t.etrflhydro-2-naphthalenyl, or 2-indany.l. optionally substituted by one or more alkoxy, halogen, haloalkyl groups; R' and R2 are hydrogen. A second class of preferred compounds is that wherein Rj is hydrogen or methyl, R is 1,2,3,4- trstrahydro-2-naphthalenyl or 2~indanyl optionally substituted by one or more alkoxy, halogen, haloalkyl groups and R1 and 12 are hydrogen. The compounds of the invention can be in the form of organic or inorganic acid addition salts. Moreover they can have one or mor asymmetric cctrbon atoms, therefore they can be used both in the form of mixtures containing more diastereoisomers in any fcl«* ral io, and >in >-Xhe form of racemic 'mixtures cont'a^nilfg" uples of onaritiomers in equal or different rat£os, and Parkinson 's-~ disea'se, Huntingdon's disease dr,-Jacute rieurodegenerativc impairments such as stroke and head injuries; in the treatment of epilepsy and depression. PRIOR ART GR pa lent. 2048852 (Continental Pharma S.A. ) discloses 2-aminoaretamide (commonly referred >to . as ylycinamide) derivatives which can be used in the treatment of epilepsy, in the treatment of dyskinesias .such as Parkinsons 'r. disease, in the treatment of memory disorders and possibly in the treatment of depression. Some of the disclosed compounds, orally ^(Iministarftd in doses of 10-100 mg/kg, showed ;»nt i convulsive effects against bicuculline-induced tonic convulsions in mouse. 2-n--Pentylaminoaceiamide (in the following referred to with the ,, nonproprietary name milacemide) and" . its hyrtrochloride were particularly studied. Milacemide was used as the reference compound to test, the pharmacological activity of the compounds of the present invention. EP-B1-0400495 (Farmitalia Carlo Erba) discloses a-m.i rioearboxamide N-phenylalkyl substituted derivatives. Examples of particularly preferred compounds are aminopropionamide (particularly alaninamide and serinamide) and aminoacetainide (glycinamide) N-phnnylalkyl substituted %$,erivatives. Said compounds are adive on Central Nervous System and can be used as i • cinliepi 1 eptics, anti-P^rkinsonsy antineuroclegeneratives, antidepressants, ihypnpln^antispastics. convulfiions. The compounds described in EPB1-0400495 are also potonl monoamino oxidase (MAO) inhibitors. WO One of the most representative compounds of the .invention in WO 94/22808 is FCE28245, chemically 2-{4-t:i-phfjnylpropyl]oxybenzyl]-ainino-3-hydroxypropanamide met hnne.sulfonate claimed to be active in the test of the electro- shock convulsions in the mouse. PCT n WO 95/18617 .(Teva-Technion) and PCT n. WO 96/21640 (Teva-Lemmon) describe 1-aminobenzocycloalkane derivatives, such as 1-aminoindans and 1-aminotetralins, which can be used in the treatment of Parkinsons's disease, dementias, epilepsy and in post-traumatic diseases. However, some of the described compounds, such as raeeiuic N-( 2-acetamido )-l-aminoindan and its optically active forms; N- ( 2-acetamido ) -6-fluoro- 1-aminoindan; N-( 2-acetamido ) -l--aminotetralin; N,N-di- ( 2-acetamido)-1-aniinoindan and N - ( 2-propi onamido )-l-aminoi ndan were not veryy effective in the anticonvulsant activity test and don't seem endowed with a particularly favourable therapeutic index. Now it has been found that α-amino acids amides of general formula (I) are characterized by a higher efficacy and/or a better pharmacological profile than the prior art compounds. The present relates to an improved and synergistic mixture of compounds of formula I having unexpected properties. The compounds of the invention can be prepared reacting amino acids reacting amino acids esters or amides of formula II (Formula Removed) wherein R1 is as defined above and X is an alkoxy group or a NHR2 group, wherein R2 is as defined above, with compounds of formula III (Formula Removed) wherein Y is an oxygen atom or a NH group, whereas R3 and R4 which are the same or different, are hydrogen or, together with the carbon atom they, are linked to, they form one of the groups R, or R1, as defined above, to give compounds of formula IV. (IV) which can then be transformed into compounds of formula I hy means of one or more of the following reactions: when X is an alkoxy group, reaction with an amine of formula R2-NH2; N-alkylation; ncylation of any hydroxy group present in R^; salificatton and/or optical resolution. elimination of any protecting groups. A first embodiment, of the process described above involves the reductive amination of a compound of formula TI or a salt thereof (generally the hycltochloride) wherein X is an alkoxy group, for example mfit.hoxy, with a compound of general formula III wherein i Y js oxygen and the subsequent, reaction with an amine of formula R2-NH2- The reductive amination is carried out according to conventional methods, using stoichiometric amounts or slight excesses of the reagents, at temperatures ranging f.tom 0 to 40C and in organic solvents such as alcohols or acetoriitrile. A hydride such as sodium cyanoborohydride or hydrogen in the presence of a catalyst such as Pd on-carbon can be used as a reducing agont.. The subsequent amidat.ion reaction is carried out ur.ing an ami no oxcer.s in water or in an organic solvent, particularly methanol or ethanol, at. room temperature or heating in a chemical reactor. A second embodiment. involves the reductive 7 ami nation of a compound II wherein X is a R2~NH group, according to the procedures already described. Finally, a third embodiment involves the Lransimination of a compound II wherein X is R2~NH- with nri imine compound (generally a phenylimine) III wherein Y is NH. The reaction is carried out in an organic solvent, for example an alcohol, methylene chloride or rtcelonitrile at a temperature from 0 to 40'C. The subsequent reduction of the resulting compound is carried out in an organic solvent, generally an alcohol such as ethanol or methanol , using a hydride such as sodium borohydride as reducing agent, at a temperature from 0' to 40 "C. Alternatively, the compounds I can also be prepared by condensation of an alfa-halogen ester of formula V wherein Fj is as defined above and preferably H, W is a ha logon atom (generally chlorine or bromine) and R5 is arv alkyl group, with an amine of formula VI wherein Rg and R^ are as defined above, and subsequent amidati.nn with the amine ^2~^^2' Tne condensation of compound V with compound VT is carried out in an organic r.olvont., for example acetonitrile, alcohol, dimethylformamido at a temperature from 40* to 140C in the presence of an acid-binding agent, for example potassium carbonate and preferably in the presence of 8 catalytic amounts of potassium iodide. The amidation is Lheri carried out as described above. It is also possible to condense an alfa-halogen amide with the amine VI. For the envisaged therapeutical uses, compounds I wiJl be formulated in suitable pharmaceutical compositions which are a further object of the invention. Said compositions will typically contain 1 to 1000 mg of active ingredient, particularly 30 to 100 mg, and will be administered one or more times a day depending cm Ihe disease, the pharmacokinetics of the selected active ingredient and the conditions (weight, sex, age) of the patient. The compositions will be prepared using conventional techniques and excipients as described for example in Remington's Pharmaceutical Sciences Handbook, Mnck. Pub., N.Y., U.S.A., and will be administered by the oral, parenteral or rectal route. Examples of formulations comprise tablets, capsules, syrups, granulates, sterile injectable solutions or suspensions, suppositories and the like. The following examples further illustrate the invention. Example 1. ) Preparation Of N-( 3-phenylprpPVl 1-L-serj.ne methyl 0 ster hydrochloride L-Serine methyl ester hydrochloride (0.9 moles, 14 g), triethylamine (0.9 moles, 9.1 g) and 3-phenylpropionaldehyde (0.9 moles, 12.1 g) are dissolved 9 in dry methauo.1 (370 ml) in a Parr bottle and hydroyenated under 45 psi in the presence of 10% Pd/C, unl.il the hydrogen absorption ceases. The catalyst is filtered off and the filtrate is cwaporated to dryness under vacuum. The re.suItiny oil is Inken up with methylene chloride (500 ml), the organic solution is washed with water and evaporated to dryness under vacuum to obtain a pale yellow oil. The product is recovered as the hydrochloride by dissolution in ethyl ether (800 ml) and acidification with methanol hydrochloric acid. The precipitate is filtered and dried under vacuum at 45'C. Yield: 17.5 g (7U.) - m.p. = 126-129'C h) Preparation' of f - )-.f S}-3~hydroxy-2-(3-phenyIpropyl- aminolpjopanamide hydrochloride, (CHF 2603.011 The product obtained in a)! (0.06 moles, 17 g) is dissolved in water (500 ml) and alkalinized with 10% aqueous potassium carbonate to pH = 8. The free base is extracted with methylene chloride and evaporated to dryness under vacuum. The resulting pale yellow oil (J6.3 g) is dissolved in methanol (150 ml). Ammonia is bubbled through the solution, cooled at -5"C, to a -15M rorioentrat.ion. The hormetical ly sealed system is reacted for 5 days at room temperature (r.t.), then evaporated lo dryness under vacuum. The product is recovered as the hydrochloride by dissolution in ethanol (40 ml), .icidification with ether HC1 and precipitation with «thyl ether (500 ml). The white r.olid is filtered and dried under vacuum at. 40C. Yield: 7.6 g (46.5%) - m.p.: 153-155'C = 1, methanol) = -13.5 Kxample 2 a) preparation o.f . W-.(2.-±fi.tralyl)-P-serine methyl ester Sodium cyanoborohydride (0.07 moles, 4.b g) is added to a solution of p-tet.ralone (0.068 moles, 10.5 g) and D-serine methyl ester hydrochloride (0.07 moles, 11 g) in 10/1 et.hanol /methanol (550 ml). The mixture is rearf.ed at r.t. for 24 hours, evaporated to dryness under vacuum, taken up with water (800 ml) and extracted with ethyl acetate (2 x 500 ml ) . The combined organic phases are extracted with IN HCl (2 x 300 ml). The aquoous? phases are alkalinizod with sodium bicarbonate and retracted with ethyl acetate (3 x 200 ml). The combined organic phases are evaporated to dryness under vacuum, to yield the product as a yellow oil. Yield: 12 Ammonia is bubbled through a solution of N-(2-tetralyl)-D-serine methyl ester (0.048 njoleo, 12 g) in met.hanol (150 ml), at O'C, to a -15M concentration. The hermetically sealed system is reacted at r.t. for 120 hours. The solution i.s evaporated to dryness under vacuum and the residual oil solidifies upon grinding in petroleum ether. Ytnld: 9 g (80%) - m.p.: 104-115'C c) Separation of CHF 2818 diastereomers Pxepar at J.QIL-OJL. 3-hydroxy-2- ( R ) nauhthalen-2-f Slvlaminol prooanamide fCHF 2983) 2-(R)-(l,2,3,4 -Te trahydro- 2- ( R , S ) -naphtha 1 eny lami-no) -3-hydroxypvopanamide (0.038 crystallized in ethyl acetate (200 ml) and the resulting solid is recrystallized in ethyl acetate (200 ml) twice ;nrid finally in ethanol (50 ml). The crystalline white solid is dried under vacuum at 45C. Yield: 1.9 g (yield 43%) - m.p. = 142-145C [a]589 (c = 1, mothariol) = +92 cl ) Preparation of 3-hvdroxv-2-(R)-( 1 . 2.3 .4-tetrahVdro-flaphthale n-2-(R)ylam i no ) propanamide ___ hydrpchloride tCHL.Aaa2.Jm The mother liquors from the first three crystallizations of CHF 2983 are combined and left at O'C for 48 hours: the precipitate is filtered off and the filtrate is evaporated to dryness under vacuum. The resulting wax solidifies by trituration in ethyl ether (hO ml) at r.t. The solid is recovered as the hydrochloride by dissolution in melhanol HC1 (3M, 2'0 nil) and evaporation to dryness under vacuum, then crystallized from 1/1 ol.hanol /ethyl acetate (400 ml). The crystalline white solid is dried under vacuum at 45'C. Yield:- '1.8 9 (36 %) - m.p. - 226 - 232'C [al™9 (c - 1, methane! )» -105.1 Example 3 3-(4-Methylphenyl)propanoic acid (0.055 moles, 9 g) is dissolved in thionyl chloride (1.008 moles, 320 g). The mixture is stirred for 30' at r.t., then refluxed for Ih 30', evaporated under vacuum to an oil and taken up with toluene and hexane, each time evaporating to 'dryness. Yield: 12.4 g b ) Preparation . of 3-- f 4-me thvlphenvl loropanal A solution of triphenylphosphine (0.117 moles, 30.8 y) in acetone (200 ml) is added under a nitrogen stream at r.t. with Cu (I) bis-(triphenyl-phosphine)-tetrahy-droborate (0.067 moles, 40.69 g), then 3-(4-methylphenyDpropanoyl chloride (0.055 moles, 10 g) dissolved in acetone (85 ml) is dropped in 45'. The mixture is stirred at r.t. under nitrogen for 1h. The precipitated solid is filtered, washing with acetone and .the 'filtrate is evaporated under vacuum. The residue is dissolved in chloroform (340 ml), added with cuprous chloride (0.135 moles, 13.38 g) and stirred under nitrogen stream for Ih at r.t. The mixture is filtered through celite, the filtrate is evaporated to dryness and the resulting residue is taken up into ethyl ether and petroleum ether, -filtered and evaporated under » vacuum to obtain an oil. Yield: 6.7 g (H3%) f) Preparation— of 3-hvdroxy-2-( 3-(4-methylph,ej3yl )-prppvlaminp 1 propanpic _ acid methyl ______ ester 2% Sodium in methanol (0.045 moles, 51.7 ml) is added to D,L~Serine methyl ester hydrochloride (0.045 uoles, 7 g), dissolved in methanol (70 ml), to obtain the free base. The formed sodium chloride is precipitated with •M.hyl ether (150 ml) and filtered off. The filtrate .is evaporated to dryness under vacuum. The resulting rosidue is dissolved in methanol (450 ml), added with 3-(4-methylphenylpropanal) (0.045 moles, 6.7 g) and id j ustod to pH 6 with acetic acid, sodium cyanohoTohydtide (0.048 moles, 3 g) is added and the ni.ixt.ure is reacted at r.t. for 24 hours. The mixture is acidified with methanol HCl, evaporated to dryness under vacuum, taken up with methylene chloride (600 ml), then alknlinjzed with triethylacnine and washed with water (3 x 500 ml). The organic phase is evaporated to dryness under vacuum and the product is recovered as the hyclroehloride taking up with ethyl ether (400 ml) and acidifying with ether HCl. The precipitated white solid is dried under vacuum at 30'C. YitOd: 8.8 g (68%) ' d) Proparatioja, of 3-hvdroxy-2-(3-(4-niethylphenvl}pro-BYlamirtolpropanamide hvdrochloride fCHF 2934.OH 3-Hydroxy-2-( 3-(4-methylphenyl Jpropy lami.no )propa~ noic acid methyl ester hydrochlori.de (0.03 moles, 8,6 g) is dissolved in water -(500 ml), alkalinized with 10% aqueous potassium carbonate to pH = 8. The free base is extracted with methylene chloride and evaporated to drynoRG under vacuum. The resulting pale yellow oil {16.3 g) is dissolved .in methanol (150 ml). Ammonia is bubbled through the solution, cooled at -5'C, to a -15M concentration. The hermetically sealed system is reacted for 5 days at r.t., then evaporated to dryness under vacuum. The product is recovered as the hydrochlorida by dissolution in ethanol (40 ml), acidification with ether HCl and precipitation with ethyl other (500 ml). The white solid is filtered and Example 4 a ) P r.ep ar a tion of 4-phenylbutanovl chlorld c 4-Phenyl-butanoic acid (0.83 moles, 13.57 g) is added to thionyl chloride (0.114 moles, 8.27 ml) and warmed to dissolve the solid. The mixture is stirred for 30 1 at r.t., then refluxed for 1.0', finally recovered as in example 3a). A 100 yield is obtained (0.083 moles, 15.09 g). b ) Preparation of 4-phenylbutanal The procedure as in 3b) is followed, starting from 4-ph'enylbutanoyl chloride (0.083 moles, 15.09 g), to obUiiri 11 g of product. 2% Sodium in methariol (0.052 moles, 59.8 ml) is ad- recovered as the hydrochloride, taking up with ethyl ether (180 ml) and acidifying with ether HCl . The precipitated white solid is dried under vacuum at 30"C. Yield: 5.83 g (40%) cl) Preparat ic.u of (Rl-3-hvdr oxv-2-(4-phenvllbutvlami- no)prunanamide (CHF.29181 (R)-3-(Hydroxy-2-( 4-phenylbutylamino)propanoic acid mothy 1 ester hydrochloride (0.02 moles, 5.83 g) is dissolved in water (250 ml) and alkalin.i7.ed with 10% aqueous sodium carbonate. The free base is extracted with methylene chloride (3 x 200 m]) and evaporated to drynt!;s under vacuum. The resulting pale yellow oil is dissolved in methanol (1 f>0 ml). Ammonia is bubbled through the solution, cooled at -5'C, to a -15M concentration. The hermetically sealed system is reacted for 5 days at r.t., then evaporated to dryness under t vacuum to obtain a thick oil. The product is obtained as a solid taking up with ethy.l. ether (25 ml) and precipitating with hexane (400 ml). The white solid is filtered and dried under vacuum at 35"C. Yield: 4.43. g (92 %) - m.p. =• 59-61'C With similar procedures as described in the examples 1 to 4 th compounds 1. to 5, 27, 28, 30, 33, 34, 38, 39, 42 to 44, 46 to 48, 52 and' 53 of Table 1 were prepared. Example 5 P i: eparntiQJl-. . __Ql (Rl-3-hvdroxv-2-( 3-ohenvlDroDvlami- no)prppanamide fCHF 2679) D-Serinamide (0.038 moles, 4 g) and 3-photiylpropanal (0.038 moles, 5.1 g) are dissolved in methanol (400 ml) in a Parr bottle and hydrogenated in t.hfi presence of 10% Pd/c (3 g) at 40 psi, until hydrogen absorption ceases. The catalyst is filtered off and the solution is evaporated to dryness under vacuum, taken up in ethyl acetate (300 ml) and washed with water (?. x 200 ml). Tho organic phase is dried and dissolved in warm elhyl ether (300 ml) to precipitate the product as a white solid by slow evaporation of the solvent at r.t. yj.c.ld: 3.8 (j (45) - m.p. = 76-78C LaJ589 (c = 1, methanol)= +13.2° With similar procedures as described in the example TJ the compounds 6 to 13, 15 to 22, 24, 26, 49 to 51 of Ttiblfi.l were prepared. Kxample 6 P reiteration of ( R 1 -2- ( 4--heptvlamino ) -3-hvdroxyDroDana- . 2870-021 A solution of D-serinamide (0.01 moles, 1 g) and 4-h«piariorie (0.01 moles, 1.1. g) in methanol (50 ml) is added with 4M methanol HCl (0.0033 moles, 0.85 ml) and HoOium cyanoborohydride (0.005 moles, 0.33 g). The mixture is reacted at r.t. for 10 days, acidified with mothanol HCl to pH = 2, and evaporated to dryness under vacuum. The residue is taken up with water (100 ml), washed with ethyl ether (100 ml), alka.l inized with sodium carbonate and extracted with chloroform (3 x 100 ml). The resulting oil (1.3 g) is dissolved in melhanol (SO ml) arid treated with 85% phosphoric acid (0.0065 moles, 0.75 g), then evaporated to dryness under vacuum to obtain the product ar. a very light solid foam. Yield: 2 g (77%) -- m.p. -. 150-156'C = +1 .9 Kx ample 7 a) Preparation pf_ ...... 3_~ .. acifl A solution of N-( 3-phenylpropyl )ser.ine methyl ester (6.4 g, 0.02V mol) in methanol. (1.50 ml) is added with 10% Pd-on-carbon (0.7 g) and 40% formic aldehyde (3.0 ml 0.04 mol) dissolved in methanol (50 ml). The mixture is stirred at. room temperature under hydrogen atmosphere, under a slight pressure (40 psi) until l lie absorption ceases. The mixture is filtered and I lie filtrate is evaporated under vacuum. The residue is I akem up in elhyl ether (300 ml), washed with water (2 x 200 ml), dried over sodium sulfate and ted under vacxium. Yield: 6.6 g The procedure of Example 3b is repeated. Ammonia is bubbled through a solution of 3-hydroxy-?.-(N~melhyl-(3-phenylpropylamino)propanoic acid methyl ftf-.tur (0.026 moles, 6.6 g) in methanol (150 m).)» at O'C, to a - 15M concentration. The system i:; reacted at T~30C for 120 hours in a closed reactor. The solution i.r: evaporated to dryness under vacuum to obtain an oil from which the product, js separated by low pressure liquid chrouialography . The resulting oil is taken up in absolute ethanol and ethyl acetate, then acidified with Ht.hfjf HC1. The mixture is stirred, adding ethyl ether, then the precipitate is filtered and dried under vacuum l -10T. Yifjltl: 3.5 g. - in. p. 112-114'C 18 With a similar procedure as described in the example 7 the following compounds were prepared: (R)-3-hydroxy-2-(N-methyl-2 -indanylami.no )propanamide hydrochloride (CMF 3440.01.; compound n. 63) ( s ) .1 -hydroxy •2--(N-methyl~2-indanylami nojpropanamide hydrochloride (CHF 3462.01; compound n. 67). Rxample R nj ..... Preparation of mothvl 2-( indanvlamino ) avfeUltfi. GJycine methyl ester (0.053 moles, 6.64 g) is dissolved in absolute ethanol (420 ml) and methanol (42 ml), added with 2-indanone (0.053 moles, 7 g), and with sodium cyanoborohydride (0.058 moles, 3.7 g) under stirring, in 40 minut.es. The mixture is left, under st. ir ring at r.t. overnight, evaporated to drynecs under vfH-uum arid the residue is taken up with water (500 ml) and ethyl acetate (SOO ml). The phases are separated and the organic phase is extracted with a 0.1M HC1 solution (3 x 200 ml). The acidic solution is adjusted to pH = 8.5-0 with a sodium bicarbonate saturated solution and oxl.rnctftd with ethyl acetate (3 x 250 ml). The organic sohir. tori is separated, dried over sodium :;ulfate and ovuporatod under vacuum. The resulting product, is dried uiidtti vacuum at r.t. Y.U-ld: f>.8 g (53.4%) h) Preparation of 2-(2--indafivlamino)acetamide hvdro- Mothyl 2- (indanylami no) acetate (0.020 moles, 5.8 g) i.s dissolved in -15M ammonia in methanol (150 ml) and k«pt in a closed test t\Jbe at r.t. for some days. The solution is evaporated to dryness under vacuum, taken up with absolute ethanol (2 x 200 ml) and evaporated each lime. The oil is taken up into methanol (30 ml) and acidified to acid pH with a. HC1 solution in dry methanol under stirring. The product is precipitated by addition of ethyl ether, filtered and dried under vacuum at 45C. Yield: 6.05 g (94.6%) - m.p. ^ 212-21.VC Kxamjple 9 £l.fiP_ar,.9tion of.. 2-(N-methvl-2-indanylamino 1 acetamide (fflF 34.0.0) 2-(2-indanylarainoJacctamide (0.016 moles, 3.00 g) js dissolved in methanol (60 ml), and potassium i-cirhonate (0.016 moles, 2.18 gi is added under stirring. Mothy.1 iodide (0.028 moles, 4.14 g) is dropped therein al. r.t. in 15 minutes. The mixture is reacted for 4 hours at r.t.., then evaporated under vacuum. The resulting solid is taken up into water (100 ml), the acrufour. solution is extracted with ethyl acetate (3 x 150 ml). The organic solution is dried over sodium sulfnte, then evaporated under vacuum to obtain an oil which is chromatographed under medium pressure through silica gel (eluent chlorofornumethanol = 00:10) Yitsld: 1.31 g (40%) - m.p. = 122-123'C Kx ample 1.0 •») Preparation of methyl (S}-3-hydroxy-Z:-(2- indanyl- aminojpropanoate L-serine methyl ester hydrochloride (0.05 moles, 7.7H g) is dissolved in absolute ethanol (400 ml) and nioth/niol (40 ml), added with 2-indanone (0.05 moles, ft.74 g) and sodium cyanoborohydride (0.55 moles, 3.64 g) under stirring in 30 minutes. The mixture is stirred at i.l. for 5 hours, then evaporated to dryness under vacuum arid the residue is taken up into water (150 ml) and ethyl acetate (150 ml). The phases are separated and the aqueous phase is further extracted with ethyl acetate (7.00 ml). The combined organic phases are extracted with a 0.2 N HCl solution (2 x 200 ml). The aqueous solution is separated, adjusted to pH = 3 wi.l.h sodium bicarbonate and extracted with ethyl acetate (2 x 300 ml). The organic solution is noparatod, dried over sodium sulfate and evaporated under vacuum. The resulting product, is dried under vacuum at r.t.. Yielfl: fl.4 g (71.4%) 1>) Preparation ... o.f (S\-3-hvdroxy-2-f 2-indanvlamino 1 -propanamide hvdrochloride fCHF 2993.011 Methyl (S)-3-hydfoxy-2-(2-indanylam.ino)propanoate (0.03b7 moles, 8.4 g) is dissolved in -12M ammonia mor.hanol (150 ml) and kept in a closed test tube at. r.t. for some days. The solution is evaporated to dryness uml«r vacuum to obtain an oil which is taken up into methanol (2 x 250 ml), evaporating to dryness each time. The resulting product (base) is taken up into ethyl acetato (170 ml) and acidified to acid pH with a HCl .solution in 4.75M dry ethyl acetate, under stirring. The product is filtered, crystallized from absolute ethanol and dried under vacuum at 40 C. YJold: 6.7 g (72.8%) - m.p. = 186-187'C [o]58C) (c=l, methanol.) = +16.6 (hydrochloride) [a]589 (c-1, methanol) = -24.6 (base) With methods known in the art the mesylate salt (CHF 2993.02) was obtained. m.p. 180-183'C £a]589 (c = 1, met.hanol) ••- + 13.4 With a similar procedure as described in the example 10 the compounds 41, 57, 61, 62, 69, 72, 75 and 76 of Table 1 were prepared. Kxiimple 1.1 PECpfirajL.ipjL.___af LSlr2r-.(2.-JJidflny lami no) -3-(.2-.me£hj£l=: propariovloxvl propanamide hydrochloride (.CHF 3542.03.1 (S) -3-hydroxy-?.- (2-iridanylami no) -propanamide hydrochloride (CHF 2993.0.1., 0.006 moles, 1.6 g) is dissolved in trifluoroacelic acid (3.75 ml) and added with 2-methylpropanoyl chloride (0.022 moles, 2.3 ml) by dropping. After 2 hours at r.t. the solution is evaporated under vacuum and the resulting oil is taken up into ethyl ether (100 ml). The product is filtered, ground in • ethyl ether (50 ml) and recovered by filtration. The solid is dried under vacuum at r.t. Yield: 1.8 g (90%) - m.p. = 171-174'C With a similar procedure as described in the example 11 the following compounds were prepared: (S) 3-- Examplo 12 PJSP.aJT.atiQIJ of fgj-3-hvdroxy-2-(2"indanvlaniiriO)-N-- m&thyJLB r_Qi> an am ide hydrochloride (CH F. .,3422. Jill N-(2-indanyl)-(S)-serine methyl ester (0.025 moles, 5.95 g) is dissolved in 8.03M methylamine solution in elhanol (155 ml) in a closed Lest tube. After 1 day the solution is evaporated under vacuum taking up the resulting oil with methanol (3 x 100 ml), petroleum et:h«jr (fract. 40-70, 100 ml) and evaporating each time. Tho resulting oil, taken up with petroleum ether (250 ml), solidifies under stirring. The filtered solid (-5.42 y) is dissolved in lukewarm ethyl acetate (250 ml) and added with HC1 in dry ethyl acetate (3.5 M) undor F.tirring until markedly acid pH. The product, is filtered, washed repeatedly with ethyl ether (150 ml) and dried In oven under vacuum. . Yield: b.33 g (77.9%) With a similar procedure as described in the example 12 the compounds 55, 56, 58, 60, 64 to 66 were pr«pared. Example 13 H) Preparation of 5.6-dimethoxy-2-hydroxvimino-inda- IlOJQe. 5.6 nimethoxy-1-indanone (0.078 moles, 15 y) is dissolved in absolute ethanol (550 ml), thormostated at fiO'C, and added with isoamyl nitrite (0.086 moles, 1.1.9 ml) and cone. HC1 (11.9 ml). After a few minutes the product precipitates. The reaction is kept at 50"C for further 3 hours, then cooled at r.t. and the solid is filtered washing with absolute ethanol (50 ml) and ethyl ether (100 ml). The product is dried in oven under varuiun «it r . I. 'Viftld: 16.3 g (94.4%) l>) Preparation of 5,6-dimethoxy-2-indanylaniin.e A solution of 5,6-dimethoxy-2-hydroxyimino-l-indanone (0.27 moles, 6 g) in glacial acetic acid (500 ml) ir. added with 96% sulfuric acid (3.3 ml) and 10% Pd/C (1.5 g). The mixture is hydrogenated in a Parr apparatus (r.t., 35 psi). When the hydrogen absorption coasor., the catalyst i filtered off through celite, washing with methanol (70 ml). The solution is evaporated to dryncss, to obtain a white solid which is dissolved in water, then extracted with ethyl areliiia (2 x 70 ml). The aqueous solution is alkalinized with a 1M sodium hyduoxide soJution to pH n-P, .5. The product is extracted with methylene chloride (2 x 70 ml). The organic solution is dried over sodium sulfate and evaporated under vacuum to obtain the solid product. Yiold: 4.6 g (88.5%) c) Preparation of 2-( 5 .6-dimethoxy-2ri nd anylaminal^. acetamide (CHF 3511). r>,6--Dimethoxy-2-iridanylamine (0.024 moles, 4.6 g) rttid r.odium bicarbonate (0.026 moles, 2.2 g) are added to n solution of chloroacetamide (0.024 moles, 2.2 g) in absolute elhariol (100 ml) and refluxed for 10 hours. The mixture is filtered at r.t. and the solution is ovaporalod to drynnr.s. The resulting oil is ctuomatographed under medium pressure through silica gel (oluo.nt: methylene chloride/methanol = 90/10) Yield: 1.95 g (32.7%) - m.p. = 135-138C With a similar procedure as described in the example 13 the following compound were preparared: 7.-(?)~f Uioro-2-indanYl arai.no )acetamide hydrochloride (CHF 3480.01); 2- ( 5,6-dif .1 uoro •?.• indariylaitiinojacetamide hydrochloride (CHF 3518.01). Tn the subsequent Table 1, the abbreviations and .structure formulae of the compounds of the examples as w»ll at» those of other compounds obtained with Che same HIMi hods as above described are reported. AnULC.onv.ulaaiLt, . The compounds of the invention were evaluated in some pharmacological tests in order to investigate their potential anticonvulsant activity. To this end, compounds were screened in the maximal electroshock (MRS) test. This model is widely used to assess the efficacy of antiepileptic agents against generalized and partial seizures. This study was performed in both rat and mouse by using the experimental procedure described in W. Lcisher et al. , Epilepsy Res., 2 (1988), 145-181. Briefly, a 60 Hz alternate current (mice 50 mA, rats 150 mA) was delivered for 0.2 sec through corneal electrods by means of an electrical stimulator. Anticonvulsant potency of a compound was determined after 60 ruin and up to 180 min from administration (p.o.) by calculation of itr. EDjo or suppression of tonic hind limb extensions. Groups of 30 animals per dose were used and the EDtjQ was calculated from the dose-effect curve accordingly to l.itchfield and Wi Icoxon (J. Pharmacol. Exp. Ther. , 96 (194 In the rat MES model only the time course of anticonvulsant activity was evaluated . Groups of 10 rats were treated at their equiactive dose 30, 60, 120, ','.40, 360 and 480 min before the establishment of the electroshock. The peak of anticonvulsanL activity and the duration of action were then evaluated. Tn another serie of experiments performed in mouse the nourotoxicity of tbe compounds was evaluated as a nnMSiire of the impaired motor function by using the horizontal screen test (L.L. Coughenour et al., Pharmacol. Bioch. and Behav., 6 (1977), 351--3S3). In thjs model mice are placed individually on top of a .«;quire wire screen which is mounted horizontally on a metal rod, which is then rotated 180 so that mice are on the bottom of the screens. Impairment of the motor function is observed from the number of animals that falls from the screen or fail to climb to the top of the screens. The medial neurological toxic dose (TDj0) is than calculated as above. The ratio of TD^Q and ED^Q refers to the therapeutic index (T.T.) for each compound. The T.I. is used to show a useful separation between neurotoxicity and antiepileptic activity. The larger the T.I. would indicate a better separation between the above activities and a good profile as anl iconvulsant.s. In the mouse MES model all the examined compounds sliowed a potency of ariLiconvulsant aqtivity expressed in moles better than that of milacemide and/or sodium valproato. The ED^Q values were comprised between 1.2 and 0.5 inmol/kg with a potency ratio ranging from 4.5 to 3f> with respect to milacemide and from 1 to 6.7 with respect to sodium valproate. The evaluation of the time course of anticorivulsant activity showed that some compounds were rapidly ahuorhed with a peak of the effect at 30 minutes after administration, whereas other compounds exerted more deferred effect:; that peaked even at three hours after /.ulmi ni strati on . A common feature Lo many compounds was a good perSistance of the effects with a suppression of the convulsions equal to or greater than 50% still stylistically significant more than three hours after administration. The duration of action was longer than that of mi laromidc which was of • about, one hour. The results of the MES test in mouse of the more representative compounds of the invention at 60 min after administration arc shown in the following Trfble 2. The activity of the compounds has boon compared wi t.h Lhat of two compounds of the prior art: FCE 28245, ;i prototype of a new , eerie of alanirie derivatives endowed with an anticonvulsant activity and TEVA compound 2 (a !• ami noindane derivative), described in WO 94/22808 and in WO 95/18617 respectively. T.T.: therapeutic index All compounds were administered as HC1 salts. The individual enantiomers of 2-aminoindane and ciminotetral ine derivatives showed a significant Icotivulsant activity. The (S)-hydroxyl-2 ami noindane derivative CHF2993 and its enantiomer (R) CHF2996 were oquipotent in the MES test. This latter compound showed ;ilso the higher T.T. (44) since its low value of ncurotoxicity (>1500 mg/kg P.O.). The introduction of a methyl-group in the mojoty of the CHF2993 resulted in a compound (CHF3440) with the same anticonvulsant activity buL with an increase of the neurotoxicity (TD5Q-689). Conversely, both the (S) 2-(2-indanylamino) propionamide an All the tested compounds were about 3-4 times more polenl than FCE20245, chemically 3-hydroxy--2-(4-(3-phenylpropyloxy)benzylamino)propanamide in.:I hanosulphonate. It is also worth noting that the 2-aminoindane derivative CHF33R1 had a higher T.I. than the prior art :l --.'•uniiioiridarie compound 2 known from WO Q5/1fi617, ch'-iinically (S)-2-( indanylamino) acetamide. Tn fact the ?.-HmLnolndane compound of the invention was more potent :hihi l.od less impairment of the motor coordination than the compound of the prior art. Further to the MES test in mouse, some compounds were also evaluated in the MES test in rat and in a chemical model of Conic convulsions induced by bicuculline accordingly to the procedure described in Swi.nyard E.A. et. al., Antiepileptic Druys, 3r(1 Rdir.ion, Kavon Press, New York (1989). Tn this model mice were observed for 30 minutes after administration of a dose of bicuculline (s.c.) that induced in 97% of. the animals » presence of tonic convulsions. In animal?: treated with compounds, abolition of the hindleg tonic-extension component is taken as the end point thus suggesting that i h« .substance under examination has the ability to pi event the seizure spread. As reference compound FCE 26743 (S)-2-(4-(3-f Iuorober\zyloxy)ben7.ylamino)pro panamide war. used, disclosed in the prior art in KP-B1-0400495. The results are shown in Table 3 as follows: time of the maxima] effect time at which tho protection is statistically significant n.t.: not tested In the rat MES test CHF2993, CHP2996 and FCE 26743 showed an anticonvulsant activity close to that found in the same moclol In mouse. In this test CHF 2983 was more potent, with an BD^Q of 19 my/kg P.O., lower than that reported .in mouse MF.S. The analysis of the kinetics of t ho pharmacological effects showed that CHF2993 had the longest duration ot action (6 hours). Tn any case the duration of action of all the tested compounds was longer than that, of the reference compound FCE 26743 (1 hour). Tn the bicuculline-induced convulsions in mice, KDrl0 fot CHF2993, CHF2983 and FCE 26743 was 65, 67 and 7.0 my/Kg P.O., respectively. Although these values were higher than those obtained in mouse MES test, still l.hns« values were in the same order of potency of their Mt:s> ariticonvulsant activity. Taken together these results/ we can conclude that, t lie compounds described herein showed a significant ant Lcorivulsarit activity in the MES model in both mouse The compounds of tho lnv«ntion can hu adapted to the typo of pathology taking into account as usual, also the route of administration, the form in which the compound is administered and the age, weight and conditions of the subject involved. Tn an embodiment the therapeutic.! ly effective amount is from about 1 ing to about 1000 mg, preferably from about 10 mg to about 300 mg. Of course, these dosage regimens may be adjusted to provide the optimal therapeutic response. The nature. of pharmaceutical compositions containing the compounds of this invention in •tKs-.ociation with pharmaceutically acceptable carriers or dijtionts will, of course, depend upon the desired route of .••u'lmi nif>tral.ion. The compositions may bo formulated in the conventional manner with the usual ingredients. For ex.-imp It;, the compounds of the invention may be administered in the form of aqueous or oily solutions or suspensions, tablets, pills, gelatine capsules, syrups, drop?: or suppositories. Thus, for oral administration, the pharmaceutical malpositions containing the compounds of this invention •••tre preferably tablets, pills or gelatine which contain ihc active substance together with diluents, such as .lactose, dextrose, sucrose, mannitol, sorbitol, o>llulose; lubricants, for instance silica, talc, r.iearic acid, magnesium or calcium stearate, and/or polyethylene ylycols; or they may also contain binders, siK'h as starches, gelatine, methylcellulose, cat boxymethylcel.lulose, gum arabic, tragacanth, polyvinylpyrrolidone; disaggregating agents, such as starches, alginic acid, alginates, sodium starch g I yen late; effervescing mixtures; dyestufts; sweeteners; wttl.ling ayenls, such as lecithin, polysorbates, lamyI sulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example hy inn an.'; of mixing, granulating, t.abletling, sucjMf-coat, ing, or film-coating processes. The liquid dispersions for oral administration may h» «.g. syr\ips, emulsion.'; arid suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or manriitol Hiid/or sorbitol. The suspension and the emulsions may r, pectin, methylcellulose, i '•••M boxymethylcel lulose, or polyviriyl alcohol. The suspensions or solutions for intramuscular injections may contain together with the active compound a ph'irmacoutlcally acceptable carrier, e.g. sterile water, (•.live? oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochlorido. The solutions for intravenous injections or .infusion may contain as carrier, for example, sterile w;it.or or preferably they may be in the form of r.terile aquwous isotoni.c saline solutions. The supposi tor ior. may contain together with the active compound a pharmaceutically acceptable carrier, e.rj. cocoa-butter, polyethylene cjlycol, a polyoxyethy-H>no r.orbitiiri fatty acid oster surfactant or lecithin. We Claim: 1. Alpha amino acid amide compounds of formula I (Formula Removed) wherein, R1 is hydrogen or methyl; R is 2-indanyl optionally substituted with alkyl, alkoxy, halogen or haloalkyl and R' and R2 are hydrogen. 2. A process for the preparation of the compounds as claimed in claim 1 which comprises reacting amino acids esters or amides of formula II (Formula Removed) wherein R1 is as defined above and X is an alkoxy group or a NHR2 group, wherein R2 is as defined above, with compounds of formula III (Formula Removed) wherein Y is an oxygen atom or a NH group, whereas R3 and R4, together with the carbon atom they are linked to form the group R as defined in claim 1, to give compounds of formula IV (Formula Removed) which can then be transformed into compounds of formula I by means of one or two more of the following reactions: -when X is an alkoxy group, reaction with ammonia; -N-alkylation; -salification and/or optical resolution; -elimination of any protecting groups. 3. Pharmaceutical compositions of alpha amino amide compounds of formula I as claimed in claim 1, and their pharmaceutically acceptable salts along with suitable excipients or carriers. 4. Alpha amino acid amide compounds of formula I, substantially as herein described with reference to the foregoing examples. 5. A process for the preparation of alpha amino acid amide compounds of formula I, substantially as herein described with reference to the foregoing examples.

Full Text

The present inventions relates to alpha-amino acid amide compounds,
process for the preparation thereof and its pharmaceutical
composition

The present invention relates to α-amino acid
amides, processes for the preparation thereof and
pharmaceutical compositions containing them.
More precisely, the invention relates to
serinamide, ylycinamide alaninamide and phenylala-uninamide derivatives of general formula (I):

(Formula Removed)
wherein:
R is straight or branched alkyl; cycloalkylalkyl;
arylaLkyl or phenylalkyl optionally substituted at the ring with alkyl, halogen or haloalkyl; fused or non-fused aryl optionally substituted with alkyl, alkoxy, halogen or haloalkyl;
R' is hydrogen; alkyl; phenyl; phenylalkyl;
R1 is optionally acylated C1 -C4 hydroxyalkyl or phenylalkyl;
R2 is hydrogen; alkyl; phenyl; phenylalkyl;
with the proviso thai when R is aryl, R, can be hydrogen
or alkyl C1 -C4.
An alkyl group if not otherwise specified is
preferably a C1 -C10 alkyl group such as methyl, ethyl,
n-propyl, isopropyl, n-hutyl, isobutyl, n-pentyl, n-
hexyl, n-heptyl , n-oct.yl, n-nonyl, 2-ethylpentyl, 1-
othylheptyl, 1-methyloctyl, 4-heptyl.
A cycloalkylalkyl group is preferably a group

having 1 to 3 carbon atoms in the alkyl moiety and 3 to 7 carbon atoms in the cycloalkyl moiety such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1 -(5-norbornylenyl)ethyl.
An optionally substituted arylalkyl or phenylalkyl group is preferably 2-naphthalenylmethyl, benzyl, phoneLhyl, pheriylpropyl, phenylbutyl, 3-(4-methyl-phenyl)propyl, 3-(4-fluorophenyl)propy), 3-(4-chlorophenyljpropyl , 3-{4-trifluoromethylphenyl)propyl, 3-phenyl-l-methylpropyl, 2-phenyl-l-methylethyl, 3-phenyl-3-methyl-propyl, 1-phenylethyl.
A fused or non-fused aryl group is preferably l,2,3,4-tetrahydro-2-naphthalenyl, 2-indanyl optionally substituted by one or more a.lkoxy, halogen or haloalkyl yiroups.
An acylated C^-C^ hydroxyalkyl group is preferably acetoxyalkyl, propanoyloxyalkyl, , 2-methylpropanoyl-oxyalkyj, benzoyloxyalkyl group.
A class of preferred compounds is that wherein:
Rx is CH2OH; R is C3-C10 alkyl, C2-C4 phenylalkyl, l,2/3,4-tetrahydro-2-naphthalenyl or 2-indanyl optionally substituted with alkyl, alkoxy, halogen or haloalkyl; R1 is hydrogen or methyl and R2 is hydrogen or methyl.
A particularly preferred sub-class is that wherein Rt is CH2OH; R is phenyl-(C2-C3)-alkyl or 1,2,3,4-t.etrflhydro-2-naphthalenyl, or 2-indany.l. optionally substituted by one or more alkoxy, halogen, haloalkyl groups; R' and R2 are hydrogen.
A second class of preferred compounds is that wherein Rj is hydrogen or methyl, R is 1,2,3,4-

trstrahydro-2-naphthalenyl or 2~indanyl optionally substituted by one or more alkoxy, halogen, haloalkyl groups and R1 and 1*2 are hydrogen.
The compounds of the invention can be in the form of organic or inorganic acid addition salts.
Moreover they can have one or mor* asymmetric cctrbon atoms, therefore they can be used both in the form of mixtures containing more diastereoisomers in any
fcl«*
ral io, and >*in >-Xhe form of racemic 'mixtures cont'a^nilfg" uples of onaritiomers in equal or different rat*£os, and

Parkinson 's-~ disea'se, Huntingdon's disease dr,-Jacute
rieurodegenerativc impairments such as stroke and head injuries; in the treatment of epilepsy and depression. PRIOR ART
GR pa lent. 2048852 (Continental Pharma S.A. ) discloses 2-aminoaretamide (commonly referred >to . as ylycinamide) derivatives which can be used in the treatment of epilepsy, in the treatment of dyskinesias .such as Parkinsons 'r. disease, in the treatment of memory disorders and possibly in the treatment of depression.
Some of the disclosed compounds, orally ^(Iministarftd in doses of 10-100 mg/kg, showed ;»nt i convulsive effects against bicuculline-induced tonic convulsions in mouse.
2-n--Pentylaminoaceiamide (in the following referred to with the ,, nonproprietary name milacemide) and" . its hyrtrochloride were particularly studied.

Milacemide was used as the reference compound to test, the pharmacological activity of the compounds of the present invention.
EP-B1-0400495 (Farmitalia Carlo Erba) discloses a-*m.i rioearboxamide N-phenylalkyl substituted derivatives.
Examples of particularly preferred compounds are aminopropionamide (particularly alaninamide and serinamide) and aminoacetainide (glycinamide) N-phnnylalkyl substituted %$,er*ivatives. Said compounds are adive on Central Nervous System and can be used as
i • cinliepi 1 eptics, anti-P^rkinsonsy antineuroclegeneratives, antidepressants, ihypnpln^antispastics.
convulfiions.
The compounds described in EP*B1-0400495 are also potonl monoamino oxidase (MAO) inhibitors.
WO One of the most representative compounds of the .invention in WO 94/22808 is FCE28245, chemically 2-{4-t:i-phfjnylpropyl]oxybenzyl]-ainino-3-hydroxypropanamide met hnne.sulfonate claimed to be active in the test of the electro- shock convulsions in the mouse.
PCT n* WO 95/18617 .(Teva-Technion) and PCT n. WO 96/21640 (Teva-Lemmon) describe 1-aminobenzocycloalkane derivatives, such as 1-aminoindans and 1-aminotetralins,
which can be used in the treatment of Parkinsons's disease, dementias, epilepsy and in post-traumatic diseases.
However, some of the described compounds, such as raeeiuic N-( 2-acetamido )-l-aminoindan and its optically active forms; N- ( 2-acetamido ) -6-fluoro- 1-aminoindan; N-( 2-acetamido ) -l--aminotetralin; N,N-di- ( 2-acetamido)-1-aniinoindan and N - ( 2-propi onamido )-l-aminoi ndan were not veryy effective in the anticonvulsant activity test and
don't seem endowed with a particularly favourable therapeutic index.
Now it has been found that α-amino acids amides of general formula (I) are
characterized by a higher efficacy and/or a better pharmacological profile than
the prior art compounds. The present relates to an improved and synergistic mixture of compounds
of formula I having unexpected properties.
The compounds of the invention can be prepared reacting amino acids reacting amino acids esters or amides of formula II
(Formula Removed)
wherein R1 is as defined above and X is an alkoxy group
or a NHR2 group, wherein R2 is as defined above,
with compounds of formula III
(Formula Removed)
wherein Y is an oxygen atom or a NH group, whereas R3 and R4 which are the same or different, are hydrogen or, together with the carbon atom they, are linked to, they form one of the groups R, or R1, as defined above, to give compounds of formula IV.

(IV)
which can then be transformed into compounds of formula I hy means of one or more of the following reactions:
when X is an alkoxy group, reaction with an amine
of formula R2-NH2;
N-alkylation;
ncylation of any hydroxy group present in R^;
salificatton and/or optical resolution.
elimination of any protecting groups.
A first embodiment, of the process described above involves the reductive amination of a compound of formula TI or a salt thereof (generally the hycltochloride) wherein X is an alkoxy group, for example mfit.hoxy, with a compound of general formula III wherein
i
Y js oxygen and the subsequent, reaction with an amine of formula R2-NH2-
The reductive amination is carried out according to conventional methods, using stoichiometric amounts or slight excesses of the reagents, at temperatures ranging f.tom 0 to 40*C and in organic solvents such as alcohols or acetoriitrile. A hydride such as sodium cyanoborohydride or hydrogen in the presence of a catalyst such as Pd on-carbon can be used as a reducing agont..
The subsequent amidat.ion reaction is carried out ur.ing an ami no oxcer.s in water or in an organic solvent, particularly methanol or ethanol, at. room temperature or heating in a chemical reactor.
A second embodiment. involves the reductive

7 ami nation of a compound II wherein X is a R2~NH group,
according to the procedures already described.
Finally, a third embodiment involves the Lransimination of a compound II wherein X is R2~NH- with nri imine compound (generally a phenylimine) III wherein Y is NH. The reaction is carried out in an organic solvent, for example an alcohol, methylene chloride or rtcelonitrile at a temperature from 0* to 40'C. The subsequent reduction of the resulting compound is carried out in an organic solvent, generally an alcohol such as ethanol or methanol , using a hydride such as sodium borohydride as reducing agent, at a temperature from 0' to 40 "C.
Alternatively, the compounds I can also be prepared by condensation of an alfa-halogen ester of formula V
wherein Fj is as defined above and preferably H, W is a ha logon atom (generally chlorine or bromine) and R5 is arv alkyl group, with an amine of formula VI
wherein Rg and R^ are as defined above, and subsequent amidati.nn with the amine ^2~^^2' Tne condensation of compound V with compound VT is carried out in an organic r.olvont., for example acetonitrile, alcohol, dimethylformamido at a temperature from 40* to 140*C in the presence of an acid-binding agent, for example potassium carbonate and preferably in the presence of

8 catalytic amounts of potassium iodide. The amidation is
Lheri carried out as described above.
It is also possible to condense an alfa-halogen amide with the amine VI.
For the envisaged therapeutical uses, compounds I wiJl be formulated in suitable pharmaceutical compositions which are a further object of the invention.
Said compositions will typically contain 1 to 1000 mg of active ingredient, particularly 30 to 100 mg, and will be administered one or more times a day depending cm Ihe disease, the pharmacokinetics of the selected active ingredient and the conditions (weight, sex, age) of the patient.
The compositions will be prepared using conventional techniques and excipients as described for example in Remington's Pharmaceutical Sciences Handbook, Mnck. Pub., N.Y., U.S.A., and will be administered by the oral, parenteral or rectal route. Examples of formulations comprise tablets, capsules, syrups, granulates, sterile injectable solutions or suspensions, suppositories and the like.
The following examples further illustrate the invention.
Example 1.
*) Preparation Of N-( 3-phenylprpPVl 1-L-serj.ne methyl
0 ster hydrochloride
L-Serine methyl ester hydrochloride (0.9 moles, 14 g), triethylamine (0.9 moles, 9.1 g) and 3-phenylpropionaldehyde (0.9 moles, 12.1 g) are dissolved

9 in dry methauo.1 (370 ml) in a Parr bottle and
hydroyenated under 45 psi in the presence of 10% Pd/C, unl.il the hydrogen absorption ceases.
The catalyst is filtered off and the filtrate is cwaporated to dryness under vacuum. The re.suItiny oil is Inken up with methylene chloride (500 ml), the organic solution is washed with water and evaporated to dryness under vacuum to obtain a pale yellow oil.
The product is recovered as the hydrochloride by dissolution in ethyl ether (800 ml) and acidification with methanol hydrochloric acid. The precipitate is filtered and dried under vacuum at 45'C. Yield: 17.5 g (7U.) - m.p. = 126-129'C h) Preparation' of f - )-.f S}-3~hydroxy-2-(3-phenyIpropyl-
aminolpjopanamide hydrochloride, (CHF 2603.011
The product obtained in a)! (0.06 moles, 17 g) is dissolved in water (500 ml) and alkalinized with 10% aqueous potassium carbonate to pH = 8. The free base is extracted with methylene chloride and evaporated to dryness under vacuum. The resulting pale yellow oil (J6.3 g) is dissolved in methanol (150 ml). Ammonia is bubbled through the solution, cooled at -5"C, to a -15M rorioentrat.ion. The hormetical ly sealed system is reacted for 5 days at room temperature (r.t.), then evaporated lo dryness under vacuum. The product is recovered as the hydrochloride by dissolution in ethanol (40 ml), .icidification with ether HC1 and precipitation with «thyl ether (500 ml).
The white r.olid is filtered and dried under vacuum at. 40*C. Yield: 7.6 g (46.5%) - m.p.: 153-155'C

= 1, methanol) = -13.5
Kxample 2
a) preparation o.f . W-.(2.-±fi.tralyl)-P-serine methyl ester Sodium cyanoborohydride (0.07 moles, 4.b g) is added to a solution of p-tet.ralone (0.068 moles, 10.5 g) and D-serine methyl ester hydrochloride (0.07 moles, 11 g) in 10/1 et.hanol /methanol (550 ml). The mixture is rearf.ed at r.t. for 24 hours, evaporated to dryness under vacuum, taken up with water (800 ml) and extracted with ethyl acetate (2 x 500 ml ) . The combined organic phases are extracted with IN HCl (2 x 300 ml). The aquoous? phases are alkalinizod with sodium bicarbonate and retracted with ethyl acetate (3 x 200 ml). The combined organic phases are evaporated to dryness under vacuum, to yield the product as a yellow oil. Yield: 12
Ammonia is bubbled through a solution of N-(2-tetralyl)-D-serine methyl ester (0.048 njoleo, 12 g) in met.hanol (150 ml), at O'C, to a -15M concentration. The hermetically sealed system is reacted at r.t. for 120 hours. The solution i.s evaporated to dryness under vacuum and the residual oil solidifies upon grinding in petroleum ether.
Ytnld: 9 g (80%) - m.p.: 104-115'C c) Separation of CHF 2818 diastereomers
Pxepar at J.QIL-OJL. 3-hydroxy-2- ( R ) nauhthalen-2-f Slvlaminol prooanamide fCHF 2983) 2-(R)-(l,2,3,4 -Te trahydro- 2- ( R , S ) -naphtha 1 eny lami-no) -3-hydroxypvopanamide (0.038

crystallized in ethyl acetate (200 ml) and the resulting solid is recrystallized in ethyl acetate (200 ml) twice ;nrid finally in ethanol (50 ml). The crystalline white solid is dried under vacuum at 45*C. Yield: 1.9 g (yield 43%) - m.p. = 142-145*C [a]589 (c = 1, mothariol) = +92
cl ) Preparation of 3-hvdroxv-2-(R)-( 1 . 2.3 .4-tetrahVdro-flaphthale n-2-(R)ylam i no ) propanamide ___ hydrpchloride
tCHL.Aaa2.Jm
The mother liquors from the first three crystallizations of CHF 2983 are combined and left at O'C for 48 hours: the precipitate is filtered off and the filtrate is evaporated to dryness under vacuum. The resulting wax solidifies by trituration in ethyl ether (hO ml) at r.t.
The solid is recovered as the hydrochloride by dissolution in melhanol HC1 (3M, 2'0 nil) and evaporation to dryness under vacuum, then crystallized from 1/1 ol.hanol /ethyl acetate (400 ml). The crystalline white solid is dried under vacuum at 45'C. Yield:- '1.8 9 (36 %) - m.p. - 226 - 232'C [al™9 (c - 1, methane! )» -105.1 Example 3
3-(4-Methylphenyl)propanoic acid (0.055 moles, 9 g) is dissolved in thionyl chloride (1.008 moles, 320 g). The mixture is stirred for 30' at r.t., then refluxed for Ih 30', evaporated under vacuum to an oil and taken up with toluene and hexane, each time evaporating to 'dryness. Yield: 12.4 g

b ) Preparation . of 3-- f 4-me thvlphenvl loropanal
A solution of triphenylphosphine (0.117 moles, 30.8 y) in acetone (200 ml) is added under a nitrogen stream at r.t. with Cu (I) bis-(triphenyl-phosphine)-tetrahy-droborate (0.067 moles, 40.69 g), then 3-(4-methylphenyDpropanoyl chloride (0.055 moles, 10 g) dissolved in acetone (85 ml) is dropped in 45'. The mixture is stirred at r.t. under nitrogen for 1h. The precipitated solid is filtered, washing with acetone and .the 'filtrate is evaporated under vacuum. The residue is dissolved in chloroform (340 ml), added with cuprous chloride (0.135 moles, 13.38 g) and stirred under nitrogen stream for Ih at r.t. The mixture is filtered through celite, the filtrate is evaporated to dryness and the resulting residue is taken up into ethyl ether and petroleum ether, -filtered and evaporated under
»
vacuum to obtain an oil. Yield: 6.7 g (H3%)
f) Preparation— of 3-hvdroxy-2-( 3-(4-methylph,ej3yl )-prppvlaminp 1 propanpic _ acid methyl ______ ester
2% Sodium in methanol (0.045 moles, 51.7 ml) is added to D,L~Serine methyl ester hydrochloride (0.045 uoles, 7 g), dissolved in methanol (70 ml), to obtain the free base.
The formed sodium chloride is precipitated with •M.hyl ether (150 ml) and filtered off. The filtrate .is evaporated to dryness under vacuum. The resulting rosidue is dissolved in methanol (450 ml), added with 3-(4-methylphenylpropanal) (0.045 moles, 6.7 g) and id j ustod to pH 6 with acetic acid, sodium

cyanohoTohydtide (0.048 moles, 3 g) is added and the ni.ixt.ure is reacted at r.t. for 24 hours. The mixture is acidified with methanol HCl, evaporated to dryness under vacuum, taken up with methylene chloride (600 ml), then alknlinjzed with triethylacnine and washed with water (3 x 500 ml). The organic phase is evaporated to dryness under vacuum and the product is recovered as the hyclroehloride taking up with ethyl ether (400 ml) and acidifying with ether HCl. The precipitated white solid is dried under vacuum at 30'C. YitOd: 8.8 g (68%) '
d) Proparatioja, of 3-hvdroxy-2-(3-(4-niethylphenvl}pro-BYlamirtolpropanamide hvdrochloride fCHF 2934.OH 3-Hydroxy-2-( 3-(4-methylphenyl Jpropy lami.no )propa~ noic acid methyl ester hydrochlori.de (0.03 moles, 8,6 g) is dissolved in water -(500 ml), alkalinized with 10% aqueous potassium carbonate to pH = 8. The free base is extracted with methylene chloride and evaporated to drynoRG under vacuum. The resulting pale yellow oil {16.3 g) is dissolved .in methanol (150 ml). Ammonia is bubbled through the solution, cooled at -5'C, to a -15M concentration. The hermetically sealed system is reacted for 5 days at r.t., then evaporated to dryness under vacuum. The product is recovered as the hydrochlorida by dissolution in ethanol (40 ml), acidification with ether HCl and precipitation with ethyl other (500 ml). The white solid is filtered and
Example 4
a ) P r.ep ar a tion of 4-phenylbutanovl chlorld c
4-Phenyl-butanoic acid (0.83 moles, 13.57 g) is added to thionyl chloride (0.114 moles, 8.27 ml) and warmed to dissolve the solid. The mixture is stirred for 30 1 at r.t., then refluxed for 1.0', finally recovered as in example 3a).
A 100* yield is obtained (0.083 moles, 15.09 g). b ) Preparation of 4-phenylbutanal
The procedure as in 3b) is followed, starting from 4-ph'enylbutanoyl chloride (0.083 moles, 15.09 g), to obUiiri 11 g of product. 2% Sodium in methariol (0.052 moles, 59.8 ml) is ad-
recovered as the hydrochloride, taking up with ethyl
ether (180 ml) and acidifying with ether HCl . The
precipitated white solid is dried under vacuum at 30"C.
Yield: 5.83 g (40%)
cl) Preparat ic.u of (Rl-3-hvdr oxv-2-(4-phenvllbutvlami-
no)prunanamide (CHF.29181
(R)-3-(Hydroxy-2-( 4-phenylbutylamino)propanoic acid mothy 1 ester hydrochloride (0.02 moles, 5.83 g) is dissolved in water (250 ml) and alkalin.i7.ed with 10% aqueous sodium carbonate. The free base is extracted with methylene chloride (3 x 200 m]) and evaporated to drynt!*;s under vacuum. The resulting pale yellow oil is dissolved in methanol (1 f>0 ml). Ammonia is bubbled through the solution, cooled at -5'C, to a -15M concentration. The hermetically sealed system is reacted for 5 days at r.t., then evaporated to dryness under
t
vacuum to obtain a thick oil. The product is obtained as a solid taking up with ethy.l. ether (25 ml) and precipitating with hexane (400 ml). The white solid is filtered and dried under vacuum at 35"C. Yield: 4.43. g (92 %) - m.p. =• 59-61'C
With similar procedures as described in the examples 1 to 4 th compounds 1. to 5, 27, 28, 30, 33, 34, 38, 39, 42 to 44, 46 to 48, 52 and' 53 of Table 1 were prepared. Example 5
P i: eparntiQJl-. . __Ql (Rl-3-hvdroxv-2-( 3-ohenvlDroDvlami-
no)prppanamide fCHF 2679)
D-Serinamide (0.038 moles, 4 g) and 3-photiylpropanal (0.038 moles, 5.1 g) are dissolved in methanol (400 ml) in a Parr bottle and hydrogenated in

t.hfi presence of 10% Pd/c (3 g) at 40 psi, until hydrogen absorption ceases. The catalyst is filtered off and the solution is evaporated to dryness under vacuum, taken up in ethyl acetate (300 ml) and washed with water (?. x 200 ml). Tho organic phase is dried and dissolved in warm elhyl ether (300 ml) to precipitate the product as a white solid by slow evaporation of the solvent at r.t. yj.c.ld: 3.8 (j (45*) - m.p. = 76-78*C LaJ589 (c = 1, methanol)= +13.2°
With similar procedures as described in the example TJ the compounds 6 to 13, 15 to 22, 24, 26, 49 to 51 of Ttiblfi.l were prepared. Kxample 6
P reiteration of ( R 1 -2- ( 4--heptvlamino ) -3-hvdroxyDroDana-
. 2870-021
A solution of D-serinamide (0.01 moles, 1 g) and 4-h«piariorie (0.01 moles, 1.1. g) in methanol (50 ml) is added with 4M methanol HCl (0.0033 moles, 0.85 ml) and HoOium cyanoborohydride (0.005 moles, 0.33 g). The mixture is reacted at r.t. for 10 days, acidified with mothanol HCl to pH = 2, and evaporated to dryness under vacuum. The residue is taken up with water (100 ml), washed with ethyl ether (100 ml), alka.l inized with sodium carbonate and extracted with chloroform (3 x 100 ml). The resulting oil (1.3 g) is dissolved in melhanol (SO ml) arid treated with 85% phosphoric acid (0.0065 moles, 0.75 g), then evaporated to dryness under vacuum to obtain the product ar. a very light solid foam.
Yield: 2 g (77%) -- m.p. -. 150-156'C
= +1 .9

Kx ample 7
a) Preparation pf_ ...... 3_~
.. acifl
A solution of N-( 3-phenylpropyl )ser.ine methyl ester (6.4 g, 0.02V mol) in methanol. (1.50 ml) is added with 10% Pd-on-carbon (0.7 g) and 40% formic aldehyde (3.0 ml 0.04 mol) dissolved in methanol (50 ml). The mixture is stirred at. room temperature under hydrogen atmosphere, under a slight pressure (40 psi) until l lie absorption ceases. The mixture is filtered and I lie filtrate is evaporated under vacuum. The residue is I akem up in elhyl ether (300 ml), washed with water (2 x 200 ml), dried over sodium sulfate and
ted under vacxium. Yield: 6.6 g
The procedure of Example 3b is repeated.
Ammonia is bubbled through a solution of 3-hydroxy-?.-(N~melhyl-(3-phenylpropylamino)propanoic acid methyl ftf-.tur (0.026 moles, 6.6 g) in methanol (150 m).)» at O'C, to a - 15M concentration. The system i:; reacted at T~30*C for 120 hours in a closed reactor. The solution i.r: evaporated to dryness under vacuum to obtain an oil from which the product, js separated by low pressure liquid chrouialography . The resulting oil is taken up in absolute ethanol and ethyl acetate, then acidified with Ht.hfjf HC1. The mixture is stirred, adding ethyl ether, then the precipitate is filtered and dried under vacuum *l -10T. Yifjltl: 3.5 g. - in. p. 112-114'C

18 With a similar procedure as described in the
example 7 the following compounds were prepared:
(R)-3-hydroxy-2-(N-methyl-2 -indanylami.no )propanamide
hydrochloride (CMF 3440.01.; compound n. 63)
( s ) .1 -hydroxy •2--(N-methyl~2-indanylami nojpropanamide
hydrochloride (CHF 3462.01; compound n. 67).
Rxample R
nj ..... Preparation of mothvl 2-( indanvlamino ) avfeUltfi.
GJycine methyl ester (0.053 moles, 6.64 g) is dissolved in absolute ethanol (420 ml) and methanol (42 ml), added with 2-indanone (0.053 moles, 7 g), and with sodium cyanoborohydride (0.058 moles, 3.7 g) under stirring, in 40 minut.es. The mixture is left, under st. ir ring at r.t. overnight, evaporated to drynecs under vfH-uum arid the residue is taken up with water (500 ml) and ethyl acetate (SOO ml). The phases are separated and the organic phase is extracted with a 0.1M HC1 solution (3 x 200 ml). The acidic solution is adjusted to pH = 8.5-0 with a sodium bicarbonate saturated solution and oxl.rnctftd with ethyl acetate (3 x 250 ml). The organic sohir. tori is separated, dried over sodium :;ulfate and ovuporatod under vacuum. The resulting product, is dried uiidtti vacuum at r.t. Y.U-ld: f>.8 g (53.4%) h) Preparation of 2-(2--indafivlamino)acetamide hvdro-
Mothyl 2- (indanylami no) acetate (0.020 moles, 5.8 g) i.s dissolved in -15M ammonia in methanol (150 ml) and k«pt in a closed test t\Jbe at r.t. for some days. The solution is evaporated to dryness under vacuum, taken up with absolute ethanol (2 x 200 ml) and evaporated

each lime. The oil is taken up into methanol (30 ml) and
acidified to acid pH with a. HC1 solution in dry
methanol under stirring. The product is precipitated by
addition of ethyl ether, filtered and dried under
vacuum at 45*C.
Yield: 6.05 g (94.6%) - m.p. ^ 212-21.VC
Kxamjple 9
£l.fiP_ar,.9tion of.. 2-(N-methvl-2-indanylamino 1 acetamide (fflF
34.0.0)
2-(2-indanylarainoJacctamide (0.016 moles, 3.00 g) js dissolved in methanol (60 ml), and potassium i-cirhonate (0.016 moles, 2.18 gi is added under stirring. Mothy.1 iodide (0.028 moles, 4.14 g) is dropped therein al. r.t. in 15 minutes. The mixture is reacted for 4 hours at r.t.., then evaporated under vacuum. The resulting solid is taken up into water (100 ml), the acrufour. solution is extracted with ethyl acetate (3 x 150 ml). The organic solution is dried over sodium sulfnte, then evaporated under vacuum to obtain an oil which is chromatographed under medium pressure through silica gel (eluent chlorofornumethanol = 00:10)
Yitsld: 1.31 g (40%) - m.p. = 122-123'C Kx ample 1.0 •») Preparation of methyl (S}-3-hydroxy-Z:-(2- indanyl-
aminojpropanoate
L-serine methyl ester hydrochloride (0.05 moles, 7.7H g) is dissolved in absolute ethanol (400 ml) and nioth/niol (40 ml), added with 2-indanone (0.05 moles, ft.74 g) and sodium cyanoborohydride (0.55 moles, 3.64 g) under stirring in 30 minutes. The mixture is stirred at

i.l. for 5 hours, then evaporated to dryness under vacuum arid the residue is taken up into water (150 ml) and ethyl acetate (150 ml). The phases are separated and the aqueous phase is further extracted with ethyl acetate (7.00 ml). The combined organic phases are extracted with a 0.2 N HCl solution (2 x 200 ml). The aqueous solution is separated, adjusted to pH = 3 wi.l.h sodium bicarbonate and extracted with ethyl acetate (2 x 300 ml). The organic solution is noparatod, dried over sodium sulfate and evaporated under vacuum. The resulting product, is dried under vacuum at r.t.. Yielfl: fl.4 g (71.4%)
1>) Preparation ... o.f (S\-3-hvdroxy-2-f 2-indanvlamino 1 -propanamide hvdrochloride fCHF 2993.011 Methyl (S)-3-hydfoxy-2-(2-indanylam.ino)propanoate (0.03b7 moles, 8.4 g) is dissolved in -12M ammonia mor.hanol (150 ml) and kept in a closed test tube at. r.t. for some days. The solution is evaporated to dryness uml«r vacuum to obtain an oil which is taken up into methanol (2 x 250 ml), evaporating to dryness each time. The resulting product (base) is taken up into ethyl acetato (170 ml) and acidified to acid pH with a HCl .solution in 4.75M dry ethyl acetate, under stirring. The product is filtered, crystallized from absolute ethanol and dried under vacuum at 40 *C. YJold: 6.7 g (72.8%) - m.p. = 186-187'C [o]58C) (c=l, methanol.) = +16.6 (hydrochloride) [a]589 (c-1, methanol) = -24.6 (base)
With methods known in the art the mesylate salt (CHF 2993.02) was obtained.

m.p. 180-183'C
£a]589 (c = 1, met.hanol) ••- + 13.4
With a similar procedure as described in the example 10 the compounds 41, 57, 61, 62, 69, 72, 75 and 76 of Table 1 were prepared. Kxiimple 1.1
PECpfirajL.ipjL.___af LSlr2r-.(2.-JJidflny lami no) -3-(.2-.me£hj£l=:
propariovloxvl propanamide hydrochloride (.CHF 3542.03.1
(S) -3-hydroxy-?.- (2-iridanylami no) -propanamide hydrochloride (CHF 2993.0.1., 0.006 moles, 1.6 g) is dissolved in trifluoroacelic acid (3.75 ml) and added with 2-methylpropanoyl chloride (0.022 moles, 2.3 ml) by dropping. After 2 hours at r.t. the solution is evaporated under vacuum and the resulting oil is taken up into ethyl ether (100 ml). The product is filtered, ground in • ethyl ether (50 ml) and recovered by filtration. The solid is dried under vacuum at r.t. Yield: 1.8 g (90%) - m.p. = 171-174'C
With a similar procedure as described in the example 11 the following compounds were prepared: (S) 3--
Examplo 12
PJSP.aJT.atiQIJ of fgj-3-hvdroxy-2-(2"indanvlaniiriO)-N--
m&thyJLB r_Qi> an am ide hydrochloride (CH F. .,3422. Jill
N-(2-indanyl)-(S)-serine methyl ester (0.025 moles, 5.95 g) is dissolved in 8.03M methylamine solution in elhanol (155 ml) in a closed Lest tube. After 1 day the solution is evaporated under vacuum taking up the resulting oil with methanol (3 x 100 ml), petroleum et:h«jr (fract. 40-70, 100 ml) and evaporating each time. Tho resulting oil, taken up with petroleum ether (250 ml), solidifies under stirring. The filtered solid (-5.42 y) is dissolved in lukewarm ethyl acetate (250 ml) and added with HC1 in dry ethyl acetate (3.5 M) undor F.tirring until markedly acid pH. The product, is filtered, washed repeatedly with ethyl ether (150 ml) and dried In oven under vacuum. . Yield: b.33 g (77.9%)
With a similar procedure as described in the example 12 the compounds 55, 56, 58, 60, 64 to 66 were pr«pared. Example 13 H) Preparation of 5.6-dimethoxy-2-hydroxvimino-inda-
IlOJQe.
5.6 nimethoxy-1-indanone (0.078 moles, 15 y) is dissolved in absolute ethanol (550 ml), thormostated at fiO'C, and added with isoamyl nitrite (0.086 moles, 1.1.9 ml) and cone. HC1 (11.9 ml). After a few minutes the product precipitates. The reaction is kept at 50"C for further 3 hours, then cooled at r.t. and the solid is

filtered washing with absolute ethanol (50 ml) and ethyl ether (100 ml). The product is dried in oven under varuiun «it r . I. 'Viftld: 16.3 g (94.4%) l>) Preparation of 5,6-dimethoxy-2-indanylaniin.e
A solution of 5,6-dimethoxy-2-hydroxyimino-l-indanone (0.27 moles, 6 g) in glacial acetic acid (500 ml) ir. added with 96% sulfuric acid (3.3 ml) and 10% Pd/C (1.5 g). The mixture is hydrogenated in a Parr apparatus (r.t., 35 psi). When the hydrogen absorption coasor., the catalyst i* filtered off through celite, washing with methanol (70 ml). The solution is evaporated to dryncss, to obtain a white solid which is dissolved in water, then extracted with ethyl areliiia (2 x 70 ml). The aqueous solution is alkalinized with a 1M sodium hyduoxide soJution to pH n-P, .5. The product is extracted with methylene chloride (2 x 70 ml). The organic solution is dried over sodium sulfate and evaporated under vacuum to obtain the solid product. Yiold: 4.6 g (88.5%) c) Preparation of 2-( 5 .6-dimethoxy-2ri nd anylaminal^.
acetamide (CHF 3511).
r>,6--Dimethoxy-2-iridanylamine (0.024 moles, 4.6 g) rttid r.odium bicarbonate (0.026 moles, 2.2 g) are added to n solution of chloroacetamide (0.024 moles, 2.2 g) in absolute elhariol (100 ml) and refluxed for 10 hours. The mixture is filtered at r.t. and the solution is ovaporalod to drynnr.s. The resulting oil is ctuomatographed under medium pressure through silica gel (oluo.nt: methylene chloride/methanol = 90/10)

Yield: 1.95 g (32.7%) - m.p. = 135-138*C
With a similar procedure as described in the example 13 the following compound were preparared: 7.-(?)~f Uioro-2-indanYl arai.no )acetamide hydrochloride (CHF 3480.01);
2- ( 5,6-dif .1 uoro •?.• indariylaitiinojacetamide hydrochloride (CHF 3518.01).
Tn the subsequent Table 1, the abbreviations and .structure formulae of the compounds of the examples as w*»ll at» those of other compounds obtained with Che same HIMi hods as above described are reported.

AnULC.onv.ulaaiLt, .
The compounds of the invention were evaluated in some pharmacological tests in order to investigate their potential anticonvulsant activity. To this end, compounds were screened in the maximal electroshock (MRS) test. This model is widely used to assess the efficacy of antiepileptic agents against generalized and partial seizures. This study was performed in both rat and mouse by using the experimental procedure described in W. Lcisher et al. , Epilepsy Res., 2 (1988), 145-181. Briefly, a 60 Hz alternate current (mice 50 mA, rats 150 mA) was delivered for 0.2 sec through corneal electrods by means of an electrical stimulator. Anticonvulsant potency of a compound was determined after 60 ruin and up to 180 min from administration (p.o.) by calculation of itr. EDjo *or suppression of tonic hind limb extensions. Groups of 30 animals per dose were used and the EDtjQ was calculated from the dose-effect curve accordingly to l.itchfield and Wi Icoxon (J. Pharmacol. Exp. Ther. , 96 (194 In the rat MES model only the time course of anticonvulsant activity was evaluated . Groups of 10 rats were treated at their equiactive dose 30, 60, 120, ','.40, 360 and 480 min before the establishment of the electroshock. The peak of anticonvulsanL activity and the duration of action were then evaluated.
Tn another serie of experiments performed in mouse the nourotoxicity of tbe compounds was evaluated as a nnMSiire of the impaired motor function by using the horizontal screen test (L.L. Coughenour et al., Pharmacol. Bioch. and Behav., 6 (1977), 351--3S3). In

thjs model mice are placed individually on top of a .«;quire wire screen which is mounted horizontally on a metal rod, which is then rotated 180* so that mice are on the bottom of the screens. Impairment of the motor function is observed from the number of animals that falls from the screen or fail to climb to the top of the screens. The medial neurological toxic dose (TDj0) is than calculated as above. The ratio of TD^Q and ED^Q refers to the therapeutic index (T.T.) for each compound. The T.I. is used to show a useful separation between neurotoxicity and antiepileptic activity. The larger the T.I. would indicate a better separation between the above activities and a good profile as anl iconvulsant.s.
In the mouse MES model all the examined compounds sliowed a potency of ariLiconvulsant aqtivity expressed in moles better than that of milacemide and/or sodium valproato. The ED^Q values were comprised between 1.2 and 0.5 inmol/kg with a potency ratio ranging from 4.5 to 3f> with respect to milacemide and from 1 to 6.7 with respect to sodium valproate.
The evaluation of the time course of anticorivulsant activity showed that some compounds were rapidly ahuorhed with a peak of the effect at 30 minutes after administration, whereas other compounds exerted more deferred effect:; that peaked even at three hours after /.ulmi ni strati on .
A common feature Lo many compounds was a good perSistance of the effects with a suppression of the convulsions equal to or greater than 50% still stylistically significant more than three hours after

administration.
The duration of action was longer than that of mi laromidc which was of • about, one hour.
The results of the MES test in mouse of the more representative compounds of the invention at 60 min after administration arc shown in the following Trfble 2.
The activity of the compounds has boon compared wi t.h Lhat of two compounds of the prior art: FCE 28245, ;i prototype of a new , eerie of alanirie derivatives endowed with an anticonvulsant activity and TEVA compound 2 (a !• ami noindane derivative), described in WO 94/22808 and in WO 95/18617 respectively.

T.T.: therapeutic index
All compounds were administered as HC1 salts. The individual enantiomers of 2-aminoindane and ciminotetral ine derivatives showed a significant Icotivulsant activity. The (S)-hydroxyl-2 ami noindane

derivative CHF2993 and its enantiomer (R) CHF2996 were oquipotent in the MES test. This latter compound showed ;ilso the higher T.T. (44) since its low value of ncurotoxicity (>1500 mg/kg P.O.). The introduction of a methyl-group in the mojoty of the CHF2993 resulted in a compound (CHF3440) with the same anticonvulsant activity buL with an increase of the neurotoxicity (TD5Q-689). Conversely, both the (S) 2-(2-indanylamino) propionamide an All the tested compounds were about 3-4 times more polenl than FCE20245, chemically 3-hydroxy--2-(4-(3-phenylpropyloxy)benzylamino)propanamide in.:I hanosulphonate.
It is also worth noting that the 2-aminoindane derivative CHF33R1 had a higher T.I. than the prior art :l --.'•uniiioiridarie compound 2 known from WO Q5/1fi617, ch'-iinically (S)-2-( indanylamino) acetamide. Tn fact the ?.-HmLnolndane compound of the invention was more potent :hihi l.od less impairment of the motor coordination than the compound of the prior art.
Further to the MES test in mouse, some compounds were also evaluated in the MES test in rat and in a

chemical model of Conic convulsions induced by bicuculline accordingly to the procedure described in Swi.nyard E.A. et. al., Antiepileptic Druys, 3r(1 Rdir.ion, Kavon Press, New York (1989). Tn this model mice were observed for 30 minutes after administration of a dose of bicuculline (s.c.) that induced in 97% of. the animals » presence of tonic convulsions. In animal?: treated with compounds, abolition of the hindleg tonic-extension component is taken as the end point thus suggesting that i h« .substance under examination has the ability to pi event the seizure spread.
As reference compound FCE 26743 (S)-2-(4-(3-f Iuorober\zyloxy)ben7.ylamino)pro panamide war. used, disclosed in the prior art in KP-B1-0400495.
The results are shown in Table 3 as follows:

time of the maxima] effect
time at which tho protection is statistically
significant n.t.: not tested
In the rat MES test CHF2993, CHP2996 and FCE 26743 showed an anticonvulsant activity close to that found in

the same moclol In mouse. In this test CHF 2983 was more potent, with an BD^Q of 19 my/kg P.O., lower than that reported .in mouse MF.S. The analysis of the kinetics of t ho pharmacological effects showed that CHF2993 had the longest duration ot action (6 hours). Tn any case the duration of action of all the tested compounds was longer than that, of the reference compound FCE 26743 (1 hour). Tn the bicuculline-induced convulsions in mice, KDrl0 fot CHF2993, CHF2983 and FCE 26743 was 65, 67 and 7.0 my/Kg P.O., respectively. Although these values were higher than those obtained in mouse MES test, still l.hns« values were in the same order of potency of their Mt:s> ariticonvulsant activity.
Taken together these results/ we can conclude that, t lie compounds described herein showed a significant ant Lcorivulsarit activity in the MES model in both mouse The compounds of tho lnv«ntion can hu
adapted to the typo of pathology taking into account as usual, also the route of administration, the form in which the compound is administered and the age, weight and conditions of the subject involved.
Tn an embodiment the therapeutic*.! ly effective amount is from about 1 ing to about 1000 mg, preferably from about 10 mg to about 300 mg.
Of course, these dosage regimens may be adjusted to provide the optimal therapeutic response.
The nature. of pharmaceutical compositions containing the compounds of this invention in •tKs-.ociation with pharmaceutically acceptable carriers or dijtionts will, of course, depend upon the desired route of .••u'lmi nif>tral.ion.
The compositions may bo formulated in the conventional manner with the usual ingredients. For ex.-imp It;, the compounds of the invention may be administered in the form of aqueous or oily solutions or suspensions, tablets, pills, gelatine capsules, syrups, drop?: or suppositories.
Thus, for oral administration, the pharmaceutical malpositions containing the compounds of this invention •••tre preferably tablets, pills or gelatine which contain ihc active substance together with diluents, such as .lactose, dextrose, sucrose, mannitol, sorbitol, o>llulose; lubricants, for instance silica, talc, r.iearic acid, magnesium or calcium stearate, and/or polyethylene ylycols; or they may also contain binders, siK'h as starches, gelatine, methylcellulose, cat boxymethylcel.lulose, gum arabic, tragacanth, polyvinylpyrrolidone; disaggregating agents, such as

starches, alginic acid, alginates, sodium starch g I yen late; effervescing mixtures; dyestufts; sweeteners; wttl.ling ayenls, such as lecithin, polysorbates, lamyI sulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example hy inn an.'; of mixing, granulating, t.abletling, sucjMf-coat, ing, or film-coating processes.
The liquid dispersions for oral administration may h*» «.g. syr\ips, emulsion.'; arid suspensions.
The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or manriitol Hiid/or sorbitol. The suspension and the emulsions may r, pectin, methylcellulose,
i
'•••M boxymethylcel lulose, or polyviriyl alcohol. The suspensions or solutions for intramuscular injections may contain together with the active compound a ph'irmacoutlcally acceptable carrier, e.g. sterile water, (•.live? oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochlorido.
The solutions for intravenous injections or .infusion may contain as carrier, for example, sterile w;it.or or preferably they may be in the form of r.terile aquwous isotoni.c saline solutions.
The supposi tor ior. may contain together with the active compound a pharmaceutically acceptable carrier, e.rj. cocoa-butter, polyethylene cjlycol, a polyoxyethy-H>no r.orbitiiri fatty acid oster surfactant or lecithin.

We Claim:
1. Alpha amino acid amide compounds of formula I

(Formula Removed)
wherein, R1 is hydrogen or methyl; R is 2-indanyl optionally substituted with alkyl, alkoxy, halogen or haloalkyl and R' and R2 are hydrogen.
2. A process for the preparation of the compounds as claimed in claim 1 which comprises reacting amino acids esters or amides of formula II

(Formula Removed)
wherein R1 is as defined above and X is an alkoxy group or a NHR2 group, wherein R2 is as defined above, with compounds of formula III
(Formula Removed)

wherein Y is an oxygen atom or a NH group, whereas R3 and R4, together with the carbon atom they are linked to form the group R as defined in claim 1, to give compounds of formula IV

(Formula Removed)
which can then be transformed into compounds of formula I by
means of one or two more of the following reactions:
-when X is an alkoxy group, reaction with ammonia;
-N-alkylation;
-salification and/or optical resolution;
-elimination of any protecting groups.
3. Pharmaceutical compositions of alpha amino amide compounds of formula I as claimed in claim 1, and their pharmaceutically acceptable salts along with suitable excipients or carriers.
4. Alpha amino acid amide compounds of formula I, substantially as herein described with reference to the foregoing examples.
5. A process for the preparation of alpha amino acid amide compounds of formula I, substantially as herein described with reference to the foregoing examples.

Documents:

0002-del-2001-abstract.pdf

0002-del-2001-claims.pdf

0002-del-2001-correspondence-others.pdf

0002-del-2001-description (complete)-27-08-2008.pdf

0002-del-2001-description (complete).pdf

0002-del-2001-form-1.pdf

0002-del-2001-form-18.pdf

0002-del-2001-form-2.pdf

0002-del-2001-form-3.pdf

0002-del-2001-gpa.pdf

2-DEL-2001-Abstract-(18-12-2008).pdf

2-DEL-2001-Abstract-(27-08-2008).pdf

2-DEL-2001-Abstract-05-12-2008.pdf

2-DEL-2001-Claims-(18-12-2008).pdf

2-DEL-2001-Claims-(27-08-2008).pdf

2-DEL-2001-Claims-05-12-2008.pdf

2-DEL-2001-Correspondence-Others-(05-01-2009).pdf

2-DEL-2001-Correspondence-Others-(05-012009).pdf

2-DEL-2001-Correspondence-Others-(18-12-2008).pdf

2-DEL-2001-Correspondence-Others-(27-08-2008).pdf

2-DEL-2001-Correspondence-Others-05-12-2008.pdf

2-DEL-2001-Description (Complete)-(18-12-2008).pdf

2-DEL-2001-Form-1-(18-12-2008).pdf

2-DEL-2001-Form-2-(27-08-2008).pdf

2-DEL-2001-Form-3-(05-01-2009).pdf

2-DEL-2001-Form-3-(18-12-2008).pdf

2-DEL-2001-Form-3-(27-08-2008).pdf

2-DEL-2001-GPA-(27-08-2008).pdf

2-DEL-2001-Petition-137-(27-08-2008).pdf

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Patent Number

231492

Indian Patent Application Number

0002/DEL/2001

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

05-Mar-2009

Date of Filing

01-Jan-2001

Name of Patentee

CHIESI FARMACEUTICI SPA

Applicant Address

VIA PALERMO 26/A. 43100 PARMA, ITALY

Inventors:

#	Inventor's Name	Inventor's Address
1	PAOLO VENTURA	VIA PALERMO 26/A, PARMA ITALY
2	PAOLO CHIESI	VIA PALERMO 26/A, PARMA ITALY
3	MAURIZIO DELCANALE	VIA PALERMO 26/A, PARMA ITALY
4	RENATO DE FANTI	VIA PALERMO 26/A, PARMA ITALY
5	ELISABETTA ARMANI	VIA PALERMO 26/A, PARMA ITALY
6	GINO VILLETTI	VIA PALERMO 26/A, PARMA ITALY
7	CLAUDIO PIETRA	VIA PALERMO 26/A, PARMA ITALY

PCT International Classification Number

A61K 31/165

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	MI96A001544	1996-07-23	Italy