Title of Invention	RING-SUBSTITUTED DIPHENYLAZETIDINONES, PROCESS FOR THEIR PREPARATION AND MEDICAMENTS COMPRISING THESE COMPOUNDS
Abstract	1. A compound of the formula I, H, F, CI, Br, I. CF3. NO2, N3, CN, COOH, COO(C1C8)alkyl, CONH2. C0NH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C8)-alkenyl, (LAG)n is selected from a sugar residue, disugar residue, trisugar residue, tetrasugar residue; a sugar acid, an amino sugar; an amino acid residue, an oligopeptide residue comprising 2 to 9 amino acids; 2. A compound of the fomiula I as claimed in claim 1, wherein R2, R4, R5, R6 Independently of one another are selected from S02-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be substituted up to two times by F, CI, Br, OH, CF3, NOj, CN, OCF3,0-(CrCeValkyl, (Ci-Ce)-alkyl, NHj; NHz, NHHCrCeValkyI, N((Ci-C6)-alkyl)2, NH(Ci-C7)-acyl. phenyl, O-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, CI, Br, I, OH. CF3. NO2, CN, OCF3. 0-{CrC6)-alkyI, (Ci-C6)-alkyl. NH2, NH(Ci-C6)-alkyl. N((Ci-C6>allcyl)2. SO2-CH3, COOH, C00-(Ci-C6)-alkyl, GONH2;

Title of Invention

RING-SUBSTITUTED DIPHENYLAZETIDINONES, PROCESS FOR THEIR PREPARATION AND MEDICAMENTS COMPRISING THESE COMPOUNDS

Abstract

1. A compound of the formula I, H, F, CI, Br, I. CF3. NO2, N3, CN, COOH, COO(C1C8)alkyl, CONH2. C0NH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C8)-alkenyl, (LAG)n is selected from a sugar residue, disugar residue, trisugar residue, tetrasugar residue; a sugar acid, an amino sugar; an amino acid residue, an oligopeptide residue comprising 2 to 9 amino acids; 2. A compound of the fomiula I as claimed in claim 1, wherein R2, R4, R5, R6 Independently of one another are selected from S02-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be substituted up to two times by F, CI, Br, OH, CF3, NOj, CN, OCF3,0-(CrCeValkyl, (Ci-Ce)-alkyl, NHj; NHz, NHHCrCeValkyI, N((Ci-C6)-alkyl)2, NH(Ci-C7)-acyl. phenyl, O-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, CI, Br, I, OH. CF3. NO2, CN, OCF3. 0-{CrC6)-alkyI, (Ci-C6)-alkyl. NH2, NH(Ci-C6)-alkyl. N((Ci-C6>allcyl)2. SO2-CH3, COOH, C00-(Ci-C6)-alkyl, GONH2;

Full Text	Ring-substituted diphenyl azetidinones, method for the production thereof, medicaments containing said compounds, and use thereof The invention relates to ring-substituted diphenylazetidinones, to their physiologically acceptable salts and to derivatives having physiological functions. Diphenylazetidinones (such as, for example, ezetimibe) and their use for treating hyperlipidemia and arteriosclerosis and hypercholesterolemia have already been described [cf. Drugs of the Future 2000, 25(7):679-685) and US 5.756,470]. It was an object of the invention to provide further compounds having a therapeutically utilizable hypolipidemic action. In particular, it was an object to find novel compounds v^'hlch, compared to the compounds described in the prior art, are absorbed to a very low extent. Very low absorption is to be understood as meaning an intestinal absorption of less than 10%, preferably less than or equal to 5%. In particular, absorption of the novel compounds must be less than that of ezetimibe. Pharmaceutically active compounds which are absorbed to a low extent generally have considerably fewer side-effects. Accordingly, the invention relates to compounds of the formula I H. F, CI, Br, I, CFs, NOz. N3, CN, COOH. C00(Ci-C6)-alkyl. CONH2. C0NH{Ci-C6)-alkyl, CON[{CrC6)-alkyl]2, {CrC6)-alkyl, (Ca-Ce^alkenyl, (C2-C6)-alkynyl, 0-(CrC6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine; SO2-NH2, S02NH(Ci-C6)-alkyl, S02N[(Ci-C6)-alkyl]2, S-(Ci-C6)-aIkyl, S-(CH2)n-phenyl, S0-(Ci-C6)-alkyl, S0-(CH2}n-phenyl. S02-{Ci-C6)-alkyl, S02-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be substituted up to two times by F, CI, Br, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-alkyl. (CrCel-aikyl, NH2; NH2, NH-(Ci-C6)-alkyi, N((Ci-C6)-aiky!)2, NH{Ci-C7)-acyl, phenyl, O-{CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, CI, Br. I, OH, CF3, NO2, CN, OCF3, 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, NH2, NH(CrC6)'alkyl, N{{Ci-C6)-alkyl)2, SO2-CH3, GOGH, C00-{CrC6)-alkyl, CONH2; R7 is F, CI, Br. I, CF3, NO2, N3. CN, COOH, C00(Ci-C6)-alkyl, CONH2, CONHlCi-CeValkyl, CON[(Ci-C6)-alkyl]2, (CrCeV-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, 0-(Ci-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine; PO3H2. SO3H, SO2-NH2, S02NH(Ci-Ce)-alkyl, S02N[(CrC6)-alkyl]2 , S-(Ci-C6)-alkyl, S-(CH2)n-phenyl, S0-(CrC6)-alkyl, S0-(CH2)n-phenyl. S02-(Ci-C6)-alkyl, S02-(CH2)n'phenyl, where n = 0 - 6 and the phenyl radical may be substituted up to two times by F, CI, Br, OH, CF3, NO2, CN, OCF3, 0-(CrC6)-alky!, (Ci-C6)-alkyl, NH2; C{NH){NH2), NH2, NH-(Ci-C6)-alkyl, N{(Ci-C6)-alkyl)2, NH(CrC7)-acyl, phenyl, 0-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, CI, Br, I, OH, CF3, NO2, CN, OCF3, 0-{Ci-CeValkyl, {Ci-CeValkyl, NH2, NH(Ci-C6)-alkyl, N((Ci-C6)-alkyl)2, SO2-CH3, COOH, C00-(Ci-C6)-aIkyl, CONH2; (l_AG)n is a sugar residue, disugar residue, trisugar residue, tetrasugar residue; a sugar acid, an amino sugar; an amino acid residue, an oligopeptide residue comprising 2 to 9 amino acids; an acyclic, mono-, di-or tricyclic trialkylammonium radical, an acyclic mono-, di- or tricyclic trialkylammoniumalkyi radical, -0-(S02)-0H; -{CH2)o-io-S03H; -{CH2)o.io-P(0)(OH}2, -(CH2)o-io-0-P(0){OH)2, -{CH2)o-io-COOH, -(CH2)o.io-C(=NH)(NH2): -(CH2)D-IO-C(-NH)(NHOH); - NR8-C(=NR9)(NR10R11); where n = 1 - 5 and R8, R9, R10 and R11 independently of one another may be H, (Ci-Cel-alkyI, phenyl, (CrCe)-alkyl-phenyl, (C3-C8)-cycloalkyl), and where In each case at least one of the radicals R1 to R6 must have the meaning {Ci-C3D)-alkylene-(LAG)n, where n = 1 - 5 and one or more carbon atoms of the alkylene radical are replaced by aryl or heteroaryl radicals substituted up to three times by R7, or by (C3-Cio)-cycloalkyl or heterocycloalkyi radicals substituted up to four times by R7 and one or more carbon atoms of the alkylene radical may be replaced by -S(0)n-. where n = 0 - 2, -0-, -(C=0)-, -{C=S)-, -CH=CH-, -CEC-. -N((Ci-C6)-alkyl)-, -N(phenyl)-, -N{(Ci-C6)-alkyl-phenyl)-. -N{CO~(CH2)i-io-COOH)- or -NH-; and their physiologically acceptable salts. Preference is given to compounds of the formula I where at least one of the radicals R1 to R6 the meaning (Ci-C3o)-alkylene-(LAG)n, where n = 1 - 5 and one or more carbon atoms of the alkylene radical are replaced by aryl or heteroaryl radicals substituted up to three times by R7, or by {C3-Cio)-cycloalkyl or heterocycloalkyi radicals substituted up to four times by R7 and one or more carbon atoms of the alkylene radical may be replaced by -S(0)n-, where n = 0 - 2, -0-, -(C=0)-, -(C=S)-, -CH=CH-. -CHC-. -N{(CrC6)-alkyi)-, -N(phenyl)-. -N((Ci-C6)-alkyl-phenyl}-, -N(CO-(CH2)i.io-COOH)-or-NH-. Particular preference is given to compounds of the formula I where one of the radicals R1 or R3 the meaning (Ci-C3o)-alkylene-(l-AG), where one or more carbon atoms of the alkylene radical are replaced by aryl or heteroaryl radicals substituted up to three times by R7, or by (C3-Cio)-cycloalkyl or heterocycloalkyi radicals substituted up to three times by R7 and one or more carbon atoms of the alkylene radical may be replaced by -S(0)n-, where n = 0 - 2, -0-, -(C=0)-, -NCCHa)-, -N{phenyl)-, -N(CO-(CH2)i.io-COOH)- or -NH-. A mono- or dicyclic trialkylammoniumalkyi radical is to be understood as meaning, for example, radicals such as purposes, very particular preference is given to using the chloride salt. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). The scope of the invention also includes salts having a pharmaceutically unacceptable anion, which salts may be useful intermediates for preparing or purifying pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications. Here, the term "derivative having physiological function" refers to any physiologically acceptable derivative of a compound according to the Invention, for example an ester, that Is able, upon administration to a mammal, for example man, to form such a compound or an active metabolite (directly or indirectly). A further aspect of this invention are prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to give a compound according to the invention. These prodrugs may or may not be active in their own right. The compounds according to the invention can also be present in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. The scope of the invention includes all polymorphous forms of the compounds according to the invention, which form a further aspect of the invention. Hereinbelow, all references to "compound(s) of the formula (I)" refer to a compound or compounds of the formula {1} as described above, and to their salts, solvates and derivatives having physiological function, as described herein. The compounds of the formula I and their pharmaceutically acceptable salts and derivatives having physiological function are Ideal medicaments for treating an impaired lipid metabolism, in particular hyperiipidemia. The compounds of the formula I are also suitable for modulating the serum cholesterol concentration and for preventing and treating arteriosclerotic manifestations. The compound(s) of the formula (I) can also be administered in combination with other active compounds. The amount of a compound of the formula (I) required to achieve the desired biological effect depends on a number of factors, for example on the specific compound chosen, on the intended use, on the mode of administration and on the clinical condition of the patient. In general, the daily dose is in the range from 0.1 mg to 100 mg (typically from 0.1 mg to 50 mg) per day per kilogram of bodyweight, for example 0.1-10 mg/kg/day. Tablets or capsules may contain, for example, from 0.01 to 100 mg, typically from 0.02 to 50 mg. In the case of pharmaceutically acceptable salts, the abovementioned weight data relate to the weight of the diphenyl-azetidlnone-ion derived from the salt. For the prophylaxis or therapy of the abovementioned conditions, the compounds of the formula (I) can be used themselves as the compound, but preferably they are present in the form of a pharmaceutical composition with an acceptable carrier. The carrier must of course be acceptable in the sense that it is compatible with the other constituents of the composition and Is not harmful to the health of the patient. The can-ier can be a solid or a liquid or both and is preferably formulated with the compound as an individual dose, for example as a tablet, which can contain from 0.05% to 95% by weight of the active compound. Further pharmaceutically active substances can also be present, including further compounds of the formula (I). The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consist in mixing the constituents with pharmacologically acceptable carriers and/or auxiliaries. Pharmaceutical compositions according to the invention are those which are suitable for oral or peroral (e.g. sublingual) administration, although the most suitable manner of administration is dependent in each individual case on the nature and severity of the condition to be treated and on the type of the compound of the formula (1) used in each case. Coated formulations and coated delayed-release formulations are also included in the scope of the invention. Acid-resistant and enteric formulations are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyimethylcelluiose phthalate and anionic polymers of methacrylic acid and methyl methacrylate. Suitable pharmaceutical compounds for oral administration can be present in separate units, such as, for example, capsules, cachets, lozenges or tablets, which in each case contain a specific amount of the compound of the formula (1); as a powder or granules; as a solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions can be prepared according to any suitable pharmaceutical method which includes a step in which the active compound and the carrier (which can consist of one or more additional constituents) are brought into contact. In general, the compositions are prepared by uniform and homogeneous mixing of the active compound with a liquid and/or finely divided solid carrier, after which the product, if necessary, is shaped. For example, a tablet can thus be prepared by pressing or shaping a powder or granules of the compound, if appropriate with one or more additional constituents. Pressed tablets can be produced by tableting the compound in free-flowing form, such as, for example, a powder or granules, if appropriate mixed with a binder, lubricant, inert diluent and/or a (number of) surface-active/ dispersing agent(s) in a suitable machine. Shaped tablets can be produced by shaping the pulverulent compound moistened with an inert liquid diluent in a suitable machine. Pharmaceutical compositions which are suitable for peroral (sublingual) administration include lozenges which contain a compound of the formula (!) with a flavoring, customarily sucrose and gum arable or tragacanth, and pastilles which include the compound in an inert base such as gelatin and glycerol or sucrose and gum arable. exampie, ezetimibe, llqueside, pamaqueside. In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR gamma agonist, such as, for example, rosiglitazone, pioglitazone, JTT-501, Gl 262570. In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR aipha agonist, such as, for exampie, GW 9578, GW 7647. In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR aipha/gamma agonist, such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847. In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate, such as, for example, fenofibrate, clofibrate, bezafibrate. In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor, such as, for example. Bay 13-9952, BMS-201038, R-103757. In one embodiment of the invention, the compounds of the formula I are administered in combination with a bile acid absorption inhibitor, such as, for example, HMR 1453. In one embodiment of the invention, the compounds of the formula 1 are administered in combination with a CETP inhibitor, such as, for example. Bay 194789. In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorber, such as, for example, cholestyramine, colesolvam. In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer, such as, for example, HMR1171,HMR1586. In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, such as, for example, avasimibe. In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant, such as, for example, OPC-14117. In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor, such as, for example, NO-1886. In one embodiment of the invention, the compounds of the formula 1 are administered in combination with an ATP citrate lyase inhibitor, such as, for example, SB-204990. In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor, such as, for example, BMS-188494. In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist, such as, for example, Cl-1027 or nicotinic acid. In one embodiment of the invention, the compounds of the formula I are REPLACEMENT SHEET (RULE 26) administered in combination with a lipase Inhibitor, such as, for example, Orlistat. In one embodiment of the invention, the compounds of the formula I are administered in combination with Insulin. In one embodiment, the compounds of the formula I are administered in combination with a sulfonylurea, such as, for example, tolbutamide, glibenclamide, glipizide or gliclazide. In one embodiment, the compounds of the formula I are administered in combination with a biguanide, such as, for example, metformin. In another embodiment, the compounds of the formula I are administered in combination with a meglitinide, such as, for example, repaglinide. In one embodiment, the compounds of the formula I are administered in combination with a thiazolidinedione, such as, for example, troglitazone, ciglltazone, pioglitazone, rosiglitazone, or the compounds disclosed by Dr. Reddy's Research Foundation in WO 97/41097, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinyt- methoxy]phenyl]methyl]-2,4-thiazolidinedione. In one embodiment, the compounds of the formula 1 are administered in combination with an a-glucosldase inhibitor, such as, for example, miglitoi or acarbose. In one embodiment, the compounds of the formula I are administered in combination with an active compound which acts on the ATP-dependent potassium channel of beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, gliazide or repaglinide. In one embodiment, the compounds of the formula I are administered in combinatton with more than one of the abovementloned compounds, for example in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazon, insulin and lovastatln, etc. In a further embodiment, the compounds of the formula I are administered In combination with CART agonists, NPY agonists, MC3 and MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, p3-agonists, MCH (melanine-concentrating hormone) antagonists, CCK agonists, serotonin reuptal^e inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, doprexin), lipase/amylase Inhibitors, PPAR modulators, RXR modulators or TR-p agonists. In one embodiment of the invention, the further active compound is leptin. In one embodiment, tlie further active compound Is dexamphetamlne or amphetamine. In one embodiment, the further active compound Is fenfluramine or dexfenfluramine. In another embodiment, the further active compound is sibutramine. In one embodiment, the further active compound is Orlistat. In one embodiment, the further active compound is mazindol or phentermine. In one embodiment, the compounds of the formula I are administered in combination with fiber, preferably insoluble fiber, such as, for example, Caromax®. The combination with Caromax® can be given in one preparation or by separate administration of compounds of the formula I and Caromax®. Here, Caromax® can also be administered in the form of food, such as, for example, in bakery goods or muesli bars. Compared to the individual active compounds, the combination of compounds of the formula I with Caromax® is, in addition to an enhanced action, in particular with respect to the lowering of LDL cholesterol, also characterized by its improved tolerability. It goes without saying that each suitable combination of the compounds according to the invention with one or more of the compounds mentioned above and optionally one or more further pharmacologically active substances is included in the scope of the present invention. The invention furthermore provides both stereoisomer mixtures of the formula I and the pure stereoisomers of the formula I, and diastereomer mixtures of the formula I and the pure diastereomers. The mixtures are separated by chromatographic means. If the sugar is substituted, the substitution is preferably at the hydrogen atom of an OH group of the sugar. Suitable protective groups for the hydroxyl groups of the sugars are substantially: benzyl, acetyl, benzoyl, pivaloyl, trityl, tert-butyldimethylsilyl, benzyiidene, cyclohexylidene or isopropylidene protective groups. The term "amino acids" or "amino acid residues" refers, for example, to the stereoisomeric forms, i.e. the D or L fonns, of the following compounds: alanine glycine proline cysteine histidine glutamine aspartic acid isoleucine arginine glutamic acid lysine serine phenylalanine leucine threonine tryptophan methionine valine tyrosine asparagine 2-aminoadipic acid 2-aminoisobutyric acid 3-aminoadipic acid 3-aminolsobutyric acid beta-alanine 2-aminoplmelic acid 2-aminobutyric acid 2,4-diaminobutyric acid 4-aminobutyric acid desmosine piperidine carboxylic acid 2,2-diaminopimelic acid 6-aminocaproic acid 2,3-diaminopropionic acid 2-aminoheptanoic acid N-ethylglycine 2-(2-thienyl)glycine 3-(2~thienyl)alanine penicillamine sarcosine N-ethylasparagine N-methylisoleucine hydroxylysine 6~N-methyllysine allo-hydroxylysine N-m ethyl valine 3-hydroxyproline norvaline 4-hydroxyproline norleucine isodesmosine ornithine allo-isoleucine N-methy [glycine For abbreviating the amino acids, the conventional notation was used (cf. Schroder, Lubke, The Peptides, Volume I. New York 1965, pages XXIt-XXIII; Houben-Weyl. Methoden der Organischen Chemie [Methods of organic chemistry]. Volume XV/1 and 2, Stuttgart 1974). The amino acid pGlu denotes pyroglutamyl, Nal denotes 3-{2-naphthyl)alanine, azagly-NH2 denotes a compound of the formula NH2-NH-CONH2 and D-Asp denotes the D form of aspartic acid. According to their chemical nature, peptides are acid amides, and on hydrolysis they decompose into amino acids. An oligopeptide is to be understood as meaning a peptide constructed of 2 to 9 of the amino acids mentioned above. Suitable protective groups (see, for example. T.W. Greene, "Protective Groups in Organic Synthesis") for amino acids are primarily: Arg{Tos), Arg(Mts), Arg(Mtr), Arg(PMV). Asp{OBzl), Asp{OBut), Cys(4-MeBzl). Cys(Acm), Cys(SBut), Glu(0b2l), Glu(Obut), His(Tos). H!S(Fmoc), His{Dnp), His(Trt), Lys(CI-Z), Lys(Boc), Met(O), Ser(Bzl), Ser(But), Thr(Bzl), Thr(But), Trp(Mts). Trp(CHO), Tyr{Br-Z), Tyr{Bzl) orTyr(But). Amino protective groups that are preferably used are the benzyloxycarbonyl (Z) radical, which can be removed by catalytic hydrogenation, the 2-(3,5-dimethyloxyphenyl)propyl(2)oxycarbonyl(Ddz) or trityl (Trt) radical, which can be removed by weak acids, the t-butylcarbamate (BOC) radical, which can be removed by 3M hydrochloric acid, and the 9-fluorenylmethyloxycarbonyl (Fmoc) radical, which can be removed using secondary amines. Tho invention furthermore relates to a process for preparing dlplienylazetidinone derivatives of formula I. The process for preparing compounds of the formula I comprises, for example, reacting an amine of the formula II with an alkylating or acylating agent which, preferably in the omega position, carries a further functionality- if appropriate in protected form. This functionality is (after deprotection) used for attaching (LAG), for example with the formation of ether, amine or amide bonds. The examples below serve to illustrate the invention in more detail, without limiting the invention to the products and embodiments described in the examples. 27 g of 3-[5-{4-f]uorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolldin-2-one, 13.6 g of tert-butyldimethylsilyl chloride and 10.2 g of imidazole are dissolved in 36 ml of dimethylformamide and stirred at eCC for 90 min. After the reaction has ended, the mixture is dissolved in ethyl acetate and extracted two times with water. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gives 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyloxazolidin-2-one (1) of molecular weight 471.65 (C26H34FN04Si); MS (ESI): 340.28 (MH- HOSi(CH3)2C(CH3)3). b) 4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-{2-0X0-4-phenyloxa2olidine-3-carbonyl)pentylamlno]benzonitrile (2): 16.2 g of 3-[5-(tert-butyldlmethylsllanyloxy)-5-{4-f]uorophenyl)-pentanoyl]-4-phenyloxa2olidin-2-one(1) are dissolved in 350 ml of dichloromethane. 19.8 ml of Hunig base and 10.14 g of 4-[(4-methoxyphenylimlno)methyl]benzonitrile are added, and the solution is cooled to -10°C. 8.52 ml of trimethylsilyl triflate are added to the cooled solution, and the mixture is stirred at-10°C for 30 min. The solution is then cooled to -30°C, and 44 ml of titanium tetrachloride solution are added. The reaction mixture is stirred at from -30 to -40°C for 2 h. The solution is then allowed to warm to room temperature and the reaction solution Is washed successively with 200 ml of 2N sulfuric acid, 300 ml of 20% strength sodium hydrogen sulfite solution and sat. sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure, and the residue is purified on silica gel using n-heptane/ethyl acetate 3/1. This gives 4-[5-(tert-butyldlmethylsilanyloxy)-5-{4-fluorophenyl)-1-{4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamino]benzonltrile (2) of molecular weight 707.93 (CAiHAeFNaOsSi); MS (ESI); 590.51 (MH - C7H5N2). c) 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-{4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1 -yllbenzonitrile (3)". 13.2gof4-[5-(tert-butyIdimethylsllany!Qxy)-5-(4-fluorophenyl)-1-{4-methoxyphenyl)-2-(2-oxo-4-phenyloxa2olidlne-3-carbonyl)pentylamino]benzonitrile (2) are dissolved In 380 ml of methyl tert-butylether, 18.6 ml of N,0-bls(trlmethylsilyl)acetamide and 1.86 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added and the mixture is stirred at room temperature for 2 h. After the reaction has ended, 10 ml of acetic add are added, the reaction mixture Is concentrated under reduced pressure and the residue is purified on silica gel using toluene/ethyl acetate 50/1. This gives 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyi]-2-(4- methoxyphenyl)-4-oxoazetidln-1-yl]-ben2onitrlle (3) of molecular weight 544.75 (CazHsTFNzOaSi); MS (ESI): 545.56 (M+H""). d) 4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoa2etidin-1-yl]-benzonitrile{4): 3.5 g of 4-[3-[3-{tert-butyldimethylsllanyloxy)-3-(4-fluorophenyl)propy(]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yll-ben2onitrile (3) are dissolved in 65 ml of tetrahydrofuran, 0.74 ml of acetic add and 8.03 ml of a 1 M solution of tetrabutylammonium fluoride In tetrahydrofuran are added and the mixture is stirred at room temperature for 2 h. Another 4.82 ml of the tetrabutylammonium fluoride solution are then added, and the mixture is stirred at reflux temperature for another 3 h. The cooled reaction mixture is concentrated under reduced pressure and the residue is purified by silica gel chromatography using n-heptane/ethyl acetate 2/1. This gives 4-[3-[3-{4-fluorophenyl)-3-hydroxypropyl]-2-{4-methoxyphenyl)-4-oxoazetidln-l-ylj-benzonitrlle (4) of molecular weight 430.48 {C26H23FN2O3); MS (ESiy.431.24(M+H). e) 1-(4-Aminomethylphenyl)-3-[3-{4'fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one (5): 1.22 g of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yll-benzonitrile (4) are dissolved in 90 ml of ethanol, 10 ml of cone, ammonia solution and an excess of Raney nickel are added, and the mixture is stirred at 60°C and a hydrogen pressure of 10 bar for 8 h. Overnight, the reaction mixture cools to room temperature, and the next day, the catalyst is removed, the filtrate Is concentrated under reduced pressure and the residue Is purified by silica gel chromatography using dichioromethane/methanol/ammonla solution 10/1/0.1. This gives 1-(4-amlnomethylphenyl)-3-[3-{4-fluorophenyl)-3-hydroxypropyl]-4-(4- methoxyphenyI)-a2etidin-2-one (5) of molecular weight 434.51 (C26H27FN2O3); MS (ESI): 418.2 (MH^-NHa). f) 2,3,4,5,6-Pentahydroxyhexylamide of 4,4'-oxybisbenzoic acid (6): At room temperature, 0.52 g of 4,4'-oxybisbenzoic acid and 0.36 g of D-glucamine are suspended in 10 ml of dry dimethylformamide, 0.31 g of HOBt and 0.39 g of EDC are added and the mixture is stirred at room temperature for 12 h. The reaction mixture is evaporated to dryness and dried under high vacuum. The residue is thoroughly titrated with water, the resulting suspension is filtered and the residue is titrated with methanol and filtered again. The filtrate is concentrated to half of its volume using a rotary evaporator, and the solution is cooled in an ice bath. The resulting precipitate is filtered off with suction, washed with a little ice-cooled methanol and dried under reduced pressure. This gives the 2,3,4,5,6-pentahydroxyhexylamide of 4,4'-oxybisbenzoic acid (6) of molecular weight 421.40 (C2oH23NOg); MS (ESI): 422.28 (MH). g) 2,3,4,5,6-Pentahydroxyhexylamide of 4-(4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoic acid (7): 87 mg of the compound prepared under e) and 90 mg of the compound prepared under f) are, at room temperature, dissolved in 3 ml of dry dimethylformamide, 31 mg of HOBt and 39 mg of EDC are added and the mixture is stirred at nDom temperature for 12 h. The reaction mixture is evaporated to dryness under high vacuum and the residue is titrated with dichloromethane, filtered off with suction, washed with dichloromethane and dried under reduced pressure. This gives the 2,3,4.5,6-Dentahvdroxvhexvlamide of 4-M-M-r3-r:^-^4-fii inrnnhpn\/h-'^_h\Hrnvwnrnm/n. 2-(4-methoxyphenyl)-4-oxoa2etidin-1 -yl]benzylcarbamoyl}phenoxy)benzoic acid (7) with & molecular weight 837.90 (C46H48FN3O11); MS (ESI): 838,39 (MH). b) 2,3,4,5,6-Pentahydroxyhexylamide of 4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2-oxo-4-phenylazetidin-1-yllbenzylcarbamoyl}phenoxy)benzoicacid(9): The benzylamine from lla is reacted with the 2,3,4,5,6-pentahydroxyhexylamide of 4,4'-oxybisbenzoic acid from If as described in Example I. This gives the 2,3,4,5,6- pentahydroxyhexylamideof4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2-oxo-4-phenylazetidin-1-yl]ben2ylcarbamoyl)phenoxy)benzoic acid (9) of molecular weight 789.89 (C45H47N3O10); MS (ESI): 790.26 (MH). Example IV 1.[4-(4-(1-(4-Fluorophenyl)-3-[3-(4-fluorQphenyl)-3-hydroxypropyll-4-oxoazetldln-2-yl}phenoxymethyl)ben2yl]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (13): 3.0 g of 1-{4-fluorophenyl)-3-[3-(4-fluorophenyS)-3-hydroxypropyl]-4-(4-hydroxyphenyl)- a2etidin-2-one (11) 7.0 g of 1,4-bisbromomethylbenzene and 5.0 g of potassium carbonate are dissolved in 100 ml of dlmethylformamide and stirred at room temperature for 90 min. After the reaction has ended, the mixture is dissolved In ethyl acetate and extracted two times with water. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography (n-heptane/ethyl acetate). Yield 3.2 g of colorless crystals (12) of molecular weight 592.49 (C32H28BrF2N03); MS (ESI): 592.2 (MH). b) 1 -[4-{4-{1 -(4-Fluorophenyl)-3-[3-{4-fluorophenyl)-3-hydroxypropyl]-4- oxoa2etidin~2-yl}phenoxymethyl)benzyl]-4-aza-1-a2onlabicyclo[2.2.2]octane bromide (13): 180 mg of (12) and 300 mg of 1,4-dlazabicyclo[2.2.2]octane (DABCO) are dissolved in 5ml of toluene and stirred at 80°C for 90 min. After the reaction has ended, the mixture is allowed to cool and the colorless solid is filtered off with suction. This gives 195 mg of product (13) of molecular weight 704.66 (C38H4oBrF2N303); MS (ESI): 624.30 (MH). Example VI 1-[2-(4-{1-(4-Fluorophenyl)-3-[3-{4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidln-2-yl}phenoxymethyI)ben2yl]-4-aza-1-a2oniabicyclo[2.2.2]octane bromide (16): b) 1-[4-{4-{1-(4'Fluorophenyl)-3-[3-{4-f]uorophenyl)-3-hydroxypropyl]-4- oxoazetidin-2-yl}phenoxymethyI)benzy!]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (16): (15) and DABCO are dissolved in toluene and reacted analogously to Example IV, giving the product (16) as a colorless solid of molecular weight 704.66 (C38H4oBrF2N303); MS (ESI): 624.30 (MH). Example VII 1-{4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]>4-(4-{2-[(2,3,4.5,6- pentahydroxyhexylamine)methyl]ben2yloxy}phenyl)azetidin-2-one(17): a) 4-[4-(3-Bromomethylbenzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3- hydroxypropyl]a2etidin-2-one (18): b) 1-[3-(4-{1-(4-Fluoropheny!)-3-[3-(4-fiuorophenyl)-3-hydroxypropyI]-4- oxoazetidin-2-yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.21octane bromide (19); (18) and OABCO are dissolved in toluene and reacted analogously to Example IV, giving the product (19) as a colorless solid of molecular weight 704.66 (C38H4DBrF2N303); MS (ESI): 624.30 (MH). (18) and glucamineare dissolved in dimethylformamide and reacted analogously to Example V, giving the product (20) as a colorless solid of molecular weight 692.76 (C38H42F2N208); MS (ESI): 693.5 (MH). Example X 1.[4'.(4-{1-(4-Fluorophenyl)-3-[3-(4-f]uorophenyl)-3-hydroxypropyl]-4-oxoa2etidin-2-yl}phenoxymethyl)biphenyi'4-ylmethyl]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (22): 1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]^-(4-hydroxyphenyl)-azetidin-2-one (11) is reacted with 4,4'-bisbromomethylbiphenyl and potassium carbonate analogously to Example IV, giving a colorless solid (21) of molecular weight 668.54 (C38H32BrF2N03); MS (ESI); 668.1 (MH). b) 1 -I4'-(4-{1 -(4-Fluorophenyl)-3-[3-(4-fIuorophenyl)-3-hydroxypropyI]-4-oxoa2etidin-2-yl}phenoxymethyl)biphenyl-4-yImethyI]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (22): (21) and DABCO are dissolved in toluene and reacted analogously to Example IV, giving the product (22) as a colorless solid of molecular weight 780.76 (C44H44BrF2N303); MS (ESI): 700.3 (MH). Example XII 1.(4-{4-[3-[3-(4_Fluorophenyl)-3-hydroxypropyl]-2-(4-methQxyphenylV4-oxoazetidin-1-yl]-phenoxymethyi}-benzyl)-4-aza-1 -azoniabicyclo[2.2.2]octane bromide (26): 3-[3-(4-Fluorophenyl)-3-hydroxyprDpyl]-1-(4-hyclroxyphenyl)-4-(4-methoxyphenyl)-a2etidin-2-one is reacted with 1,4-bisbromomethylben2ene and potassium carbonate analogously to Example IV, giving a colorless solid (25) of molecular weight 604.52 (C33H3iBrFN04); MS (ESI): 605.2 (MH). c) 1-(4-{4-I3-I3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4'methoxyphenyl)-4- oxoazetidin-1-yl]-phenoxymethyl}-benzyl)-4-aza-1-azoniabicyGlo[2.2.2]octane bromide (26): (25) and DABCO are dissolved in toluene and reacted analogously to Example IV, giving the product (26) as a colorless solid of molecular weight 716.70 (C39H43BrFN304); MS (ESI): 636.3 (MH^). Example XIV 1-[4-{4-{3-[1-(4-Fluorophenyl)-2'{4-methoxyphenyl)-4-oxoazetidin-3-yl]-1-hydroxypropyl}-phenoxymethyl)'benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (30): b) 3-{3-[4-(4-Bromomethylbenzyloxy)-phenyl]-3-hydroxypropyl}-1-{4-fluorophenyl)-4-(4-methoxyphenyl)-azetldin-2-one(29): c) 1-[4-{4-{3-[1-{4-Fluorophenyl)-2-(4-methoxyphenyl)-4-oxoa2etidin-3-yl]-1-hydroxypropyl}-phenoxymethyl)-benzyl]-4-a2a-1-azoniabicyclo[2.2.2]octane bromide (30); (29) and DABCO are dissolved in toluene and reacted analogously to Example IV, giving the product (30) as a colorless solid of molecular weight 716.70 (C39H43BrFN304); MS (ESI): 636.3 (MH). Example XV 1-{4-[(4-{1-{4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetldin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-4-aza"1-azoniablcyclo[2.2.2]octane trifiuoroacetate (35): b) 4-[5-{4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)-pentyl]-benzonitrile(32): Under argon, 2.5 g of 3-[5-{4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one are dissolved in 30 ml of dichloromethane, 3.9 g of 4-[(4-fluorophenylimino)-methyl]-benzonitrile are added and the mixture is cooled to -lOX. 6.4 ml of diisopropyiethylamine and, over a period of 30 min, 4.05 ml of trim ethyls ilyl chloride are added to this mixture so that the temperature does not exceed -S^C. The mixture is stirred at this temperature for 1 additional hour and then cooled to -25'C. 0.8 ml of titanium tetrachloride are then added slov^ly. The dark mixture is stirred at from - 25 to -30°C overnight and then decomposed using 35 ml of a 7 percent strength solution of tartaric acid and then stirred at room temperature for another hour. 15 ml of a 20 percent strength solution of sodium bicarbonate are then added, and the mixture is again stirred for 1 hour. Following phase separation, the organic phase is washed with 30 ml of water, dried over magnesium sulfate and concentrated to about 10 ml. Following the addition of 2 ml of bistrimethylsilylacetamlde, the mixture is heated at reflux for 30 min and then concentrated under reduced pressure. The residue is crystallized using ethyl acetate/heptape. The product is filtered off with suction and dried under reduced pressure. This gives the product of molecular weight 653.81 (C37H37F2N304Si); MS (ESI+): 654.3 (M+H). 582.2 (M+H-Si{CH3)3). c) {1-(4-Fluorophenyl)-3-[3-{4-fluorophenyl)-3-hydroxypropyl]-4-oxoa2etidin-2-yl}-benzonitrile (33): 2 g of 4-[5-(4-Fluorophenyl)-1 -(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyl-oxazotidine-3-carbonyI>-pentyt]-benzonitrile are dissolved in 20 mi of methyMert-butyl ether and, together with 100 mg of tetrabutylammonium fluoride trihydrate and 1.3 ml of bistrimethylsilyl acetamide, heated at 40°C for about 1 h. The reaction is monitored by thin-layer chromatography. After the reaction has ended, 0.2 ml of glacial acetic acid is initially added and the mixture is stirred for 30 min and then concentrated. 20 ml of a mixture of isopropanol/2N sulfuric acid = 10:1 are added to the residue, and the mixture is stirred for 1 hour. Following addition of a spatula tip of solid sodium bicarbonate, the mixture is again concentrated under reduced pressure, the residue is taken up in ethyl acetate and the organic phase is washed with water and dried, and the residue Is, after removal of the solvent, purified by column chromatography (Si02, CHaCymethanol = 100:1). This gives the product of molecular weight 418.45 (C25H2oF2N202); MS {DCI+): 419 (M+H). d) 4-(4-Aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one (34): 100 mg of {1-(4-fluorophenyl)-3'[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-/l}-benzonitrile are dissolved in 20 ml of ethanol and, with 0.5 ml of cone, ammonia, hydrogenated over Raney nickel at a hydrogen pressure of 75 bar and at 25'C for 30 hours. The cataiyst is filtered off with suction, the mixture is concentrated under reduced pressure and the residue is purified by column filtration (Si02, CH2Cl2/methanol/conc. NH3 = 100:10:1). This gives the productof molecular weight 422.5 (C25H22F2N202); MS (DCI+): 423 (M+H), 405 (M+H- H2O). e) 1 -{4-[(4-{1 -(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-4-aza-1-azonia-bicyclo[2.2.2]octane; trifluoroaestate (35): A solution of 70 mg 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyI)-3-hydroxypropyl]-azetidin-2-one, and 23 pi of triethylamine in 0.5 ml of dimethylformamide is added to a solution of 84 mg of 1-(4-carboxymethylbenzyl)-4-aza-1-azoniabicyclo[2.2.2]oetane bromide, 64 pi of diisopropylearbodiimide and 56 mg of hydroxy be nzotriazole in 2 ml of dimethylformamide, and the mixture is stirred at room temperature for 12 h. The reaction solution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C1B, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) = 80/20 -> 10/90). This gives the product of molecular weight 665.81 (cation: C40H43F2N4O3); MS (ESI) 665.33 (M""). Example XVI 1-{4-[(4-{1-(4-Fluorophenyl)-3-t3-(4-f]uorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1-azoniabicyclo[2.2.2]octane trifluoroacetate (37): b) 1-{4-[{4-{1-(4-Fluorophenyl)-3-[3-{4-fluorophenyl)-3-hydroxypropyl]-4-oxoa2etidin-2-yl}-ben2yicarbamoyl)-methyl]-benzyl}-1-azoniabicycloI2.2.2]octane trifluoroacetate (37): The synthesis is carried out analogously to Example XVe) starting with 70 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-flucrophenyl)-3-hydroxypropyl]-azetidin-2-one and 85 mg of 1-{4-carboxymethylbenzyl)-1-azoniabicyclo[2.2.2]octane bromide. This gives the product of molecular weight 664.82 (cation: C4iH44F2N303); MS (ESI) 664.33 (M). Example XVII 1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-{4-fluorophenyl}-3-hydroxypropyl]-4-oxoazetldin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4-dimethylplpera2in-1 -ium trifluoroacetate (39): b) 1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropylH- oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4-dimethyl-piperaztn-1-ium trifluoroacetate (39): The synthesis is carried out analogously to Example XVe) starting with 70 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2~one and 86 mg of 1-(4-carboxymethylbenzyl)-1,4-dimethylpiperazin-1-ium bromide. This gives the product of molecular weight 667.82 (cation: C40H45F2N4O3); MS (ESI) 667.34 (M). Example XVltl 4-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzyloarbamoyI)-methyI]-benzyl}-4-m ethyl mo rphorm-4-ium trifluoroacetate (41): b) 1-{4-[{4-{1-{4-Fluorophenyl)-3-i;3-(4-fluorophenyi)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzyicarbamoyl)-methyl]-benzyl}-1,4,7-trimethyl-[1,4,7]tnazonan-1-ium trifluoroacetate (43): The synthesis is carried out analogously to Example XVe) starting 70 mg of 4-{4- aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]- azetidin-2-one and 200 mg of 1,4,7-trimethyl-1-[4-{2-oxopropyl)-benzyl]- [1,4,7]triazonan-lHum bromide. This gives the product of molecular weight 724.92 (cation: C40H45F2N4O3'); MS (ESI) 724.40 (M). The synthesis is carried out analogously to Example XVe) starting 60 mg of 1-(4-amlnomethylphenyl)-3'(3-hydroxy-3-phenylpropyl)-4-phenylazetidln-2-one (8) and 82 mg of 1-(4-carboxymethylbenzylH-aza-1-a2oniabicyclo[2.2.2]octane bromide. This gives the product of molecular weight 629.83_(cation: C40H45F2N4O3); MS (ESI) 629.35 (M""). Example XXI N-(4_{1,{4-Fluorophenyl)-3-[3-(4-fluorophenyl}-3-hydroxypropyl]-4-oxoazetidin-2-^}- benzyl)'2-{4-[(2,3,4,5,6-pentahydroxyhexylamino)-methyll-phenyl}-acetamideC46): b) N-(4-{1-{4-Fluorophenyl)-3-[3-{4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzyl)-2-(4-{[methyl-(2,3,4,5,6-pentahydroxyhexyl)-a mi no]-methyl}-phenyl)-acetamide (48): The synthesis is carried out analogously to Example XVe) starting 70 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-{4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one and 114 mg of {4-{[methyl-(2,3,4,5,6-pentahydroxyhexyl)-amino]-methyl}-phenyl)-acetic acid. This gives the product of molecular weight 747.84 (C41H47F2N3O8): MS (ESI) 748.35 {M + H). Using the method described below, the activity of the compounds of the formula I according to the invention was examined: Effect on cholesterol absorption + ^H-taurochollc acid excretion using fecal excrement of mice, rats or hamsters NMRI mice, Wistar rats, or Golden Syrian hamsters (in groups of n=4-6) are kept in metabolic cages, where they are fed with a standard diet (Altromin, Lage (Lippe)). The afternoon prior to the administration of the radioactive tracers (^'C-cholesterol), the feed Is removed and the animals are adapted to grates. Additionally, the animals are labeled s.c. with ^H-TCA (taurochollc acid) (for example 1 pCi/mouse up to 5 pCi/rat) 24 hours prior to the peroral administration of the test meal (^'C-cholesterol in Intralipid® 20, Pharmacia-Upjohn). Cholesterol absorption test: 0.25 ml/mouse Intralipid ©20 (Pharmacia-Upjohn) ((spiked with 0.25 pCI of ^"C-cholesterol in 0.1 mg of cholesterol) is administered perorally by gavage. Test substances are prepared separately in 0.5% methylcellulose (Sigma)/5% Solutol (BASF, Ludvi^igshafen) or a suitable vehicle. The administration volume of the test substance is 0.5 ml/mouse. The test substance is administered immediately prior to the test meal (Intralipid labeled with ^'C-cholesterol) (cholesterol absorption test). The feces are collected over a period of 24 h: fecal elimination of ^'C-cholesterol and ^H-taurocholic acid (TCA) is determined after 24 hours. The livers are removed and homogenized, and aliquots are incinerated in an oximate (Model 307, Packard) to determine the amount of """C-cholesterol which had been taken up/absorbed. XV XXIII 0.3 XXV 0.3 XXVI 0.1 XXVII 0.3 XXIX 0.3 XXXI 0.3 XXXVI 0.03 XXXVII 0.1 XXXVIII 0.1 XLI 0.03 XLIII 0.3 XLIV 0.3 XLVI 0.3 XLVIII 0.03 L 0.1 Lll 0.3 UN 0.03 As can be seen from the table, the compounds of the formula I have very good cholesterol-lowering action. Bioabsorption: The bioabsorption of the compounds of the formula I was examined using the Caco cell model (A.R. Hilgers et al., Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa, Pharm. Res. 1990, 7, 902). From the measured data, it can be seen that the bioabsorption of the compounds of the formula 1 according to the invention is considerably lower than that of the compounds described in the prior art (reference structure): WE CLAIM: 1. A compound of the formula I, H, F, CI, Br, I. CF3. NO2, N3, CN, COOH, COO(C1C8)alkyl, CONH2. C0NH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C8)-alkenyl, (LAG)n is selected from a sugar residue, disugar residue, trisugar residue, tetrasugar residue; a sugar acid, an amino sugar; an amino acid residue, an oligopeptide residue comprising 2 to 9 amino acids; 2. A compound of the fomiula I as claimed in claim 1, wherein R2, R4, R5, R6 Independently of one another are selected from S02-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be substituted up to two times by F, CI, Br, OH, CF3, NOj, CN, OCF3,0-(CrCeValkyl, (Ci-Ce)-alkyl, NHj; NHz, NHHCrCeValkyI, N((Ci-C6)-alkyl)2, NH(Ci-C7)-acyl. phenyl, O-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, CI, Br, I, OH. CF3. NO2, CN, OCF3. 0-{CrC6)-alkyI, (Ci-C6)-alkyl. NH2, NH(Ci-C6)-alkyl. N((Ci-C6>allcyl)2. SO2-CH3, COOH, C00-(Ci-C6)-alkyl, GONH2; and where in each case at least one of the radicals R1 or R3 must have the meaning (CrC3o)-alkylene-(LAG), where one or more carbon atoms of the alkylene radical are replaced by up to trisubstituted aryl or heteroaryl radicals or by up to trisubstituted (C3-Cio)-cycloalkyl or heterocycloalkyl radicals and may additionally be replaced by -S(0)n-, Where n = 0 - 2. -0-, -{C=0)-, -N(CH3)-. -N(phenyl)-, -N(CO-(CH2)i-io- COOH)-or-NH-; and its physiologically acceptable salts. 3. A compound of the formula I as claimed in claim 1 or 2, wherein aikylene-(C'=0)o-i-N(R13)o.i-(LAG); where one or more carbon atoms of the alkyiene radicai are replaced by aryl or heteroaryl radicals substituted up to three times by R7, or by {C3-Cio)-cycloalkyl or heterocycloalkyi radicals substituted up to three times by R7 and where one or more carbon atoms of the alkyiene radical may be replaced by oxygen atoms; R7 is selected from F. CI. Br, I, CF3, NO2. N3, CN, COOH, C0O(C1-C6)-alkyl, CONH2. C0NH(C,-C6)-alkyl, CON[(C1C6)-aIkyl]2. (C1-C6)-alkyl. (C2-C6)lkenyl, (C2-C6)-alkynyl, 0-(Ci-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine; PO3H2. SO3H, SO2-NH2, S02NH(Ci-C6)-alkyl. SOzNKCi-CeValkylJz , S-(Ci-C6)-alkyl. S-(CH2)n-phenyl, S0-(Ci-C6)-alkyl, S0-(CH2)n-phenyl, S02-(Ci-C6)-alkyl, S02-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be substituted up to two times by F, CI, Br, OH, CF3, NO2, CN. OCF3, 0-{CrC6)-alkyl, (Ci-Cs^alkyt, NH2; C(NH)(NH2), NH2, NH-(Ci-C6)-alkyl. N{(Ci-C6)-alkyl)2, NH(Ci-C7)-acyl. phenyl, 0-(CH2)n-phenyl, where n - 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, CI, Br. 1, OH, CF3, NO2. CN, OCF3, 0-(C^-C6)alkyl, {C,-C6)-alkyl, NH2. NH(Ci-C6)-alkyl, N({Ci-C6)-alkyl)2, SO2-CH3, COOH, C00-{Ci-C6)-alkyl. CONH2; and where in each case at least one of the radicals R1 or R3 must have the meaning -(CH2)o-i-NH-(C'=0)o.i-(Co-C25)-alMene-(C=0)o.i-N(R13)o-i-(LAG)or-(CH2)o.i-(C=0)o.i-NH-(Co-C25)-allcycloalkyl or heterocycloailtyl radicals and may additionally be replaced by -S(0)n-, where n = 0 - 2, -0-, -(C=0)-, -N(CHa)-. -N(phenyl)-or-NH-; and its physiologically acceptable salts. 4. A compound of the formula I as claimed in one or more of claims 1 to 3, wherein LAG is selected from a monosugar residue, an acyclic mono-, di- or tricyclic trialkylammoniumalkyl radical, a sulfonic add or a carboxyllc acid, and its pharmaceuticaiiy acceptable salts. 5. A medicament comprising one or more compounds as claimed in one or more of claims 1 to 4. 6. The medicament as claimed in claim 5, comprising, further active compound, which are one or more compounds which normalize Hpid metaboHsm. 7. The medicament as claimed in claim 5 or 6, which comprises, as further active compound, one or more antidiabetics, hypoglycemically active compounds, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbers, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, a-glucosidase inhibitors, active compounds which act on the ATP- dependent potassium channel of the beta cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, p3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin-reuptake iiJiibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-p-agonists or amphetamines.

Full Text

Ring-substituted diphenyl azetidinones, method for the production thereof, medicaments containing said compounds, and use thereof
The invention relates to ring-substituted diphenylazetidinones, to their physiologically acceptable salts and to derivatives having physiological functions.
Diphenylazetidinones (such as, for example, ezetimibe) and their use for treating hyperlipidemia and arteriosclerosis and hypercholesterolemia have already been described [cf. Drugs of the Future 2000, 25(7):679-685) and US 5.756,470].
It was an object of the invention to provide further compounds having a therapeutically utilizable hypolipidemic action. In particular, it was an object to find novel compounds v^'hlch, compared to the compounds described in the prior art, are absorbed to a very low extent. Very low absorption is to be understood as meaning an intestinal absorption of less than 10%, preferably less than or equal to 5%.
In particular, absorption of the novel compounds must be less than that of ezetimibe. Pharmaceutically active compounds which are absorbed to a low extent generally have considerably fewer side-effects.

Accordingly, the invention relates to compounds of the formula I

H. F, CI, Br, I, CFs, NOz. N3, CN, COOH. C00(Ci-C6)-alkyl. CONH2. C0NH{Ci-C6)-alkyl, CON[{CrC6)-alkyl]2, {CrC6)-alkyl, (Ca-Ce^alkenyl, (C2-C6)-alkynyl, 0-(CrC6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine;
SO2-NH2, S02NH(Ci-C6)-alkyl, S02N[(Ci-C6)-alkyl]2, S-(Ci-C6)-aIkyl, S-(CH2)n-phenyl, S0-(Ci-C6)-alkyl, S0-(CH2}n-phenyl. S02-{Ci-C6)-alkyl, S02-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be

substituted up to two times by F, CI, Br, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-alkyl. (CrCel-aikyl, NH2;
NH2, NH-(Ci-C6)-alkyi, N((Ci-C6)-aiky!)2, NH{Ci-C7)-acyl, phenyl, O-{CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, CI, Br. I, OH, CF3, NO2, CN, OCF3, 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, NH2, NH(CrC6)'alkyl, N{{Ci-C6)-alkyl)2, SO2-CH3, GOGH, C00-{CrC6)-alkyl, CONH2;
R7 is F, CI, Br. I, CF3, NO2, N3. CN, COOH, C00(Ci-C6)-alkyl, CONH2,
CONHlCi-CeValkyl, CON[(Ci-C6)-alkyl]2, (CrCeV-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, 0-(Ci-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine;
PO3H2. SO3H, SO2-NH2, S02NH(Ci-Ce)-alkyl, S02N[(CrC6)-alkyl]2 , S-(Ci-C6)-alkyl, S-(CH2)n-phenyl, S0-(CrC6)-alkyl, S0-(CH2)n-phenyl. S02-(Ci-C6)-alkyl, S02-(CH2)n'phenyl, where n = 0 - 6 and the phenyl radical may be substituted up to two times by F, CI, Br, OH, CF3, NO2, CN, OCF3, 0-(CrC6)-alky!, (Ci-C6)-alkyl, NH2; C{NH){NH2), NH2, NH-(Ci-C6)-alkyl, N{(Ci-C6)-alkyl)2, NH(CrC7)-acyl, phenyl, 0-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, CI, Br, I, OH, CF3, NO2, CN, OCF3, 0-{Ci-CeValkyl, {Ci-CeValkyl, NH2, NH(Ci-C6)-alkyl, N((Ci-C6)-alkyl)2, SO2-CH3, COOH, C00-(Ci-C6)-aIkyl, CONH2;
(l_AG)n is a sugar residue, disugar residue, trisugar residue, tetrasugar residue;
a sugar acid, an amino sugar;
an amino acid residue, an oligopeptide residue comprising 2 to 9 amino acids;
an acyclic, mono-, di-or tricyclic trialkylammonium radical, an acyclic mono-, di- or tricyclic trialkylammoniumalkyi radical, -0-(S02)-0H; -{CH2)o-io-S03H; -{CH2)o.io-P(0)(OH}2, -(CH2)o-io-0-P(0){OH)2, -{CH2)o-io-COOH, -(CH2)o.io-C(=NH)(NH2): -(CH2)D-IO-C(-NH)(NHOH); -

NR8-C(=NR9)(NR10R11); where n = 1 - 5 and R8, R9, R10 and R11 independently of one another may be H, (Ci-Cel-alkyI, phenyl, (CrCe)-alkyl-phenyl, (C3-C8)-cycloalkyl),
and where In each case at least one of the radicals R1 to R6 must have the meaning {Ci-C3D)-alkylene-(LAG)n, where n = 1 - 5 and one or more carbon atoms of the alkylene radical are replaced by aryl or heteroaryl radicals substituted up to three times by R7, or by (C3-Cio)-cycloalkyl or heterocycloalkyi radicals substituted up to four times by R7 and one or more carbon atoms of the alkylene radical may be replaced by -S(0)n-. where n = 0 - 2, -0-, -(C=0)-, -{C=S)-, -CH=CH-, -CEC-. -N((Ci-C6)-alkyl)-, -N(phenyl)-, -N{(Ci-C6)-alkyl-phenyl)-. -N{CO~(CH2)i-io-COOH)- or -NH-; and their physiologically acceptable salts.
Preference is given to compounds of the formula I where at least one of the radicals R1 to R6 the meaning (Ci-C3o)-alkylene-(LAG)n, where n = 1 - 5 and one or more carbon atoms of the alkylene radical are replaced by aryl or heteroaryl radicals substituted up to three times by R7, or by {C3-Cio)-cycloalkyl or heterocycloalkyi radicals substituted up to four times by R7 and one or more carbon atoms of the alkylene radical may be replaced by -S(0)n-, where n = 0 - 2, -0-, -(C=0)-, -(C=S)-, -CH=CH-. -CHC-. -N{(CrC6)-alkyi)-, -N(phenyl)-. -N((Ci-C6)-alkyl-phenyl}-, -N(CO-(CH2)i.io-COOH)-or-NH-.
Particular preference is given to compounds of the formula I where one of the radicals R1 or R3 the meaning (Ci-C3o)-alkylene-(l-AG), where one or more carbon atoms of the alkylene radical are replaced by aryl or heteroaryl radicals substituted up to three times by R7, or by (C3-Cio)-cycloalkyl or heterocycloalkyi radicals substituted up to three times by R7 and one or more carbon atoms of the alkylene radical may be replaced by -S(0)n-, where n = 0 - 2, -0-, -(C=0)-, -NCCHa)-, -N{phenyl)-, -N(CO-(CH2)i.io-COOH)- or -NH-.

A mono- or dicyclic trialkylammoniumalkyi radical is to be understood as meaning, for example, radicals such as

purposes, very particular preference is given to using the chloride salt. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
The scope of the invention also includes salts having a pharmaceutically unacceptable anion, which salts may be useful intermediates for preparing or purifying pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.
Here, the term "derivative having physiological function" refers to any physiologically acceptable derivative of a compound according to the Invention, for example an ester, that Is able, upon administration to a mammal, for example man, to form such a compound or an active metabolite (directly or indirectly).
A further aspect of this invention are prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to give a compound according to the invention. These prodrugs may or may not be active in their own right.
The compounds according to the invention can also be present in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. The scope of the invention includes all polymorphous forms of the compounds according to the invention, which form a further aspect of the invention.
Hereinbelow, all references to "compound(s) of the formula (I)" refer to a compound or compounds of the formula {1} as described above, and to their salts, solvates and derivatives having physiological function, as described herein.
The compounds of the formula I and their pharmaceutically acceptable salts and derivatives having physiological function are Ideal medicaments for treating an impaired lipid metabolism, in particular hyperiipidemia. The compounds of the

formula I are also suitable for modulating the serum cholesterol concentration and for preventing and treating arteriosclerotic manifestations.
The compound(s) of the formula (I) can also be administered in combination with other active compounds.
The amount of a compound of the formula (I) required to achieve the desired biological effect depends on a number of factors, for example on the specific compound chosen, on the intended use, on the mode of administration and on the clinical condition of the patient. In general, the daily dose is in the range from 0.1 mg to 100 mg (typically from 0.1 mg to 50 mg) per day per kilogram of bodyweight, for example 0.1-10 mg/kg/day. Tablets or capsules may contain, for example, from 0.01 to 100 mg, typically from 0.02 to 50 mg. In the case of pharmaceutically acceptable salts, the abovementioned weight data relate to the weight of the diphenyl-azetidlnone-ion derived from the salt. For the prophylaxis or therapy of the abovementioned conditions, the compounds of the formula (I) can be used themselves as the compound, but preferably they are present in the form of a pharmaceutical composition with an acceptable carrier. The carrier must of course be acceptable in the sense that it is compatible with the other constituents of the composition and Is not harmful to the health of the patient. The can-ier can be a solid or a liquid or both and is preferably formulated with the compound as an individual dose, for example as a tablet, which can contain from 0.05% to 95% by weight of the active compound. Further pharmaceutically active substances can also be present, including further compounds of the formula (I). The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consist in mixing the constituents with pharmacologically acceptable carriers and/or auxiliaries.
Pharmaceutical compositions according to the invention are those which are suitable for oral or peroral (e.g. sublingual) administration, although the most suitable manner of administration is dependent in each individual case on the nature and severity of

the condition to be treated and on the type of the compound of the formula (1) used in each case. Coated formulations and coated delayed-release formulations are also included in the scope of the invention. Acid-resistant and enteric formulations are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyimethylcelluiose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Suitable pharmaceutical compounds for oral administration can be present in separate units, such as, for example, capsules, cachets, lozenges or tablets, which in each case contain a specific amount of the compound of the formula (1); as a powder or granules; as a solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions can be prepared according to any suitable pharmaceutical method which includes a step in which the active compound and the carrier (which can consist of one or more additional constituents) are brought into contact. In general, the compositions are prepared by uniform and homogeneous mixing of the active compound with a liquid and/or finely divided solid carrier, after which the product, if necessary, is shaped. For example, a tablet can thus be prepared by pressing or shaping a powder or granules of the compound, if appropriate with one or more additional constituents. Pressed tablets can be produced by tableting the compound in free-flowing form, such as, for example, a powder or granules, if appropriate mixed with a binder, lubricant, inert diluent and/or a (number of) surface-active/ dispersing agent(s) in a suitable machine. Shaped tablets can be produced by shaping the pulverulent compound moistened with an inert liquid diluent in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual) administration include lozenges which contain a compound of the formula (!) with a flavoring, customarily sucrose and gum arable or tragacanth, and pastilles which include the compound in an inert base such as gelatin and glycerol or sucrose and gum arable.

exampie, ezetimibe, llqueside, pamaqueside.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR gamma agonist, such as, for example, rosiglitazone, pioglitazone, JTT-501, Gl 262570.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR aipha agonist, such as, for exampie, GW 9578, GW 7647.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR aipha/gamma agonist, such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate, such as, for example, fenofibrate, clofibrate, bezafibrate.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor, such as, for example. Bay 13-9952, BMS-201038, R-103757.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a bile acid absorption inhibitor, such as, for example, HMR 1453.
In one embodiment of the invention, the compounds of the formula 1 are administered in combination with a CETP inhibitor, such as, for example. Bay 194789.
In one embodiment of the invention, the compounds of the formula I are

administered in combination with a polymeric bile acid adsorber, such as, for example, cholestyramine, colesolvam.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer, such as, for example, HMR1171,HMR1586.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, such as, for example, avasimibe.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant, such as, for example, OPC-14117.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor, such as, for example, NO-1886.
In one embodiment of the invention, the compounds of the formula 1 are administered in combination with an ATP citrate lyase inhibitor, such as, for example, SB-204990.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor, such as, for example, BMS-188494.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist, such as, for example, Cl-1027 or nicotinic acid.
In one embodiment of the invention, the compounds of the formula I are
REPLACEMENT SHEET (RULE 26)

administered in combination with a lipase Inhibitor, such as, for example, Orlistat.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with Insulin.
In one embodiment, the compounds of the formula I are administered in combination
with a sulfonylurea, such as, for example, tolbutamide, glibenclamide, glipizide or
gliclazide.
In one embodiment, the compounds of the formula I are administered in combination
with a biguanide, such as, for example, metformin.
In another embodiment, the compounds of the formula I are administered in
combination with a meglitinide, such as, for example, repaglinide.
In one embodiment, the compounds of the formula I are administered in combination
with a thiazolidinedione, such as, for example, troglitazone, ciglltazone, pioglitazone,
rosiglitazone, or the compounds disclosed by Dr. Reddy's Research Foundation in
WO 97/41097, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinyt-
methoxy]phenyl]methyl]-2,4-thiazolidinedione.
In one embodiment, the compounds of the formula 1 are administered in combination
with an a-glucosldase inhibitor, such as, for example, miglitoi or acarbose.
In one embodiment, the compounds of the formula I are administered in combination
with an active compound which acts on the ATP-dependent potassium channel of
beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, gliazide or
repaglinide.
In one embodiment, the compounds of the formula I are administered in combinatton
with more than one of the abovementloned compounds, for example in combination
with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and
metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazon,
insulin and lovastatln, etc.
In a further embodiment, the compounds of the formula I are administered In combination with CART agonists, NPY agonists, MC3 and MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin

agonists, p3-agonists, MCH (melanine-concentrating hormone) antagonists, CCK agonists, serotonin reuptal^e inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, doprexin), lipase/amylase Inhibitors, PPAR modulators, RXR modulators or TR-p agonists.
In one embodiment of the invention, the further active compound is leptin.
In one embodiment, tlie further active compound Is dexamphetamlne or
amphetamine.
In one embodiment, the further active compound Is fenfluramine or dexfenfluramine.
In another embodiment, the further active compound is sibutramine.
In one embodiment, the further active compound is Orlistat.
In one embodiment, the further active compound is mazindol or phentermine.
In one embodiment, the compounds of the formula I are administered in combination with fiber, preferably insoluble fiber, such as, for example, Caromax®. The combination with Caromax® can be given in one preparation or by separate administration of compounds of the formula I and Caromax®. Here, Caromax® can also be administered in the form of food, such as, for example, in bakery goods or muesli bars. Compared to the individual active compounds, the combination of compounds of the formula I with Caromax® is, in addition to an enhanced action, in particular with respect to the lowering of LDL cholesterol, also characterized by its improved tolerability.
It goes without saying that each suitable combination of the compounds according to the invention with one or more of the compounds mentioned above and optionally one or more further pharmacologically active substances is included in the scope of the present invention.
The invention furthermore provides both stereoisomer mixtures of the formula I and

the pure stereoisomers of the formula I, and diastereomer mixtures of the formula I and the pure diastereomers. The mixtures are separated by chromatographic means.

If the sugar is substituted, the substitution is preferably at the hydrogen atom of an OH group of the sugar.

Suitable protective groups for the hydroxyl groups of the sugars are substantially: benzyl, acetyl, benzoyl, pivaloyl, trityl, tert-butyldimethylsilyl, benzyiidene, cyclohexylidene or isopropylidene protective groups.
The term "amino acids" or "amino acid residues" refers, for example, to the stereoisomeric forms, i.e. the D or L fonns, of the following compounds:

alanine glycine proline
cysteine histidine glutamine
aspartic acid isoleucine arginine
glutamic acid lysine serine
phenylalanine leucine threonine
tryptophan methionine valine
tyrosine asparagine
2-aminoadipic acid 2-aminoisobutyric acid
3-aminoadipic acid 3-aminolsobutyric acid
beta-alanine 2-aminoplmelic acid
2-aminobutyric acid 2,4-diaminobutyric acid
4-aminobutyric acid desmosine
piperidine carboxylic acid 2,2-diaminopimelic acid
6-aminocaproic acid 2,3-diaminopropionic acid
2-aminoheptanoic acid N-ethylglycine
2-(2-thienyl)glycine 3-(2~thienyl)alanine
penicillamine sarcosine
N-ethylasparagine N-methylisoleucine
hydroxylysine 6~N-methyllysine
allo-hydroxylysine N-m ethyl valine
3-hydroxyproline norvaline
4-hydroxyproline norleucine

isodesmosine ornithine
allo-isoleucine
N-methy [glycine
For abbreviating the amino acids, the conventional notation was used (cf. Schroder, Lubke, The Peptides, Volume I. New York 1965, pages XXIt-XXIII; Houben-Weyl. Methoden der Organischen Chemie [Methods of organic chemistry]. Volume XV/1 and 2, Stuttgart 1974). The amino acid pGlu denotes pyroglutamyl, Nal denotes 3-{2-naphthyl)alanine, azagly-NH2 denotes a compound of the formula NH2-NH-CONH2 and D-Asp denotes the D form of aspartic acid. According to their chemical nature, peptides are acid amides, and on hydrolysis they decompose into amino acids.
An oligopeptide is to be understood as meaning a peptide constructed of 2 to 9 of the amino acids mentioned above.
Suitable protective groups (see, for example. T.W. Greene, "Protective Groups in Organic Synthesis") for amino acids are primarily:
Arg{Tos), Arg(Mts), Arg(Mtr), Arg(PMV). Asp{OBzl), Asp{OBut), Cys(4-MeBzl). Cys(Acm), Cys(SBut), Glu(0b2l), Glu(Obut), His(Tos). H!S(Fmoc), His{Dnp), His(Trt), Lys(CI-Z), Lys(Boc), Met(O), Ser(Bzl), Ser(But), Thr(Bzl), Thr(But), Trp(Mts). Trp(CHO), Tyr{Br-Z), Tyr{Bzl) orTyr(But).
Amino protective groups that are preferably used are the benzyloxycarbonyl (Z) radical, which can be removed by catalytic hydrogenation, the 2-(3,5-dimethyloxyphenyl)propyl(2)oxycarbonyl(Ddz) or trityl (Trt) radical, which can be removed by weak acids, the t-butylcarbamate (BOC) radical, which can be removed by 3M hydrochloric acid, and the 9-fluorenylmethyloxycarbonyl (Fmoc) radical, which can be removed using secondary amines.

Tho invention furthermore relates to a process for preparing dlplienylazetidinone derivatives of formula I.

The process for preparing compounds of the formula I comprises, for example, reacting an amine of the formula II with an alkylating or acylating agent which, preferably in the omega position, carries a further functionality- if appropriate in protected form. This functionality is (after deprotection) used for attaching (LAG), for example with the formation of ether, amine or amide bonds.

The examples below serve to illustrate the invention in more detail, without limiting the invention to the products and embodiments described in the examples.

27 g of 3-[5-{4-f]uorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolldin-2-one, 13.6 g of tert-butyldimethylsilyl chloride and 10.2 g of imidazole are dissolved in 36 ml of dimethylformamide and stirred at eCC for 90 min. After the reaction has ended, the mixture is dissolved in ethyl acetate and extracted two times with water. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gives 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyloxazolidin-2-one (1) of molecular weight 471.65 (C26H34FN04Si); MS (ESI): 340.28 (MH*- HOSi(CH3)2C(CH3)3).

b) 4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-{2-0X0-4-phenyloxa2olidine-3-carbonyl)pentylamlno]benzonitrile (2):
16.2 g of 3-[5-(tert-butyldlmethylsllanyloxy)-5-{4-f]uorophenyl)-pentanoyl]-4-phenyloxa2olidin-2-one(1) are dissolved in 350 ml of dichloromethane. 19.8 ml of Hunig base and 10.14 g of 4-[(4-methoxyphenylimlno)methyl]benzonitrile are added, and the solution is cooled to -10°C. 8.52 ml of trimethylsilyl triflate are added to the cooled solution, and the mixture is stirred at-10°C for 30 min. The solution is then cooled to -30°C, and 44 ml of titanium tetrachloride solution are added. The reaction mixture is stirred at from -30 to -40°C for 2 h. The solution is then allowed to warm to room temperature and the reaction solution Is washed successively with 200 ml of 2N sulfuric acid, 300 ml of 20% strength sodium hydrogen sulfite solution and sat. sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure, and the residue is purified on silica gel using n-heptane/ethyl acetate 3/1. This gives 4-[5-(tert-butyldlmethylsilanyloxy)-5-{4-fluorophenyl)-1-{4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamino]benzonltrile (2) of molecular weight 707.93 (CAiHAeFNaOsSi); MS (ESI); 590.51 (MH* - C7H5N2).
c) 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-{4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1 -yllbenzonitrile (3)".
13.2gof4-[5-(tert-butyIdimethylsllany!Qxy)-5-(4-fluorophenyl)-1-{4-methoxyphenyl)-2-(2-oxo-4-phenyloxa2olidlne-3-carbonyl)pentylamino]benzonitrile (2) are dissolved In 380 ml of methyl tert-butylether, 18.6 ml of N,0-bls(trlmethylsilyl)acetamide and 1.86 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added and the mixture is stirred at room temperature for 2 h. After the reaction has ended, 10 ml of acetic add are added, the reaction mixture Is concentrated under reduced pressure and the residue is purified on silica gel using toluene/ethyl acetate 50/1. This gives 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyi]-2-(4-

methoxyphenyl)-4-oxoazetidln-1-yl]-ben2onitrlle (3) of molecular weight 544.75 (CazHsTFNzOaSi); MS (ESI): 545.56 (M+H"").
d) 4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoa2etidin-1-yl]-benzonitrile{4):
3.5 g of 4-[3-[3-{tert-butyldimethylsllanyloxy)-3-(4-fluorophenyl)propy(]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yll-ben2onitrile (3) are dissolved in 65 ml of tetrahydrofuran, 0.74 ml of acetic add and 8.03 ml of a 1 M solution of tetrabutylammonium fluoride In tetrahydrofuran are added and the mixture is stirred at room temperature for 2 h. Another 4.82 ml of the tetrabutylammonium fluoride solution are then added, and the mixture is stirred at reflux temperature for another 3 h. The cooled reaction mixture is concentrated under reduced pressure and the residue is purified by silica gel chromatography using n-heptane/ethyl acetate 2/1. This gives 4-[3-[3-{4-fluorophenyl)-3-hydroxypropyl]-2-{4-methoxyphenyl)-4-oxoazetidln-l-ylj-benzonitrlle (4) of molecular weight 430.48 {C26H23FN2O3); MS (ESiy.431.24(M+H*).
e) 1-(4-Aminomethylphenyl)-3-[3-{4'fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one (5):
1.22 g of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yll-benzonitrile (4) are dissolved in 90 ml of ethanol, 10 ml of cone, ammonia solution and an excess of Raney nickel are added, and the mixture is stirred at 60°C and a hydrogen pressure of 10 bar for 8 h. Overnight, the reaction mixture cools to room temperature, and the next day, the catalyst is removed, the filtrate Is concentrated under reduced pressure and the residue Is purified by silica gel chromatography using dichioromethane/methanol/ammonla solution 10/1/0.1. This gives 1-(4-amlnomethylphenyl)-3-[3-{4-fluorophenyl)-3-hydroxypropyl]-4-(4-

methoxyphenyI)-a2etidin-2-one (5) of molecular weight 434.51 (C26H27FN2O3); MS (ESI): 418.2 (MH^-NHa).
f) 2,3,4,5,6-Pentahydroxyhexylamide of 4,4'-oxybisbenzoic acid (6):
At room temperature, 0.52 g of 4,4'-oxybisbenzoic acid and 0.36 g of D-glucamine are suspended in 10 ml of dry dimethylformamide, 0.31 g of HOBt and 0.39 g of EDC are added and the mixture is stirred at room temperature for 12 h. The reaction mixture is evaporated to dryness and dried under high vacuum. The residue is thoroughly titrated with water, the resulting suspension is filtered and the residue is titrated with methanol and filtered again. The filtrate is concentrated to half of its volume using a rotary evaporator, and the solution is cooled in an ice bath. The resulting precipitate is filtered off with suction, washed with a little ice-cooled methanol and dried under reduced pressure. This gives the 2,3,4,5,6-pentahydroxyhexylamide of 4,4'-oxybisbenzoic acid (6) of molecular weight 421.40 (C2oH23NOg); MS (ESI): 422.28 (MH*).
g) 2,3,4,5,6-Pentahydroxyhexylamide of 4-(4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoic acid (7):
87 mg of the compound prepared under e) and 90 mg of the compound prepared under f) are, at room temperature, dissolved in 3 ml of dry dimethylformamide, 31 mg of HOBt and 39 mg of EDC are added and the mixture is stirred at nDom temperature for 12 h. The reaction mixture is evaporated to dryness under high vacuum and the residue is titrated with dichloromethane, filtered off with suction, washed with dichloromethane and dried under reduced pressure. This gives the 2,3,4.5,6-Dentahvdroxvhexvlamide of 4-M-M-r3-r:^-^4-fii inrnnhpn\/h-'^_h\*Hrnvwnrnm/n.

2-(4-methoxyphenyl)-4-oxoa2etidin-1 -yl]benzylcarbamoyl}phenoxy)benzoic acid (7) with & molecular weight 837.90 (C46H48FN3O11); MS (ESI): 838,39 (MH*).

b) 2,3,4,5,6-Pentahydroxyhexylamide of 4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2-oxo-4-phenylazetidin-1-yllbenzylcarbamoyl}phenoxy)benzoicacid(9):
The benzylamine from lla is reacted with the 2,3,4,5,6-pentahydroxyhexylamide of 4,4'-oxybisbenzoic acid from If as described in Example I. This gives the 2,3,4,5,6-

pentahydroxyhexylamideof4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2-oxo-4-phenylazetidin-1-yl]ben2ylcarbamoyl)phenoxy)benzoic acid (9) of molecular weight 789.89 (C45H47N3O10); MS (ESI): 790.26 (MH*).

Example IV
1.[4-(4-(1-(4-Fluorophenyl)-3-[3-(4-fluorQphenyl)-3-hydroxypropyll-4-oxoazetldln-2-yl}phenoxymethyl)ben2yl]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (13):

3.0 g of 1-{4-fluorophenyl)-3-[3-(4-fluorophenyS)-3-hydroxypropyl]-4-(4-hydroxyphenyl)- a2etidin-2-one (11) 7.0 g of 1,4-bisbromomethylbenzene and 5.0 g of potassium carbonate are dissolved in 100 ml of dlmethylformamide and stirred at room temperature for 90 min. After the reaction has ended, the mixture is dissolved In ethyl acetate and extracted two times with water. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography (n-heptane/ethyl acetate). Yield 3.2 g of colorless crystals (12) of molecular weight 592.49 (C32H28BrF2N03); MS (ESI): 592.2 (MH*).
b) 1 -[4-{4-{1 -(4-Fluorophenyl)-3-[3-{4-fluorophenyl)-3-hydroxypropyl]-4-
oxoa2etidin~2-yl}phenoxymethyl)benzyl]-4-aza-1-a2onlabicyclo[2.2.2]octane bromide (13):
180 mg of (12) and 300 mg of 1,4-dlazabicyclo[2.2.2]octane (DABCO) are dissolved in 5ml of toluene and stirred at 80°C for 90 min. After the reaction has ended, the mixture is allowed to cool and the colorless solid is filtered off with suction. This gives

195 mg of product (13) of molecular weight 704.66 (C38H4oBrF2N303); MS (ESI): 624.30 (MH*).

Example VI
1-[2-(4-{1-(4-Fluorophenyl)-3-[3-{4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidln-2-yl}phenoxymethyI)ben2yl]-4-aza-1-a2oniabicyclo[2.2.2]octane bromide (16):

b) 1-[4-{4-{1-(4'Fluorophenyl)-3-[3-{4-f]uorophenyl)-3-hydroxypropyl]-4-
oxoazetidin-2-yl}phenoxymethyI)benzy!]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (16):
(15) and DABCO are dissolved in toluene and reacted analogously to Example IV, giving the product (16) as a colorless solid of molecular weight 704.66 (C38H4oBrF2N303); MS (ESI): 624.30 (MH*).

Example VII
1-{4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]>4-(4-{2-[(2,3,4.5,6-
pentahydroxyhexylamine)methyl]ben2yloxy}phenyl)azetidin-2-one(17):

a) 4-[4-(3-Bromomethylbenzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3- hydroxypropyl]a2etidin-2-one (18):

b) 1-[3-(4-{1-(4-Fluoropheny!)-3-[3-(4-fiuorophenyl)-3-hydroxypropyI]-4-
oxoazetidin-2-yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.21octane bromide (19);
(18) and OABCO are dissolved in toluene and reacted analogously to Example IV, giving the product (19) as a colorless solid of molecular weight 704.66 (C38H4DBrF2N303); MS (ESI): 624.30 (MH*).

(18) and glucamineare dissolved in dimethylformamide and reacted analogously to Example V, giving the product (20) as a colorless solid of molecular weight 692.76 (C38H42F2N208); MS (ESI): 693.5 (MH*).
Example X
1.[4'.(4-{1-(4-Fluorophenyl)-3-[3-(4-f]uorophenyl)-3-hydroxypropyl]-4-oxoa2etidin-2-yl}phenoxymethyl)biphenyi'4-ylmethyl]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (22):

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]^-(4-hydroxyphenyl)-azetidin-2-one (11) is reacted with 4,4'-bisbromomethylbiphenyl and potassium carbonate analogously to Example IV, giving a colorless solid (21) of molecular weight 668.54 (C38H32BrF2N03); MS (ESI); 668.1 (MH*).

b) 1 -I4'-(4-{1 -(4-Fluorophenyl)-3-[3-(4-fIuorophenyl)-3-hydroxypropyI]-4-oxoa2etidin-2-yl}phenoxymethyl)biphenyl-4-yImethyI]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (22):
(21) and DABCO are dissolved in toluene and reacted analogously to Example IV, giving the product (22) as a colorless solid of molecular weight 780.76 (C44H44BrF2N303); MS (ESI): 700.3 (MH*).

Example XII
1.(4-{4-[3-[3-(4_Fluorophenyl)-3-hydroxypropyl]-2-(4-methQxyphenylV4-oxoazetidin-1-yl]-phenoxymethyi}-benzyl)-4-aza-1 -azoniabicyclo[2.2.2]octane bromide (26):

3-[3-(4-Fluorophenyl)-3-hydroxyprDpyl]-1-(4-hyclroxyphenyl)-4-(4-methoxyphenyl)-a2etidin-2-one is reacted with 1,4-bisbromomethylben2ene and potassium carbonate analogously to Example IV, giving a colorless solid (25) of molecular weight 604.52 (C33H3iBrFN04); MS (ESI): 605.2 (MH*).
c) 1-(4-{4-I3-I3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4'methoxyphenyl)-4-
oxoazetidin-1-yl]-phenoxymethyl}-benzyl)-4-aza-1-azoniabicyGlo[2.2.2]octane bromide (26):
(25) and DABCO are dissolved in toluene and reacted analogously to Example IV, giving the product (26) as a colorless solid of molecular weight 716.70 (C39H43BrFN304); MS (ESI): 636.3 (MH^).

Example XIV
1-[4-{4-{3-[1-(4-Fluorophenyl)-2'{4-methoxyphenyl)-4-oxoazetidin-3-yl]-1-hydroxypropyl}-phenoxymethyl)'benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (30):

b) 3-{3-[4-(4-Bromomethylbenzyloxy)-phenyl]-3-hydroxypropyl}-1-{4-fluorophenyl)-4-(4-methoxyphenyl)-azetldin-2-one(29):

c) 1-[4-{4-{3-[1-{4-Fluorophenyl)-2-(4-methoxyphenyl)-4-oxoa2etidin-3-yl]-1-hydroxypropyl}-phenoxymethyl)-benzyl]-4-a2a-1-azoniabicyclo[2.2.2]octane bromide (30);
(29) and DABCO are dissolved in toluene and reacted analogously to Example IV, giving the product (30) as a colorless solid of molecular weight 716.70 (C39H43BrFN304); MS (ESI): 636.3 (MH*).
Example XV
1-{4-[(4-{1-{4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetldin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-4-aza"1-azoniablcyclo[2.2.2]octane trifiuoroacetate (35):

b) 4-[5-{4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)-pentyl]-benzonitrile(32):
Under argon, 2.5 g of 3-[5-{4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one are dissolved in 30 ml of dichloromethane, 3.9 g of 4-[(4-fluorophenylimino)-methyl]-benzonitrile are added and the mixture is cooled to -lOX. 6.4 ml of diisopropyiethylamine and, over a period of 30 min, 4.05 ml of trim ethyls ilyl chloride are added to this mixture so that the temperature does not exceed -S^C. The mixture is stirred at this temperature for 1 additional hour and then cooled to -25'C. 0.8 ml of titanium tetrachloride are then added slov^ly. The dark mixture is stirred at from - 25 to -30°C overnight and then decomposed using 35 ml of a 7 percent strength solution of tartaric acid and then stirred at room temperature for another hour. 15 ml of a 20 percent strength solution of sodium bicarbonate are then added,

and the mixture is again stirred for 1 hour. Following phase separation, the organic phase is washed with 30 ml of water, dried over magnesium sulfate and concentrated to about 10 ml. Following the addition of 2 ml of bistrimethylsilylacetamlde, the mixture is heated at reflux for 30 min and then concentrated under reduced pressure. The residue is crystallized using ethyl acetate/heptape. The product is filtered off with suction and dried under reduced pressure. This gives the product of molecular weight 653.81 (C37H37F2N304Si); MS (ESI+): 654.3 (M+H*). 582.2 (M+H*-Si{CH3)3).
c) {1-(4-Fluorophenyl)-3-[3-{4-fluorophenyl)-3-hydroxypropyl]-4-oxoa2etidin-2-yl}-benzonitrile (33):
2 g of 4-[5-(4-Fluorophenyl)-1 -(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyl-oxazotidine-3-carbonyI>-pentyt]-benzonitrile are dissolved in 20 mi of methyMert-butyl ether and, together with 100 mg of tetrabutylammonium fluoride trihydrate and 1.3 ml of bistrimethylsilyl acetamide, heated at 40°C for about 1 h. The reaction is monitored by thin-layer chromatography. After the reaction has ended, 0.2 ml of glacial acetic acid is initially added and the mixture is stirred for 30 min and then concentrated. 20 ml of a mixture of isopropanol/2N sulfuric acid = 10:1 are added to the residue, and the mixture is stirred for 1 hour. Following addition of a spatula tip of solid sodium bicarbonate, the mixture is again concentrated under reduced pressure, the residue is taken up in ethyl acetate and the organic phase is washed with water and dried, and the residue Is, after removal of the solvent, purified by column chromatography (Si02, CHaCymethanol = 100:1). This gives the product of molecular weight 418.45 (C25H2oF2N202); MS {DCI+): 419 (M+H*).
d) 4-(4-Aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one (34):

100 mg of {1-(4-fluorophenyl)-3'[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-/l}-benzonitrile are dissolved in 20 ml of ethanol and, with 0.5 ml of cone, ammonia, hydrogenated over Raney nickel at a hydrogen pressure of 75 bar and at 25'C for 30 hours. The cataiyst is filtered off with suction, the mixture is concentrated under reduced pressure and the residue is purified by column filtration (Si02, CH2Cl2/methanol/conc. NH3 = 100:10:1). This gives the productof molecular weight 422.5 (C25H22F2N202); MS (DCI+): 423 (M+H*), 405 (M+H*- H2O).
e) 1 -{4-[(4-{1 -(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-4-aza-1-azonia-bicyclo[2.2.2]octane; trifluoroaestate (35):
A solution of 70 mg 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyI)-3-hydroxypropyl]-azetidin-2-one, and 23 pi of triethylamine in 0.5 ml of dimethylformamide is added to a solution of 84 mg of 1-(4-carboxymethylbenzyl)-4-aza-1-azoniabicyclo[2.2.2]oetane bromide, 64 pi of diisopropylearbodiimide and 56 mg of hydroxy be nzotriazole in 2 ml of dimethylformamide, and the mixture is stirred at room temperature for 12 h. The reaction solution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C1B, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) = 80/20 -> 10/90). This gives the product of molecular weight 665.81 (cation: C40H43F2N4O3); MS (ESI) 665.33 (M"").
Example XVI
1-{4-[(4-{1-(4-Fluorophenyl)-3-t3-(4-f]uorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1-azoniabicyclo[2.2.2]octane trifluoroacetate (37):

b) 1-{4-[{4-{1-(4-Fluorophenyl)-3-[3-{4-fluorophenyl)-3-hydroxypropyl]-4-oxoa2etidin-2-yl}-ben2yicarbamoyl)-methyl]-benzyl}-1-azoniabicycloI2.2.2]octane trifluoroacetate (37):
The synthesis is carried out analogously to Example XVe) starting with 70 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-flucrophenyl)-3-hydroxypropyl]-azetidin-2-one and 85 mg of 1-{4-carboxymethylbenzyl)-1-azoniabicyclo[2.2.2]octane bromide. This gives the product of molecular weight 664.82 (cation: C4iH44F2N303*); MS (ESI) 664.33 (M*).
Example XVII
1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-{4-fluorophenyl}-3-hydroxypropyl]-4-oxoazetldin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4-dimethylplpera2in-1 -ium trifluoroacetate (39):

b) 1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropylH-
oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4-dimethyl-piperaztn-1-ium trifluoroacetate (39):
The synthesis is carried out analogously to Example XVe) starting with 70 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2~one and 86 mg of 1-(4-carboxymethylbenzyl)-1,4-dimethylpiperazin-1-ium bromide. This gives the product of molecular weight 667.82 (cation: C40H45F2N4O3*); MS (ESI) 667.34 (M*).
Example XVltl
4-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzyloarbamoyI)-methyI]-benzyl}-4-m ethyl mo rphorm-4-ium trifluoroacetate (41):

b) 1-{4-[{4-{1-{4-Fluorophenyl)-3-i;3-(4-fluorophenyi)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzyicarbamoyl)-methyl]-benzyl}-1,4,7-trimethyl-[1,4,7]tnazonan-1-ium trifluoroacetate (43):
The synthesis is carried out analogously to Example XVe) starting 70 mg of 4-{4-
aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-
azetidin-2-one and 200 mg of 1,4,7-trimethyl-1-[4-{2-oxopropyl)-benzyl]-
[1,4,7]triazonan-lHum bromide. This gives the product of molecular weight 724.92
(cation: C40H45F2N4O3'); MS (ESI) 724.40 (M*).

The synthesis is carried out analogously to Example XVe) starting 60 mg of 1-(4-amlnomethylphenyl)-3'(3-hydroxy-3-phenylpropyl)-4-phenylazetidln-2-one (8) and 82 mg of 1-(4-carboxymethylbenzylH-aza-1-a2oniabicyclo[2.2.2]octane bromide. This gives the product of molecular weight 629.83_(cation: C40H45F2N4O3*); MS (ESI) 629.35 (M"").
Example XXI
N-(4_{1,{4-Fluorophenyl)-3-[3-(4-fluorophenyl}-3-hydroxypropyl]-4-oxoazetidin-2-^}-
benzyl)'2-{4-[(2,3,4,5,6-pentahydroxyhexylamino)-methyll-phenyl}-acetamideC46):

b) N-(4-{1-{4-Fluorophenyl)-3-[3-{4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzyl)-2-(4-{[methyl-(2,3,4,5,6-pentahydroxyhexyl)-a mi no]-methyl}-phenyl)-acetamide (48):
The synthesis is carried out analogously to Example XVe) starting 70 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-{4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one and 114 mg of {4-{[methyl-(2,3,4,5,6-pentahydroxyhexyl)-amino]-methyl}-phenyl)-acetic acid. This gives the product of molecular weight 747.84 (C41H47F2N3O8*): MS (ESI) 748.35 {M + H*).

Using the method described below, the activity of the compounds of the formula I according to the invention was examined:
Effect on cholesterol absorption + ^H-taurochollc acid excretion using fecal excrement of mice, rats or hamsters
NMRI mice, Wistar rats, or Golden Syrian hamsters (in groups of n=4-6) are kept in metabolic cages, where they are fed with a standard diet (Altromin, Lage (Lippe)). The afternoon prior to the administration of the radioactive tracers (^'*C-cholesterol), the feed Is removed and the animals are adapted to grates.
Additionally, the animals are labeled s.c. with ^H-TCA (taurochollc acid) (for example 1 pCi/mouse up to 5 pCi/rat) 24 hours prior to the peroral administration of the test meal (^'C-cholesterol in Intralipid® 20, Pharmacia-Upjohn).
Cholesterol absorption test: 0.25 ml/mouse Intralipid ©20 (Pharmacia-Upjohn) ((spiked with 0.25 pCI of ^"C-cholesterol in 0.1 mg of cholesterol) is administered perorally by gavage.
Test substances are prepared separately in 0.5% methylcellulose (Sigma)/5% Solutol (BASF, Ludvi^igshafen) or a suitable vehicle.
The administration volume of the test substance is 0.5 ml/mouse. The test substance is administered immediately prior to the test meal (Intralipid labeled with ^'C-cholesterol) (cholesterol absorption test).
The feces are collected over a period of 24 h: fecal elimination of ^'C-cholesterol and ^H-taurocholic acid (TCA) is determined after 24 hours.
The livers are removed and homogenized, and aliquots are incinerated in an oximate (Model 307, Packard) to determine the amount of """C-cholesterol which had been taken up/absorbed.

XV XXIII 0.3
XXV 0.3
XXVI 0.1
XXVII 0.3
XXIX 0.3
XXXI 0.3
XXXVI 0.03
XXXVII 0.1
XXXVIII 0.1
XLI 0.03
XLIII 0.3
XLIV 0.3
XLVI 0.3
XLVIII 0.03
L 0.1
Lll 0.3
UN 0.03
As can be seen from the table, the compounds of the formula I have very good cholesterol-lowering action.
Bioabsorption:
The bioabsorption of the compounds of the formula I was examined using the Caco cell model (A.R. Hilgers et al., Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa, Pharm. Res. 1990, 7, 902).
From the measured data, it can be seen that the bioabsorption of the compounds of the formula 1 according to the invention is considerably lower than that of the compounds described in the prior art (reference structure):

WE CLAIM:
1. A compound of the formula I,

H, F, CI, Br, I. CF3. NO2, N3, CN, COOH, COO(C1C8)alkyl, CONH2. C0NH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C8)-alkenyl,

(LAG)n is selected from
a sugar residue, disugar residue, trisugar residue, tetrasugar residue; a sugar acid, an amino sugar;

an amino acid residue, an oligopeptide residue comprising 2 to 9 amino acids;

2. A compound of the fomiula I as claimed in claim 1, wherein R2, R4, R5, R6 Independently of one another are selected from

S02-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be

substituted up to two times by F, CI, Br, OH, CF3, NOj, CN, OCF3,0-(CrCeValkyl, (Ci-Ce)-alkyl, NHj;
NHz, NHHCrCeValkyI, N((Ci-C6)-alkyl)2, NH(Ci-C7)-acyl. phenyl, O-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, CI, Br, I, OH. CF3. NO2, CN, OCF3. 0-{CrC6)-alkyI, (Ci-C6)-alkyl. NH2, NH(Ci-C6)-alkyl. N((Ci-C6>allcyl)2. SO2-CH3, COOH, C00-(Ci-C6)-alkyl, GONH2;

and where in each case at least one of the radicals R1 or R3 must have the meaning (CrC3o)-alkylene-(LAG), where one or more carbon atoms of the alkylene radical are replaced by up to trisubstituted aryl or heteroaryl radicals or by up to trisubstituted (C3-Cio)-cycloalkyl or heterocycloalkyl radicals and may additionally be replaced by

-S(0)n-, Where n = 0 - 2. -0-, -{C=0)-, -N(CH3)-. -N(phenyl)-, -N(CO-(CH2)i-io-
COOH)-or-NH-;
and its physiologically acceptable salts.
3. A compound of the formula I as claimed in claim 1 or 2, wherein

aikylene-(C'=0)o-i-N(R13)o.i-(LAG); where one or more carbon atoms of the alkyiene radicai are replaced by aryl or heteroaryl radicals substituted up to three times by R7, or by {C3-Cio)-cycloalkyl or heterocycloalkyi radicals substituted up to three times by R7 and where one or more carbon atoms of the alkyiene radical may be replaced by oxygen atoms;

R7 is selected from
F. CI. Br, I, CF3, NO2. N3, CN, COOH, C0O(C1-C6)-alkyl, CONH2. C0NH(C,-C6)-alkyl, CON[(C1C6)-aIkyl]2. (C1-C6)-alkyl. (C2-C6)lkenyl, (C2-C6)-alkynyl, 0-(Ci-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine;
PO3H2. SO3H, SO2-NH2, S02NH(Ci-C6)-alkyl. SOzNKCi-CeValkylJz , S-(Ci-C6)-alkyl. S-(CH2)n-phenyl, S0-(Ci-C6)-alkyl, S0-(CH2)n-phenyl, S02-(Ci-C6)-alkyl, S02-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be substituted up to two times by F, CI, Br, OH, CF3, NO2, CN. OCF3, 0-{CrC6)-alkyl, (Ci-Cs^alkyt, NH2; C(NH)(NH2), NH2, NH-(Ci-C6)-alkyl. N{(Ci-C6)-alkyl)2, NH(Ci-C7)-acyl. phenyl, 0-(CH2)n-phenyl, where n - 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, CI, Br. 1, OH, CF3, NO2. CN, OCF3, 0-(C^-C6)alkyl, {C,-C6)-alkyl, NH2. NH(Ci-C6)-alkyl, N({Ci-C6)-alkyl)2, SO2-CH3, COOH, C00-{Ci-C6)-alkyl. CONH2;

and where in each case at least one of the radicals R1 or R3 must have the meaning -(CH2)o-i-NH-(C'=0)o.i-(Co-C25)-alMene-(C=0)o.i-N(R13)o-i-(LAG)or-(CH2)o.i-(C=0)o.i-NH-(Co-C25)-allcycloalkyl or heterocycloailtyl radicals and may additionally be replaced by -S(0)n-, where n = 0 - 2, -0-, -(C=0)-, -N(CHa)-. -N(phenyl)-or-NH-; and its physiologically acceptable salts.
4. A compound of the formula I as claimed in one or more of claims 1 to 3, wherein
LAG is selected from
a monosugar residue, an acyclic mono-, di- or tricyclic trialkylammoniumalkyl radical, a sulfonic add or a carboxyllc acid,
and its pharmaceuticaiiy acceptable salts.
5. A medicament comprising one or more compounds as claimed in one or more

of claims 1 to 4.
6. The medicament as claimed in claim 5, comprising, further active compound, which
are one or more compounds which normalize Hpid metaboHsm.
7. The medicament as claimed in claim 5 or 6, which comprises, as further active
compound, one or more antidiabetics, hypoglycemically active compounds,
HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma
agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP
inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid
adsorbers, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase
inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a)
antagonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides,
thiazolidinediones, a-glucosidase inhibitors, active compounds which act on the ATP-
dependent potassium channel of the beta cells, CART agonists, NPY agonists, MC4
agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP
antagonists, urocortin agonists, p3 agonists, MSH (melanocyte-stimulating hormone)
agonists, CCK agonists, serotonin-reuptake iiJiibitors, mixed serotonin and
noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists,
growth hormones, growth hormone-releasing compounds, TRH agonists, decoupling
protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, doprexin),
lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-p-agonists or
amphetamines.

Documents:

2826-chenp-2004 abstract duplicate.pdf

2826-chenp-2004 claims duplicate.pdf

2826-chenp-2004 claims.pdf

2826-chenp-2004 correspondence others.pdf

2826-chenp-2004 correspondence po.pdf

2826-chenp-2004 description (complete) duplicate.pdf

2826-chenp-2004 description (complete).pdf

2826-chenp-2004 form-1.pdf

2826-chenp-2004 form-13.pdf

2826-chenp-2004 form-18.pdf

2826-chenp-2004 form-3.pdf

2826-chenp-2004 form-5.pdf

2826-chenp-2004 pct.pdf

2826-chenp-2004 petition.pdf

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Patent Number

227980

Indian Patent Application Number

2826/CHENP/2004

PG Journal Number

10/2009

Publication Date

06-Mar-2009

Grant Date

27-Jan-2009

Date of Filing

14-Dec-2004

Name of Patentee

SANOFI-AVENTIS DEUTSCHLAND GmbH

Applicant Address

BRUNINGSTRASSE 50, D-65929 FRANKFURT AM MAIN

Inventors:

#	Inventor's Name	Inventor's Address
1	HEUER, HUBERT	OTTO, AM SPORTFELD 74, D-55270 SCHWABENHEIM,
2	SCHAEFER, HANS-LUDWIG	STEINGASSE 7, 65239 HOCHHEIM,
3	JAEHNE, GERHARD	SEEBACHATRASSE 22, 65929 FRANKFURT
4	FRICK, WENDELIN	SCHORNMUHLSTRASSE 3, 65510 HUINSTETTEN-BEUERBACH,
5	FLOHR, STEFANIE	WILHELM REUTERSTRASSE 5, 65817 EPPSTEIN,
6	LINDENSCHMIDT, ANDREAS	BRAHMSSTRRASSE 4, 65812 BAD SODEN,
7	GLOMBIK, HEINER	AM LOTZENWALD 42, 65719 HOFHEIM,
8	KRAMER, WERNER	HENRY-MOISAND-STRASSE 19, 55130 MAINZ-LAUBENHEIM,

PCT International Classification Number

CO7D 205/08

PCT International Application Number

PCT/EP03/05815

PCT International Filing date

2003-06-04

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	102 27 506.8	2002-06-19	Germany