OA12868A - Ring-substituted diphenyl azetidinones, method forthe production thereof, medicaments containing sa id compounds and use thereof. - Google Patents

Abstract

Disclosed are ring-substituted diphenyl azetidinones of formula I, a method for the production thereof, medicaments containing said compounds, and the use thereof for treating hyperlipidemia, arteriosclerosis, and hypercholesterolemia.

Description

1 012868

Description

Ring-substituted diphenyl azetidinones, method for the production thereof, 5 médicaments containing said compounds, and use thereof

The invention relates to ring-substituted diphenylazetidinones, to their physioiogicallyacceptable salts and to dérivatives having physiological functions. 10 Diphenylazetidinones (such as, for example, ezetimibe) and their use for treatinghyperlipidemia and arteriosclerosis and hypercholesterolemia hâve already beendescribed [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 15 therapeutically utilizable hypolipidémie action. In particular, it was an object to findnovel compounds which, compared to the compounds described in the prior art, areabsorbed to a very low extent. Very low absorption is to be understood as meaningan intestinal absorption of less than 10%, preferably less than or equal to 5%. 20 In particular, absorption of the novel compounds must be less than that of ezetimibe.Pharmaceutically active compounds which are absorbed to a low extent generallyhâve considerably fewer side-effects. 012868

Accordingly, the invention relates to compounds of the formula I

5 in which 10 15 R1, R2, R3, R4, R5, R6 independently of one another are (Ci-C30)- alkylene-(l_AG)ni where n = 1 - 5 and where one or more carbon atomsof the alkylene radical are replaced by aryl or heteroaryl radicalssubstituted up to three times by R7, or by (C3-C10)-cycloalkyl orheterocycloalkyl radicals substituted up to four times by R7and one or more carbon atoms of the alkylene radical may be replacedby -S(O)n-, where n = 0 - 2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -CEC-,-N((Ci-Ce)-alkyl)-, -N(phenyl), -N((CrC6)-alkyl-phenyl)- , -N(CO-(CH2)i.1Q-COOH)-or -NH-; H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2,CONH(Ci-C6)-alkyl, CONffCrCe^-alkylh, (CrC6)-alkyl, (C2-C6)-alkenyl,(C2-C6)-alkynyl, O-(CrC6)-alkyl, where one, more or ail hydrogens in the 20 alkyl radicals may be replaced by fluorine; SO2-NH2, SOzNHtCrCB^alkyl, SOsN^C^Cs^alkylJz, S-tCrCeû-alkyl, S-(CH2)n-phenyl, SO-(Ct-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(Ci-C6)-alkyl,SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, 0-(CrCe^alkyl, (CrCs)-alkyl, NH2; NH2l NH-(CrC6)-alkyl, N((CrC6)-alkyl)2, NHiCrC/J-acyl, phenyl, 0-(CH2)n-phenyl, where π = 0 - 6, where the phenyl ring may be mono- totrisubstituted by F, Cl, Br, I, OH, CF3, N02, CN, OCF3, O-iCvCeJ-alkyl,(CrCeJ-alkyl, NH2, NH^-CgJ-alkyl, N((CrC6)-alkyl)2, S02-CH3, COOH,COO-iCrCaJ-alkyl, CONH2; is F, Cl, Br, I, CF3, N02, N3, CN, COOH, COO(CrC6)-alkyl, CONH2,CONH(CrC6)-alkyl, CONKCrCsJ-alkylJz, (CvCeJ-alkyl, (C2-Ce)-alkenyl,(C2-Cs)-alkynyl, O-(C-rCg)-alkyl, where one, more or ail hydrogens in thealkyl radicals may be replaced by fluorine; PO3H2, SO3H, SO2-NH2, SO2NH(C-i-C6)-alkyl, SO2N[(CrC6)-alkyl]2 , S-(Ci-C6)-alkyl, S-(CH2)n-phenyl, SO-(Ci-C6)-alkyl, SO-(CH2)n-phenyl,SO2-(Ci~Ce)-alkyl, SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenylradical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2,CN, OCF3, O-(CrC6)-alkyl, (CrCeJ-alkyl, NH2; C(NH)(NH2), NH2, NH-(CvC6)-alkyl, N((CrC6)-alkyl)2, NH(CrC7)-acyl,phenyl, O-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may bemono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(CtC6)-alkyl, (CrC6)-alkyl, NH2, NH(CrC8)-alkyl, N((CrC6)-alkyl)2, SO2-CH3, COOH, COO-(CrC6)-alkyl, CONH2; 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 aminoacids; an acyclic, mono-, di- or tricyclic trialkylammonium radical, an acyclicmono-, di- or tricyclic trialkylammoniumalkyl radical, -O-(SO2)-OH;-(CH2)q.iq-SO3H; -(CH2)o-io-P(0)(OH)2, -(CH2)0.10-O-P(O)(OH)2,-(CH2)q.10-COOH, -(CH2)0.10-C(=NH)(NH2); -(CH2)0.1Q-C(=NH)(NHOH); -

NR8-C(=NR9)(NR10R11); where n = 1 - 5 and R8, R9, R10 and R11independently of one another may be H, (CrCgJ-alkyl, phenyl, (C-i-Cg)-alkyl-phenyl, (C3-Ca)-cycl.oalkyl), 5 and where in each case at least one of the radicals R1 to RS must hâve the meaning(Ci-C3o)-alkylene-(LAG)n, where n = 1 - 5 and one or more carbon atoms of thealkyiene radical are replaced by aryl or heteroaryl radicals substituted up to threetimes by R7, or by (C3-C10)-cycioalkyl or heterocycloalkyl radicals substituted up tofour times by R7 and one or more carbon atoms of the alkyiene radical may be 10 replaced by -S(O)n-, where n = 0 - 2, -O-, -(C=O>-, -(C=S)-, -CH=CH-, -C=C-, ^((CTCg^alkyl)-, -N(phenyl)-, -N^CvC^-alkyl-phenyl)-, -N(CO-(CH2)i-io-COOH)- or-NH-; and their physiologically acceptable salts. 15 Preference is given to compounds of the formula I where at least one of the radicalsR1 to R6 the meaning (Ci-C3o)-alkylene-(LAG)n, where n = 1 - 5 and one or morecarbon atoms of the alkyiene radical are replaced by aryl or heteroaryl radicalssubstituted up to three times by R7, or by (C3-C-i0)-cycloalkyl or heterocycloalkylradicals substituted up to four times by R7 and one or more carbon atoms of the 20 alkyiene radical may be replaced by -S(O)n-, where n = 0 - 2, -O-, -(C=O)-, -(C=S)-,-CH=CH-, -CEC-, -N((Ci-C6)-alkyl)-, -N(phenyl)-, -N((C1-C6)-alkyl-phenyl)-l -N(CO-(CH2)i-io-COOH)- or -NH-.

Particular preference is given to compounds of the formula I where one of the 25 radicals R1 or R3 the meaning (C-i-C3o)-alkylene-(LAG), where one or more carbonatoms of the alkyiene radical are replaced by aryl or heteroaryl radicals substitutedup to three times by R7, or by (C3-C1Q)-cycloalkyl or heterocycloalkyl radicalssubstituted up to three times by R7 and one or more carbon atoms of the alkyieneradical may be replaced by -S(O)n-, where n = 0 - 2, -O-, -(C=O)-, -N(CH3)-, - 30 N(phenyl)-, -N(CO-(CH2)i--io-COOH)- or-NH-. 5 012868

Very particular preference is given to compounds of the formula I where at least oneof the radicals R1 or R3 the meaning -(CH2)o-i-NH-(C=0)o-i-(Co-C2s)-alkylene-(C=O)0.rN(R13)o.r(LAG) or -(CH2)0.1-(C=0)o.rNH-(C0-C25)-alkylene-(C=0)0.1-N(R13)o-i-(LAG); 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 heterocycloalkyl radicals substituted up to three times by R7 andone or more carbon atoms of the alkylene radical may be replaced by oxygen atoms,NH, N(CH3) or SO2 , and where R13 may be H or CH3.

Preference is furthermore given to compounds of the formula I where the group LAGis a monosugar residue, an acyclic mono-, di- or tricyclic trialkylammoniumalkylradical, a suifonic acid or a carboxylic acid.

An aryl radical is to be understood as meaning a phenyl, naphthyl, biphenyl,tetrahydronaphthyl, alpha or beta-tetralone, indanyl or indan-1-onyl radical. A heteroaryl radical is to be understood as meaning a pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyridazin-3-onyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, indolyl,benzimidazolyl, thienyl, furyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl radical.

Heterocycloalkyl radicals are to be understood as meaning (C3-C-io)-cycloalkylradicals in which at least one and up to three carbon atoms independently of oneanother are replaced by NR8, O or S(O)n, where n = 0 - 2. Examples are theazetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 1,4-dioxanyl, tetrahydrofuryl,piperazinyl or thiepanyl radical.

An acyclic trialkylammonium radical is to be understood as meaning the followinggroup 6

in which n = 0 to 10 and Al^ and Alk2 independently of one another each dénoté astraight-chain or branched alkyl radical having 1 to 20 carbon atoms. 5 An acyclic trialkylammoniumalkyl radical is to be understood as meaning thefollowing group

Alk,

L N--Alk- \ 10

Alk3 in which n = 0 to 10 and Alk1( Alk2l Alk3 independently of one another each dénoté astraight-chain or branched alkyl radical having 1 to 20 carbon atoms. A mono- or di- or tricyclic trialkylammonium radical is to be understood as meaning,for example, radicals such as

15 where n, m and p independently of one another can be 0 - 10 and one or more CH2groups independently of one another may be replaced by O, S(O)n, where n = 0-2,NH, N-{Ci-Cio)-alkyl, N-phenyl or N-CH2-phenyl. A mono- or dicyclic trialkylammoniumalkyl radical is to be understood as meaning, 20 for example, radicals such as 012888 7

or

\ (CH.)m—1—N ... (CH2)n —> . Aïk; (chî)p where n, m and p independently of one another can be 0 - 10 and one or more CH2groups independently of one another may be replaced by O, S(O)n, where n = 0-2, 5 NH, N-(CrCiq)-alkyl, N-phenyl or N-CH2-phenyl and Alki is a straight-chain orbranched alkyl radical having 1 to 20 carbon atoms.

Owing to their increased solubility in water, compared to the parent compounds,pharmaceutically acceptable salts are particularly suitable for medical applications.These salts must hâve a pharmaceutically acceptable anion or cation. Suitable 10 pharmaceutically acceptable acid addition salts of the compounds according to theinvention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid,phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, andof organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid,ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic 15 acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p- toluenesulfonic acid, tartaric acid and trifluoroacetic acid, for example. For medical 012868 purposes, very particular preference is given to using the chloride sait. Suitablepharmaceutically acceptable basic salts are ammonium salts, alkali métal salts (suchas sodium and potassium salts) and alkaline earth métal salts (such as magnésiumand calcium salts). 5

The scope of the invention also includes salts having a pharmaceuticallyunacceptable anion, which salts may be useful intermediates for preparing orpurifying pharmaceutically acceptable salts and/or for use in nontherapeutic, forexample in vitro, applications. 10

Here, the term "dérivative having physiological function" refers to any physiologicallyacceptable dérivative of a compound according to the invention, for example anester, that is able, upon administration to a mammal, for example man, to form sucha compound or an active métabolite (directly or indirectly). 15 A further aspect of this invention are prodrugs of the compounds according to theinvention. Such prodrugs can be metabolized in vivo to give a compound accordingto the invention. These prodrugs may or may not be active in their own right. 20 The compounds according to the invention can also be présent in various polymorphous forms, for example as amorphous and crystalline polymorphousforms. The scope of the invention includes ail polymorphous forms of thecompounds according to the invention, which form a further aspect of the invention. 25 Hereinbelow, ail references to "compound(s) of the formula (I)" refer to a compoundor compounds of the formula (I) as described above, and to their salts, solvatés anddérivatives having physiological function, as described herein.

The compounds of the formula I and their pharmaceutically acceptable salts and 30 dérivatives having physiological function are idéal médicaments for treating an impaired lipid metabolism, in particular hyperlipidemia. The compounds of the 9 012868 formula I are also suitable for modulating the sérum cholestérol concentration andfor preventing and treating arteriosclerotic manifestations.

The compound(s) of the formula (I) can also be administered in combination with5 · other active compounds.

The amount of a compound of the formula (!) required to achieve the desiredbiological effect dépends on a number of factors, for example on the spécifiecompound chosen, on the intended use, on the mode of administration and on the

I 10 clinical condition of the patient. In general, the daily dose is in the range from 0.1 mgto 100 mg (typically from 0.1 mg to 50 mg) per day per kilogram of bodyweight, forexample 0.1-10 mg/kg/day. Tablets or capsules may contain, for example, from 0.01to 100 mg, typically from 0.02 to 50 mg. In the case of pharmaceutically acceptablesalts, the abovementioned weight data relate to the weight of the diphenyl- 15 azetidinone-ion derived from the sait. For the prophylaxis or therapy of theabovementioned conditions, the compounds of the formula (I) can be usedthemselves as the compound, but preferably they are présent in the form of apharmaceutical composition with an acceptable carier. The carrier must of coursebe acceptable in the sense that it is compatible with the other constituents of the 20 composition and is not harmful to the health of the patient. The carrier can be a solidor a liquid or both and is preferably formulated with the compound as an individualdose, for example as a tablet, which can contain from 0.05% to 95% by weight of theactive compound. Further pharmaceutically active substances can also be présent,including further compounds of the formula (I). The pharmaceutical compositions 25 according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consist in mixing the constituents with pharmacologicallyacceptable carriers and/or auxiliaries.

Pharmaceutical compositions according to the invention are those which are suitable 30 for oral or pérorai (e.g. sublingual) administration, although the most suitable mannerof administration is dépendent in each individual case on the nature and severity of 012868 10 the condition to be treated and on the type of the compound of the formula (I) usedin each case. Coated formulations and coated delayed-release formulations are alsoincluded in the scope of the invention. Acid-resistant and enteric formulations arepreferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl 5 acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl méthacrylate.

Suitable pharmaceutical compounds for oral administration can be présent inseparate units, such as, for example, capsules, cachets, lozenges ortablets, which 10 in each case contain a spécifie amount of the compound of the formula (I); as apowder or granules; as a solution or suspension in an aqueous or nonaqueousliquid; or as an oil-in-water or water-in-oil émulsion. As already mentioned, thesecompositions can be prepared according to any suitable pharmaceutical methodwhich includes a step in which the active compound and the carrier (which can 15 consist of one or more additional constituents) are brought into contact. In general,the compositions are prepared by uniform and homogeneous mixing of the activecompound with a liquid and/orfinely divided solid carrier, after which the product, ifnecessary, is shaped. For example, a tablet can thus be prepared by pressing orshaping a powder or granules of the compound, if appropriate with one or more 20 additional constituents. Pressed tablets can be produced by tableting the compoundin free-flowing form, such as, for example, a powder or granules, if appropriate mixedwith a binder, lubricant, inert diluent and/or a (number of) surface-active/dispersing agent(s) in a suitable machine. Shaped tablets can be produced byshaping the pulvérulent compound moistened with an inert liquid diluent in a suitable 25 machine.

Pharmaceutical compositions which are suitable for pérorai (sublingual)administration include lozenges which contain a compound of the formula (!) with aflavoring, customarily sucrose and gum arable or tragacanth, and pastilles which 30 include the compound in an inert base such as gelatin and glycerol or sucrose andgum arabic. 11 012868

Suitable other active compounds for the combination préparations are: ali antidiabetics mentioned in Rote Liste 2001, Chapter 12. They can be combinedwith the compounds of the formula I according to the invention in particular toachieve a synergistically enhanced action. The active compound combination can beadministered either by separate administration of the active compounds to thepatient or in the form of combination préparations comprising a plurality of activecompounds in a pharmaceutical préparation.

Antidiabetics include insulin and insulin dérivatives, such as, for example, Lantus® orHMR 1964, GLP-1 dérivatives, such as, for example, those disclosed by NovoNordisk AJS in WO 98/08871, and oral hypoglycémie active compounds.

The oral hypoglycémie active compounds preferably include sulfonylureas,biguadines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidaseinhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers, suchas, for example, those disclosed by Novo Nordisk A/S in WO 97/26265 andWO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in stimulatinggluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compoundswhich modulate lipid metabolism, such as antihyperlipidemic active compounds andantilipidemic active compounds, compounds which reduce food intake, PPAR andPXR agonists and active compounds which act on the ATP-dependent potassiumchannel of the beta cells.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin,rosuvastatin.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholestérol absorption inhibitor, such as, for 12 example, ezetimibe, tiqueside, 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, 5 rosiglitazone, pioglitazone, JTT-501, Gl 262570.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a PPAR alpha agonist, such as, for example, GW9578, GW 7647. 10 in one embodiment of the invention, the compounds of the formula I areadministered in combination with a mixed PPAR aipha/gamma agonist, such as, forexample, GW 1536, AVE 8042, AVE 8134, AVE 0847. 15 in one embodiment of the invention, the compounds of the formula I are administered in combination with a fïbrate, such as, for example, fenofibrate,clofibrate, bezafibrate.

In one embodiment of the invention, the compounds of the formula I are 20 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 areadministered in combination with a bile acid absorption inhibitor, such as, for 25 example, HMR 1453.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a CETP inhibitor, such as, for example, Bay194789. 30

In one embodiment of the invention, the compounds of the formula l are 13 012868 administered in combination with a polymeric bile acid adsorber, such as, forexample, cholestyramine, colesolvam.

In one embodiment of the invention, the compounds of the formula I areadministered 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 areadministered 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 I 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, forexample, BMS-1.88494.

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,CI-1027 or nicotinic acid.

In one embodiment of the invention, the compounds of the formula I are 012868 14 administered in combination with a lipase inhibitor, such as, for example, Orlistat.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with insulin. 5 · In one embodiment, the compounds of the formula I are administered in combinationwith a sulfonylurea, such as, for example, tolbutamide, glibenclamide, glipizide orgliclazide.

In one embodiment, the compounds of the formula I are administered in combinationwith a biguanide, such as, for example, metformin. 10 In another embodiment, the compounds of the formula l are administered incombination with a meglitinide, such as, for example, repaglinide.

In one embodiment, the compounds of the formula I are administered in combinationwith a thiazolidinedione, such as, for example, troglitazone, ciglitazone, pioglitazone,rosiglitazone, or the compounds disclosed by Dr. Reddy’s Research Foundation in 15 WO 97/41097, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinyl-methoxy]phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment, the compounds of the formula I are administered in combinationwith an α-glucosidase inhibitor, such as, for example, miglitol or acarbose.

In one embodiment, the compounds of the formula I are administered in combination 20 with an active compound which acts on the ATP-dependent potassium channel ofbeta cells, such as, for example, tolbutamide, glibenclamide, glipizide, gliazide orrepaglinide.

In one embodiment, the compounds of the formula I are administered in combinationwith more than one of the abovementioned compounds, for example in combination 25 with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide andmetformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazon,insulin and lovastatin, etc.

In a further embodiment, the compounds of the formula I are administered in 30 combination with CART agonists, NPY agonists, MC3 and MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin 012868 15 agonists, p3-agonists, MCH (melanine-concentrating hormone) antagonists, CCKagonists, serotonin reuptake inhibitors, mixed serotonin and noradrenergiccompounds, 5HT agonists, bombesin agonists, galanin antagonists, growthhormone, growth hormone-releasing compounds, TRH agonists, decoupling protein2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, doprexin),lipase/amylase inhibitors, PPAR moduiators, RXR modulators orTR-β agonists.

In one embodiment of the invention, the further active compound is leptin.

In one embodiment, the further active compound is dexamphetamine oramphétamine.

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 combinationwith fiber, preferably insoluble fiber, such as, for example, Caromax®. Thecombination with Caromax® can be given in one préparation or by separateadministration of compounds of the formula I and Caromax®. Here, Caromax® canalso be administered in the form of food, such as, for example, in bakery goods ormuesli bars. Compared to the individual active compounds, the combination ofcompounds of the formula I with Caromax® is, in addition to an enhanced action, inparticular with respect to the lowering of LDL cholestérol, also characterized by itsimproved tolerability.

It goes without saying that each suitable combination of the compounds according tothe invention with one or more of the compounds mentioned above and optionallyone or more further pharmacologically active substances is included in the scope ofthe présent invention.

The invention furthermore provides both stereoisomer mixtures of the formula I and 012868 16 the pure stereoisomers of the formula I, and diastereomer mixtures of the formula Iand the pure diastereomers. The mixtures are separated by chromatographiemeans. 5 Preference is given to both racemic and enantiomerically pure compounds of theformula I of the following structure: R1

R4

Sugar residues are to be understood as meaning compounds which are derived from10 aldoses and ketoses which hâve 3 to 7 carbon atoms and may belong to the D or the L sériés; also included are amino sugars, sugar alcohols or sugar acids. Glucose,mannose, fructose, galactose, ribose, erythrose, glycerolaldehyde, sedoheptulose,glucosamine, galactosamine, glucuronic acid, galacturonic acid, gluconic acid,galactonic acid, mannonic acid, glucamine, 3-amino-1,2-propanediol, glucaric acid 15 and galactaric acid may be mentioned by way of example.

Disugars are saccharides composed of two sugar units. Di-, tri- or tetrasaccharidesare formed by acetal-like binding of two or more sugars. Here, the bonds may be inthe a- or β-form. Lactose, maltose and cellobiose may be mentioned by way of 20 example.

If the sugar is substituted, the substitution is preferably at the hydrogen atom of anOH group of the sugar. 012868 17

Suitable protective groups for the hydroxyl groups of the sugars are substantially:benzyl, acetyl, benzoyl, pivaloyl, trityl, tert-butyldimethylsilyl, benzylidene,cyclohexylidene or isopropylidene protective groups.

The term “amino acids" or “amino acid residues” refers, for example, to thestereoisomeric forms, i.e. the D or L forms, of the following compounds: alanine glycine proline cysteine histidine glutamine aspartic acid isoleucine arginine glutamic acid lysine serine phenyialanine leucine threonine tryptophan méthionine valine tyrosine asparagine 2-aminoadipic acid 2-aminoisobutyric acid 3-aminoadipic acid 3-aminoisobutyric acid beta-alanine 2-aminopime!ic 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-methylvaline 3-hydroxyproline norvaline 4-hydroxyproline norleucine 18 012888 isodesmosine omithine allo-isoleucine N-methylglycine 5 For abbreviating the amino acids, the conventional notation was used (cf. Schroder,Lübke, The Peptides, Volume I, New York 1965, pages XXII-XXIII; Houben-Weyl,Methoden der Organischen Chemie [Methods of organic chemistry], Volume XV/1and 2, Stuttgart 1974). The amino acid pGlu dénotés pyroglutamyl, Nal dénotés 3-(2-naphthyl)alanine, azagly-NH2 dénotés a compound of the formula NH2-NH-CONH2 10 and D-Asp dénotés the D form of aspartic acid. According to their Chemical nature, . peptides are acid amides, and on hydrolysis they décomposé into amino acids.

An oligopeptide is to be understood as meaning a peptide constructed of 2 to 9 ofthe amino acids mentioned above. 15

Suitable protective groups (see, for example, T.W. Greene, "Protective Groups inOrganic Synthesis") for amino acids are primarily.

Arg(Tos), Arg(Mts), Arg(Mtr), Arg(PMV), Asp(OBzi), Asp(OBut), Cys(4-MeBzl),Cys(Acm), Cys(SBut), Glu(Obzl), Glu(Obut), His(Tos), His(Fmoc), His(Dnp), His(Trt), 20 Lys(CI-Z), Lys(Boc), Met(O), Ser(Bzl), Ser(But), Thr(Bzl), Thr(But), Trp(Mts),Trp(CHO), Tyr(Br-Z), Tyr(Bzl) or Tyr(But).

Amino protective groups that are preferably used are the benzyloxycarbonyl (Z)radical, which can be removed by catalytic hydrogénation, the 2-(3,5- 25 dimethyloxyphenyl)propyl(2)oxycarbonyl(Ddz) or trityl (Trt) radical, which can beremoved by weak acids, the t-butylcarbamate (BOC) radical, which can be removedby 3M hydrochloric acid, and the 9-fluorenylmethyloxycarbonyl (Fmoc) radical, whichcan be removed using secondary amines. 19 012868

The invention furthermore relates to a process for preparing diphenylazetidinonedérivatives of formula I.

Y can be S, O, (C=O), (C=S), CH=CH, CEC, N((C1-C6)-alkyl), N(phenyl), N((CrC6)-alkyl-phenyl), N(CO-(CH2)i-io-COOH) or NH; R12 can be H or, if Y = (C=O) or (C=S), OH; W can, independentiy of Y, be an up to trisubstituted aryl or heteroaryi radical or an10 up to tetrasubstituted (C3-Cio)-cycioalkyl or heterocycloalkyl radical or -S(O)n-, where n = 0 - 2, -O-, -(0=0)-, -(C=S)-, -CH=CH-, -CEC-, -N((Ci-Ce)-alkyl)-, -N(phenyl), -N((C1-Cs)-alkyl-phenyl)-, -N(CO-(CH2)i.io-COOH)- or -NH- or a bond;v, x, y and z independentiy of one another can be 0 to 10.

In compound 11, -(CH2)x-Y-R1 2 can alternative^ also be attached to one of the other15 two phenyl rings.

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 oméga position, carries a further functionality- if appropriate in 20 protected form. This functionality is (after deprotection) used for attaching (LAG), forexample with the formation of ether, amine or amide bonds. 012868 20

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

Example I 5 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): O—

a) 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyl-oxazolidin-2-one (1 ):

15 27 g of 3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one, 13.6 g of tert-butyldimethylsilyl chloride and 10.2 g of imidazole are dissolved in 36 ml ofdimethylformamide and stirred at 60°C for 90 min. After the reaction has ended, themixture is dissolved in ethyl acetate and extracted two times with water. The organicphase is dried over magnésium sulfate, filtered and concentrated under reduced 20 pressure. This gives 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyioxazolidin-2-one (1) of molecular weight 471.65 (C26H34FNO4S1); MS (ESI):340.28 (MH+ - HOSi(CH3)2C(CH3)3). 012868 21 b) 4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fiuorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo- 4-phenyloxazoIidine-3-carbonyl)pentylamino]benzonitrile (2): 16.2 g of 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyloxazolidin-2-one (1) are dissolved in 350 ml of dichloromethane. 19.8 ml ofHünig base and 10.14 g of 4-[(4-methoxyphenylimino)methyl]benzonitriIe are added,and the solution is cooled to -10°C. 8.52 ml of trimethylsilyl triflate are added to thecooled solution, and the mixture is stirred at -10°C for 30 min. The solution is thencooled to -30°C, and 44 ml of titanium tetrachloride solution are added. The reactionmixture is stirred at from -30 to -40°C for 2 h. The solution is then allowed to warm toroom température and the reaction solution is washed successively with 200 ml of2N sulfuric acid, 300 ml of 20% strength sodium hydrogen sulfite solution and sat.sodium chloride solution. The organic phase is dried over magnésium sulfate andconcentrated under reduced pressure, and the residue is purified on silica gel usingn-heptane/ethyl acetate 3/1. This gives 4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1 -(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3- carbonyl)pentylamino]benzonitriie (2) of molecular weight 707.93 (C4iH46FN3O5Si);MS (ESI): 590.51 (MH+- C7H5N2). c) 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1 -yljbenzonitrile (3): 13.2 g of 4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyioxazolidine-3-carbonyl)pentylamino]benzonitrile (2) are dissolvedin 380 ml of methyl tert-butylether, 18.6 ml of N,O-bis(trimethylsilyl)acetamide and 1.86 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran areadded and the mixture is stirred at room température for 2 h. After the réaction hasended, 10 ml of acetic acid are added, the reaction mixture is concentrated underreduced pressure and the residue is purified on silica gel using toluene/ethyl acetate50/1. This gives 4-[3-[3-(tert-butyldimethylsi!anyloxy)-3-(4-fluorophenyl)propyl]-2-(4- 22 methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitriIe (3) of molecular weight 544.75(C32H37FN2O3S1); MS (ESI): 545.56 (M+H+). 5 d) 4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyi)-4-oxoazetidin- 1-yl]- benzonitrile (4): 3.5 g of 4-[3-[3-(tert-butyldimethyisiIanyloxy)-3-(4-fIuorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (3) are dissolved in 65 ml of 1.0 tetrahydrofuran, 0.74 ml of acetic acid and 8.03 ml of a 1 M solution of tetrabutylammonium fiuoride in tetrahydrofuran are added and the mixture is stirredat room température for 2 h. Another 4.82 ml of the tetrabutylammonium fiuoridesolution are then added, and the mixture is stirred at reflux température for another3 h. The cooled reaction mixture is concentrated under reduced pressure and the 15 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-methoxyphenylH-oxoazetidin-1-yl]-benzonitrile (4) of molecular weight 430.48 (C26H23FN2O3); MS(ESI): 431.24 (M+H+). 20 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- 25 oxoazetidin-1-yl]-benzonitrile (4) are dissolved in 90 ml of éthanol, 10 ml of conc.ammonia solution and an excess of Raney nickel are added, and the mixture isstirred at 5Q°C and a hydrogen pressure of 10 bar for 8 h. Overnight, the reactionmixture cools to room température, and the next day, the catalyst is removed, thefiltrate is concentrated under reduced pressure and the residue is purified by silica 30 gel chromatography using dichloromethane/methanol/ammonia solution 10/1/0.1.

This gives 1 -(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4- 23 012868 methoxyphenyl)-azetidin-2-one (5) of molecular weight 434.51 (C26H27FN2O3); MS(ESI): 418.2 (MH+-NH3). 5, f) 2,3,4,5,6-Pentahydroxyhexylamide of 4,4'-oxybisbenzoic acid (6):

At room température, 0.52 g of 4,4'-oxybisbenzoic acid and 0.36 g of D-glucamineare suspended in 10 ml of dry dimèthylformamide, 0.31 g of HOBt and 0.39 g ofEDC are added and the mixture is stirred at room température for 12 h. The réaction 10 mixture is evaporated to dryness and dried under high vacuum. The residue is thoroughly titrated with water, the resulting suspension is fiitered and the residue istitrated with methanol and fiitered again. The filtrate is concentrated to half of itsvolume using a rotary evaporator, and the solution is cooled in an ice bath. Theresulting precipitate is fiitered off with suction, washed with a little ice-cooled 15 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(CzoHssNOg); MS (ESI): 422.28 (MH+). 20 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 25 under f) are, at room température, dissolved in 3 ml of dry dimèthylformamide, 31mg of HOBt and 39 mg of EDC are added and the mixture is stirred at roomtempérature for 12 h. The reaction mixture is evaporated to dryness under highvacuum and the residue is titrated with dichloromethane, fiitered off with suction,washed with dichloromethane and dried under reduced pressure. This gives the 30 2,3,4,5,6-pentahydroxyhexylamide of 4-(4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]- 24 01286 5 2-(4-methoxyphenyl)-4-oxoazetidin-1 -yl]benzylcarbamoyl}phenoxy)benzoic acid (7)with a molecular weight 837.90 (CAelWNaOn); MS (ESI): 838,39 (MH*).

Example 11 2,3,4,5,6-Pentahydroxyhexylamide of 4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2-oxo-4-phenylazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoic acid (9):

10 a) 1-(4-Aminomethylphenyl)-3-(3-hydroxy-3-phenylpropyl)-4-phenylazetidin-2-

This compound is prepared as described above for 1-(4-aminomethylphenyl)-3-[3-(415 fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one, except that 3-[5· (tert-butyldimethylsilanyloxy)-5-phenylpentanoyl]-4-phenyloxazolidin-2-one and 4-(benzylideneamino)benzonitrile are used. This gives 1-(4-aminomethylphenyl)-3-(3-hydroxy-3-phenylpropyl)-4-phenylazetidin-2-one (8) of molecular weight 386.50(C25H26N2O2); MS (ESI): 370.2 (MH*-NH3). 20 b) 2,3,4,5,6-Pentahydroxyhexylamide of 4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2·oxo-4-phenylazetidin-1 -yl]benzylcarbamoyl}phenoxy)benzoic acid (9): 25 The benzylamine from lia 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- 25 012868 pentahydroxyhexylamide of 4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2-oxo-4- phenylazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoic acid (9) of molecular weight 789.89 (C45H47N3OK,); MS (ESI): 790.26 (MH*).

Example III 2,3,4,5,6-Pentahydroxyhexylamide of 4-(4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzylcarbamoyl}-benzyl)-benzoic acid (10): 0—

The compound of Example III is obtained analogously to the procedure of Example I,except that the 2,3,4,5,6-pentahydroxyhexylamide of diphenylmethane-4,4'-dicarboxylic acid is used. This gives the 2,3,4,5,6-pentahydroxyhexylamide of 4-(4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzylcarbamoyl}benzyl)benzoic acid (10) of molecular weight 835.93.(C47H50FN3O10); MS (ESI): 836.18 (MH+).

Example IV 1-[4-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropylp4-oxoazetidin-2-yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (13): 26 012868

a) 4-[4-(4-Bromomethylbenzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-5 fluorophenyl)-3- hydroxypropyl]azetidin-2-one (12):

3.0 g of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)- azetidin-2-one (11) 7.0 g of 1,4-bisbromomethylbenzene and 5.0 g 10 of potassium carbonate are dissolved in 100 ml of dimethylformamide and stirred atroom température for 90 min. After the reaction has ended, the mixture is dissolvedin ethyl acetate and extracted two times with water. The organic phase is dried overmagnésium sulfate, filtered and concentrated under reduced pressure. The residueis purified by flash chromatography (n-heptane/ethyl acetate). Yield 3.2 g of colorless 15 crystals (12) of molecular weight 592.49 (CaaHzaBrFzNOa); MS (ESI): 592.2 (MH+). b) 1 -[4-(4-{ 1 -(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4- oxoazetidin-2- yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane 20 bromide(13): 180 mg of (12) and 300 mg of 1,4-diazabicyclo[2.2.2]octane (DABCO) are dissolved in 5ml of toluene and stirred at 80°C for 90 min. After the réaction has ended, the mixture is allowed to cool and the colorless solid is filtered off with suction. This gives 27 01286 195 mg of product (13) of moiecular weight 704.66 (C38H4oBrF2N303); MS (ESI):624.30 (MH+).

Example V 1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{4-[(2,3,4,5,6-pentahydroxyhexylamine)methyl]benzyloxy}phenyl)azetidin-2-one (14)

60 mg of (12) and 150 mg of glucamine are dissolved in 5ml of dimethylfomnamideand stirred at 80°C for 90 min. After the reaction has ended the mixture is dissolvedin ethyl acetate and extracted two times with water. The organic phase is dried overmagnésium sulfate, filtered and concentrated under reduced pressure. The residueis purified by flash chromatography (methylene chloride/methanol/conc. ammonia30/10/3). Yield 33 mg of a colorless solid (14) of moiecular weight 692.76(CaalWzNzOa); MS (ESI): 693.5 (MH+).

Example VI 1-[2-(4~{1-(4-FIuorapheriyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (16): 28

a) 4-[4-(2-Bromomethylbenzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-5 fluorophenyl)-3-hydroxypropyl]-azetidin-2-one (15):

1-(4-Fluorophenyl)-3-[3-(4-fIuorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyi)- 10 azetidin-2-one (11) is reacted with 1,2-bisbromomethylbenzene and potassiumcarbonate analogously to Example IV, giving a colorless solid (15) of molecularweight 592.49 (C32H28BrF2NO3); MS (ESI): 592.2 (MH+). 15 b) 1-[4-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4- oxoazetidin-2- yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octanebromide (16): (15) and DABCO are dissolved in toluene and reacted analogously to Example IV, 20 giving the product (16) as a colorless solid of molecular weight 704.66 (C38H40BrF2N3O3); MS (ESI): 624.30 (MH+). 29 Ο 1286 8

Example Vil 1-(4-FIuorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{2-[(2,3,4,5,6-pentahydroxyhexylamine)methyl]benzyloxy}phenyl)azetidin-2-one (17):

(15) and glucamine are dissolved in dimethylformamide and reacted analogously toExample V, giving the product (17) as a colorless solid of molecular weight 692.76 10 (C38H42F2N2O8); MS (ESI): 693.5 (MH+).

Example VIII 15 1 -[3-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2- yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane bromide (19):

a) 4-[4-(3-Bromomethylbenzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3- hydroxypropyl]azetidin-2-one (18): 30 012868

1-(4-FIuorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one (11) is reacted with 1,3-bisbromomethylbenzene and 5 potassium carbonate analogously to Example IV, giving a colorless solid (18) ofmqlecular weight 592.49 (C32H28BrF2NO3); MS (ESI): 592.2 (MH+). b) 1 -[3-(4-{1 -(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-10 oxoazetidin-2- yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane bromide(19): (18) and DABCO are dissolved in toluene and reacted analogously to Example IV,giving the product (19) as a colorless solid of molecular weight 704.66 15 (C38H40BrF2N3O3); MS (ESI): 624.30 (MH+).

Example IX 20 1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{3-[(2,3,4,5,6- pentahydroxyhexylamine)methyl]benzyloxy}phenyl)azetidin-2-one (20):

31 012868 (18) and glucamine are dissolved in dimethylformamide and reacted analogously toExample V, giving the product (20) as a colorless solid of molecular weight 692.76(C38H42F2N2O8); MS (ESI): 693.5 (MH+).

Example X 1 -[4’-(4-{ 1 -(4-Fluorophenyl)-3-[3-(4-fIuorophenyl)-3-hydroxypropyI]-4-oxoazetidin-2-yl}phenoxymethyl)biphenyl-4-ylmethyl]-4-aza-1-azoniabicyclo[2.2.2]octane bromide 10 (22):

15 a) 4-[4-(4'-Bromomethylbiphenyl-4-ylmethoxy)phenyl]-1 -(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (21 ):

20 1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyI]-4-(4-hydroxyphenyl)-azetidin-2-one (11) is reacted with 4,4'-bisbromomethylbiphenyl and potassiumcarbonate analogously to Example IV, giving a colorless solid (21) of molecularweight 668.54 (CaaFhBrFzNOa); MS (ESI): 668.1 (MH+). 32 Ο 1 286 8 b) 1 -[4'-(4-{1 -(4-Fluorophenyl)-3-[3-(4-fIuorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2- yl}phenoxymethyl)biphenyI-4-ylmethyl]-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(C^H^BrFsNaOa); MS (ESI): 700.3 (MH+).

Example XI 1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropy!]-4-(4-{4'-[(2,3,4,5,6-pentahydroxyhexylamine)-methyl]-biphenyI-4-ylmethoxy}-phenyl)-azetidin-2-one (23):

(21) and glucamine are dissolved in dimethylformamide and reacted analogously toExample V giving the product (23) as a colorless solid of molecular weight 768.86 20 (C^FUsFzNzOg); MS (ESI): 769.3 (MH+).

Example XII 25 1 -(4-{4-[3-[3-(4-FIuorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1 - yl]-phenoxymethyl}-benzyl)-4-aza-1 -azoniabicyclo[2.2.2]octane bromide (26): 33

a) 3-[3-(4-Fluoraphenyl)-3-hydroxypropyl]-1 -(4-hydroxyphenyl)-4-(4-methoxyphenyl)-azetidin-2-one (24):

This compound is prepared as described above for 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyi)-azetidin-2-one (steps a, b, c, 10 . and d), except that 4-[(4-methoxybenzylidene)-amino]-phenol is used. This gives 3-[3-(4-fiuorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-azetidin-2-one (24) of molecular weight 421.47 (C25H24FNO4); MS (ESI): 422.2(MH+). 15 b) 1-[4-(4-bromomethylbenzyloxy)-phenyl]-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one (25):

20 012868 34 3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-a2etidin-2-one is reacted with 1,4-bisbromomethylbenzene and potassium carbonateanalogously to Example IV, giving a colorless solid (25) of molecular weight 604.52(C33H31BrFNO4); MS (ESI): 605.2 (MH+). c) 1-(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4- oxoazetidin-1-yl]-phenoxymethyl}-benzyl)-4-aza-1-azoniabicyclo[2.2.2]octanebromide (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(C3gH43BrFN3O4); MS (ESI): 636.3 (MH+).

Example Xlll 3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-1-(4-{4-{(2,3,4,5,6-pentahydroxyhexylamine)-methyl]-benzyloxy}-phenyi)-azetidin-2-one (27):

(25) and glucamine are dissolved in dimethylformamide and reacted analogously toExample V, giving the product (27) as a colorless solid of molecular weight 704.80 25 (C39H45FN20g); MS (ESI): 705.31 (MH+). 35 Ο 1 286 8

Example XIV 1-[4-(4-{3-[1-(4-FIuorophenyl)-2-(4-methoxyphenyl)~4-oxoazetidin-3-yl]-1- hydroxypropyl}-phenoxymethyl)-benzyl]-4-aza-1-azoniabicyclo[2.2.2)octane,bromide 5 (30):

a) 1-(4-Fluorophenyl)-3-[3-hydroxy-3-(4-hydroxyphenyl)-propyl]-4-(4-10 methoxyphenyl)-azetidin-2-one (28):

This compound is prepared as described above for 1-(4-aminomethylphenyl)-3-[3-(4-15 fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one, except that 3-[5- (4-hydroxyphenyl)-5-hydroxypentanoyl]-4-phenyIoxazolidin-2-one and (4-fluorophenyl)-(4-methoxybenzylidene)-amine are used. This gives 1-(4-fluorophenyl)-3-[3-hydroxy-3-(4-hydroxyphenyl)-propyl]-4-(4-methoxyphenyl)-azetidin-2-one (28) ofmolecular weight 421.47 (C25H24FNO4); MS (ESI): 422.2 (MH+). 20 b) 3-{3-[4-(4-Bromomethylbenzyloxy)-phenyl]-3-hydroxypropyl}-1-(4-fluorophenyl)-4-(4-methoxyphenyl)-azetidin-2-one (29): 36 012868

1-(4-Fluorophenyl)-3-[3-hydroxy-3-(4-hydroxyphenyl)-propyl]-4-(4-methoxyphenyl)-azetidin-2-one is reacted with 1,4-bisbromomethylbenzene and potassium carbonate 5 analogously to Example IV, giving a colorless solid (29) of molecular weight 604.52(C33H31BrFNO4); MS (ESI): 605.2 (MH*). c) 1 -[4-(4-{3-[1 -(4-Fluorophenyl)-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl]-1 -10 hydroxypropyl}-phenoxymethyl)-benzyl]-4-aza-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 15 (C39H43BrFN3O4); MS (ESI): 636.3 (MH*).

Example XV 20 1 -{4-[(4-{1 -(4-Fluorophenyl)-3-[3-(4-fIuorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2- yl)-benzylcarbamoyl)-methyl]-benzyl}-4-aza-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (35): 37 012868

a)· 1-(4-Carboxymethylbenzyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromide (31):

At 70°C, 1.0 g of (3-bromomethylphenyl) acetic acid in 5 ml of dimethyl sulfoxide areadded to. a solution of 1.5 g of 1,4-diazabicyclo[2.2.2]octane in 10 ml of dimethylsulfoxide. After 1 h, 100 ml of water are added and the mixture is freeze-dried. Theresidue is digested with acetone. The residue contains the product of molecularweight 261.35 (cation: C15H21N2O2+); MS (ESI) 261.1 (M+). 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-fluorophenyI)-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 -10°C. 6.4 ml ofdiisopropylethylamine and, over a period of 30 min, 4.05 ml of trimethylsilyl chlorideare added to this mixture so that the température does not exceed -5°C. Themixture is stirred at this température for 1 additional hour and then cooled to -25°C.0.8 ml of titanium tetra chloride are then added slowly. The dark mixture is stirred atfrom - 25 to -30°C overnight and then decomposed using 35 ml of a 7 percentstrength solution of tartaric acid and then stirred at room température for anotherhour. 15 ml of a 20 percent strength solution of sodium bicarbonate are then added, 012868 38 and the mixture is again stirred for 1 hour. Following phase séparation, the organicphase is washed with 30 ml of water, dried over magnésium sulfate andconcentrated to about 10 ml. Following the addition of 2 ml ofbistrimethylsilylacetamide, the mixture is heated at reflux for 30 min and then 5 concentrated under reduced pressure. The residue is crystailized using ethylacetate/heptane. The product is filtered off with suction and dried under reducedpressure. This gives the product of molecular weight 653.81 (C37H37F2N3O4Si); MS(ESI+): 654.3 (M+H+), 582.2 (M+H+-Si(CH3)3). 10 , c) {1 -(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzonitrile (33): 2 g of 4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyl-15 oxazolidine-3-carbonyl)-pentyl]-benzonitriIe are dissolved in 20 ml of methyl-tert-butyl ether and, together with 100 mg of tetrabutylammonium fluoride trihydrate and 1.3 mlof bistrimethylsilyl acetamide, heated at 40°C for about 1 h. The reaction ismonitored by thin-iayer chromatography. After the reaction has ended, 0.2 ml ofglacial acetic acid is initialJy added and the mixture is stirred for 30 min and then 20 concentrated. 20 ml of a mixture of isopropanol/2N sulfuric acid = 10:1 are added tothe residue, and the mixture is stirred for 1 hour. Following addition of a spatula tip ofsolid 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 waterand dried, and the residue is, after removal of the solvent, purified by column 25 chromatography (SiO2l CH2CI2/methanol = 100:1). This gives the product ofmolecular weight 418.45 (C25H2oF2N202); MS (DCI+): 419 (M+H+). d) 4-(4-Aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3- 30 hydroxypropyl]-azetidin-2-one (34): 39 0128^8 200 mg of (1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzonitrile are dissolved in 20 ml of éthanol and, with 0.5 ml of conc. ammonia,hydrogenated over Raney nickel at a hydrogen pressure of 75 bar and at 25°C for 30hours. The catalyst is filtered off with suction, the mixture is concentrated upderreduced pressure and the residue is purified by column filtration (SiO2,ChkC^/methanol/conc. NH3 = 100:10:1). This gives the product of molecular weight 422.5 (C25H22F2N2O2); 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; trifluoroacetate (35): A solution of 70 mg 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one, and 23 pl of triethylamine in 0.5 ml ofdimethylformamide is added to a solution of 84 mg of 1-(4-carboxymethylbenzyl)~4-aza-1-azoniabicyclo[2.2.2]octane bromide, 64 μΙ of diisopropylcarbodiimide and56 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture isstirred at room température for 12 h. The reaction solution is concentrated andseparated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroaceticacid)/acetonitrile (0.1% trifluoroacetic acid) = 80/20 -> 10/90). This gives the productof molecular weight 665.81 (cation: C4QH43F2N4O3); MS (ESI) 665.33 (M*).

Example XVI 1-{4-[(4-{1 -(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzy!carbamoyl)-methyl]-benzyl}-1-azoniabicyclo[2.2.2]octane trifluoroacetate(37): 40 012868

a) 1-(4-Carboxymethylbenzyl)-1-azoniabicyclo[2.2.2]octane bromide (36): I , 5 The synthesis is carried out analogously to Example XVa) starting with 1.67 g of 1-azabicyclo[2.2.2]octane. This gives the product of molecular weiqht 260.36 (cation:C^HzzhhOz*); MS (ESI) 260.1 (M+). 10 b) 1 -{4-[(4-{ 1 -(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzy!}-1 -azoniabicyclo[2.2.2]octane trifluoroacetate (37):

The synthesis is carried out analogously to Example XVe) starting with 70 mg of 4- 15 (4-aminomethylphenyl)-1-(4-fIuorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one and 85 mg of 1-(4-carboxymethylbenzyl)-1-azoniabicyclo[2.2.2]octanebromide. This gives the product of molecular weight 664.82 (cation: C4iH44F2N3O3+);MS (ESI) 664.33 (M+).

Example XVII 1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2- yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4-dimethylpiperazin-1-ium trifluoroacetate 25 (39): 41

a) 1-(4-Carboxymethylbenzyl)-1,4-dimethylpiperazin-1-ium bromide (38): 5

The synthesis is carried out analogously to Example XVa) starting with 1.02 ml of1,4-dimethylpiperazine. This gives the product of molecular weight 263.36 (cation:C1SH23N2O2+); MS (ESI) 263.1 (M+). 10 b) 1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fIuorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4-dimethyl-piperazin-1-ium trifluoroacetate (39): 15 The synthesis is carried out analogously to Example XVe) starting with 70 mg of 4- (4-aminomethylphenyl)-1-(4-fIuorophenyl)-3-[3-(4-fluorophenyI)-3-hydroxypropyl]-azetidin-2-one and 86 mg of 1-(4-carboxymethylbenzyl)-1,4-dimethylpiperazin-1-iumbromide. This gives the product of molecular weight 667.82 (cation: C40H45F2N4O3*);MS (ESI) 667.34 (M+).

Example XVIII 4-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2- 25 yi}-benzylcarbamoyl)-methyl]-benzyl}-4-methylmorpholin-4-ium trifluoroacetate (41): 42 012868

a) , 4-(4-Carboxymethylbenzyl)-4-methylmorpholin-4-ium bromide (40): 5

The synthesis is carried out analogously to Example XVa) starting with 1.65 ml of N-methylmorpholine. This gives the product of molecular weight 250.32_(cation:CuHzoNnOa*); MS (ESI) 250.1 (M+). 10 b) 4-{4-[(4-{1-(4-FIuorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-4-methylmorpholin-4-iumtrifluoroacetate (41): 15 The synthesis is carried out analogously to Example XVe) starting 70 mg of 4-(4-aminomethylphenyl)-1-(4-fIuorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one and 82 mg of 4-(4-carboxymethylbenzyl)-4-methylmorpholin-4-iumbromide. This gives the product of molecular weight 654.78 (cation: C39H42F2N3O4+);MS (ESI) 654.31 (M+). 20

Example XIX 1 -{4-[(4-{1 -(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2- 25 yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4,7-trimethyl-[1,4,7]triazonan-1-ium trifluoroacetate (43): 43 012868

5 a) 1,4,7-Trimethyl-1-(4-(2-oxopropyl)-bén2yl]-[1,4.7]triazonan-1-ium bromide(42):

The synthesis is carried out analogously to Example XVa) starting with 500 mg of 1,4.7-trimethyl-[1,4,7]triazonane. This gives the product of molecular weight 321.47 10 (cation: C10H31N3O2+); MS (ESI) 321.2 (M*). b) 1-{4-[(4-{1-(4-FluorophenyI)-3-[3-(4-fIuorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4,7-trimethyl- 15 [1,4,7]triazonan-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]- 20 [1,4,7]triazonan-1 -ium bromide. This gives the product of molecular weight 724.92 (cation: C4oH45F2N403+); MS (ESI) 724.40 (M+). 44

Example XX 1-[4-({4-[3-(3-Hydroxy-3-phenylpropyl)-2-oxo-4-phenylazetidin-1-yl]- benzylcarbamoyl}-methyl)-benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane trifluoroacetate(44):

The synthesis is carried out analogously to Example XVe) starting 60 mg of 1-(4-aminomethylphenyl)-3-(3-hydroxy-3-phenylpropyI)-4-phenylazetidin-2-one (8) and 82 10 mg of 1-(4-carboxymethylbenzyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromide. Thisgives the product of molecular weight 629.83_(cation: C4qH45F2N4O3+); MS (ESI)629.35 (M+).

Example XXI N-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzyl)-2-{4-[(2,314,5,6-pentahydroxyhexylamino)-methyl]-phenyl}-acetamide (46): 45 012868

a) {4-[(2,3,4,5,6-Pentahydroxyhexylamino)-methyl]-phenyl}-acetic acid (45):

The synthesis is carried out analogously to Example XVa) starting with 989 mg of 6-aminohexane-1,2,3,4,5-pentaol. This gives the product of molecular weight 329.35(CnsHzaN^); MS (ESI) 330.2 (M + H+). b) N-(4-{1 -(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidih-2-yl}-benzyl)-2-{4-[(2,3J4,5,6-pentahydroxyhexylamino)-methyl]-phenyl}-acetamide (46):

The synthesis is carried out analogously to Example XVe) starting 70 mg of 4-(4- ·aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fiuorophenyl)-3-hydroxypropyl]-azetidin-2-one and 110 mg of {4-((2,3,4,5,6-pentahydroxyhexylamino)-methyl]-phenyl}-acetic acid. This gives the product of molecular weight 733.82(C4oH45F2N3Ob+); MS (ESI).734.32 (M + H+).

Example XXII 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)-amino]-methyl}-phenyl)-acetamide (48): 012868 46

5 a) (4-{[Methyl-(2,3,4,5,6-pentahydroxyhexyl)-amino]-methyl}-phenyl)-acetic acid(47): . The synthesis is carried out analogously to Example XVa) starting with 1.06 g of 6-methylaminohexane-1,2,3,4,5-pentaol. This gives the product of molecular weight 10 343.38_(C16H25N1O7);.MS (ESI) 344.2 (M + H+). 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)-amino]-methyl}- 15 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-(213,4,5,6-pentahydroxyhexyl)-amino]- 20 methyl}-phenyl)-acetic acid. This gives the product of molecular weight 747.84(C41H47F2N3Oa+); MS (ESI) 748.35 (M + H+). 47 012868

Table 1 : Compounds of the formula I

R4 012868 48

Ex. R1,R2 R3, R4 R5, R6 Salz Molecularwelghtof the free baseor acid(calculated) Molecular welght (found) XXIII -H para-F, H para- F.H cr 651.78 651.31 (M+) XXIV Ç/V7\ h para-F, H para-F. H cf3c 00' 651.78 651.31 (M+) XXV XH ·» /—N '-f OH para ·M para-F, H para- F.H 567.64 577.25 (MH*) XXVI para-F, H para- F.H 662.69 663.22 (MH*) XXVII para-O-CHa, H para-F, H CF3C OOH 745.85 746.34 (MH*) XXVIII para-O-CH3, H ^jn · “S » « para-F, H CF3C OOH 759.88 760.35 (MH*) XXIX r - ”· ÇÇC- " CM CM para-F, H para-F, H 739.82 740.33 (MH*) XXX para-F, H para- F,H CF3C 00' 695.84 659.34 (M*) XXXI -/s para-F, H para- F.H CF3C 00' 709.86 709.35 (M*) XXXII ΟγΟΗ - ,h 0 OH para-F, H para-F, H 614.60 597.18 (MH*- H2O) 49 012868 XXXIII pa. rs γθγ° 0 OH para-F, H para-F, H 620.65 621.24 (MH*) XXXIV para ‘. para-F, H para- F.H 606.65 607.32 (MH*) XXXV n, para-F, H para-F, H CF3C 00‘ 681.33 681.5 (M*) XXXVI para-O-CH3, H e para-F. H cr 755.92 755.36 (M*) XXXVII para-O-CH3, H -¾ » O»'OH H, H 615.71 616.21 (MH*) XXXVIII para-F, H para- F,H CF3C OOH 554.65 555.20 (MH*) XXXIX 40^” ·- ^NH '-r 0 para para-F, H para- F.H 606.65 607.39 (MH*) XL para-O-CHi, H para-F, H cr 775.95 775,40 (M*) xu para-O-CH3, H para- F.H cr 699.85 699.33 (M*) XLII para-O-CH3, H para- F.H HCl 651.74 652.38 (MH*) XLIII para-O-CH3, H para- F.H Br' 360.51 860.6 (M*) XL1V para-O-CH3t H ιΗ 0 para-F, H 595.67 596.38 (MH*) 50 01286 XLV para-O-CH3, H .h NM para- F.H CF3C OOH 652.73 653.37 (MH+) XLVI para-O-CH3, H 0 para-F, H 610.63 617.33 (M-H*: measured In négative mode XLVII para-O-CH3, H T para-F, H 730.31 731.41 (MH*) XLVIII para-O-CH3, H HQ para- F.H 672.76 655.28 (MH+- H2O) IL para-O-CH3, H 0 .H 0 para-F, H 658.73 659.27 (MH+) L para-O-CH3l H HO para- F,H 710.78 693.25 (MH*- H2O) Ll para-O-CH3, H ”'JXM - para-F. H Cl' 663,82 663.28 (M+) LU para-O-CH3, H 0 para-F. H 588.68 589.34 (MH*) LUI para-O-CHa, H 0 para-F, H 674.73 657.35 (MH+- H20) LIV para-O-CH3, H Para \ N tj ïü/ " □" "0H para-F, H 633.70 615.70 (M*- H2O) 51 012868 LV para-O-CH3, H' "Λχφ - para-F, H Br 666.72 666.33 (M+) LVI ·» para-F, H para-F, H Br 654.68 654.31 (M+) LVII ΖΟ-τ-φ.. 0 para-F, H para-F, H Γ 687.35 687.4 (M? LVIII para Osï//0 ,H 0' "OH para-F, H para-F. H 571.65 572.4 (MH+) L1X ,OH H H para-F, H para- F,H 621.66 622.33 (MH+) LX para-O-CH3, H 5 ο M para-F, H 801.98 784.21 (M+- H20) LXl para-O-CH3, H i ο N « para- F.H 775.90 758.18 (M+- H2O) LXI! para-O-CH3, H S 11 . <” para- F,H 882.04 883.49 (MH+) 52 012868

Using the method described below, the activity of the compounds of the formula Iaccording to the invention was examined:

Effect on cholestérol absorption + 3H-taurocholic acid excrétion using fecal5 excrement of mice, rats or hamsters NMRI mice, Wistar rats, or Golden Syrian hamsters (in groups of n=4-6) are kept inmetabolic cages, where they are fed with a standard diet (Altromin, Lage (Lippe)).The aftemoon prior to the administration of the radioactive tracers (14C-cholesterol), 10 the feed is removed and the animais are adapted to grates.

Additionally, the animais are labeled s.c. with 3H-TCA (taurocholic acid) (for example1 pCi/mouse up to 5 pCi/rat) 24 hours prior to the pérorai administration of the testmeal (14C-cholesterol in Intralipid® 20, Pharmacia-Upjohn). 15

Cholestérol absorption test: 0.25 ml/mouse Intralipid ® 20 (Pharmacia-Upjohn)((spiked with 0.25 pCi of 14C-cholesterol in 0.1 mg of cholestérol) is administeredperorally by gavage. 20 Test substances are prepared separately in 0.5% methylcellulose (Sigma)/5%

Solutol (BASF, Ludwigshafen) or a suitable vehicle.

The administration volume of the test substance is 0.5 ml/mouse. The test substanceis administered immediately prior to the test meal (Intralipid labeled with 14C-cholesterol) (cholestérol absorption test). 25

The feces are collected over a period of 24 h: fecal élimination of 14C-cholesterol and3H-taurocholic acid (TCA) is determined after 24 hours.

The livers are removed and homogenized, and aliquots are incinerated in an oximate30 (Model 307, Packard) to détermine the amount of 14C-cholesterol which had been taken up/absorbed. 53

Evaluation:

Feces samples:

The total weight is determined, the sample is made up with water to a definedvolume and then homogenized, and an aliquot is evaporated to dryness andincinerated in an oximate (Model 307 from Packard for the incinération ofradioactively labeied samples): the amount of radioactive 3H-H2O and 14C-CO2 isextrapolated to the amount of 3H-taurocholic acid and 14C-cholesterol, respectively,that is excreted (dual isotope technique). The ED200 values as dose from a dose-effect curve are interpolated as those doses at which the excrétion of TCA orcholestérol is doubled, based on a control group treated at the same time.

Liver samples:

The amount of 14C-cholesterol taken up by the liver is based on the administereddose. The ED50 values are interpolated from a dose-effect curve as the dose atwhich the uptake of 14C-cholesterol by the liver is halved (50%), based on a controlgroup.

The ED50 values below demonstrate the activity of the compounds of the formula Iaccording to the invention

Example No. ED50 (liver) [mg/mouse] <0.1

II

IV

VI

VII

VIII

IX < 1.0 <0.1 <0.1 0.3 < 1.0 < 1.0 <0.1 012868 XV 54 < 1.0 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 XLl 0.03 XLIII 0.3 XLIV 0.3 XLVI 0.3 XLVIII 0.03 L 0.1 LII 0.3 LUI 0.03 20 As can be seen from the table, the compounds of the formula I hâve very goodcholesterol-lowering action.

Bioabsorption: 25 The bioabsorption of the compounds of the formula I was examined using the Cacocell model (A.R. Hilgers et al., Caco-2 cell monolayers as a model for drug transportacross the intestinal mucosa, Pharm. Res. 1990, 7, 902).

From the measured data, it can be seen that the bioabsorption of the compounds of 30 the formula I according to the invention is considerably lower than that of thecompounds described in the prior art (reference structure): 01286 8 55

F

Reference structure:Ezetimibe

Claims (13)

1. 012868 56 Patent daims:

   1. A compound of the formula I,

   10 in which R1, R2, R3, R4, R5, R6 independently of one another are (C-|-C30)- alkylene-(LAG)n< where n = 1 - 5 and where one or more carbon atomsof the alkylene radical are replaced by aryl or heteroaryl radicais 15 substituted up to three times by R7, or by (C3-C10)-cycloalkyl or heterocycloalkyl radicais substituted up to four times by R7and where one or more carbon atoms of the alkylene radical may bereplaced by -S(O)n-, where n = 0 - 2, -O-, -(C=O)-, -(C=S)-, -CH=CH-,-CEC-, -NKCrCgJ-alkyl)-, -N(phenyl), -N((CrC6)-alkyl-phenyl)- , -N(CO- 20 (CH2)1-io-COOH)- or -NH-; H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(CrC6)-alkyl, CONH2,CONH(Ci-C6)-alkyl, CON[(CrC6)-alkyl]2, (CrC5)-alkyl, (C2-C6)-alkenyl 57 012868 (C2-C6)-alkynyl, O-(Ci-C6)-alkyl, where one, more or ail hydrogens in thealkyl radicals may be replaced by fluorine; SO2-NH2, SO2NH(CrC6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(CrC6)-alkyl, S-(CH2)n-phenyl, SO-(CrC6)-alkyl, SO-(CH2)n-phenyl, SOHCrCeJ-alkyl,SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may besubstituted up to two times by F, Cl, Br, OH, CF3l NO2, CN, OCF3, 0-(CrC6)-alkyl, (C-i-Cg)-alkyl, NH2; NH2, NH-(Ci-C6)-alkyl, N((C1-Cg)-alkyl)2, NH(Ci-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- totrisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-alkyl,(Ci-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SOz-CHa, COOH,COO-(Ci-C6)-alkyl, CONH2; is F, Cl, Br, I, CF3, N02, N3, CN, COOH, COO(CrC6)-alkyl, CONH2,CONH(C1-C6)-alkyl, CONKCrCsJ-alkylJz, (Çn-C6)-alkyl, (C2-C6)-alkenyl,(C2-C6)-alkynyl, O-(C-i-C6)-alkyl, where one, more or ail hydrogens in thealkyl radicals may be replaced by fluorine; PO3H2, SO3H, SO2-NH2i SOzNHtCrCeî-alkyl, SOzN^-Cg^alkylk , S-(CrC6)-alkyl, S-(CH2)n-phenyl, SO-(Ci-C6)-alkyl, SO-(CH2)n-phenyl,SO2-(C-i-Cs)-alkyl, SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenylradical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2,CN, OCF3, O-(C-,-C6)-alkyl, (CrC6)-alkyl, NH2; C(NH)(NH2), NH2i NH-(CrC6)-alkyl, N^CvCgl-alkyOz, NH^r^-acyl,phenyl, O-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may bemono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C·,-C6)-aikyl, (Ci-C6)-alkyl, NH2, NH(CrC6)-alkyl, N((CrC6)-alkyl)2, SO2-CH3, COOH, COO-(Ci-C6)-alkyl, CONH2; is a sugar residue, disugar residue, trisugar residue, tetrasugar residue;a sugar acid, an amino sugar; 012868 58 an amino acid residue, an oligopeptide residue comprising 2 to 9 aminoacids; an acyclic, mono-, di- or tricyclic trialkylammonium radical, an acyclicmono-, di- or tricyclic trialkylammoniumalkyl radical, -O-(SO2)-:OH; 5 -(CH2)q.10-SO3H; -(CH2)0_10-P(O)(OH)2, -(CH2)o-io-0-P(0)(OH)2, -(CH2)o.10-COOH, -(CH2)o.1o-C(=NH)(NH2); -{CH2)0.10-C(=NH)(NHOH);-NR8-C(=NR9)(NR10R11 ); where n = 1 - 5 and R8, R9, R10 and R11independently of one another may be H, (C-t-Cgpalkyl, phenyl, (Ct-C6)-aikyl-phenyl, (C3-C8)-cycloalkyl), 10 and where in each case at least one of the radicals R1 to R6 must hâve the meaning(Ci-C30)-alkylene-(LAG)n, where n = 1 - 5 and one or more carbon atoms of thealkylene radical are replaced by up to trisubstituted aryl or heteroaryl radicals or byup to tetrasubstituted (C3-Ci0)-cycloalkyl or heterocycloalkyl radicals and may 15 additionally be replaced by -S(O)n-, where n = 0 - 2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -CEC-, -N((C-i-C6)-alkyl)-, -N(phenyl)-, -N((C1-C6)-alkyl-phenyl)-, -N(CO-(CH^o-COOH^or-NH-; and its pharmaceutically acceptable salts. 20
2. 2. A compound of the formula I as claimed in claim 1, wherein R2, R4, R5, R6 independently of one another are H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(CrC6)-alkyl, CONH2, CONH(C1-C6)-alkyl, 25 CON[(C1-C6)-alkyl]2, (CrCeJ-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O- (Ci-Ce)-alkyl, where one, more or ail hydrogens in the alkyl radicals maybe replaced by fluorine; SO2-NH2, SO2NH(CrC6)-alkyl, SO^KCrC^-alkylk , S-(CrC6)-alkyl, S-(CH2)n-phenyl, SO-iCrCgJ-alkyl, SO-(CH2)n-phenyl, SO2-(CrC6)-alkyl,SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be 30 012868 59 substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, 0-(Ci-C6)-alkyl, (C-j-Cg)-alkyl, NH2; NH2, NH-iCrCgJ-alkyl, N((CrC6)-alkyl)2l ΝΗ^-Ογ^Ι, phenyl, 0-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- totrisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-^-CeJ-alkyl,(Ci-C6)-alkyl, NH2, NH(CrC6)-alkyl, NftCrCsJ-alkylfe, SO2-CH3, COOH,COO-(CrC6)-alkyl, CONH2; R1, R3 independently of one another are (C-rC3o)-a!kylene-(LAG), where one ormore carbon atoms of the alkylene radical are replaced by aryl orheteroaryl radicals substituted up to three times by R7, or by (C3-C10)-cycloalkyl or heterocycloalkyl radicals substituted up to three times byR7 and where one or more carbon atoms of the alkylene radical may bereplaced by -S(O)n-, where n = 0 - 2, -O-, -(C=O)-, -N(CH3)-,-N(phenyl)-, -NiCO-ÎCH^o-COOH)- or-NH-, H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(CrC6)-alkyl, CONH2,CONH(Ci-C6)-alkyl, CON[(CrC6)-alkyl]2, (CrCgJ-alkyl, (C2-C6)-alkenyl,(C2-C6)-alkynyl, O-(Ci-C6)-alkyl, where one, more or ail hydrogens in thealkyl radicals may be replaced by fluorine; SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C,-C6)-alkyl]2 , S-(Ci-C6)-alkyl, S-(CH2)n-phenyl, SO-(CrC6)-alkyl, SO-(CH2)n-phenyl, SOz-^-CgJ-alkyl,SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may besubstituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-alkyl, (C-i-C^-alkyl, NH2; NH2, NH-(C-i-C6)-alkyl, N((CrC6)-alkyl)2, NH^-Cyj-acyl, phenyl, O-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- totrisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O^CrCgJ-alkyl, • (CrC6)-alkyl, NH2, NH(CrC6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH,COO-iCrCeJ-alkyl, CONH2;

   60 R7 is F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(CrC6)-alkyl, CONH2, CONHCCrCej-alkyl, CON[(C1-C6)-alkyl]2, (CrC6)-alkyl, (C2-C6)-alkenyl,(C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or ail hydrogens in thealkyl radicals may be replaced by fluorine; 5 PO3H2, SO3H, SO2-NH2i SO2NH(C1-C6)-alkyl, SOzNKCrCeJ-alkylk , S- (ÇrC6)-alkyl, S-(CH2)n-phenyl, SO-(CrC6)-alkyl, SO-(CH2)n-phenyl,SO2-(Ci-C6)-alkyl, SO2-(CH2)n-phenyl, where n = 0 - 6 and where thephenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3,NO2l CN, OCF3, O-(CrC6>alkyl, (CrC6)-alkyl, NH2; 10 C(NH)(NH2), NH2i NH-(CrC6)-alkyl, N((CrC6)-alkyl)2, NH(CrC7)-acyl, phenyl, O-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may bemono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(CrC6)-alkyl, (Ci-C6)-alkyl, NH2, NHiCrCeJ-alkyl, N((C1-C6)-alkyl)2, SO2-CH3l COOH, COO-(CrC6)-alkyl, CONH2; 15 (LAG) 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 aminoacids; 20 an acyclic, mono-, di- or tricyclic trialkylammonium radical, an acyclic mono-, di- or tricyclic trialkylammoniumalkyl radical, -O-(SO2)-OH;-(CH2)o--io-S03H; -(CH2)0.10-P(O)(OH)2, -(CH2)0.10-O-P(O)(OH)2i-(CH2)0.10-COOH, -(CH2)o.10-C(=NH)(NH2); -(CH2)0.10-C(=NH)(NHOH);-NR8-C(=NR9)(NR10R11 ); where n = 1 - 5 and R8, R9, R10 and R11 25 independently of one another may be H, (Ci-Cg)-alkyl, phenyl, (C-i-Cg)- alkyl-phenyl, (C3-Ca)-cycloalkyl), and where in each case at least one of the radicals R1 or R3 must hâve the meaning(Ci-C3o)-alkylene-(LAG), where one or more carbon atoms of the alkylene radical are 30 replaced by up to trisubstituted aryl or heteroaryl radicals or by up to trisubstituted(C3-C-io)-cycloalkyl or heterocycloalkyi radicals and may additionally be replaced by 61 -S(O)n-, where n = 0 - 2, -O-, -(C=O)-, -N(CH3)-, -N(phenyl)-, -N(CO-(CH2)Vio-COOH)-or-NH-; and ils physiologically acceptable salts.
3. 3. A compound of the formula I as claimed in claim 1 or 2, wherein R2, R4, R5, R6 independently of one another are H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(Ci-C6)-alkyl, CONH2, CONH(CrC6)-alkyl,CON[(C-|-C6)-alkyl]2. (CT-Cs^alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C-i-C6)-alkyl, where one, more or ail hydrogens in the alkyl radicale maybe replaced by fluorine; SO2-NH2> SO2NH(CrC6)-aIkyl, SOzN^C^C^-alkyllz , S-iCrCeJ-alkyl, S-(CH2)n-phenyl, SO-(Ci-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(Ci-C6)-alkyl,SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may besubstituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O- (CrC6)-alkyl, (Ci-CB)-alkyl, NH2; NH2, NH-(Ci-C6)-alkyl, NtfCrCsJ-alkylk, NH^^-acyl, phenyl, 0-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may be mono- totrisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-CCn-CeJ-alkyl,(CrC6)-alkyl, NH2, NH(CrC6)-alkyl, N((CrC6)-alkyl)2, SO2-CH3, COOH,COO-(CrC6)-a!kyl, CONH2; R1, R3 independently of one another are -(CH2)0.i-NH-(C=O) o-i-(Co-C25)- alkylene-(C=O)0.1-N(R13)0-i-(LAG) or -(CH2)0-i-(C=O)0-i-NH-(C0-C25)-alkylene-(C=0)o-i-N(R13)0_i-(LAG); where one or more carbon atoms ofthe alkylene radical are replaced by aryl or heteroaryl radicalssubstituted up to three times by R7, or by (C3-Cio)-cycloalkyl orheterocycloalkyl radicals substituted up to three times by R7 and whereone or more carbon atoms of the alkylene radical may be replaced byoxygen atoms; 62 072868 H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(Cn-C6)-alkyl, CONH2,CONH(CrC6)-alkyl, CON[(C,-C6)-alkyl]2, (CrC6)-alkyi, (C2-C6)-alkenyl, 5 (C2-C6)-alkynyl, O-(Ci-C6)-alkyl, where one, more or ail hydrogens in the alkyl radicals may be replaced by fluorine; SO2-NH2, SO2NH(Ci-C6)-alkyl, SO2N[(C-i-C6)-alkyl]2, S-iCrCel-alkyl, S-(CH2)n-phenyl, SO-(CrC6)-alkyl, SO-(CH2)n-phenyl, SO2-(Ci-C6)-alkyl,SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be 10 substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O- (CrCeJ-alkyl, (CrC6)-aIkyl, NH2; NH2, NH-iCn-Cei-alkyl, N((CrC6)-alkyl)2, NHCCrCyJ-acyl, phenyl, 0-(CH2)n-phenyl, where n = 0 - 6, the phenyl ring may be mono- totrisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-alkyl, 15 (CvCsJ-alkyl, NH2, NH(CrC6)-alkyl, NftCrCej-alkylk, SO2-CH3, COOH, COO-(Ci-C6)-alkyl, CONH2; R7 is F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(CrC6)-alkyl, CONH2, CONH(Ci-C6)-alkyl, CON[(CrC6)-alkyl]2, (CrCeJ-alkyl, (C2-C6)-alkenyl, .20 (C2-C6)-alkynyl, O-(C1-Ce)-alkyl, where one, more or ail hydrogens in the alkyl radicals may be replaced by fluorine; PO3H2, SO3H, SO2-NH2i SO2NH(Ci-C6)-alkyl, SOzNRCÆyalkylb , S-(CrC6)-alkyl, S-(CH2)n-phenyl, SO-(C-i-C6)-alkyl, SO-(CH2)n-phenyl,SO2-(Ci-C6)-alkyl, SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl 25 radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(CrC6)-alkyl, (CrC6)-alkyl, NH2; C(NH)(NH2), NH2i NH-(CrC6)-alkyl, N((C1-C6)-alkyi)2, NH(CrC7)-acyl,phenyl, O-(CH2)n-phenyl, where n = 0 - 6, where the phenyl ring may bemono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(Cr 30 C6)-alkyl, (CrCsJ-alkyl, NH2, NH(CrC6)-alkyl, N((C1-C6)-alkyl}2, SO2- CH3, COOH, COO-(CrC6)-alkyl, CONH2; 63

   (LAG)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 aminoacids; an acyclic, mono-, di- ortricyclic trialkylammonium radical, an acyclic mono-, di- or tricyclic trialkylammoniumalkyl radical, -O-(SO2)-OH;-(CH2)o-io-S03H; -(CH2)o-10-P(0)(OH)2, -{CH2)0.10-O-P(O)(OH)2i-(CH2)q.10-COOH, -(CH2)o-io-C(=NH)(NH2); -(CH2)0.10-C(=NH)(NHOH);-NR8-C(=NR9)(NR10R11); where n = 1 - 5 and R8, R9, R10 and R11independently of one another may be H, (C-i-CeJ-alkyl, phenyl, (Ci-C6)-alkyl-phenyl, (C3-Ca)-cycloalkyl), R13 . isHorCH3; and where in each case at least one of the radicals R1 or R3 must hâve the meaning-(CH2)o.1-NH-(C=0) o.1-(C0-C25)-alkylene-(C=0)o.1-N(R13)o-r(LAG) or -(CH2)0-i-(C=0)o.i-NH-(C0-C25)-alkylene-(C=0)o-i-N(R13)o-i-(LAG) and one or more carbonatoms of the alkylene radical are replaced by up to trisubstituted aryl or heteroarylradicals or by up to trisubstituted (C3-C10)-cycloalkyl or heterocycloalkyl radicals andmay additionally be replaced by -S(O)n-, where n = 0 - 2, -0-, -(C=O)-, -N(CH3)-,-N(phenyl)-or-NH-; and its physiologically acceptable salts.
4. 4. A compound of the formula I as claimed in one or more of daims 1 to 3, wherein LAG is a monosugar residue, an acyclic mono-, di- or tricyclic trialkylammoniumalkyl radical, a sulfonic acid or a carboxylic acid, and its pharmaceutically acceptable salts.
5. 5. A médicament comprising one or more compounds as claimed in one or more 64 012868 of daims 1 to 4.
6. 6. A médicament comprising one or more compounds as ciaimed in one or moreof daims 1 to 4 and at least one further active compound. 5
7. 7. The médicament as ciaimed in daim 6, comprising, as further activecompound, one or more compounds which normaiize lipid metaboiism.
8. 8. The médicament as ciaimed in daim 6 or 7, which comprises, as further 10 active compound, one or more . antidiabetics, hypoglycemically active compounds, HMGCoA reductase inhibitors,cholestérol 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 15 inhibitors, antioxidants, iipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins;sulfonylureas, biguanides, meglitinides, thiazolidinediones, α,-glucosidase inhibitors,active compounds which act on the ATP-dependent potassium channel of the betacells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, 20 TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists,MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin-reuptakeinhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesinagonists, galanin antagonists, growth hormones, growth hormone-releasingcompounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA 25 agonists (bromocriptine, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-p-agonists or amphétamines.
9. 9. A compound as ciaimed in one or more of daims 1 to 4 for use as amédicament for the treatment of impaired lipid metaboiism.
10. 10. A process for preparing a médicament comprising one or more of the 30 65 Ο 12 β g g compounds as claimed in one or more of daims 1 to 4, which comprises mixing theactive compound with a pharmaceuticaily acceptable carrier and bringing this mixtureinto a.form suitable for administration. 5 '11. The use of the compounds as claimed in one or more of daims 1 to 4 forpreparing a médicament for treating hyperlipidemia.
11. 12. The use of the compounds as claimed in one or more of daims 1 to 4 forpreparing a médicament for lowering the sérum cholestérol concentration. 10
12. 13. The use of the compounds as claimed in one or more of daims 1 to 4 forpreparing a médicament for treating arteriosclerotic manifestations.
13. 14. The use of the compounds as claimed in one or more of daims 1 to 4 for15 preparing a médicament for treating insulin résistance.