OA12869A - Diphenyl azetidinones substituted by acidic groups, method for their production, medicaments containing said compounds and use thereof. - Google Patents

Diphenyl azetidinones substituted by acidic groups, method for their production, medicaments containing said compounds and use thereof. Download PDF

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OA12869A
OA12869A OA1200400331A OA1200400331A OA12869A OA 12869 A OA12869 A OA 12869A OA 1200400331 A OA1200400331 A OA 1200400331A OA 1200400331 A OA1200400331 A OA 1200400331A OA 12869 A OA12869 A OA 12869A
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alkyl
crc6
phenyl
cooh
compounds
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OA1200400331A
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Gerhard Jaehne
Wendelin Frick
Stefanie Flohr
Andreas Lindenschmidt
Heiner Glombik
Werner Kramer
Hubert Heuer
Hans-Ludwig Schaefer
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Aventis Pharma Gmbh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/568—Four-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract

The invention relates to compounds of formula (I), in which R1, R2, R3, R4, R5 and R6 are defined as cited, in addition to their physiologically compatible salts. The compounds are suitable for use e.g. as hypolipidaemics.

Description

1 01286
Description
Diphenyl azetidinones substituted by acidic groups, method fortheir productionmédicaments containing said compounds and use thereof
The invention relates to acid-group-substituted diphenylazetidinones, to theirphysiologically acceptable salts and to dérivatives having physiological functions.
Diphenylazetidinones (such as, for example, ezetimibe) and their use for treating 10 hyperlipidemia 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 atherapeutically utilizable hypolipidémie action. In particular, it was an object to find 15 novel 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 Îess than 10%, preferably less than or equal to 5%.
In particular, absorption of the novel compounds must be less than that of ezetimibe. 20 Pharmaceutically active compounds which are absorbed to a low extent generallyhâve considerably fewer side-effects. 012869
Accordingly, the invention relates to compounds of the formula I
5 in which R1, R2, R3, R4, R5, R6 independently of one another are (C0-C30)- alkylene-(LAG)n, where n may be 1 - 5 and where one or more carbonatoms of the alkylene radical may be replaced by -S(O)n-, where η = Ο - Ι 0 2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -CEC-, -N((C-,-C6)-alkyl)-, -N(phenyl), -N((Ci-C6)-alkyl-phenyl)- , -NCCO-ÎCHzjvw-COOH)- or -NH-; H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(Ci-CB)-alkyl, CONH2,CONHiCrCeJ-alkyl, CONRCrCe^alkylh, (CvCeJ-alkyl, (C2-C6)-alkenyl, 15 (C2-C6)-alkynyl, O-(Ci-C6)-alkyl, where one, more or ail hydrogens in the alkyl radicals may be replaced by fluorine; C(=NH)(NH2), PO3H2, SO3H, SO2-NH2i SO2NH(C1-C6)-alkyl,SOzNKCrCeJ-alkylfc , S-(CrC6)-alkyl, S-(CH2)n-phenyl, SO-(CrC6)-alkyl, SO-(CH2)n-phenyl, SO^CrOeJ-alkyl, SO2-(CH2)n-phenyl, where n 20 may be 0 - 6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-alkyl, (CrCeJ-alkyl,NH2; NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NHiCrC^-acyl, phenyl,O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring may be 25 mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, 0-(Cr 012869 C6)-alkyl, (CrC6)-alkyl, NH2) NH(CrC6)-alkyl, N((CrC6)-alkyl)2, SO2-CH3i COOH, COO-(CrC6)-alkyl( CONH2; (LAG)n is -(CHzÎMo-SOaH, -(CH2)0.10-P(O)(OH)2, (CH2)0-10-O-P(O)(OH)2,-(CH2)0-io-COOH and n may be 1 - 5; where in each case at least one of the radicals R1 to R6 must hâve the meaning(Co-C3o)-alkylene-(LAG)n, where n = 1 - 5 and where one or more carbon atoms ofthe alkylene radical are replaced by -S(O)n-, where n = 0 - 2, -0-, -(C=O)-, -(C=S)-,-CH=CH-, -CEC-, -N((Ci-C6)-alkyl)-, -N(phenyl)-, -N^CvCg^alkyl-phenyl)-,-N(CO-(CH2),.10-COOH)- or -NH-, and their pharmaceutically acceptable salts; except for the compound 2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonic acidand those compounds in which the radicals R1 - R6 hâve the meaning-O-(CH2)1.10-COOH, (CrCeValkylene-COOH or-COOH.
Preference is given to compounds of the formula I where at least one of the radicalsR1 to R6 has the meaning (Co-C3o)-alkylene-(LAG), where one or more carbonatoms of the alkylene radical may be replaced by -O-, -(C=O)-, -N((CrC6)-alkyl)-,-NCCO-CCHzJmo-COOH)- or -NH-.
Particular preference is given to compounds of the formula I where one of theradicals R1 or R3 has the meaning (Co-C3o)-alkylene-(LAG), where one or morecarbon atoms of the alkylene radical may be replaced by -O-, -(C=O)-, -N(CH3)-, or-NH-.
Very particular preference is given to compounds of the formula l where one of theradicals R1 or R3 has the meaning -(CH2)o.i-Y-W-(Co-C25)-alkylene-Y’-W’-(LAG);where one or more carbon atoms of the alkylene radical may be replaced by oxygenatoms and where Y and W independently of one another may be NH, NCH3, C=O, 4 012869 O, a bond or S(O)n, where n = 0 - 2, and Y’ and W’ independently of one anothermay be NH, NCH3, C=O, O, a bond or S(O)n, where n = 0 - 2, or Y-W or Y’-W’ ineach case together may be a bond.
Preference is furthermore given to compounds of the formula I where the group LAGis a carboxylic acid radical or a sulfonic acid radical.
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. Suitablepharmaceutically 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, lacticacid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid, for example. For medicalpurposes, 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).
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/orfor use in nontherapeutic, forexample in vitro, applications.
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).
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.
The compounds according to the invention can also be présent in variouspolymorphous.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.
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 anddérivatives having physiological function are idéal médicaments for treating animpaired lipid metabolism, in particular hyperlipidemia. The compounds of theformula 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 withother active compounds.
The amount of a compound of the formula (I) 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 theclinical 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-azetidinone-ion derived from the sait. For the prophylaxis or therapy of theabovementioned conditions, the compounds of the formula (I) can be used 012869 themselves as the compound, but preferably they are présent in the form of apharmaceutical composition with an acceptable carrier. The carrier must of coursebe acceptable in the sense that it is compatible with the other constituents of thecomposition 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 compositionsaccording to the invention can be prepared by one of the known pharmaceuticalmethods, which essentially consist in mixing the constituents with pharmacologicallyacceptable carriers and/or auxiliaries.
Pharmaceutical compositions according to the invention are those which are suitablefor oral or pérorai (e.g. sublingual) administration, although the most suitable mannerof administration is dépendent in each individual case on the nature and severity ofthe 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, polyvinylacetate 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, whichin 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 canconsist 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/or finely divided solid carrier, after which the product, if necessary, 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 moreadditional 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 suitablemachine.
I
Pharmaceutical compositions which are suitable for pérorai (sublingual) administration include lozenges which contain a compound of the formula (I) with aflavoring, customarily sucrose and gum arabic ortragacanth, and pastilles whichinclude the compound in an inert base such as gelatin and glycerol or sucrose andgum arabic.
Suitable other active compounds for the combination préparations are: ail antidiabetics mentioned in Rote Liste 2001, Chapter 12. They can be combinedwith the compounds of the formula I according to the invention in particulartoachieve 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 A/S in WO 98/08871, and oral hypoglycémie active compounds.
The oral hypoglycémie active compounds preferably include sulfonylureas,biguadines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidaseinhibitors, glucagon antagoniste, 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, compounds 012869 which 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 areadministered in combination with an HMGCoA reductase inhibitor such assimvastatin, fiuvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin,rosuvastatin.
In one embodiment of the invention, the compounds of the formula l areadministered in combination with a cholestérol absorption inhibitor, such as, forexample, ezetimibe, tiqueside, pamaqueside.
In one embodiment of the invention, the compounds of the formula I areadministered 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 areadministered in combination with a PPAR alpha agonist, such as, for example, GW9578, GW 7647.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with a mixed PPAR alpha/gamma agonist, such as, forexample, GW 1536, AVE 8042, AVE 8134, AVE 0847.
In one embodiment of the invention, the compounds of the formula I areadministered 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- 6 9 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, forexample, HMR 1453.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, such as, for example, Bay194789.
In one embodiment of the invention, the compounds of the formula I are 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 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 I are administered in combination with an ATP citrate lyase inhibitor, such as, for example,SB-204990. 10 012869
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-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,CI-1027 or nicotinic acid.
In one embodiment of the invention, the compounds of the formula I are 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 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.
In another embodiment, the compounds of the formula I 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 inWO 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 combinationwith an active compound which acts on the ATP-dependent potassium channel of 012869 11 beta 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 combinationwith 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 incombination with CART agonists, NPY agonists, MC3 and MC4 agonists, orexinagonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortinagonists, 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 modulators, 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 or-muesli bars. Compared to the individual active compounds, the combination of 01286 9 12 compounds 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 andthe pure stereoisomers of the formula I, and diastereomer mixtures of the formula Iand the pure diastereomers. The mixtures are separated by chromatographiemeans.
Preference is given to both racemic and enantiomerically pure compounds of theformula I of the following structure: R1
R4
Amino protective groups that are preferably used are the benzyloxycarbonyl (Z)radical, which can be removed by catalytic hydrogénation, the 2-(3,5-dimethyloxyphenyl)propyl(2)oxycarbonyl(Ddz) ortrityl (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. 012869 13
The invention furthermore relates to a process for preparing diphenylazetidinonedérivatives of formula I.
5 Y can be S, O, (C=O), (C=S), CH=CH, CEC, N((Ci-C6)-alkyl), N(phenyl), N((CrC6)-alkyl-phenyl), N(CO-(CH2)i-io-COOH) or NH; R11 can be H or, if Y = (C=O) or (C=S), OH; W, Y' and W’ can, independently of one another and of Y, be -S(O)n-, where n = 0 - 10 2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -CEC-, -N((CrC6)-alkyl)-, -N(phenyl), -N((C1-C6)- alkyl-phenyl)-, -N(CO-(CH2)i-io-COOH)- or -NH- or a bond;x, y and z independently of one another can be 0 to 10.
In compound II, -(CH2)x-Y-R11 can alternatively also be attached to one of the other 15 two phenyl rings.
The process for preparing compounds of the formula I comprises reacting, forexample, an amine or a hydroxy compound of the formula II with an alkylating oracylating agent which, preferably in the oméga position, carries a further 20 functionality- if appropriate in protected form. This functionality is (after deprotection)used for attaching (LAG), for example with the formation of ether, amine or amidebonds. 012869 14
The examples below serve to illustrate the invention in more detail, without limitingthe invention to the products and embodiments described in the examples.
5 Example I 4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylamino}butane-1-sulfonic acid (6):
10 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-fluorophenyI)-pentanoylJ-4-phenyloxazolidin-2-one (1) of molecular weight471.65 (C26H34FNO4S1); MS (ESI):340.28 (MH+- HOSi(CH3)2C(CH3)3). 012865 15 b) 4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo- 4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile (2): 16.2 g of 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fIuorophenyl)-pentanoyl]-4-phenyl-oxazolidin-2-one are dissolved in 350 ml of dichloromethane. 19.8 ml of Hünig baseand 10.14 g of 4-[(4-methoxyphenylimino)methyl]benzonitrile are added, and thesolution is cooled to -10°C. 8.52 ml of trimethylsilyl triflate are added to the cooledsolution, 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 isstirred at from -30 to -40°C for 2 h. The solution is then allowed to warm to roomtempérature and the reaction solution is washed successively with 200 ml of 2Nsulfuric 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-fluoro-phenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentyl-aminojbenzonitrile (2)of molecular weight 707.93 (C41H46FN3O5S1); MS (ESI): 590.51(MH+- C7H5N2). c) 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1 -yl]benzonitrile (3): 13.2 g of 4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile are dissolved in380 ml of methyl tert-butylether, 18.6 ml of N,O-bis(trimethylsilyl)acetamide and 1.86ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added andthe mixture is stirred at room température for 2 h. After the reaction has ended, 10ml of acetic acid are added, the réaction mixture is concentrated under reducedpressure and the residue is purified on silica gel using toluene/ethyl acetate 50/1.
This gives 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4- 012869 16 methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (3) of molecular weight 544.75(C32H37FN2O3S1); MS (ESI): 545.56 (M+H+). d) 4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]- benzonitrile (4): 3.5 g of 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile are dissolved in 65 ml oftetrahydrofuran, 0.74 ml of acetic acid and 8.03 ml of a 1 M solution oftetrabutylammonium fluoride in tetrahydrofuran are added and the mixture is stirredat room température for 2 h. Another 4.82 ml of the tetrabutylammonium fluoridesolution are then added, and the mixture is stirred at reflux température for another3 h. The cooled reaction mixture is concentrated under reduced pressure and theresidue 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-oxoazetidin-1-yl]-benzonitrile (4) of molecular weight 430.48 (C26H23FN2O3); MS(ESI): 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-yl]-benzonitrile 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 60°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 silicagel chromatography using dichloromethane/methanol/ammonia solution 10/1/0.1.This gives 1 -(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4- 17 012869 methoxyphenyl)-azetidin-2-one (5) of molecular weight 434.51 (C26H27FN2O3); MS(ESI): 418.2 (MH+-NH3). f) 4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxo-azetidin-1-yl]benzylamino}butane-1-sulfonic acid (6):
At room température, 87 mg of the above benzylamine are dissolved in 3 ml of dryacetonitrile, 40 pl of 1,4-butanesultone are added and the mixture is heated underreflux for 12 h. The cooled reaction solution is concentrated under reduced pressureand purified chromatographically (silica gel; dichloromethane/methanol 85/15 + 10%water). This gives 4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylamino}butane-1-sulfonic acid (6) of molecular weight 570.69(CaoHssFNzOeS); MS (ESI): 553.28 (MH+- H2O).
Example II 2-[(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyI)-4-oxoazetidin-1-yl]phenoxy}butyl)methylamino]ethylsulfonic acid (8): OMe
OH 130 mg of 3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(4-fluorobutoxy)phenyl]-4-(4-methoxyphenyl)azetidin-2-one (7) are dissolved in 6 ml of absolute methanol. 120 mgof N-methyltaurine in 2 ml of water and 60 mg of potassium carbonate are thenadded. The mixture is stirred at 50°C for 24 h. The reaction mixture is concentratedusing a rotary evaporator and the residue is purified by préparative chromatography.Freeze-drying gives the product (50 mg) as an oil. 18 012869 C32H39FN2O7S ESIMS m/z: 614 (M+)
5 Example III
[2-(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenoxy}butylamino)ethyl]phosphonic acid (9):
// s
O OH 10 200 mg of 3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(4-fluorobutoxy)phenyl]-4-(4-methoxyphenyl)azetidin-2-one (7) are dissolved in 6 ml of absolute methanol. 165 mgof 1-aminoethylphosphate and 247 mg of potassium carbonate dissolved in 3 ml ofwater are then added. The mixture is stirred at 90°C for 8 h. The reaction mixture is 15 concentrated using a rotary evaporator and the residue is purified by préparativechromatography. Freeze-drying gives the product (47 mg) as an oil. C3iH38FN2O7P ESIMS m/z: 600 (M+) 20
Example IV
Phosphoric acid mono-{6-[4-(4-{1 -(4-fluorophenyI)-3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-y!}phenoxy)butylamino]hexyl}ester (10):
19 012869 115 mg of 1-(4-fluorofluorophenyl)-3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-4-[4-(2-fluoromethoxyethoxy)phenyl]azetidin-2-one (7) are dissolved in 6 ml of absolutemethanol. 130 mg of 6-amino-1-hexyl phosphate in 1.5 ml of waterand 107 mg ofpotassium carbonate are then added. The mixture is stirred at 70°C overnight. Thereaction mixture is concentrated using a rotary evaporator and the residue is purifiedby préparative chromatography. Freeze-drying gives the product as an oil.C34H43F2N2O7P ESIMS m/z: 660 (M+)
Example V 4-{4-[3-[3-(4-fluorofluorophenyl)-3-hydroxypropyI]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenoxy)butane-1-sulfonic acid (12): OMe
OH 160 mg of 3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)azetidin-2-one (11 ) are dissolved in 4 ml of absolute dimethylformamide.210 mg of powdered potassium carbonate and 42 mg of 1,4,-butanesultone are added.The mixture is stirred at room température overnight. The reaction solution isconcentrated under oil pump vacuum, taken up in dichloromethane and washed 1 x withwater. The aqueous phase is acidified with 2N hydrochloric acid and extracted 2x withdichloromethane. The combined organic phases are dried over sodium sulfate andconcentrated. The residue is chromatographed on a 10 g S1O2 cartridge(dichloromethane/ methanol = 5/1). The product (72 mg) is obtained as an oil. C29H32FNO7S ESIMS m/z: 557 (M+)
20
Example VI 4-(4-(1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-phenoxy)butane-1-sulfonic acid (13):
o 250 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxy-phenyl)azetidin-2-one (7) are dissolved in 6 ml of absolute dimethylformamide. 337 mg 10 of powdered potassium carbonate and 69 pl of 1,4,-butanesultone are added. The.mixture is stirred at room température overnight. The reaction solution is filtered andconcentrated under oil pump vacuum. The residue is chromatographed on a 10 g SiO2cartridge (dichloromethane/methanol = 5/1) and crystallized from diethyl ether. Theproduct (131 mg) is obtained as a solid. 15 C28H29F2NO6S ESIMS m/z: 546 (M+)
Example VII 20 3-(4-(1 -(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}- phenoxy)propan-1-sulfonin acid (14): 21 012869
F
25Q mg of 1-(4-fIuorophenyl)-3-[3-(4-fiuorophenyl)-3-hydroxypropyl]-4-(4-hydroxy-pheny!)azetidin-2-one (7) are dissolved in 6 ml of absolute dimethylformamide. 337 mg 5 of powdered potassium carbonate and 59 μΙ of 1,3,-propanesultone are added. Themixture is stirred at room température overnight. The reaction solution is filtered andconcentrated under ail pump vacuum. The residue is chromatographed on a 10 g SiO2cartridge (dichloromethane/methanol = 5/1) and crystallized from diethyl ether. Theproduct (250 mg) is obtained as a solid. 10 C27H27F2NO6S ESIMS m/z: 532 (l\T)
Example VIII 15 (4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-y!}-benzylcarbamoyl)methanesulfonic acid (18):
20 072869 22 a) 4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)-pentyl]-benzonitrile (15):
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)-methylj-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. The mixtureis stirred at this température for 1 additional hour and then cooled to -25°C. 0.8 ml oftitanium tetrachloride are then added slowly. The dark mixture is stirred at from -25to -30°C overnight and then decomposed using 35 ml of a 7 percent strengthsolution of tartaric acid and then stirred at room température for another hour. 15 mlof a 20 percent strength solution of sodium bicarbonate are then added, and themixture is again stirred for 1 hour. Following phase séparation, the organic phase iswashed with 30 ml of water, dried over magnésium sulfate and concentrated to about10 ml. Following the addition of 2 ml of bistrimethylsilylacetamide, the mixture isheated at reflux for 30 min and then concentrated under reduced pressure. Theresidue is crystallized using ethyl acetate/heptane. The product is filtered off withsuction and dried under reduced pressure. This gives the product of molecularweight 653.81 (C37H37F2N3O4Si); MS (ESI+): 654.3 (M+H+), 582.2 (M+H+-Si(CH3)3). b) {1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzonitrile (16): 2 g of 4-[5-(4-Fluorophenyl)-1 -(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyl-oxazolidine-3-carbonyl)-pentyl]-benzonitrile (15) are dissolved in 20 ml of methyl-tert-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 ismonitored by thin-layer chromatography. Aller the reaction has ended, 0.2 ml ofglacial acetic acid is initially added and the mixture is stirred for 30 min and thenconcentrated. 20 ml of a mixture of isopropanol/2N sulfuric acid = 10:1 are added to 012869 23 the residue, and the mixture is stirred for 1 hour. Foilowing 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 columnchromatography (SiO2, CH2Cl2/methanol = 100:1). This gives the product ofmolecular weight 418.45 (C25H20F2N2O2); MS (DCI+): 419 (M+lT). c) 4-(4-Aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-» hydroxypropyl]-azetidin-2-one (17): 200 mg of {1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzonitrile (16) 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 at25°C for 30 hours. The catalyst is filtered off with suction, the mixture is concentratedunder reduced pressure and the residue is purified by column filtration (SiO2,ChhCh/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). d) (4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)methanesulfonic acid (18): A solution of 120 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluoro-phenyl)-3-hydroxypropyl]azetidin-2-one (17), 48 μ! of diisopropylethylamine in 1 ml ofdimethylformamide is added to a solution of 40 mg of sulfoacetic acid, 110 μΙ ofdiisopropylcarbodiimide, 76 mg of hydroxybenzotriazole in 2 ml of dimethyl-formamide, and the mixture is stirred at room température for 12 h. The reactionsolution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C18,water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) = 80/20 ->10/90). This gives the product of molecular weight 544.58 (C27H26F2N2O6S1); MS(ESI) 527.10 (M + H+- H2O) 24 012869
Example IX 5 {4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzylcarbamoyl}methanesulfonic acid (19):
10 A solution of 60 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-
propyl]-4-(4-methoxyphenyl)azetidin-2-one (5) in 1 ml of dimethylformamide is addedto a solution of 20 mg of sulfoacetic acid, 55 pl of diisopropylcarbodiimide, 38 mg ofhydroxybenzotriazole in 1 ml of dimethylformamide, and the mixture is stirred at roomtempérature for 12 h. The reaction solution is concentrated and separated by HPLC 15 (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1%trifluoroacetic acid) = 80/20 -> 10/90). This gives the product of molecular weight556.61 (CzsHbFTNzOySi); MS (ESI) 539.05 (M + H+- H2O) 20
Example X N-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzyl)succinaminic acid (20): 25 012869
A solution of 100 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluoro-phenyl)-3-hydroxypropyl]azetidin-2-one (17), 33 pl of triethylamine in 2 ml of 5 dimethylformamide is added to a solution of 279 mg of succinic acid, 92 pl ofdiisopropylcarbodiimide, 80 mg of hydroxybenzotriazole in 2 ml of dimethyl-formamide, and the mixture is stirred at room température for 12 h. The reactionsolution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C18,water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) = 80/20 ->
10 10/90). This gives the product of molecular weight 522.55 (C27H26p2N2O6St); MS (ESI) 545.19 (M + Na+)
15 Example XI {2-[2-({4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin1-yl]benzylcarbamoyl}methoxy)ethoxy]ethoxy}acetic acid (21):
A solution of 64 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy- 26 propyl]-4-(4-methoxyphenyl)azetidin-2-one (5), 21 pl of triethylamine in 1 ml ofdimethylformamide are added to a solution of 327 mg of 3,6,9-trioxaundecanedioicacid, 57 μΙ of diisopropylcarbodiimide, 50 mg of hydroxybenzotriazole in 2 ml ofdimethylformamide, and the mixture is stirred at room température for 12 h. Thereaction solution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonîtrile (0.1% trifluoroacetic acid) =80/20 -> 10/90). This givesthe product of molecular weight 638.70 (Ca^gF^Og);MS (ESI) 639.27 (M + H+)
Example XII 4-((3-Carboxypropionyl)-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxy-phenyl)-4-oxoazetidin-1 -yl]benzyl}amino)-4-oxobutyric acid (22):
A solution of 70 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-propyl]-4-(4-methoxyphenyl)azetidin-2-one (5), 23 μΙ of triethylamine in 1 ml ofdimethylformamide is added to a solution of 190 mg of succinic acid, 63 μΙ ofdiisopropylcarbodiimide, 55 mg of hydroxybenzotriazole in 2 ml of dimethyl-formamide, and the mixture is stirred at room température for 12 h. The reactionsolution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C18,water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) = 80/20 ->10/90). This gives the product of molecular weight 634.4 (C34H35F1N2O9); MS (ESI-neg.) 633.22 (M - H+) 27 012869
Example XIII 11-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}undecanoic acid (23):
. A solution of 70 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-propyl]-4-(4-methoxyphenyl)azetidin-2-one (5), 23 pl of triethylamine in 1 ml of10 dimethylformarnide is added to a solution of 371 mg of dodecanedioic acid, 63 μΙ of diisopropylcarbodiimide, 55 mg of hydroxybenzotriazole in 2 ml ofdimethylformarnide, and the mixture is stirred at room température for 12 h. Thereaction solution is concentrated and separated by HPLC(Knauer Eurospher-100-10C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) = 80/20 15 . -> 10/90). This gives the product of molecular weight 646.81 (CseFUyFtNzOe); MS(ESI) 647.35 (M + H+)
Table 1: Compounds of the formula I
012869 28
Ex. R1, R2 R3, R4 R5, R6 Molecularweightof the free baseor acid(calculated) Molecular weight (found) XIV 0../,° para '"OH para-F, H para-F, H 531.58 532.4 (MH+) XV H 0 para . H /"OH para-F, H para-F, H 502.54 503.3 (MH+) XVI para-F, H H P para \ , H o"S'» para-F, H 514.58 515.4 (MH+) XVII para-O-CH3, H 0 0 _ AA/V° .h para H * OH para-F, H 599.68 599.21 (M+) XVIII para-O-CK3, H /"'"Sz - pars para-F, H 739.95 740.42 (MH+) XIX para-O-CH3, H iî o ~ X .^j/ par.'^'N^N OH .H OH para-F, H 599.60 600.34 (MH+) XX para-O-CH3, H 0 pars , h H OH para-F, H 534.59 534.4 (MH+) XXI « Ï H per· Jk. ‘ " 0 para-F, H para-F, H 578.66 561.25 (MH+- H2O) XXII P"» JL .H Y ^OH 0 para-F, H para-F, H 634.77 617.31 (MH+- H2O) XXIII para-F, H 0 0 ·η para-F, H 585.65 567.70 (MH+- h20) XXIV para-O-CH3, H 0../° .h para-F, H 557.64 557.19 (M+) 29 012869 XXV H 0 VO para V χ-ν. x·*^ Xs. χ·^ ,P. . h Para-F, H para-F, H 650.70 660.28 (M+) XXVI para-O-CH3, H « 0- para-F, H 600.62 600.24 (M*) XXVII para-O-CH3, H I «« .H o' *0 para-F, H 614.73 597.32 (M- H2O)+1 XXVIII LJ U 0 H H h para .H /"on para-F, H para-F, H 559.64 560.4 (MH*) XXIX χ-\ ζχ,χίί .H para/ n x$ H θ'' OH para-F, H para-F, H 545.61 546.3 (MH*) XXX - JT\ pa. para-F, H para-F, H 727.91 710.23 (MH+- H2O) XXXI para-O-CH3, H cf^S/ - "'X h pat? para-F, H 753.93 752.32 (M-H*); measured in négative mode XXXII °>-R Λ« -H para n*» ü OH para-F,H para-F, H 573.62 572.09 (M-H+); measured in négative mode XXXIII /VS para z H HN-^ ·M V ,?^OH 0 para-F, H para-F, H 587.67 586.18 (M-H+); measured in négative mode
Usirg the method described below, the activity of the compounds of the formula Iaccording to the invention was examined: 30 012869
Effect on cholestérol absorption + 3H-taurocholic acid excrétion using fecal 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 afternoon prior to the administration of the radioactive tracers (14C-cholesterol),the feed is removed and the animais are adapted to grates.
Additionally, the animais are labeled s.c. with 3H-TCA (taurocholic acid) (for example.1 pCi/mouse up to 5 pCi/rat) 24 hours prior to the pérorai administration of the testmeal (14C-cholesterol in Intralipid® 20, Pharmacia-Upjohn).
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.
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).
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 oximate(Model 307, Packard) to détermine the amount of 14C-cholesteroI which had beentaken up/absorbed.
Evaluation:
Feces samples: 31
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 labeled samples): the amount of radioactive 3H-H2O and 14C-CO2 is extrapolated 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.
I
Liver samples:
The amount of 14C-cholesterol taken up by the liver is based on the administereddose. The ED5o values are interpolated from a dose-effect curve as the dose at whichthe uptake of 14C-cholesterol by the liver is halved (50%), based on a control group.
The ED50 values below demonstrate the activity of the compounds of the formula Iaccording to the invention
Example No. ED50 (liver) [mg/mouse] I 1.0 II > 0.1 IV 0.3 VIII 0.3 IX < 1.0 X < 1.0 XIII < 0.1 XVIII 0.005 XXI 0.1 XXII 0.1 XXV 0.3 XXVIII 0.3
32
As can be seen from the table, the compounds of the formula I hâve very goodcholesterol-lowering action.
Bioabsorption:
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). 10 From the measured data, it can be seen that the bioabsorption of the compounds ofthe formula I according to the invention is considerably lower than that of thecompounds described in the prior art (reference structure):
OH
Reference structure:Ezetimibe

Claims (14)

  1. 33 012869 Patent daims:
    1. A compound of the formula I,
    in which R1, R2, R3, R4, R5, R6 independently of one another are (C0-C30)- alkylene-(LAG)n, where n may be 1 - 5 and where one or more carbonatoms of the alkylene 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((Ci-C6)-alkyl-phenyl)-, -N(CO-(CH2)i.10-COOH)- or -NH-; H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COOiCrCeJ-alkyl, CONH2,CONH(CrC6)-alkyl, CONKC-rCeJ-alkylh. (CvCeJ-alkyl, (C2-C6)-alkenyl,(C2-C6)-alkynyl, O-(CrC6)-alkyl, where one, more or ail hydrogens in thealkyl radicals may be replaced by fluorine; C(=NH)(NH2), PO3H2i SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(CrC6)-alkyl]2, S-CCrCeJ-alkyl, S-(CH2)n-phenyl, SO-(CrC6)-alkyl, SO-(CH2)n-phenyl, SO2-(Ci-C6)-alkyl, SO2-(CH2)n-phenyl, where n = 0 - 6and the phenyl radical may be substituted up to two times by F, CI, Br,OH, CF3, NO2i CN, OCF3, O-(CrC6)-alkyl, (CrC6)-alkyl, NH2; 012869 34 NH2, NH-iCrCeJ-alkyl, N((CrC6)-alkyl)2, NH(CrC7)-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring may bemono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(CrC6)-alkyl, (CrC6)-alkyl, NH2, NH(CrC6)-alkyl, N((CrC6)-alkyl)2, SO2-CH3, COOH, COO-(CrC6)-alkyl, CONH2; (LAG)n is -(CHzK-.o-SOsH, -(CH2)0.10-P(O)(OH)2, -(CH2)0.10-O-P(O)(OH)2,-(CH2)o-io-COOH and n may be 1 - 5; where in each case at least one of the radicals R1 to R6 must hâve the meaning(Co-C3O)-alkylene-(LAG)n, where n = 1 - 5 and where one or more carbon atoms ofthe alkylene 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((CrC6)-alkyl-phenyl)- ,-NtCO-CCH^.w-COOH)- or -NH-, and its pharmaceutically acceptable salts; except for the compound 2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonic acidand those compounds in which the radicals R1 - R6 hâve the meaning-O-(CH2)i.i0-COOH, (CrCel-alkylene-COOH or -COOH.
  2. 2. A compound of the formula I as claimed in daim 1, wherein R2, R4, R5, R6 independently of one another are H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COOiCrCeJ-alkyl, CONH2, CONHCCrCsJ-alkyl,CON[(Ci-C6)-alkyl]2, (C-i-C6)-aIkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl,O-(C-i-Cs)-alkyl, where one, more or ail hydrogens in the alkyl radicalsmay be replaced by fluorine; C(=NH)(NH2), PO3H2i SO3H, SO2-NH2i SO2NH(Ci-C6)-alkyl, SO2N[(CrCe)-alkyl]2, S-(CrC6)-alkyl, S-(CH2)n-phenyl, SO-(CrC6)-alkyl, SO-(CH2)n-phenyl, SO2-(Ci-C6)-aIkyl, SO2-(CH2)n-phenyl, where n may be 012869 35 0 - 6 and the phenyl radical may be substituted up to two times by F, Cl,Br, OH, CF3, NO2, CN, OCF3, O-iCi-CeJ-alkyl, (Ci-C6)-alkyl, NH2; NH2, NH-(Ci-C6)-alkyl, N((CrC6)-alkyl)2, NH(C1-C?)-acyl, phenyl,O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring, may bemono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(CrCp)-alkyl, (CrC6)-alkyl, NH2, NH(C-i-C6)-alkyl, N((Ci-C6)-alkyl)2, SO2-CH3, COOH, COO-(Ci-C6)-alkyl, CONH2; R1, R3 independently of one another are (Co-C30)-alkylene-(LAG) and whereone or more carbon atoms of the alkylene radical may be replaced by-O-, -(C=O)-, -N(CH3)- or -NH-, H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(Ci-C6)-alkyl, CONH2,CONHiCrCe^alkyl, CON[(Ci-C6)-alkyl]2, (CrC6)-alkyl, (C2-C6)-alkenyl,(C2-C6)-alkynyl, O-(CrC6)-alkyl, where one, more or ail hydrogens in thealkyl radicals may be replaced by fluorine; C(=NH)(NH2), PO3H2i SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(CrC6)-alkyl]2, S-(Ci-C6)-alkyl, S-(CH2)n-phenyl, SO-(C-,-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(Ci-C6)-alkyl, SO2-(CH2)n-phenyl, where n may be0-6 and the phenyl radical may be substituted up to two times by F, Cl,Br, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-alkyl, (Ci-C6)-alkyl, NH2; NH2, NH-(Ci-C6)-alkyl, N((CrC6)-alkyl)2, NH(Ci-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring may bemono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-alkyl, (Ci-C6)-aIkyl, NH2, NH(Ci-C6)-alkyl, N((Ci-C6)-alkyl)2, SO2-CH3, COOH, COO-iCrCeJ-alkyl, CONH2; (LAG) is -(CH2)1.10-SO3H, -(CH2)0-io-P(0)(OH)2, -(CH2)0-io-0-P(0)(OH)2,-(CH2)0.10-COOH; where in each case at least one of the radicals R1 or R3 must hâve the meaning 012869 36 (Co-C3O)-alkylene-(LAG) and where one or more carbon atoms of the alkylene radicalmay be replaced by -O-, -(C=O)-, -N(CH3)- or -NH-,and its pharmaceutically acceptable salts; except for the compound 2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonic acidand those compounds in which the radicals R1 - R6 hâve the meaning-0-(CH2)i-io-COOH, (CrC6)-alkylene-COOH or-COOH.
  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(CrC6)-alkyl, CONH2, CONH(Ci-C6)-alkyl,CON[(C-i-C6)-alkyl]2, (CrC6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(CrC6)-alkyl, where one, more or ail hydrogens in the alkyl radicals maybe replaced by fluorine; C(=NH)(NH2), PO3H2i SO3H, SO2-NH2i SO2NH(CrC6)-alkyl, SO2N[(CrC6)-alkyl]2, S-(CrC6)-alkyl, S-(CH2)n-phenyl, SCHCTCel-alkyl, SO-(CH2)n-phenyl, SO2-(CrC6)-alkyl, SO2-(CH2)n-phenyl, where n may be 0- 6 and the phenyl radical may be substituted up to two times by F, Cl,Br, OH, CF3, NO2i CN, OCF3, O-(CrC6)-alkyl, (CrC6)-alkyl, NH2; NH2, NH-(Ci-C6)-alkyl, N^CrCel-alkylk, NH^-Cri-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring may bemono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(CrC6)-alkyl, (CT-Cel-alkyl, NH2, NH(CrC6)-alkyl, N((Ci-C6)-alkyl)2, SO2-CH3, COOH, COO-iCrCeJ-alkyl, CONH2; R1, R3 independently of one another are -(CH2)o-i-Y-W-(Co-C25)-alkylene-Y’-W’-(LAG), where one or more carbon atoms of the alkylene radical maybe replaced by -O-; λ 0 î 2 8 r 37 Η, F, Cl, Br, I, CF3, ΝΟ2, Ν3, CN, COOH, COO(CrC6)-alkyl, CONH2, CONH(CrC6)-alkyl, CON^CrC^-alkylh, (Ci-C6)-alkyl, (C2-C6)-alkenyl,(C2-C6)-alkynyl, O-(CrC6)-aIkyl, where one, more or ail hydrogens in thealkyl radicale may be replaced by fluorine; C(=NH)(NH2), PO3H2, SO3H, SO2-NH2i SO2NH(Ci-C6)-alkyl, SO2N[(CrC6)-alkyl]2, S-iCrCeyalkyl, S-(CH2)n-phenyl, SO-(CrC6)-alkyl, SO-(CH2)n-phenyl, SO2-(CrC6)-alkyl, SO2-(CH2)n-phenyl, where n may be0-6 and the phenyl radical may be substituted up to two times by F, Cl,Br, OH, CF3, NO2, CN, OCF3, O-(CrC6)-alkyl, (CrCeJ-alkyl, NH2; NH2, NH-(Ci-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C-,-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, the phenyl ring may be mono- totrisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-alkyl,(C1-C5)-alkyl, NH2, NH(C1-C6)-alkyl, N((Ci-C6)-alkyl)2, SO2-CH3, COOH,COO-(CrC6)-alkyl, CONH2; Y, W, Y' W' independently of one another are NH, NCH3, C=O, O, a bond or S(O)n,where n = 0-2; or Y-W or Y’-W’ in each case together are a bond. (LAG) is -(CH2)1.10-SO3H, -(CH2)0.10-P(O)(OH)2i (CH2)0-i0-O-P(O)(OH)2,-(CH2)o-10-COOH; where in each case at least one of the radicals R1 or R3 must hâve the meaning-(CH2)O-i-Y-W-(Co-C25)-alkylene-Y’-W’-(LAG), where one or more carbon atoms ofthe alkylene radical may be replaced by -Ο-; and its pharmaceutically acceptable salts; except for the compound 2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-y!}phenoxy)buty!]methylamino}ethanesulfonic acidand those compounds in which the radicals R1 - R6 hâve the meaning-O-(CH2)m0-COOH, (CrC6)-alkylene-COOH or-COOH. 38 01286 9
  4. 4. A compound of the formula I as claimed in one or more of daims 1 to 3, wherein (LAG) is a carboxylic acid radical or a sulfonic acid radical, and its. pharmaceutically acceptable salts.
  5. 5. A médicament comprising one or more compounds as claimed in one or moreof daims 1 to 4.
  6. 6. A médicament comprising one or more compounds as claimed in one or more.of daims 1 to 4 and at least one further active compound.
  7. 7. The médicament as claimed in daim 6, comprising, as further activecompound, one or more compounds which normalize lipid metabolism.
  8. 8. The médicament as claimed in daim 6 or 7, which comprises, as further activecompound, 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, ACATinhibitors, antioxidants, lipoprotein 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,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, DAagonists (bromocriptine, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR 39 modulators or TR-p-agonists or amphétamines. '
  9. 9. A compound as claimed in one or more of daims 1 to 4 for use as amédicament for the treatment of impaired lipid metabolism. 5
  10. 10. A process for preparing a médicament comprising one or more of thecompounds as claimed in one or more of daims 1 to 4, which comprises mixing theactive compound with a pharmaceutically acceptable carrier and bringing this mixtureinto a form suitable for administration. 10
  11. 11. The use of the compounds as claimed in one or more of daims 1 to 4 forpreparing a médicament for treating hyperlipidemia.
  12. 12. The use of the compounds as claimed in one or more of daims 1 to 4 for15 preparing a médicament for lowering the sérum cholestérol concentration.
  13. 13. The use of the compounds as claimed in one or more of daims 1 to 4 forpreparing a médicament for treating arteriosclerotic manifestations.
  14. 14. The use of the compounds as claimed in one or more of daims 1 to 4 for preparing a médicament for treating insulin résistance.
OA1200400331A 2002-06-19 2003-06-04 Diphenyl azetidinones substituted by acidic groups, method for their production, medicaments containing said compounds and use thereof. OA12869A (en)

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