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WO2003014088A1 - Thioamides de biphenyle comme antagonistes de recepteurs de l'integrine - Google Patents

Thioamides de biphenyle comme antagonistes de recepteurs de l'integrine Download PDF

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Publication number
WO2003014088A1
WO2003014088A1 PCT/EP2002/007797 EP0207797W WO03014088A1 WO 2003014088 A1 WO2003014088 A1 WO 2003014088A1 EP 0207797 W EP0207797 W EP 0207797W WO 03014088 A1 WO03014088 A1 WO 03014088A1
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formula
compound
compounds
meanings given
solvates
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German (de)
English (en)
Inventor
Wolfgang Stähle
Alfred Jonczyk
Oliver Schadt
Simon Goodman
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Merck Patent GmbH
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the invention relates to new compounds of formula I.
  • B OR or NRR can be RH, A ', C 3 -C 4 cycloalkyl, C 6 -C 0 aryl, C 7 -Cu aralkyl, which can be substituted one or more times with R 3 and their
  • Alkyl carbon chain can be interrupted by O,
  • R 1 , R 1 ' , R independently of one another H, F, Cl, Br, J, NO 2 , NH, NHR,
  • R 2 , R 2 ' , R 2 " independently of one another H, F, Cl, Br, J, NO 2 , NH, NHR,
  • Het 1 is a mono- or dinuclear heterocycle with 1 to 4 N-
  • NHA ', NA' 2 and / or NH can be substituted, A 'alkyl with 1 to 8 carbon atoms
  • Integrins are membrane-bound, heterodimeric glycoproteins that consist of an ⁇ subunit and a smaller ⁇ subunit. The relative
  • Affinity and specificity for ligand binding is determined by combining the different ⁇ and ⁇ subunits.
  • the compounds of WO 96/22966 A1 selectively inhibit the ⁇ 4 integrin receptor and the compounds of WO 97/08145 A1 selectively inhibit the v 3 integrin receptor.
  • the compounds of WO 00/48996 A2 primarily inhibit ⁇ v ⁇ 3 and ⁇ ⁇ ⁇ integrin receptors.
  • the invention was based on the task of finding new compounds with valuable properties, in particular those which
  • the compounds of the formula I, their stereoisomers and their salts have very valuable pharmacological properties with good tolerability.
  • the compounds are particularly notable for their very high activity. They work here as antagonists of integrin receptors, especially the ⁇ v ß3, oc v ß5 and / or the ⁇ v ß 6 integrin receptors. They also have very favorable distribution coefficients in octanol water (logD values).
  • an active ingredient is added to a mixture of octanol / water, it is distributed between the two phases at a given pH value according to its lipophilicity / hydrophilicity.
  • the ratio of the distribution of the active substance between the octanol and water phase is called the distribution coefficient.
  • the absorption of active ingredients requires that they dissolve in aqueous media as well as the corresponding ones
  • Penetrate membranes For the latter, a certain lipophilicity of the active ingredient is required. The lipophilicity required results from the lipophilicity of the respective membrane.
  • Absorption in the intestine requires a logD value> -1, 50 and passage through the blood-brain barrier requires a logD value> 0.5. (Lipinski C.A: Adv. Drug Del. Rev. 23 (1997), 3-25).
  • a favorable logD value is an essential prerequisite for the absorption of an active ingredient.
  • the integrins have different physiological and pathological functions, the following for example in detail
  • Huttenlocher-A Microsc-Res-Tech. 1998 Dec 1; 43 (5): 412-9, The ro / e of integrins in the malignant phenotype ofgliomas.
  • Uhm JH; Gladson-CL; Rao-JS front biosci. 1999 Feb 15; 4: D188-99, or Sperm disintegrins, egg integrins, and other cell adhesion molecules of mammalian gamete plasma membrane interactions.
  • Evans-JP Front Biosci 1999 Jan 15; 4:
  • the ⁇ v integrins play an important role in this, such as in The role ofalpha v integrins in tumor progression and metastasis; Marshall JF; Hard IR Semin Cancer Biol. 1996 Jun; 7 (3): 129-38 or The role ofalpha v-integrins during angiogenesis; Eliceiri-BP and Cheresh-DA Molecular
  • integrins there are also ⁇ v ß ⁇ epithelial integrins. Sheppard-D bioessays. 1996 Aug; 18 (8): 655-60 and the two integrins ⁇ v ß 3 and ⁇ v ßs, which represent known adhesion receptors, the biological meaning of which, for example, in JA Varner et al. Cell Adhesion and Communication 3, 367-374 (1995) and in J. Samanen et al. Curr. Pharmaceutical Design, 3, 545-584 (1997).
  • ctvß ⁇ is a relatively rare integrin (Busk et al., 1992 J. Biol. Chem. 267 (9),
  • ⁇ v esse plays a role in the respiratory epithelium (Weinacker et al., 1995, Am. J. Respir. Cell Mol. Biol. 12 (5), 547), so that corresponding agonists / antagonists of this integrin in respiratory diseases, such as bronchitis,
  • v ß ⁇ also plays a role in the intestinal epithelium, so that appropriate integrin agonists could find / antagonists in the treatment of inflammation, tumors and wounds of the stomach / intestinal tract using.
  • Microorganisms and viruses also have integrin receptors, in particular v ⁇ ⁇ receptors.
  • v ßs receptors are adenovirus or ⁇ v ßs / v ßs receptors for HIV.
  • the integrin antagonists / agoists could therefore also be used to treat infections, in particular viral infections.
  • the compounds also act as inhibitors of the ⁇ v ⁇ 3 or ⁇ v ⁇ 5 integrin receptors and as inhibitors of glycoprotein IIb / IIla.
  • the ⁇ v ß 3 integrin for example, is expressed on a number of cells, for example endothelial cells, cells of the smooth vascular muscles, for example the aorta, cells for breaking down bone matrix (osteoclasts) or tumor cells.
  • v ß 3 antagonists or antibodies against ⁇ v ß 3 were described which cause tumors to shrink by inducing apoptosis.
  • the compounds of the formula I can inhibit the binding of metalloproteinases to integrins and thus prevent the cells from being able to use the enzymatic activity of the proteinase.
  • One example is the inhibibility of the binding of MMP-2- (matrix metallo-proteinase-2) to the vitronectin
  • micro-aggregates can attach themselves to the vessel walls, which facilitates further penetration of tumor cells into the tissue. Since the formation of the microthrombi is mediated by ligand binding to the corresponding integrin receptors, eg ⁇ v ß 3 or ⁇ n b ß 3 , on activated platelets, the corresponding antagonists can be regarded as effective metastasis inhibitors.
  • the compounds can be administered to humans or animals locally or systemically, orally, intravenously, intraperitoneally, intramuscularly, subcutaneously, transdermally, nasally, buccally or iontophoretically.
  • a measure of the absorption of an active pharmaceutical ingredient into an organism is its bioavailability.
  • the active pharmaceutical ingredient is added intravenously to the organism in the form of a solution for injection, its absolute bioavailability lies, i.e. the proportion of the drug that remains unchanged in the systemic blood, i.e. gets into the big cycle, at 100%.
  • the active ingredient When a therapeutic active ingredient is administered orally, the active ingredient is usually present as a solid in the formulation and must therefore first dissolve in order for it to overcome the entry barriers, for example the
  • Gastrointestinal tract, the oral mucosa, nasal membranes or the Skin, especially the stratum corneum, can overcome or be absorbed by the body.
  • Data on pharmacokinetics, ie on bioavailability, can be obtained analogously to the method of J. Shaffer et al, J. Pharm. Sciences, 1999, 88, 313-318.
  • a measure of its resorbability can be a measure of its resorbability.
  • the compounds of formula I have at least one chiral center and can therefore occur in several stereoisomeric forms. All of these forms (e.g. D and L forms) and their mixtures (e.g. the DL-
  • Shapes are included in the formula.
  • prodrug derivatives are also included in the compounds according to the invention, i.e. with e.g. Alkyl or acyl groups, sugars or oligopeptides modified compounds of
  • Solvates of the compounds of the formula I are understood to mean the addition of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or
  • Addition compounds with alcohols e.g. with methanol or ethanol.
  • the invention relates to the compounds of the formula II
  • a 'is alkyl is linear or branched, and has 1 to 8, preferably 1, 2, 3, 4, 5 or 6 carbon atoms.
  • a ' is the alkyl groups mentioned, which, however, can be substituted one or more times by shark or NO 2 , preferably trifluoromethyl, 2,2,2-trifluoroethyl or 2-nitroethyl, or alkyl groups whose carbon chain is -O- can be interrupted, preferably -CH 2 -O-CH 3 , -CH 2 -O-CH 2 -CH 3 or -CH 2 -CH 2 -O-CH 3 .
  • Methyl or ethyl is particularly preferred for A '.
  • C 3 -C -cycloalkyl has 3 to 14 C atoms and preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, particularly preferably cyclohexyl.
  • Cycloalkyl also means mono- or bicyclic terpenes, preferably p-menthan, menthol, pinane,
  • Bornan or camphor including any known stereoisomeric form, or adamantyl.
  • C 7 -Cu-aralkyl is preferably benzyl, phenethyl, naphth-1-yl-methyl,
  • C 6 -C ⁇ o-aryl is preferably unsubstituted or poly-substituted
  • Phenyl or naphthyl in particular unsubstituted, mono-, di- or triple by A ⁇ OH, OA ', NH 2 , NHA', NA ' 2 , NO 2 , CF 3 , CN, F, Cl, Br, J, CO- A ', S0 3 A', SO 2 A ', SA' substituted phenyl or naphthyl.
  • Het 1 is an unsubstituted or substituted mono- or dinuclear aromatic heterocyclic ring system with 1, 2, 3 or 4, preferably 1 or 2 N atoms. Het 1 is preferably unsubstituted or 1-, mono- or disubstituted by A ', NHA' NA ' 2 and / or NH 2 ,
  • 2- or 3-pyrrolyl 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-
  • Het 1 can, for. B. also mean 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyI, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 4,5-dihydro-imidazol-2-yl, 2,3-dihydro- 1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4- pyrazolyl, 1, 4-dihydro-1-, -2-, -3- or -4-pyridyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4 -Piperidinyl,
  • Het 1 is preferably present in A as Het 1 -NH. It is particularly preferred
  • Pyridin-2-ylamino is very particularly preferred.
  • R 1 , R 1 " , R 1" and R 2 , R 2 ' , R 2 " are preferably H, F, Cl, Br, I, NO 2 , NH 2 , NHA',
  • Amino protecting group preferably means formyl, acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOG, 2-iodoethoxycarbonyl, CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl.
  • B is particularly preferably H, methoxy, ethoxy or benzyloxy, of which in particular H.
  • n is preferably 2, 3 or 4, very particularly preferably n is 2 or 3.
  • Multiple substituted means one, two, three or four times substituted.
  • Pol means a solid phase without a terminal functional group, as explained in more detail below.
  • the term solid phase and resin is used synonymously in the following.
  • the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • Some preferred groups of compounds can be expressed by the following sub-formulas la) to Ig), which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
  • Het 1 is a mono- or dinuclear unsubstituted or mono- or disubstituted by A ', NHA', NH 2 , and / or NA ' 2 aromatic or partially or completely hydrogenated heterocyclic ring system with 1 or 2 N-
  • C ( NH) -NH-, Het 1 - or Het 1 -NH-, where the primary amino groups can also be provided with conventional amino protecting groups, B OR or NRR RH, A ⁇ C 6 -Ci 4 -cycloalkyl, C 7 -C 14 -aralkyl, which can be mono- or disubstituted with R 3 and whose alkyl carbon chain can be interrupted by O, R 1 , R 1 ' , R 1 " independently of one another H, F, Cl, Br, J, NO 2 ,
  • R 2 , R 2 , R 2 independently of one another H, F, Cl, Br, J, NO 2 ,
  • R H A ', cyclohexyl, benzyl, phenylethyl,
  • R 1 , R 1 ' , R 1 " independently of one another H, F, Cl, Br, J, NO 2 ,
  • R 1 , R 1 , R 1 independently of one another H, F, Cl, Br, J, NO 2>
  • R 1 , R,, R 1 independently of one another H, F, Cl, Br, J, NO 2 ,
  • R 2 , R 2 ' , R 2 independently of one another H, F, Cl, Br, J, NO 2 , NHA', NA ' 2 , OA', CO-A ', A A" alkyl with 1 to 6 C. Atoms, n 2, 3 or 4,
  • R 1 , R 1 ' , R 1 " independently of one another H, F, Cl, Br, J, NO 2 ,
  • R 2 , R 2 ' , R 2 " independently of one another H, F, Cl, Br, J, NO 2 ,
  • a 'alkyl with 1 to 4 carbon atoms A 'alkyl with 1 to 4 carbon atoms
  • YO n 2, 3 or 4 means.
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I according to claim 1.
  • amino protecting group is generally known and refers to groups which are suitable for protecting (blocking) an amino group against chemical reactions.
  • acyl group is to be understood in the broadest sense in connection with the present process. It encompasses acyl groups derived from aliphatic, araliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, alkenyloxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as phenoxyacetyl; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Alkenyloxycarbonyl such as allyloxycarbonyl (aloe), aralkyloxycarbonyl such as CBZ (synonymous with Z), 4-methoxybenzyloxycarbonyl (MOZ), 4-nitrobenzyloxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmoc); 2- (phenylsulfonyl) ethoxycarbonyl; Trimethylsilylethoxycarbonyl (Teo
  • hydroxyl protecting group is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl,
  • Aroyl or acyl groups also also alkyl groups, alkyl, aryl or aralkyl silyl groups or 0, O or O, S acetals.
  • the nature and size of the Hydroxy protective groups are not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred.
  • hydroxy protecting groups include aralkyl groups such as benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, aroyl groups such as benzoyl or p-nitrobenzoyl, acyl groups such as acetyl or pivaloyl, p-toluenesulfonyl, alkyl groups such as methyl or tert-butyl, but also allyl, Alkylsilyl groups such as trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) or triethylsilyl, trimethylsilylethyl, aralkylsilyl groups such as tert.-butyldiphenylsilyl (TBDPS), cyclic acetals such as isopropylidene,
  • aralkyl groups such as benzyl, 4-methoxybenzyl or 2,4
  • Particularly preferred hydroxyl protecting groups are benzyl, acetyl, tert-butyl or
  • the groups BOC and O-tert-butyl can e.g. preferably with TFA in dichloromethane or with about 3 to 5 N HCl in dioxane at 15-30 ° C, the Fmoc group with an about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 ° C.
  • the aloe group can be gently analyzed using precious metal catalysis
  • a preferred catalyst is tetrakis (triphenyl-phosphine) palladium (0). Acid amides are converted into the corresponding thioamides by methods known per se, for example by reaction with Lawesson reagent, with P4S10 (Link, A .; Zaharevitz, DW; Kunick, C; Pharmazie 1999, 54 (3), 163-166) , with Heimgartner's reagent
  • reaction is preferably carried out with 2,4-bis (4-methoxyphenyl) -2,4-dithioxo-1, 2,3,4-dithiaphospethane (Lawesson reagent) in a suitable solvent, such as, for example, toulol.
  • a suitable solvent such as, for example, toulol.
  • thioamides of the formulas IV and IX can be prepared from the corresponding acid amides as described above. In case of
  • Thioamide compounds of the formula IV are used here compounds of the formula III.
  • the coupling reaction is preferably carried out in the presence of a
  • Dehydrating agent e.g. a carbodiimide such as dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) or diisopropylcarbodiimide (DIC), further e.g. Propanephosphonic anhydride (see Angew. Chem. 1980, 92, 129), diphenylphosphorylazide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, e.g.
  • a carbodiimide such as dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) or diisopropylcarbodiimide (DIC), further e.g. Propanephosphonic anhydride (
  • a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as acetonitrile, in dimethyl sulfoxide or in the presence of these solvents, at temperatures between about -10 and 40, preferably between 0 and
  • the reaction time is between a few minutes and several days depending on the conditions used.
  • the addition of the coupling reagent TBTU (0- (benzotriazol-1-yl) -N, N, N ', N , -tetramethyl-uronium-tetrafluoroborate) or O- (benzotriazol-1 -yl) -N has proven particularly advantageous.
  • N, N ', N'-tetramethyl uronium hexafluorophosphate have been proven, since only a slight racemization occurs in the presence of one of these compounds and no cytotoxic by-products arise.
  • Derivatives of compounds of formula V and / or IX preferably a preactivated carboxylic acid, or a carboxylic acid halide, a symmetrical or mixed anhydride or an active ester can be used.
  • residues for activating the carboxy group in typical aeylation reactions are in the literature (e.g. in the standard works such as
  • esters are expediently formed in situ, eg by adding HOBt (1-hydroxybenzotriazole) or N-hydroxysuccinimide.
  • the reaction is usually carried out in an inert solvent, when using a carboxylic acid halide in the presence of an acid-binding agent, preferably an organic base such as triethylamine, dimethylaniline, pyridine or quinoline.
  • an acid-binding agent preferably an organic base such as triethylamine, dimethylaniline, pyridine or quinoline.
  • Alkali or alkaline earth metals preferably potassium, sodium, calcium or cesium, can be favorable.
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • acids that provide physiologically acceptable salts are suitable for this implementation. So inorganic acids can be used, e.g. Sulfuric acid, sulfurous acid, dithionic acid,
  • Nitric acid hydrohalic acids such as hydrochloric acid or hydrobromic acid
  • phosphoric acids such as e.g. Orthophosphoric acid, sulfamic acid, also organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. formic acid,
  • the compounds of the formula I can also be synthesized on a solid phase, the binding to the solid phase being effected via OH of the carboxyl group.
  • the carboxyl group is substituted with OPol, where Pol means a solid phase without a terminal functional group.
  • Pol stands for the polymeric carrier material as well as for all atoms of the anchor group of a solid phase, except for the terminal functional group.
  • the anchor groups of a solid phase also called linkers, are necessary for the connection of the connection to be functionalized to the solid phase.
  • Solid phases which are particularly suitable for the synthesis of the compounds according to the invention are solid phases with a hydroxyl group as terminal functionality, for example the Wang resin or polystyrene A OH.
  • the invention also relates to the compounds of the formula I as claimed in claim 1, their stereoisomers and their physiologically acceptable salts or solvates as active pharmaceutical ingredients.
  • the invention furthermore relates to compounds of the formula I according to
  • Claim 1 their stereoisomers and their physiologically acceptable salts or solvates as integrin receptor antagonists.
  • the invention also relates to the compounds of the formula I according to claim 1, their stereoisomers and their physiologically acceptable
  • Salts or solvates for the therapy and prophylaxis of diseases are included in the composition.
  • the invention further relates to pharmaceutical preparations containing at least one compound of the formula I, its stereoisomers and / or one of its physiologically acceptable salts or solvates.
  • the compounds of the formula I can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active compounds.
  • the invention therefore also relates to the use of compounds of the formula I, their stereoisomers and / or their physiologically acceptable salts or solvates for the production of a medicament.
  • Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils,
  • Benzyl alcohols alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, Vaseline. Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use
  • the new compounds can also be lyophilized and the resulting lyophilisates e.g. can be used for the production of injectables.
  • the specified preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, taste and / or several other active substances, e.g. one or more vitamins.
  • sprays can be used which contain the active ingredient either dissolved or suspended in a propellant gas or propellant gas mixture (for example CO 2 or fluorocarbon hydrocarbons).
  • a propellant gas or propellant gas mixture for example CO 2 or fluorocarbon hydrocarbons.
  • the active ingredient is expediently used in micronized form, it being possible for one or more additional physiologically compatible solvents to be present, for example ethanol.
  • Inhalation solutions can be administered using standard inhalers.
  • the compounds of formula I, their stereoisomers and / or their physiologically acceptable salts can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for
  • Prophylaxis and / or therapy of diseases of the circulatory system pulmonary fibrosis, pulmonary embolism, thrombosis, in particular deep vein thrombosis, heart attack, arteriosclerosis, aneurysm dissecans, transient ischemic attacks, apoplexy, angina pectoris, in particular unstable angina pectoris, tumor diseases, such as
  • osteolytic diseases such as osteoporosis, hyperparathyroidism, Paget's disease, malignant Hypercalcaemia, incompatible blood transfusion, pathologically angiogenic diseases such as inflammation, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, corneal transplantation, ocular histoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, morbidity
  • the use for is particularly preferred
  • the substances according to the invention are preferably in
  • the daily dosage is preferably between about 0.01 and 2 mg / kg body weight.
  • the specific dose for each patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and severity the respective disease to which the therapy applies.
  • the compounds of the formula I contain one or more chiral centers and can therefore be present in racemic or in optically active form. Racemates obtained can be separated mechanically or chemically into the enantiomers by methods known per se.
  • the racemic mixture is preferably reacted formed with an optically active release agent diastereomers.
  • Suitable release agents are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphor sulfonic acids such as ⁇ -camphor sulfonic acid.
  • Enantiomer separation using a column filled with an optically active separating agent is also advantageous; a mixture of hexane / isopropanol / acetonitrile, for example in a volume ratio of 82: 15: 3, is suitable as the mobile phase.
  • an optically active separating agent for example dinitrobenzoyl-phenylglycine
  • optically active compounds of the formula I by the methods described above by using starting materials which are already optically active.
  • customary work-up means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is dried and dried organic phase over sodium sulfate, evaporated and purified by chromatography
  • MS- FAB MS- FAB (M + H) + .
  • logD values given above and below are distribution coefficients of the compounds in question in octanol / water at a pH of 7.4 (logD (7 , 4) ).
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • Example B Suppositories A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH 2 PO 4 • 2H 2 O, 28.48 g Na 2 HPO 4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double- distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • a mixture of 1 kg of active ingredient of the formula I, 4 kg of laetose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example G capsules
  • a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.
  • the solution can be sprayed into the mouth or nose.
  • One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

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Abstract

L'invention concerne de nouveaux dérivés de biphényle de formule générale (I), dans laquelle A, B, X, Y, Z, R<1>, R<1'>, R<1">, R<2>, R<2'>, R<2"> et n ont les significations indiquées dans la revendication 1, ainsi que leurs stéréoisomères et leurs sels ou solvates physiologiquement acceptables, lesquels sont de nouveaux antagonistes de récepteurs de l'intégrine, en particulier des récepteurs d'intégrine alpha v beta 3, alpha v beta 5 et/ou alpha v beta 6. Ces nouveaux composés peuvent être utilisés comme médicaments.
PCT/EP2002/007797 2001-08-08 2002-07-12 Thioamides de biphenyle comme antagonistes de recepteurs de l'integrine Ceased WO2003014088A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10139059A DE10139059A1 (de) 2001-08-08 2001-08-08 Thioamide
DE10139059.9 2001-08-08

Publications (1)

Publication Number Publication Date
WO2003014088A1 true WO2003014088A1 (fr) 2003-02-20

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Application Number Title Priority Date Filing Date
PCT/EP2002/007797 Ceased WO2003014088A1 (fr) 2001-08-08 2002-07-12 Thioamides de biphenyle comme antagonistes de recepteurs de l'integrine

Country Status (2)

Country Link
DE (1) DE10139059A1 (fr)
WO (1) WO2003014088A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004094468A3 (fr) * 2003-04-23 2005-03-24 Hansa Medical Res Ab Procédé et traitement
ES2243131A1 (es) * 2004-05-07 2005-11-16 Consejo Sup. Investig. Cientificas Tiamidas derivadas de bifenilo como inhibidores de calpaina.

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000048996A2 (fr) * 1999-02-20 2000-08-24 Merck Patent Gmbh DERIVES DE LA β-ALANINE

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000048996A2 (fr) * 1999-02-20 2000-08-24 Merck Patent Gmbh DERIVES DE LA β-ALANINE

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BURGER, A. IN PROGRESS IN DRUG RESEARCH: "Isosterism and bioisosterism in drug design", 1991, BIRKHÄUSER VERLAG, BASEL, XP002220224 *
DUGGAN, M. E.; HUTCHINSON, J. H.: "Ligands to the integrin receptor alpha-v-beta-3", EXP. OPIN. THER. PATENTS, vol. 10, no. 9, 2000, pages 1367 - 1383, XP002220223 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004094468A3 (fr) * 2003-04-23 2005-03-24 Hansa Medical Res Ab Procédé et traitement
ES2243131A1 (es) * 2004-05-07 2005-11-16 Consejo Sup. Investig. Cientificas Tiamidas derivadas de bifenilo como inhibidores de calpaina.
WO2005108354A1 (fr) * 2004-05-07 2005-11-17 Consejo Superior De Investigaciones Científicas Thioamides derives de biphenyle utilises en tant qu'inhibiteurs de calpaine
ES2243131B1 (es) * 2004-05-07 2007-02-01 Consejo Sup. Investig. Cientificas Tiamidas derivadas de bifenilo como inhibidores de calpaina.
US7476754B2 (en) 2004-05-07 2009-01-13 Consejo Superior De Investigaciones Cientificas Biphenyl derived thiamides as calpain inhibitors

Also Published As

Publication number Publication date
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