WO1997044333A1 - 1,2,4-oxadiazoles utilises comme antagonistes du recepteur d'adhesion - Google Patents

1,2,4-oxadiazoles utilises comme antagonistes du recepteur d'adhesion Download PDF

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Publication number
WO1997044333A1
WO1997044333A1 PCT/EP1997/002555 EP9702555W WO9744333A1 WO 1997044333 A1 WO1997044333 A1 WO 1997044333A1 EP 9702555 W EP9702555 W EP 9702555W WO 9744333 A1 WO9744333 A1 WO 9744333A1
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Prior art keywords
formula
phenyl
acid
oxadiazole
amino
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PCT/EP1997/002555
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German (de)
English (en)
Inventor
Horst Juraszyk
Joachim Gante
Hanns Wurziger
Sabine Bernotat-Danielowski
Guido Melzer
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Merck Patent Gmbh
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Priority to AU29579/97A priority Critical patent/AU2957997A/en
Publication of WO1997044333A1 publication Critical patent/WO1997044333A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to compounds of the formula I.
  • -C ( NH) -NH 2 substituted phenyl, an unsubstituted or simply substituted by NH 2 pyrimidinyl, tetrahydropyrimidinyl, pyridyl or tetrahydropyridyl, an unsubstituted or simply substituted by pyridyl
  • R 2 , R 2 each independently of one another are H, A-CO, AO-CO, A-sulfonyl, an unsubstituted or mono-, di- or triple by shark, A, AO, AO-CO, CONH 2 , NH 2 or NO 2 substituted benzoyl, heteroaroyl or phenylsulfonyl radical,
  • R 3 OH, AO, NH-COOR 4 an amino acid residue selected from a group consisting of Ala, ⁇ -Ala, 3-amino-3-alkylpropionic acid, 3-amino-3-alkynylpropionic acid, 3-amino-3-phenyl - propionic acid, aminomalonic acid, Asn, Asp, Arg, Cys, Gin, Glu, Gly, His, lle, Leu, Lys, Met, Phe, Pro, Sar, Ser, Thr, Trp, Taurin, Tyr, Val,
  • U is a bond or O
  • V is a bond, O, CONH or S (O) k ,
  • X, Y are each independently N or O, where X ⁇ Y,
  • n, n ', q each independently of one another 0 or 1,
  • k, p are each independently 0, 1 or 2
  • the object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. Above all, they act as integrin inhibitors, in particular inhibiting the interactions of the ⁇ v integrin receptors with ligands.
  • the compounds show particular effectiveness in the case of the integrins ⁇ v p 3 and ⁇ v ßs.
  • the compounds are particularly effective as adhesion receptor antagonists for the vitronectin receptor ⁇ vß 3. This effect can be demonstrated, for example, by the method described by JW Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).
  • the compounds of the formula I according to the invention can therefore be used as active pharmaceutical ingredients, in particular for the treatment of tumor diseases, osteoporoses, osteolytic diseases and for suppressing angiogenesis in the pathological environment of the organism.
  • micro-aggregates micro thrombi
  • the spread of tumor cells from a local tumor into the vascular system takes place through the formation of micro-aggregates (micro thrombi) through interaction of the tumor cells with platelets.
  • the tumor cells are shielded by the protection in the micro-aggregate and are not recognized by the cells of the immune system.
  • the 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 fibrinogen binding to the fibrinogen receptors on activated platelets, the GPIIa / IIIb antagonists can be regarded as effective metastasis inhibitors.
  • compounds of the formula I In addition to the binding of fibrinogen, fibronectin and the Willebrand factor to the fibrinogen receptor of the platelets, compounds of the formula I also inhibit the binding of other adhesive proteins, such as vitro- nectin, collagen and laminin, to the corresponding receptors on the surface of different cell types. In particular, they prevent the formation of platelet thrombi and can therefore be used to treat thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis.
  • other adhesive proteins such as vitro- nectin, collagen and laminin
  • the properties of the compounds can also be demonstrated by methods which are described in EP-A1-0462 960.
  • the inhibition of fibrinogen binding to the fibrinogen receptor can be demonstrated by the method specified in EP-A1-0 381 033.
  • the antiplatelet effect can be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962).
  • the invention accordingly relates to compounds of the formula I according to claim 1 and / or their physiologically acceptable salts for the preparation of a medicament for use as integrin inhibitors.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, for the prophylaxis and / or therapy of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, tumor diseases, osteolytic diseases such as osteoporosis, pathologically angiogenic diseases such as B.
  • ophthalmic diseases diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative coiitis, Crohn's disease, atherosclerosis, psoriasis, restenosis, viral infection, biosafety, biosafety in acute kidney failure and in wound healing to support the healing processes.
  • the compounds of formula I can be used as antimicrobial substances in operations where biomaterials, implants, catheters or pacemakers are used. They have an antiseptic effect.
  • the effectiveness of the antimicrobial activity can be by P.Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988).
  • the invention relates to the compounds of the formula I and their salts and to a process for the preparation of these compounds and theirs
  • R 1 , U, R 2 , m and n ' have the meanings given in claim 1 and L is Cl, Br, I, OH or a reactive esterified OH group or a nucleophilically substitutable leaving group,
  • V, W, R 2 , R 3 , Ar, n, p and q are those specified in claim 1
  • R 1 , R 3 , U, V, W, X, Y, Ar, m, n, p and q are those specified in claim 1
  • L is Cl, Br, I, OH or a reactive esterified OH group or a nucleophilically substitutable leaving group
  • Trt trityl (triphenylmethyl).
  • amino acids can occur in several enantiomeric forms, then above and below, for. B. as a component of the compounds of the formula I, including all these forms and also their mixtures (for example the DL forms). Furthermore, the amino acids, e.g. B. as part of compounds of formula I, provided with corresponding protective groups known per se.
  • alkyl has 1 to 6, preferably 1, 2, 3 or 4, carbon atoms.
  • Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert.
  • -Butyl also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4- Methylpentyl, 1, 1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1- Ethyl-2-methylpropyl, 1, 1,2- or 1,2,2-trimethylpropyl. - to-
  • alkyl means cyclobutyl, methylene cyclobutyl, cyclopentyl, methylene cyclopentyl, cyclohexyl or methylene cyclohexyl, methylene cyclopropyl or cyclopropyl.
  • Alkylene preferably means methylene, ethylene, propylene, but also butylene, pentylene or hexylene.
  • Alkynyl is preferably ethynyl, propynyl, butynyl, pentynyl or hexynyl.
  • Alkanoyl preferably means formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, furthermore nonanoyl or decanoyl.
  • Ar is phenyl, preferably - as indicated - monosubstituted phenyl, in particular preferably phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-aminophenyl, o-, m- or p-aminocarbonylphenyl, o-, m- or p-nitrophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromopheny
  • Aralkanoyl is preferably benzoyl, unsubstituted, preferably - as indicated - monosubstituted phenylacetyl, in particular preferably phenylacetyl, o-, m- or p-methoxyphenylacetyl, o-, m- or p-ethoxyphenylacetyl, o-, m- or p-fluorophenylacetyl, o-, m- or p- - ⁇ ⁇ - -
  • Alkoxycarbonyl preferably means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, further also isopropoxycarbonyl, tert-butoxycarbonyl or hexyloxycarbonyl.
  • Alkylsulfonyl preferably means methylsulfonyl, furthermore ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl or tert. -Butylsulfonyl, also pentylsulfonyl or 1-, 2- or 3-methylbutylsulfonyl.
  • Heteroaroyl is preferably furan-2- or 3-carbonyl, thiophene-2-or 3-carbonyl, pyrrole-1-, 2- or 3-carbonyl, imidazole-1-, 2-, 4- or 5-carbonyl, pyrazole- 1-, 3-, 4- or 5-carbonyl, oxazole-2-, 4- or 5-carbonyl, isoxazole-3-, 4- or 5-carbonyl, thiazole-2-, 4- or 5-carbonyl, isothiazole -3-, 4- or 5-carbonyl, pyridine-2-, 3- or 4-carbonyl, pyrimidine-2-, 4-, 5- or 6-carbonyl, further preferably 1, 2,3-triazole-1- , -4- or -5-carbonyl, 1,2,4-triazole-1-, -3- or 5-carbonyl, tetrazole-1- or 5-carbonyl, 1,2,3-oxadiazole-4- or - 5-carbonyl, 1, 2,4-oxadiazole-3
  • Piperazinyl, 4- (4-pyridyl) -piperazin-1-yl, more preferably a phenyl radical substituted by -C ( NH) -NH 2 , 5-pyrimidinyl or 2-amino-5-pyrimidinyl, 1, 4, 5,6-tetrahydropyrimidinyl or 2-amino-1,4,5,6-tetra-hydropyrimidinyl, 2-amino-3,4,5,6-tetrahydropyridin-4- or 5-yl, 3- or 4- Piperidinyl or 1- (4-pyridyl) -piperidin-3- or 4-yl, furthermore 2-, 3- or 4-pyridyl or 2-amino-4- or 5-pyridyl.
  • R 2 is preferably H, alkanoyl, alkoxycarbonyl, alkylsulfonyl, unsubstituted benzoyl, heteroaroyl or alkylsulphonyl, preferably - as indicated - monosubstituted benzoyl, in particular preferably benzoyl, o-, m- or p-methylbenzoyl, o-, m- or p- Ethylbenzoyl, o-, m- or p-propylbenzoyl, o-, m- or p- isopropylbenzoyl, o-, m- or p-tert-butylbenzoyl, o-, m- or p-aminobenzoyl, o-, m- or p-aminocarbonyl benzoyl, o-, m- or p-nitrobenzoyl, o-, m- or p-methoxy
  • amino acids and amino acid residues mentioned for R 3 can also be derivatized, the N-methyl, N-ethyl, N-propyl, N-benzyl, N-phenethyl or C ⁇ -methyl derivatives being preferred are.
  • R 3 very particularly preferably denotes hydroxy, alkoxy, Ala, ⁇ -Ala, 3-amino-3-alkylpropionic acid, 3-amino-3-alkynylpropionic acid, 3-amino-3-phenylpropionic acid, Asn, Asp, Gly, Pro, Sar, Ser, N-benzylglycine, N-phenethylglycine, N-benzyl-ß-alanine, N-phenethyl-ß-alanine, aminomalonic acid, and the alkyl esters, especially the methyl or ethyl esters of the above amino acids or amino acid derivatives.
  • Alkoxy preferably means methoxy, ethoxy, propoxy, butoxy or tert-butoxy.
  • the propyl, butyl, tert-butyl, neopentyl or benzyl esters of the carboxy groups are further preferred.
  • Amino protecting group preferably means acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl.
  • 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 Ia 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
  • WV u is a bond, m, n, n ', p and q 0, XO,
  • V is a bond and w is CO;
  • WV u is a bond, m, n and n '0,
  • W is CO
  • u is a bond, n, n 'and p 0,
  • V is a bond and w is CO;
  • U is a bond, m, n, n ', p and q 0, X O,
  • V represents a bond and W SO 2 ; ⁇ >
  • W is CO
  • Phenyl radical 4-piperidyl or 4-pyridyl
  • V is a bond or O, w CO,
  • u is a bond, m and n '0,
  • P 1, n 1 and w represent CO;
  • 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.
  • the compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis or by hydrogenolysis.
  • Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, preferably those which instead of an H atom, which is connected to an N atom carry an amino protective group, in particular those which carry an R'-N group instead of an HN group, in which R ! represents an amino protective group, and / or those which carry a hydroxyl protective group instead of the H atom of a hydroxyl group, for example those which correspond to the formula I, but carry a group -COOR "instead of a group -COOH, where R" denotes a hydroxyl protective group.
  • amino protecting group is generally known and refers to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other locations in the molecule is. Typical of such groups are special unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms.
  • acyl group is to be understood in the broadest sense in connection with the present process.
  • acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are
  • Alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy”), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr.
  • Preferred Preferred
  • Amino protecting groups are BOC and Mtr, also CBZ, Fmoc, benzyl and acetyl.
  • hydroxyl protecting group is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the unsubstituted or substituted aryl, aralkyl or acyl groups mentioned above, and also alkyl groups.
  • the nature and size of the hydroxyl protective groups is 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 Benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.
  • the COOH groups in aspartic acid and glutamic acid are preferably protected in the form of their tert-butyl esters (eg Asp (OBut)).
  • Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1.
  • the reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
  • the groups BOC, OBut and Mtr can e.g. B. preferably with TFA in dichloromethane or with about 3 to 5N HCl in dioxane at 15-30 °, the FMOC group with an about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15 -30 °.
  • the trityl group is used to protect the amino acids histidine, asparagine, glutamine and cysteine. Depending on the desired end product, the cleavage takes place with TFA / 10% thiophenol, the trityl group being cleaved from all of the amino acids mentioned
  • TFA / anisole or TFA / thioanisole only cleaves the trityl group from His, Asn and Gin, whereas it remains on the Cys side chain.
  • Hydrogenolytically removable protective groups can e.g. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal).
  • a catalyst z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal.
  • Suitable solvents are the above, especially z. B. alcohols such as methanol or ethanol or amides such as DMF.
  • Hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° and pressure between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds e.g. B. good on 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °.
  • Compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
  • the starting compounds of the formula II and III are generally new. However, they can be produced by methods known per se.
  • L is preferably Cl, Br, I or a reactively modified OH group such as e.g. an activated ester or an imidazolide, which are commonly used in the various peptide coupling methods.
  • the reaction is usually carried out in an inert solvent, in the presence of an acid-binding agent, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metal or alkaline earth metal, preferably potassium, sodium, calcium or cesium.
  • an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the amide component of the formula II or the alkylation derivative of the formula III can also be favorable.
  • the reaction time is between a few minutes and 14 days, the reaction temperature is between about 0 ° and 150 °, normally between 20 ° and 130 °.
  • Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Ni
  • reaction of the compounds of formula IV with compounds of formula V is preferably carried out in an inert solvent, with the addition of a base and at temperatures as indicated above.
  • L is preferably Cl or Br.
  • Derivatives with a free primary or secondary amino group are expediently implemented in protected form.
  • the aforementioned groups can be used as protective groups.
  • a corresponding aminophenyl compound can be treated with an amidinating agent.
  • 1-Amidino-3,5-dimethylpyrazole (DPFN) which is used in particular in the form of its nitrate, is preferred as the amidizing agent.
  • DPFN 1-Amidino-3,5-dimethylpyrazole
  • a base such as triethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, for example water / dioxane, at temperatures between 0 and 120 ° C., preferably between 60 and 120 ° C.
  • the addition is preferably carried out in several stages by, in a manner known per se, a) converting the nitrile with H 2 S into a thioamide, which is converted into the corresponding S-alkylimidothioester using an alkylating agent, for example CH 3 I, which in turn, reacts with NH 3 to form the amidine, b) converting the nitrile with an alcohol, for example ethanol in the presence of HCl, into the corresponding imidoester and treating it with ammonia, or c) reacting the nitrile with lithium bis (trimethylsilyl) amide and the product then hydrolyzed.
  • an alkylating agent for example CH 3 I
  • free amino groups can be acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between 60 and + 30 °.
  • 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.
  • inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polycarbonate, sulfone - or sulfuric acids, e.g.
  • compounds of formula I with bases can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salts.
  • the invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. They 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 ingredients.
  • the invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.
  • 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, petroleum jelly.
  • Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used in particular for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants for which are used for parenteral use topical application ointments, creams or powder.
  • the new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables.
  • the specified preparations can be sterilized and / or auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active ingredients, for example one or more vitamins.
  • auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active ingredients, for example one or more vitamins.
  • Salts can be used to combat diseases, particularly hypertension and heart failure.
  • the substances according to the invention are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit.
  • the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
  • the specific dose for each patient depends on a wide 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, and on the rate of excretion , Drug combination and severity of the respective disease to which the therapy applies. Oral application is preferred.
  • 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, separated, dried organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel, the isomers described below also being separated and / or by crystallization. Rf values on silica gel; Mobile solvent: ethyl acetate / methanol 9: 1.
  • a solution of 3.25 g of 4- (1-BOC-piperidin-4-yl) butyric acid and 2.43 g of 1,1'-carbonyldiimidazole in 60 ml of THF is heated under reflux for 1.5 hours.
  • 2.16 g of 4- [amino- (hydroxyimino) methyl] benzoic acid ("A") are dissolved in 60 ml of water with the addition of 4.1 ml of 2N sodium hydroxide solution.
  • the solution of the butyric acid imidazolide derivative is dropped into this solution.
  • the mixture is stirred for one hour, worked up as usual and 4- [4- (1- BOC-piperidin-4-yl) butyrylamino (hydroxyimino) methyl] benzoic acid, mp 157-159 °, is obtained.
  • Example 2 Analogously to Example 1, starting from 3-cyanophenol and hydroxylamine hydrochloride, the 3- [amino- (hydroxyimino) methyl-] phenol, hydrochloride, melting point 220 ° is obtained. Subsequent reaction with 4- (1-BOC-piperidin-4-yl) butyric acid analogously to Example 3 gives 3- [5- (1-BOC-piperidin-4-ylpropyl) -1, 2,4-oxadiazol-3 -yl] phenol.
  • Example 2 Analogously to Example 1, the compound is obtained from 4-cyanobenzoyl chloride and 3- [3- (amino- (hydroxyimino) methyl) benzene sulfonamido] propionic acid ("D")
  • 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 glass contains 5 mg of active ingredient.
  • a solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O 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 lactose, 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
  • each capsule contains 20 mg of the active ingredient.
  • 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, under sterile conditions. -34- lyophilized and sterile sealed. Each ampoule contains 10 mg of active ingredient.

Abstract

L'invention concerne des nouveaux composés de la formule (I), dans laquelle R?1, R2, R2', R3¿, U, V, W, X, Y, Ar, m, n, n', p et q ont la notation mentionnée dans la revendication 1, ainsi que leurs sels. Ces composés et leurs sels inhibent la liaison du fibrinogène au récepteur correspondant et peuvent s'utiliser dans le traitement de thromboses, d'ostéoporoses, d'affections tumorales, d'apoplexie, d'infarctus du myocarde, d'ischémies, d'inflammations, d'inflammations, d'artériosclérose et de maladies ostéolytiques.
PCT/EP1997/002555 1996-05-17 1997-05-20 1,2,4-oxadiazoles utilises comme antagonistes du recepteur d'adhesion WO1997044333A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU29579/97A AU2957997A (en) 1996-05-17 1997-05-20 1,2,4-oxadiazoles as adhesion-receptor antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19620041.5 1996-05-17
DE19620041A DE19620041A1 (de) 1996-05-17 1996-05-17 Adhäsionsrezeptor-Antagonisten

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WO1997044333A1 true WO1997044333A1 (fr) 1997-11-27

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PCT/EP1997/002555 WO1997044333A1 (fr) 1996-05-17 1997-05-20 1,2,4-oxadiazoles utilises comme antagonistes du recepteur d'adhesion

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AR (1) AR007160A1 (fr)
AU (1) AU2957997A (fr)
DE (1) DE19620041A1 (fr)
WO (1) WO1997044333A1 (fr)
ZA (1) ZA974234B (fr)

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US6465471B1 (en) 1998-07-03 2002-10-15 Celltech Therapeutics Limited Cinnamic acid derivatives
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AU2957997A (en) 1997-12-09
AR007160A1 (es) 1999-10-13
DE19620041A1 (de) 1998-01-29

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