N-substituted 1-amino-1,1-dialkylcarboxylic acid derivatives

Description

[0001] The invention relates to compounds of the formula I

[0002] in which

[0003] R1 is H, Cl, F, OH, OA, O—(CH2)n—Ar, NH2, NHCOA, NHCOOA, NH—(CH2)n—Ar, CN, CONH2, CSNH2, C(═NH)SA, C(═NH)NH2, C(═NH—OH)—NH2, C(═NH—O—COA)—NH2, C(═NH—O—COAr)—NH2, C(═NH—O—COHet)-NH2, C(═NH)—OA, C(═NH)NHNH2, C(═NH)NHNHA, C(═NH)NH—COOA, C(═NH)NH—COA, C(═NH)NH—COO—(CH2)m—Ar, C(═NH)NH—COO—(CH2)m-Het, NH—C(═NH)NH2, NH—C(═NH)NH—COOA, NHC(═NH)NH—COO—(CH2)m—Ar,

[0004] R2, R2′ and R2″ are each, independently of one another, H, A, CF3, Cl, F, COA, COOH, COOA, CONH2, CONHA, CONA2, CH2NH2, CH2NHCOA, CH2NHCOOA, OH, OA, OCF3, NO2, SO2A, SO2NH2, SO2NHA or SO2NA2,

[0005] R3 is A, (CH2)n—Ar or (CH2)n-Het,

[0006] R4 is A,

[0007] R3 and R4 together are alternatively (CH2)p, (CH2)n—N(R8)—(CH2)2, (CH2)2—CH(NH2)—(CH2)2—, (CH2)2—CH(NH—COOA)-(CH2)2—, (CH2)2—CH(NH—CH2—COOA)-(CH2)2—, (CH2)2—CH[NH—CH(A)-COOA]-(CH2)2—, (CH2)2—O—(CH2)2, (CH2)2—S(O)m—(CH2)2 or

[0008] R5, R5′, R5″,

[0009] R5′″ and R5″″ are each, independently of one another, (CH2)n—COOH, (CH2)n—COOA, (CH2)n—COO—(CH2)m—Ar, (CH2)n—COO—(CH2)m-Het, Ar, Py or R2,

[0010] R6 is OH, A or Ar,

[0011] R7, R7′ R7″

[0012] and R7′″ are each, independently of one another, H, Hal, OH, OA, COOH, COOA, COO(CH2)mAr, CONH2, CONHA or CONA2,

[0013] R8 is H, A, COA, COOA, (CH2)n—COOH, (CH2)m—COOA, COO—(CH2)m—Ar, COO—(CH2)m-Het, (CH2)n—COO—(CH2)m—Ar, (CH2)n—COO—(CH2)m-Het, (CH2)m—CONH2, (CH2)m—CONHA, (CH2)m—CONA2, SO2A or SO3H,

[0014] R9 is H, A or benzyl,

[0015] U is CO or CH2,

[0016] V is NH or CO,

[0017] W is absent or is CO,

[0018] X is CH or N,

[0019] Y is absent or is CH2, CO or SO2,

[0020] A is unbranched, branched or cyclic alkyl having 1-20 carbon atoms, in which one or two CH2 groups may have been replaced by O or S atoms, —CH═CH— or —C≡C— and/or 1-7 H atoms may have been replaced by F,

[0021] Ar is phenyl or naphthyl, each of which is unsubstituted or mono-substituted, disubstituted or trisubstituted by A, CF3, Hal, OH, OA, OCF3, SO2A, SO2NH2, SO2NHA, SO2NA2, NH2, NHA, NA2, NHCHO, NHCOA, NHCOOA, NACOOA, NHSO2A, NHSO2Ar, COOH, COOA, COO—(CH2)m—Ar′, COO—(CH2)m-Het, CONH2, CONHA, CONA2, CONHAr′, CHO, COA, COAr′, CH2Ar′, (CH2)mNH2, (CH2)mNHA, (CH2)mNA2, (CH2)mNHCHO, (CH2)mNHCOA, (CH2)mNHCOOA, (CH2)mNHCOO—(CH2)mAr′, (CH2)mNHCOO—(CH2)mHet, NO2, CN, CSNH2, C(═NH)SA, C(═NH)OA, C(═NH)NH2, C(═NH)NHOH, C(═NH)NHCOOA or C(═NH)NHCOOAr′

[0022] Ar′ is phenyl or naphthyl, each of which is unsubstituted or mono-substituted, disubstituted or trisubstituted by A, OR9, N(R9)2, NO2, CN, Hal, NHCOA, COOR9, CON(R9)2, COR9 or S(O)2A,

[0023] Het is a monocyclic or bicyclic saturated, unsaturated or aromatic heterocyclic radical having 1-4 N, O and/or S atoms, bonded via N or C, which is unsubstituted or monosubstituted, disubstituted, trisubstituted or tetrasubstituted by A, CF3, Hal, OH, OA, OCF3, SO2A, SO2—(CH2)m—Ar, SO2NH2, SO2NHA, SO2NA2, NH2, NHA, NA2, NHCHO, NHCOA, NHCOOA, NACOOA, NHSO2A, NHSO2Ar, COOH, COOA, COO—(CH2)m—Ar′, CONH2, CONHA, COA, COAr′, CH2NH2, CH2NHA, CH2NHCHO, CH2NHCOA, CH2NHCOOA, NO2, CN, CSNH2, C(═NH)SA, C(═NH)OA, C(═NH)NH2, C(═NH)NHOH, C(═NH)NHCOOA, C(═NH)COOAr′ and/or carbonyl oxygen,

[0024] Py is 2-, 3- or 4-pyridyl which is unsubstituted or monosubstituted or polysubstituted by A, Hal, ON, CONH2, CONHA, COOH, COOA, CH2NH2, CH2NHA, CH2NHCHO, CH2NHCOA, CH2NHCOOA, CH2OH, CH2OA, CH2OAr, CH2OCOA, NO2, NH2, NHA or NA2,

[0025] Hal is F, Cl, Br or I,

[0026] n is 1 or 2,

[0027] m is 0, 1 or,2,

[0028] p is 2, 3, 4 or 5,

[0029] and their pharmaceutically tolerated salts, solvates and stereoisomers.

[0030] The invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates, for example alcoholates, of these compounds.

[0031] The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.

[0032] It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties and are well tolerated. In particular, they exhibit factor Xa-inhibiting properties and can therefore be employed for combating and preventing thromboembolic illnesses, such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris, restenosis after angioplasty and claudicatio intermittens.

[0033] The compounds of the formula I according to the invention may furthermore be inhibitors of the coagulation factors factor VIIa, factor IXa and thrombin in the blood coagulation cascade.

[0034] Aromatic amidine derivatives having an antithrombotic action are disclosed, for example, in EP 0 540 051 B1, WO 98128269, WO 00171508, WO 00/71511, WO 00/71493, WO 00/71507, WO 00171509, WO 00/71512, WO 00171515 and WO 00/71516. Cyclic guanidines for the treatment of thromboembolic illnesses are described, for example, in WO 97/08165. Aromatic heterocyclic compounds having factor Xa-inhibitory activity are disclosed, for example, in WO 96110022. Substituted N-[(aminoiminomethyl )phenylalkyl]azaheterocyclylamides as factor Xa inhibitors are described in WO 96/40679.

[0035] The antithrombotic and anticoagulant effect of the compounds according to the invention is attributed to the inhibitory action against activated coagulation protease, known by the name factor Xa, or to the inhibition of other activated serine proteases, such as factor VIIa, factor IXa or thrombin.

[0036] Factor Xa is one of the proteases involved in the complex process of blood coagulation. Factor Xa catalyses the conversion of prothrombin into thrombin. Thrombin cleaves fibrinogen into fibrin monomers, which, after crosslinking, make an elementary contribution to thrombus formation. Activation of thrombin may result in the occurrence of thromboembolic illnesses. However, inhibition of thrombin may inhibit the fibrin formation involved in thrombus formation.

[0037] The inhibition of thrombin can be measured, for example, by the method of G. F. Cousins et al. in Circulation 1996, 94, 1705-1712.

[0038] Inhibition of factor Xa can thus prevent the formation of thrombin. The compounds of the formula I according to the invention and their salts engage in the blood coagulation process by inhibiting factor Xa and thus inhibit the formation of thrombuses.

[0039] The inhibition of factor Xa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by conventional in-vitro or in-vivo methods. A suitable method is described, for example, by J. Hauptmann et al. in Thrombosis and Haemostasis 1990, 63, 220-223.

[0040] The inhibition of factor Xa can be measured, for example, by the method of T. Hara et al. in Thromb. Haemostas. 1994, 71, 314-319.

[0041] Coagulation factor VIIa initiates the extrinsic part of the coagulation cascade after binding to tissue factor and contributes to the activation of factor X to give factor Xa. Inhibition of factor VIIa thus prevents the formation of factor Xa and thus subsequent thrombin formation.

[0042] The inhibition of factor VIIa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by conventional in-vitro or in-vivo methods. A conventional method for the measurement of the inhibition of factor VIIa is described, for example, by H. F. Ronning et al. in Thrombosis Research 1996, 84, 73-81.

[0043] Coagulation factor IXa is generated in the intrinsic coagulation cascade and is likewise involved in the activation of factor X to give factor Xa. Inhibition of factor IXa can therefore prevent the formation of factor Xa in a different way.

[0044] The inhibition of factor IXa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by conventional in-vitro or in-vivo methods. A suitable method is described, for example, by J. Chang et al. in Journal of Biological Chemistry 1998, 273, 12089-12094.

[0045] The compounds according to the invention may furthermore be used for the treatment of tumours, tumour illnesses and/or tumour metastases. A correlation between tissue factor TF/factor VIIa and the development of various types of cancer has been indicated by T. Taniguchi and N. R. Lemoine in Biomed. Health Res. (2000), 41 (Molecular Pathogenesis of Pancreatic Cancer), 57-59.

[0046] The compounds of the formula I can be employed as medicament active ingredients in human and veterinary medicine, in particular for the treatment and prevention of thromboembolic illnesses, such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris, restenosis after angioplasty, claudicatio intermittens, venous thrombosis, pulmonary embolism, arterial thrombosis, myocardial ischaemia, unstable angina and strokes based on thrombosis.

[0047] The compounds according to the invention are also employed for the treatment or prophylaxis of atherosclerotic diseases, such as coronary arterial disease, cerebral arterial disease or peripheral arterial disease. The compounds are also employed in combination with other thrombolytic agents in the case of myocardial infarction, furthermore for prophylaxis for reocclusion after thrombolysis, percutaneous transiuminal angioplasty (PTCA) and coronary bypass operations.

[0048] The compounds according to the invention are furthermore used for the prevention of rethrombosis in microsurgery, furthermore as anticoagulants in connection with artificial organs or in haemodialysis.

[0049] The compounds are furthermore used in the cleaning of catheters and medical aids in vivo in patients, or as anticoagulants for the preservation of blood, plasma and other blood products in vitro. The compounds according to the invention are furthermore used for illnesses in which blood coagulation makes a crucial contribution to the course of the illness or represents a source of secondary pathology, such as, for example, in cancer, including metastasis, inflammatory disorders, including arthritis, and diabetes.

[0050] In the treatment of the illnesses described, the compounds according to the invention are also employed in combination with other thrombolytically active compounds, such as, for example, with “tissue plasminogen activator” t-PA, modified t-PA, streptokinase or urokinase. The compounds according to the invention are given either at the same time as or before or after the other substances mentioned.

[0051] Particular preference is given to simultaneous administration with aspirin in order to prevent recurrence of the clot formation.

[0052] The compounds according to the invention are also used in combination with blood platelet glycoprotein receptor (IIb/IIIa) antagonists, which inhibit blood platelet aggregation.

[0053] The invention relates to the compounds of the formula I and their salts and to a process for the preparation of the compounds of the formula I according to claim 1 and their salts, characterised in that they are liberated from one of their functional derivatives by treatment with a solvolysing and/or hydrogenolysing agent by

[0054] i) liberating an amidino group from their oxadiazole derivative or oxazolidinone derivative by hydrogenolysis or solvolysis,

[0055] ii) replacing a conventional amino-protecting group with hydrogen by treatment with a solvolysing or hydrogenolysing agent or liberating an amino group protected by a conventional protecting group, and/or converting a base or acid of the formula I into one of its salts.

[0056] For all radicals which occur more than once, their meanings are independent of one another.

[0057] Above and below, the radicals and parameters R1, R2, R2′, R2″, R3, R4, R5, R5′, R5″, R5′″, R5″″, X, Y, U, V and W are as defined under the formula I, unless expressly stated otherwise.

[0058] A is alkyl, is unbranched (linear) or branched, and has 1 to 20, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, particularly preferably 1, 2, 3, 4, 5, or 6 carbon atoms. A is therefore particularly preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore 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.

[0059] A is also cycloalkyl and is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. It is also possible for one or two CH2 groups to be replaced by O or S atoms, —CH═CH— or —C≡C— and/or for 1-7 H atoms to be replaced by F. A is therefore also, for example, CF3 or C2F5.

[0060] A very particularly preferably methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or CF3.

[0061] Hal is preferably F, Cl or Br, but also I.

[0062] The compounds of the formula I in which R1 is, for example, an amidino, amino or guanidino group and these groups are in substituted form are so-called prodrug compounds. The unprotected compounds are easily liberated therefrom in the organism by hydrolysis. Preference is given here to prodrug compounds of the formula I in which

[0063] R1 is NHCOA, NHCOOA, NH—(CH2)n—Ar, C(═NH—OH)—NH2, C(═NH—O—COA)-NH2, C(═NH—O—COAr)—NH2, C(═NH—O—COHet)-NH2, C(═NH)NH—COOA, C(═NH)NH—COA, C(═NH)NH—COO—(CH2)m—Ar, C(═NH)NH—COO—(CH2)m-Het, NH—C(═NH)NH—COOA, NHC(═NH)NH—COO—(CH2)m—Ar,

[0064] and the other radicals in the compounds of the formula I are as defined in claim 1.

[0065] Prodrug compounds are also compounds of the formula I in which R8≠H.

[0066] R1 is preferably CN, C(═NH)NH2, C(═NH—OH)—NH2 or 5-methyl-1,2,4-oxadiazol-3-yl, particularly preference being given to amidino.

[0067] R2, R2′ and R2″ are preferably, for example, H or F, very particularly preferably H.

[0068] R3 is preferably A or CH2Ar, where A is preferably alkyl having 1, 2, 3 or 4 carbon atoms, and Ar is preferably phenyl. R3 is particularly preferably alkyl having 1, 2, 3 or 4 carbon atoms.

[0069] R4 is preferably A or CH2Ar, where A is preferably alkyl having 1, 2, 3 or 4 carbon atoms, and Ar is preferably phenyl. R4 is particularly preferably alkyl having 1, 2, 3 or 4 carbon atoms.

[0070] R3 and R4 together are preferably, for example, (CH2)4, (CH2)5, (CH2)2NHCH2, (CH2)2NH(CH2)2, (CH2)2O(CH2)2, (CH2)2—S(O)m—(CH)22, (CH2)—N(COOA)-CH2, (CH2)—N(CH2COOA)-CH2 or (CH2)—N(CH2COOH)—CH2, where A is preferably alkyl having 1, 2, 3 or 4 carbon atoms.

[0071] R5 is preferably, for example, SO2NH2, SO2NHA, CH2COOH, phenyl which is monosubstituted by SO2NHA, SO2NH2 or SO2A, or 4-pyridyl which is unsubstituted or monosubstituted by CONH2. R5 is very particularly preferably, for example, 4-pyridyl or phenyl which is monosubstituted by SO2NHA, SO2NH2 or SO2A.

[0072] R6 is preferably, for example, methyl.

[0073] R7 is preferably, for example, H, methyl, ethyl, propyl, butyl or phenyl, but very particularly preferably H.

[0074] R7′, R7″ and R7′″ are preferably H.

[0075] R8 is preferably, for example, H, CH2COOH, CH2CH2COOH, COOA, CH2COOA, CH2CH2COOA, COOphenyl, CH2COOphenyl, COOCH2phenyl, CH2COOCH2phenyl or CH2CONH2, where A is preferably alkyl having 1, 2, 3 or 4 carbon atoms. R8 is very particularly preferably CH2COOH, COOA or CH2COOA, where A is preferably alkyl having 1, 2, 3 or 4 carbon atoms.

[0076] R8 is furthermore, for example, SO2CH3.

[0077] R9 is preferably, for example, H, methyl, ethyl or benzyl.

[0078] U is preferably, for example, CO.

[0079] V is preferably, for example, NH.

[0080] W is preferably absent.

[0081] Y is preferably absent, furthermore is also, for example, SO2 or CO.

[0082] Ar is unsubstituted or monosubstituted, disubstituted or trisubstituted phenyl or naphthyl. Preferred substituents for phenyl or naphthyl are, for example, methyl, ethyl, propyl, butyl, trifluoromethyl, F, Cl, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, methylsulfonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, formanido, acetamido, methoxycarbonylamino, ethoxycarbonylamino, methoxycarbonyl-N-methylamino, methylsulfonylamino, phenylsulfonylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 1-methylpiperidin-4-yl-oxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, anilinocarbonyl, formyl, acetyl, propionyl, benzoyl, benzyl, aminomethyl, aminoethyl, methylaminomethyl, dimethylamine-methyl, formylamino, formylaminomethyl, acetamido, acetamidomethyl, methoxycarbonylamino, methoxycarbonylaminomethyl, phenoxycarbonylamino, benzyloxycarbonylamino, phenoxycarbonylaminomethyl, benzyl-oxycarbonylaminomethyl, furyloxycarbonylamino, nitro, cyano, thio-carbamyl, amidino, N-hydroxyamidino or N-methoxycarbonylamidino.

[0083] Ar′ is preferably, for example, unsubstituted or monosubstituted, disubstituted or trisubstituted phenyl. Preferred substituents are, for example, methyl, methoxy, trifluoromethoxy, F, Cl, cyano, acetamido, methoxycarbonyl, carboxyl or methylsulfonyl. Ar′ is very particularly preferably phenyl.

[0084] Het is preferably, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quin-azolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, furthermore preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

[0085] The heterocyclic radicals may also be partially or fully hydrogenated. Het may thus, for example, also be 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, 4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or 4-imidazolyl, 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, 2-, 3-, or 4-, morpholinyl, tetrahydro-2-, -3- or 4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or 4-pyridazinyl, hexahydro-1-, -2-, 4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, 6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8- 3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoro-methylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxo-methylenedioxy)-phenyl or also 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

[0086] Het is very particularly preferably, for example, furyl, thionyl, thiazolyl, imidazolyl, 2,1,3-benzothiadiazolyl, oxazolyl, pyridyl, indolyl, 1-methyl-piperidinyl, piperidinyl or pyrrolidinyl, very particularly preferably pyridyl, 1-methylpiperidin-4-yl or piperidin-4-yl.

[0087] Py is preferably, for example, 2-, 3- or 4-pyridyl which is unsubstituted or monosubstituted by aminocarbonyl.

[0088] The compounds of the formula I may have one or more chiral centres and therefore occur in various stereoisomeric forms. The formula I covers all these forms.

[0089] Accordingly, the invention relates, in particular, to the compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds may be expressed by the following sub-formulae Ie to Ij, which conform to the formula I and in which the radicals not designated in greater detail are as defined under the formula I, but in which

[0090] in Ia

[0091] R1 is Cl, F, NH2, NHCOA, NHCOOA, NH—(CH2)n—Ar, CN, CONH2, CSNH2, C(═NH)SA, C(═NH)NH2, C(═NH—OH)—NH2, C(═NH—O—COA)-NH2, C(═NH—O—COAr)—NH2, C(═NH—O—COHet)-NH2, C(═NH)NH—COOA, C(═NH)NH—COA, C(═NH)NH—COO—(CH2)m—Ar, C(═NH)NH—COO—(CH2)m-Het, NH—C(═NH)NH—COOA, NHC(═NH)NH—COO—(CH2)m—Ar,

[0092] in Ib

[0093] R1 is F, NH2, NHCOA, NHCOOA, NH—(CH2)n—Ar, CN, CONH2, CSNH2, C(═NH)SA, C(═NH)NH2, C(═NH—OH)—NH2, C(═NH—O—COA)-NH2, C(═NH—O—COAr)—NH2, C(═NH)NH—COOA, C(═NH)NH—COA, C(═NH)NH—COO—(CH2)m—Ar, NH—C(═NH)NH—COOA, NHC(═NH)NH—COO—(CH2)m—Ar,

[0094] Ar is phenyl;

[0095] in Ic

[0096] R1 is F, NH2, NHCOA, NHCOOA, NH—(CH2)n—Ar, CN, CONH2, CSNH2, C(═NH)SA, C(═NH)NH2, C(═NH—OH)—NH2, C(═NH—O—COA)-NH2, C(═NH—O—COAr)—NH2, C(═NH)NH—COOA, C(═NH)NH—COA, C(═NH)NH—COO—(CH2)m—Ar, NH—C(═NH)NH—COOA, NHC(═NH)NH—COO—(CH2)m—Ar,

[0097] R2, R2′ and R2″ are each, independently of one another, H or F,

[0098] Ar is phenyl;

[0099] in Id

[0100] R1 is F, NH2, NHCOA, NHCOOA, NH—(CH2)2—Ar, CN, CONH2, CSNH2, C(═NH)SA, C(═NH)NH2, C(═NH—OH)—NH2, C(═NH—O—COA)-NH2, C(═NH—O—COAr)—NH2, C(═NH)NH—COOA, C(═NH)NH—COA, C(═NH)NH—COO—(CH2)m—Ar, NH—C(═NH)NH—COOA, NHC(═NH)NH—COO—(CH2)m—Ar,

[0101] R2, R2′ and R2″ are each, independently of one another, H or F,

[0102] Ar is phenyl,

[0103] R3 is alkyl having 1, 2, 3 or 4 carbon atoms,

[0104] R4 is alkyl having 1, 2, 3 or 4 carbon atoms,

[0105] R3 and R4 together are alternatively (CH2)4, (CH2)5, (CH2)2NHCH2, (CH2)2NH(CH2)2, (CH2)—N(COOA)-CH2, (CH2)—N(CH2COOA)-CH2, (CH2)—N(CH2COOH)—CH2, (CH2)—N(CH2COOA)-(CH2)2, (CH2)—N(CH2COOH)—(CH2)2, COOCH(A)-, (CH2)2—S(O)m—(CH2)2 or (CH2)2—O—(CH2)2,

[0106] where A is alkyl having 1, 2, 3 or 4 carbon atoms;

[0107] in Ie

[0108] R1 is F, NH2, NHCOA, NHCOOA, NH—(CH2)n—Ar, CN, CONH2, CSNH2, C(═NH)SA, C(═NH)NH2, C(═NH—OH)—NH2, C(═NH—O—COA)-NH2, C(═NH—O—COAr)—NH2, C(═NH)NH—COOA, C(═NH)NH—COA, C(═NH)NH—COO—(CH2)m—Ar, NH—C(═NH)NH—COOA, NHC(═NH)NH—COO—(CH2)m—Ar,

[0109] R2, R2′ and R2″ are each, independently of one another, H or F,

[0110] Ar is phenyl,

[0111] R3 is alkyl having 1, 2, 3 or 4 carbon atoms,

[0112] R4 is alkyl having 1, 2, 3 or 4 carbon atoms,

[0113] R3 and R4 together are alternatively (CH2)4, (CH2)5, (CH2)2NHCH2, (CH2)2NH(CH2)2, (CH2)—N(COOA)-CH2, (CH2)—N(CH2COOA)-CH2, (CH2)—N(CH2COOH)—CH2, (CH2)—N(CH2COOA)-(CH2)2, (CH2)—N(CH2COOH)—(CH2)2, COOCH(A)-, (CH2)2—S(O)m—(CH2)2 or (CH2)2—O—(CH2)2,

[0114] where A is alkyl having 1, 2, 3 or 4 carbon atoms,

[0115] R5 is SO2NH2, SO2NHA, CH2COOH,

[0116] phenyl which is monosubstituted by SO2NHA, SO2NH2 or SO2A, where A is alkyl having 1, 2, 3 or 4 carbon atoms, or unsubstituted 4-pyridyl,

[0117] R5′, R5″,

[0118] R5′″ and

[0119] R5″″ are H;

[0120] in If

[0121] R1 is H, Cl, F, NH2, NHCOA, NHCOOA, NH—(CH2)n—Ar, CN, CONH2, CSNH2, C(═NH)SA, C(═NH)NH2, C(═NH—OH)—NH2, C(═NH—O—COA)-NH2, C(═NH—O—COAr)—NH2, C(═NH)—OA, C(═NH)NHNH2, C(═NH)NHNHA, C(═NH)NH—COOA, C(═NH)NH—COA, C(═NH)NH—COO—(CH2)m—Ar, NH—C(═NH)NH2, NH—C(═NH)NH—COOA, NHC(═NH)NH—COO—(CH2)m—Ar,

[0122] R2, R2′ and R2″ are each, independently of one another, H or F,

[0123] R3 is alkyl having 1, 2, 3 or 4 carbon atoms,

[0124] R4 is alkyl having 1, 2, 3 or 4 carbon atoms,

[0125] R3 and R4 together are alternatively (CH2)4, (CH2)5, (CH2)2NHCH2, (CH2)2NH(CH2)2, (CH2)—N(COOA)—CH2, (CH2)—N(CH2COOA)-CH2, (CH2)—N(CH2COOH)—CH2, (CH2)—N(CH2COOA)-(CH2)2, (CH2)—N(CH2COOH)—(CH2)2, COOCH(A)-, (CH2)2—S(O)m—(CH2)2 or (CH2)2—O—(CH2)2,

[0126] where A is alkyl having 1, 2, 3 or 4 carbon atoms,

[0127] R5 is SO2NH2, SO2NHA, CH2COOH,

[0128] phenyl which is monosubstituted by SO2NHA, SO2NH2 or SO2A, or

[0129] unsubstituted 4-pyridyl,

[0130] R5′, R5″,

[0131] R5′″ and

[0132] R5″″ are H,

[0133] R6 is OH, A or Ar,

[0134] R7 is H, A or Ar,

[0135] R8 is H, (CH2)n—COOH, (CH2)m—COOA, (CH2)m—COO—(CH2)n—Ar, (CH2)m—CONH2, (CH2)m—CONHA or (CH2)m—CONA2,

[0136] R9 is H, A or benzyl,

[0137] U is CO,

[0138] V is NH,

[0139] W is absent,

[0140] X is CH or N,

[0141] Y is absent,

[0142] A is alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms or CF3,

[0143] Ar is phenyl,

[0144] n is 1 or 2,

[0145] m is 0, 1 or 2,

[0146] p is 4 or 5;

[0147] in Ig

[0148] R1 is F, NH2, NH—(CH2)n—Ar, CN, CSNH2, C(═NH)SA, C(═NH)NH2 or C(═NH—OH)—NH2,

[0149] R2, R2′ and R2″ are each, independently of one another, H or F,

[0150] R3 is alkyl having 1, 2, 3 or 4 carbon atoms,

[0151] R4 is alkyl having 1, 2, 3 or 4 carbon atoms,

[0152] R3 and R4 together are alternatively (CH2)4, (CH2)5, (CH2)2NHCH2, (CH2)2NH(CH2)2, (CH2)—N(COOA)-CH2, (CH2)—N(CH2COOA)-CH2, (CH2)—N(CH2COOH)—CH2, (CH2)—N(CH2COOA)-(CH2)2, (CH2)—N(CH2COOH)—(CH2)2, (CH2)2—S(O)m—(CH2)2 or (CH2)2—O—(CH2)2,

[0153] where A is alkyl having 1, 2, 3 or 4 carbon atoms,

[0154] R5 is SO2NH2, SO2NHA, CH2COOH,

[0155] phenyl which is monosubstituted by SO2NHA, SO2NH2 or SO2A,

[0156] or unsubstituted 4-pyridyl,

[0157] R5′, R5″,

[0158] R5′″, and

[0159] R5″″ are H,

[0160] R7 is H, A or Ar,

[0161] R8 is (CH2)n—COOH, (CH2)m—COOA, (CH2)m—COO—(CH2)n—Ar, (CH2)m—COO—(CH2)n-Het, (CH2)m—CONH2, (CH2)m—CONHA or (CH2)m—CONA2,

[0162] R9 is H, A or benzyl,

[0163] U is CO,

[0164] V is NH,

[0165] W is absent,

[0166] X is CH or N,

[0167] Y is absent,

[0168] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF3,

[0169] Ar is phenyl,

[0170] n is 1 or 2,

[0171] m is 0, 1 or 2,

[0172] p is 4 or 5;

[0173] in Ih

[0174] R1 is H,

[0175] R2 is CH2NH2, CH2NHCOA or CH2NHCOOA,

[0176] R2′ and R2″ are each, independently of one another, H,

[0177] R3 is alkyl having 1, 2, 3 or 4 carbon atoms,

[0178] R4 is alkyl having 1, 2, 3 or 4 carbon atoms,

[0179] R3 and R4 together are alternatively (CH2)4, (CH2)5, (CH2)2NHCH2, (CH2)2NH(CH2)2, (CH2)—N(COOA)-CH2, (CH2)—N(CH2COOA)-CH2, (CH2)—N(CH2COOH)—CH2, (CH2)—N(CH2COOA)-(CH2)2, (CH2)—N(CH2COOH)—(CH2)2, (CH2)2—S(O)m—(CH2)2 or (CH2)2—O—(CH2)2,

[0180] where A is alkyl having 1, 2, 3 or 4 carbon atoms,

[0181] R5 is SO2NH2, SO2NHA, CH2COOH,

[0182] phenyl which is monosubstituted by SO2NHA, SO2NH2 or SO2A,

[0183] or unsubstituted 4-pyridyl,

[0184] R5′ is F,

[0185] R5″, R5′″

[0186] and R5″″ are H,

[0187] R7 is H, A or Ar,

[0188] R8 is H, (CH2)n—COOH, (CH2)m—COOA, (CH2)m—COO—(CH2)n—Ar, (CH2)m—COO—(CH2)n-Het, (CH2)m—CONH2, (CH2)m—CONHA or (CH2)m—CONA2,

[0189] R9 is H, A or benzyl,

[0190] U is CO,

[0191] V is NH,

[0192] W is absent,

[0193] X is CH,

[0194] Y is absent,

[0195] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF3,

[0196] Ar is phenyl,

[0197] n is 1 or 2,

[0198] m is 0, 1 or 2,

[0199] p is 4 or 5;

[0200] in Ii

[0201] R1 is CN, C(═NH)NH2, C(═NH—OH)—NH2

[0202] R2, R2′ and R2″ are H,

[0203] R3 is alkyl having 1, 2, 3 or 4 carbon atoms,

[0204] R4 is alkyl having 1, 2, 3 or 4 carbon atoms,

[0205] R3 and R4 together are alternatively (CH2)4, (CH2)5, (CH2)2NHCH2, (CH2)2NH(CH2)2, (CH2)—N(COOA)-CH2, (CH2)—N(CH2COOA)-CH2, (CH2)—N(CH2COOH)—CH2, (CH2)—N(CH2COOA)-(CH2)2, (CH2)—N(CH2COOH)—(CH2)2, (CH2)2—S(O)m—(CH2)2 or (CH2)2—O—(CH2)2,

[0206] where A is alkyl having 1, 2, 3 or 4 carbon atoms,

[0207] R5 is SO2NH2, SO2NHA, CH2COOH,

[0208] phenyl which is monosubstituted by SO2NHA, SO2NH2 or SO2A,

[0209] or unsubstituted 4-pyridyl,

[0210] R5′, R5″,

[0211] R5′″ and

[0212] R5″″ are H,

[0213] R6 is methyl,

[0214] R7 is H, A or Ar,

[0215] R8 is (CH2)n—COOH, (CH2)m—COOA, (CH2)m—COO—(CH2)n—Ar, (CH2)m—COO—(CH2)n-Het, (CH2)m—CONH2, (CH2)m—CONHA or (CH2)m—CONA2,

[0216] R9 is H, A or benzyl,

[0217] U is CO,

[0218] V is NH,

[0219] W is absent,

[0220] X is CH or N,

[0221] Y is absent,

[0222] A is alkyl having 1, 2, 3, 4, 5 or 6 C atoms or CF3,

[0223] Ar is phenyl,

[0224] n is 1 or2,

[0225] m is 0, 1 or2,

[0226] p is 4 or 5;

[0227] in Ij

[0228] R1 is CN, C(═NH)NH2, C(═NH—OH)—NH2

[0229] R2, R2′ and R2″ are H,

[0230] R3 is alkyl having 1, 2, 3 or 4 carbon atoms,

[0231] R4 is alkyl having 1, 2, 3 or 4 carbon atoms,

[0232] R3 and R4 together are, alternatively (CH2)4, (CH2)5, (CH2)2NHCH2, (CH2)2NH(CH2)2, (CH2)—N(COOA)-CH2, (CH2)—N(CH2COOA)-CH2, (CH2)—N(CH2COOH)—CH2, (CH2)—N(CH2COOA)-(CH2)2, (CH2)—N(CH2COOH)—(CH2)2, (CH2)2—S(O)m—(CH2)2 or (CH2)2—O—(CH2)2,

[0233] where A is alkyl having 1, 2, 3 or 4 carbon atoms,

[0234] R5 is SO2NH2, SO2NHA, CH2COOH,

[0235] phenyl which is monosubstituted by SO2NHA, SO2NH2 or SO2A,

[0236] or unsubstituted 4-pyridyl,

[0237] R5′, R5″,

[0238] R5′″ and

[0239] R5″″ are H,

[0240] R6 is methyl,

[0241] R7 is H, A or Ar,

[0242] R8 is (CH2)n—COOH, (CH2)m—COOA, (CH2)m—COO—(CH2)n—Ar, (CH2)m—COO—(CH2)n-Het, (CH2)m—CONH2, (CH2)m—CONHA or (CH2)m—CONA2,

[0243] R9 is H, A or benzyl,

[0244] U is CO,

[0245] V is NH,

[0246] W is absent,

[0247] X is CH or N,

[0248] Y is absent, SO2 or CO,

[0249] A is alkyl having 1, 2, 3, 4, 5 or 6 C atoms or CF3,

[0250] Ar is phenyl,

[0251] n is 1 or 2,

[0252] m is 0, 1 or 2,

[0253] p is 4 or 5;

[0254] and their pharmaceutically tolerated salts, solvates and stereoisomers.

[0255] The compounds of the formula I and also the starting materials for their preparation are, in addition, prepared by methods known per se, as described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail.

[0256] If desired, the starting materials can also be formed in situ so that they are not isolated from the reaction mixture, but instead are immediately converted further into the compounds of the formula I.

[0257] Compounds of the formula I can preferably be obtained by liberating compounds of the formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.

[0258] Preferred starting materials for the solvolysis or hydrogenolysis are those which conform to the formula I, but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom bonded to an N atom, in particular those which carry an R′—N group, in which R′ is an amino-protecting group, instead of an HN group, and/or those which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group, for example those which conform to the formula I, but carry a —COOR″ group, in which R″ is an hydroxyl-protecting group, instead of a —COOH group.

[0259] Preferred starting materials are also the oxadiazole derivatives which can be converted into the corresponding amidino compounds.

[0260] The liberation of the amidino group from its oxadiazole derivative can be carried out, for example, by treatment with hydrogen in the presence of a catalyst (for example Raney nickel). Suitable solvents are those indicated below, in particular alcohols, such as methanol or ethanol, organic acids, such as acetic acid or propionic acid, or mixtures thereof. The hydrogenolysis is generally carried out at temperatures between about 0 and 100° and pressures between about 1 and 200 bar, preferably at 20-30° (room temperature) and 1-10 bar.

[0261] The oxadiazole group is introduced, for example, by reaction of the cyano compounds with hydroxylamine and reaction with phosgene, dialkyl carbonate, chloroformates, N,N′-carbonyldiimidazole or acetic anhydride.

[0262] It is also possible for a plurality of—identical or different—protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protecting groups present are different from one another, they can in many cases be cleaved off selectively.

[0263] The term “amino-protecting group” is known in general terms and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), their type and size is furthermore not crucial; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term “acyl group” is to be understood in the broadest sense in connection with the present process. It includes 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 and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and toluyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxy-carbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ (“carbobenzoxy”), 4-methoxybenzyloxycarbonyl and FMOC; and aryl-sulfonyl, such as Mtr. Preferred amino-protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.

[0264] The compounds of the formula I are liberated from their functional derivatives—depending on the protecting group used—for example using strong acids, advantageously using TFA or perchloric acid, but also using other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but is not always necessary. 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, furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the above-mentioned solvents are furthermore suitable. TFA is preferably used in excess without addition of a further solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9.1. The reaction temperatures for the cleavage are advantageously between about 0 and about 50°, preferably between 15 and 30° (room temperature).

[0265] The BOC, OBut and Mtr groups can, for example, preferably be cleaved off using TFA in dichloromethane or using approximately 3 to 5N HCl in dioxane at 15-30°, and the FMOC group can be cleaved off using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°.

[0266] Protecting groups which can be removed hydrogenolytically (for example CBZ, benzyl or the liberation of the amidino group from its oxadiazole derivative) can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon). Suitable solvents here are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at temperatures between about 0 and 100° and pressures between about 1 and 200 bar, preferably at 20-30° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°.

[0267] Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, trifluoromethylbenzene, 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 or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents.

[0268] The biphenyl-SO2NH2 group is preferably employed in the form of its tert-butyl derivative. The tert-butyl group is cleaved off, for example, using TFA with or without addition of an inert solvent, preferably with addition of a small amount of anisole (1% by volume).

[0269] A cyano group is converted into an amidino group by reaction with, for example, hydroxylamine followed by reduction of the N-hydroxyamidine using hydrogen in the presence of a catalyst, such as, for example, Pd/C. In order to prepare an amidine of the formula I, it is also possible to add ammonia onto a nitrile. The adduction is preferably carried out in a multi-step process by, in a manner known per se, a) converting the nitrile into a thioamide using H2S, converting the thioamide into the corresponding S-alkylimidothioester using an alkylating agent, for example CH3I, and in turn reacting the thioester with NH3 to give the amidine, b) converting the nitrile into the corresponding imidoester using an alcohol, for example ethanol, in the presence of HCl, and treating this ester with ammonia, or c) reacting the nitrile with lithium bis(trimethylsilyl)amide, and subsequently hydrolysing the product.

[0270] Esters can be saponified, for example, using acetic acid or using NaOH or KOH in water, water/THF or water/dioxane at temperatures between 0 and 100°.

[0271] Furthermore, free amino groups can be acylated in a conventional manner using an acid chloride or anhydride or alkylated using 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°.

[0272] A base of the formula I can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as ethanol, followed by evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, or sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono-basic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids, and laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and/or purification of the compounds of the formula I.

[0273] On the other hand, compounds of the formula I can be converted into the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, or into the corresponding ammonium salts using bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate). It is also possible to use physiologically acceptable organic bases, such as, for example, ethanolamine.

[0274] Compounds of the formula I according to the invention may be chiral owing to their molecular structure and may accordingly occur in various enantiomeric forms. They can therefore exist in racemic or in optically active form.

[0275] Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed as such in the synthesis.

[0276] In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N-benzoylproline) or N-benzenesulfonylproline), or the various optically active camphorsulfonic acids. Also advantage is chromatographic enantiomer resolution with the aid of an optically active resolving agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatised methacrylate polymers immobilised on silica gel). Examples of suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/acetonitrile, for example in the ratio 82:15:3.

[0277] The invention furthermore relates to the use of compounds of the formula I and/or their physiologically acceptable salts for the preparation of pharmaceutical preparations, in particular by non-chemical methods. They can be converted here into a suitable dosage form together with at least one solid, liquid and/or semiliquid excipient or assistant and, if desired, in combination with one or more further active ingredients.

[0278] The invention furthermore relates to pharmaceutical preparations comprising at least one compound of the formula I and/or one of its pharmaceutically acceptable salts.

[0279] These preparations can be used as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc or vaseline. Suitable for oral administration are, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal administration are suppositories, suitable for parenteral administration are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical application are ointments, creams or powders. The novel compounds may also be lyophilised and the resultant lyophilisates used, for example, to prepare injection preparations. The preparations indicated may be sterilised and/or comprise assistants, such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifying agents, salts for modifying the osmotic pressure, buffer substances, colorants and flavours and/or a plurality of further active ingredients, for example one or more vitamins.

[0280] The compounds of the formula I and/or their physiologically acceptable salts can be used for combating and preventing thromboembolic illnesses, such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris, restenosis after angioplasty and claudicatio intermittens.

[0281] In general, the substances according to the invention are preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit. The daily dose is preferably between about 0.02 and 10 mg/kg of body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and method of administration, on the excretion rate, medicament combination and severity of the particular illness to which the therapy applies. Oral administration is preferred.

[0282] Above and below, all temperatures are given in ° C. In the following examples, ‘conventional work-up’ means that water is added if necessary, the pH is adjusted, if necessary, to between 2 and 10, depending on the constitution of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the product is purified by chromatography on silica gel and/or by crystallisation. Rf values on silica gel; eluent: ethyl acetate/methanol 9:1.

[0283] Mass spectrometry (MS):

[0284] EI (electron ionisation) M+

[0285] FAB (fast atom bombardment) (M+H)+

[0286] The α-disubstituted amino acid N-arylations described in Examples 1 and 2 are carried out analogously to methods known from the literature (Tetrahedron: Asymmetry, Vol. 7, No. 11, page 3075, 1996).

EXAMPLE 1

[0287] A solution of 5.36 g of 2-methylalanine, 11.91 g of iodobenzonitrile, 3.03 g of tetrakis(triphenylphosphine)palladium(O), 0.49 g of copper(I) iodide, 7.186 g of potassium carbonate, 3.25 g of tetra-n-butylammonium iodide in 100 ml of 1-methyl-2-pyrrolidone, 40 ml of pyridine and 10 ml of water is stirred at 100° for 4 hours. Conventional work-up gives 2-(3-cyanophenyl-amino)-2-methylpropionic acid (“AA”), FAB 205.

[0288] The following compounds are obtained analogously

[0289] 1-(3-cyanophenylamino)cyclopentanecarboxylic acid,

[0290] 1-(3-cyanophenylamino)cyclohexanecarboxylic acid,

[0291] mono-tert-butyl 4-(3-cyanophenylamino)piperidine-1,4-dicarboxylate,

[0292] 4-(3-cyanophenylamino)tetrahydropyran-4-carboxylic acid,

[0293] 4-(3-cyanophenylamino)tetrahydrothiopyran-4-carboxylic acid,

[0294] 4-(3-cyanophenylamino)-1,1-dioxotetrahydrothiopyran-4-carboxylic acid.

EXAMPLE 2

[0295] Analogously to Example 1, 3-(3-iodophenyl)-5-methyl-1,2,4-oxadiazole (obtainable by heating 3-iodobenzonitrile and hydroxylamine hydrochloride in pyridine) and 2-methylalanine give the compound 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl )phenylamino]-2-methylpropionic acid (“AB”), FAB 262.

[0296] The following compounds are obtained analogously

[0297] 1-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenylamino]cyclopentanecarboxylic acid,

[0298] 1-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenylamino]cyclohexanecarboxylic acid,

[0299] mono-tert-butyl 4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenylamino]-piperidine-1,4-dicarboxylate,

[0300] 4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenylamino]tetrahydropyran-4-carboxylic acid,

[0301] 4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenylamino]tetrahydrothiopyran-4-carboxylic acid,

[0302] 4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenylamino]-1,1-dioxotetrahydrothiopyran-4-carboxylic acid.

EXAMPLE 3

[0303] A solution of 1.13 g of “AA”, 1.68 g of N-tert-butyl4-aminobiphenyl-2-sulfonamide (“CA”), 1.41 g of 2-chloro-1-methylpyridinium iodide and 0.94 ml of N-ethyldiisopropylamine in 40 ml of ethyl acetate is refluxed for 6 hours. The mixture is subjected to conventional work-up, and the residue is chromatographed on silica gel, giving 0.38 g of N-(2′-tert-butylsulfamoyl-biphenyl-4-yl)-2-(3-cyanophenylamino)-2-methylpropionamide (“CB”), m. p. 190-193°, FAB 491

[0304] Analogous reaction of “CA” with the compounds obtained in Example 1 gives the following products

[0305] N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-1-(3-cyanophenylamino)cyclopentanecarboxamide,

[0306] N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-1-(3-cyanophenylamino)cyclohexanecarboxamide,

[0307] tert-butyl 4-(2′-tert-butylsulfamoylbiphenyl-4-ylcarbamoyl)-4-(3-cyanophenylamino)piperidine-1-carboxylate,

[0308] N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-4-(3-cyanophenylamino)tetrahydropyran-4-carboxamide,

[0309] N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-4-(3-cyanophenylamino)tetrahydrothiopyran-4-carboxamide,

[0310] N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-4-(3-cyanophenylamino)-1,1-dioxotetrahydrothiopyran-4-carboxamide.

EXAMPLE 4

[0311] Analogously to Example 3, reaction of 4′-aminobiphenyl-2-sulfonamide with the compounds obtained in Example 2 gives the following products

[0312] N-(sulfamoylbiphenyl-4-yl)-2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl-amino]-2-methylproplonamide (“DB”), FAB 492;

[0313] N-(sulfamoylbiphenyl-4-yl)-1-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenylamino]cyclopentanecarboxamide,

[0314] N-(sulfamoylbiphenyl-4-yl)-1-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenylamino]cyclohexanecarboxamide,

[0315] tert-butyl 4-(2′-sulfamoylbiphenyl-4-ylcarbamoyl)-4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenylamino]piperidine-1-carboxylate,

[0316] N-(sulfamoylbiphenyl-4-yl)-4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenylamino]tetrahydropyran-4-carboxamide,

[0317] N-(sulfamoylbiphenyl-4-yl)-4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenylamino]tetrahydrothiopyran-4-carboxamide,

[0318] N-(sulfamoylbiphenyl-4-yl)-4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenylamino]-1,1-dioxotetrahydrothiopyran-4-carboxamide.

EXAMPLE 5

[0319] A solution of 0.32 g of “CB”, 0.45 g of hydroxylammonium chloride, 1.04 g of sodium carbonate in 30 ml of methanol and 0.3 ml of water is refluxed for 3 hours. Conventional work-up gives 0.38 g of N-(2′-tert-butylsulfamoyl-biphenyl-4-yl)-2-[3-(N-hydroxyamidino)phenylamino]-2-methylpropionamide (“EA”), FAB 524.

[0320] Analogous reaction of the compounds obtained in Example 3 gives the following products

[0321] N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-1-[3-(N-hydroxyamidino)phenylamino]cyclopentanecarboxamide,

[0322] N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-1-[3-(N-hydroxyamidino)phenylamino]cyclohexanecarboxamide,

[0323] tert-butyl 4-(2′-tert-butylsulfamoylbiphenyl-4-ylcarbamoyl)4-[3-(N-hydroxy-amidino)phenylamino]piperidine-1-carboxylate,

[0324] N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-4-[3-(N-hydroxyamidino)phenylamino]tetrahydropyran-4-carboxamide,

[0325] N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-4-[3-(N-hydroxyamidino)phenylamino]tetrahydrothiopyran-4-carboxylic acid-amid,

[0326] N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-4-[3-(N-hydroxyamidino)phenylamino]-1,1-dioxotetrahydrothiopyran-4-carboxamide.

EXAMPLE 6

[0327] 1 drop of acetic acid and water-moist Raney nickel are added to a solution of 0.26 g of “EA” in 30 ml of methanol, and the mixture is stirred under an H2 atmosphere for 24 hours. Removal of the catalyst and conventional work-up gives 0.4 g of N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-2-(3-amidino-phenylamino)-2-methylpropionamide acetate (“FA”), m.p. 153°, FAB 508.

[0328] Analogous hydrogenation of the compounds obtained in Example 5 gives the following products

[0329] N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-1-(3-amidino-phenylamino)cyclopentancarboxamide acetate;

[0330] N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-1-(3-amidino-phenylamino)cyclohexanecarboxamide acetate;

[0331] tert-butyl 4-(2′-tert-butylsulfamoylbiphenyl-4-ylcarbamoyl)-4-(3-amidino-phenylamino)piperidine-1-carboxylate acetate;

[0332] N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-4-(3-amidino-phenylamino)tetrahydropyran-4-carboxamide acetate;

[0333] N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-4-(3-amidino-phenylamino)tetrahydrothiopyran-4-carboxamide acetate;

[0334] N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-4-(3-amidino-phenylamino)-1,1-dioxotetrahydrothiopyran-4-carboxamide acetate.

EXAMPLE 7

[0335] A solution of 0.128 g of “FA” in 20 ml of trifluoroacetic acid and 1.4 ml of anisole is stirred at room temperature for 3 hours. After the solvent has been removed, the residue is triturated with ether, giving 0.13 g of N-(2′-sulfamoylbiphenyl-4-yl)-2-(3-amidinophenylamino)-2-methylpropionamide, trifluoroacetate (“GA”), m.p. 197°, FAB 452.

[0336] The compounds obtained in Example 6 give the following products analogously

[0337] N-(2′-sulfamoylbiphenyl-4-yl)-1-(3-amidinophenylamino)cyclopentanecarboxamide trifluoroacetate;

[0338] N-(2′-sulfamoylbiphenyl-4-yl)-1-(3-amidinophenylamino)cyclohexanecarboxamide trifluoroacetate;

[0339] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylamino)piperidine-4-carboxamide trifluoroacetate;

[0340] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylamino)tetrahydropyran-4-carboxamide trifluoroacetate;

[0341] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylamino)tetrahydrothiopyran-4-carboxamide trifluoroacetate;

[0342] N-(2′-sulfamoylbiphenyl-4-yl)-(3-amidinophenylamino)-1,1-dioxotetrahydrothiopyran-4-carboxamide trifluoroacetate.

EXAMPLE 8

[0343] Reaction of the compounds obtained in Example 5 analogously to Example 7 gives the following products

[0344] N-(2′-sulfamoylbiphenyl-4-yl)-2-[3-(N-hydroxyamidino)phenylamino]-2-methylpropionamide trifluoroacetate;

[0345] N-(2′-sulfamoylbiphenyl-4-yl)-1-[3-(N-hydroxyamidino)phenylamino]-cyclopentanecarboxamide trifluoroacetate, m.p. 108°, FAB 494;

[0346] N-(2′-sulfamoylbiphenyl-4-yl)-1-[3-(N-hydroxyamidino)phenylamino]-cyclohexanecarboxamide

[0347] N-(2′-sulfamoylbiphenyl-4-yl)-4-[3-(N-hydroxyamidino)phenylamino]-piperidine-4-carboxamide,

[0348] N-(2′-sulfamoylbiphenyl-4-yl)-4-[3-(N-hydroxyamidino)phenylamino]-tetrahydropyran-4-carboxamide

[0349] N-(2′-sulfamoylbiphenyl-4-yl)-4-[3-(N-hydroxyamidino)phenylamino]-tetrahydrothiopyran-4-carboxamide

[0350] N-(2′-sulfamoylbiphenyl-4-yl)-4-[3-(N-hydroxyamidino)phenylamino]-1,1-dioxotetrahydrothiopyran-4-carboxamide.

EXAMPLE 9

[0351] The compounds obtained in Example 4 give the following products analogously to Example 6

[0352] N-(2′-sulfamoylbiphenyl-4-yl)-2-(3-amidinophenylamino)-2-methylpropionamide acetate, FAB 478;

[0353] N-(2′-sulfamoylbiphenyl-4-yl)-1-(3-amidinophenylamino)cyclopentanecarboxamide acetate

[0354] N-(2′-sulfamoylbiphenyl-4-yl)-1-(3-amidinophenylamino)cyclohexanecarboxamide acetate, FAB 492;

[0355] tert-butyl 4-(2′-sulfamoylbiphenyl-4-ylcarbamoyl)-4-(3-amidinophenyl-amino)piperidine-1-carboxylate acetate

[0356] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylamino)tetrahydropyran-4-carboxamide acetate

[0357] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylamino)tetrahydrothiopyran-4-carboxamide acetate

[0358] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylamino)-1,1-dioxotetrahydrothiopyran-4-carboxamide acetate,

EXAMPLE 10

[0359] Starting from 2′-methanesulfonylbiphenyl-4-ylamine and the compounds obtained in Example 1, the reaction analogous to Examples 3, 5 and 6 and salt formation with trifluoroacetic acid gives the following compounds

[0360] N-(2′-methanesulfonylbiphenyl-4-yl)-2-(3-amidinophenylamino)-2-methylpropionamide trifluoroacetate;

[0361] N-(2′-methanesulfonylbiphenyl-4-yl)-1-(3-amidinophenylamino)cyclopentanecarboxamide trifluoroacetate;

[0362] N-(2′-methanesulfonylbiphenyl-4-yl)-1-(3-amidinophenylamino)cyclohexanecarboxamide trifluoroacetate;

[0363] N-(2′-methanesulfonylbiphenyl-4-yl)-4-(3-amidinophenylamino)piperidine-4-carboxamide trifluoroacetate;

[0364] N-(2′-methanesulfonylbiphenyl-4-yl )-4-(3-amidinophenylamino)tetrahydropyran-4-carboxamide trifluoroacetate;

[0365] N-(2′-methanesulfonylbiphenyl-4-yl)-4-(3-amidinophenylamino)tetrahydrothiopyran-4-carboxamide trifluoroacetate;

[0366] N-(2′-methanesulfonylbiphenyl-4-yl )-4-(3-amidinophenylamino)-1,1-dioxotetrahydrothiopyran-4-carboxamide trifluoroacetate.

EXAMPLE 11

[0367] Analogously to Example 5, starting from

[0368] N-(2′-methanesulfonylbiphenyl-4-yl)-2-(3-cyanophenylamino)-2-methylpropionamide

[0369] N-(2′-methanesulfonylbiphenyl-4-yl)-1-(3-cyanophenylamino)cyclopentanecarboxamide,

[0370] N-(2′-methanesulfonylbiphenyl-4-yl)-1-(3-cyanophenylamino)cyclohexanecarboxamide,

[0371] tert-butyl 4-(2′-methanesulfonylbiphenyl-4-ylcarbamoyl)-4-(3-cyanophenyl-amino)piperidine-1-carboxylate,

[0372] N-(2′-methanesulfonylbiphenyl-4-yl)-4-(3-cyanophenylamino)tetrahydropyran-4-carboxamide,

[0373] N-(2′-methanesulfonylbiphenyl-4-yl)-4-(3-cyanophenylamino)tetrahydrothiopyran-4-carboxamide,

[0374] N-(2′-methanesulfonylbiphenyl-4-yl)-4-(3-cyanophenylamino)-1,1-dioxotetrahydrothiopyran-4-carboxamide,

[0375] N-(2′-sulfamoylbiphenyl-4-yl)-1-(3-cyanophenylamino)cyclohexanecarboxamide,

[0376] followed by salt formation with trifluoroacetic acid, the following compounds are obtained

[0377] N-(2′-methanesulfonylbiphenyl-4-yl)-2-[3-(N-hydroxyamidino)phenylamino]-2-methylpropionamide trifluoroacetate;

[0378] N-(2′-methanesulfonylbiphenyl-4-yl)-1-[3-(N-hydroxyamidino)phenylamino]cyclopentanecarboxamide trifluoroacetate,

[0379] N-(2′-methanesulfonylbiphenyl-4-yl)-1-[3-(N-hydroxyamidino)phenylamino]cyclohexanecarboxamide trifluoroacetate;

[0380] N-(2′-methanesulfonylbiphenyl-4-yl)-4-[3-(N-hydroxyamidino)phenylamino]piperidine-4-carboxamide trifluoroacetate;

[0381] N-(2′-methanesulfonylbiphenyl-4-yl)-4-[3-(N-hydroxyamidino)phenylamino]tetrahydropyran-4-carboxamide trifluoroacetate;

[0382] N-(2′-methanesulfonylbiphenyl-4-yl)-4-[3-(N-hydroxyamidino)phenylamino]tetrahydrothiopyran-4-carboxamide trifluoroacetate;

[0383] N-(2′-methanesulfonylbiphenyl-4-yl)-4-[3-(N-hydroxyamidino)phenyl-amino]-1,1 -dioxotetrahydrothiopyran-4-carboxamide trifluoroacetate,

[0384] N-(2′-sulfamoylbiphenyl-4-yl)-1-[3-(N-hydroxyamidino)phenylamino]cyclohexanecarboxamide trifluoroacetate, FAB 508.

EXAMPLE 12

[0385] The following compounds are obtained analogously to Example 10

[0386] N-(2′-methanesulfonylbiphenyl-4-yl)-4-(3-amidinophenylamino)piperidine-1-ethoxycarbonyl-4-carboxamide,

[0387] N-(2′-methanesulfonylbiphenyl-4-yl)-4-(3-amidinophenylamino)piperidine-1-methoxycarbonylmethyl-4-carboxamide,

[0388] N-(2′-methanesulfonylbiphenyl-4-yl)-4-(3-amidinophenylamino)piperidine-1-carboxymethyl-4-carboxamide.

EXAMPLE 13

[0389] The following compounds are obtained analogously to Example 7

[0390] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylamino)piperidine-1-ethoxycarbonyl-4-carboxamide,

[0391] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylamino)piperidine-1-methoxycarbonylmethyl-4-carboxamide,

[0392] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylamino)piperidine-1-carboxymethyl-4-carboxamide.

EXAMPLE 14

[0393] The following compounds are obtained analogously starting from 4-pyridin-4-ylphenylamine

[0394] N-[4-(pyridin-4-yl)phenyl]-2-(3-amidinophenylamino)-2-methylpropionamide,

[0395] N-[4-(pyridin-4-yl)phenyl]-1-(3-amidinophenylamino)cyclopentanecarboxamide

[0396] N-[4-(pyridin-4-yl)phenyl]-1-(3-amidinophenylamino)cyclohexanecarboxamide,

[0397] N-[4-(pyridin-4-yl)phenyl]-4-(3-amidinophenylamino)piperidine-4-carboxamide,

[0398] N-[4-(pyridin-4-yl)phenyl]-4-(3-amidinophenylamino)tetrahydropyran-4-carboxamide,

[0399] N-[4-(pyridin-4-yl)phenyl]-4-(3-amidinophenylamino)tetrahydrothiopyran4-carboxamide,

[0400] N-[4-(pyridin-4-yl)phenyl]-4-(3-amidinophenylamino)-1,1-dioxotetrahydrothiopyran-4-carboxamide,

[0401] N-[4-(pyridin-4-yl)phenyl]-4-(3-amidinophenylamino)piperidine-1-ethoxycarbonyl-4-carboxamide,

[0402] N-[4-(pyridin-4-yl)phenyl]-4-(3-amidinophenylamino)piperidine-1-methoxycarbonylmethyl-4-carboxamide,

[0403] N-[4-(pyridin-4-yl)phenyl]-4-(3-amidinophenylamino)piperidine-1-carboxymethyl-4-carboxamide.

EXAMPLE 15

[0404] Coupling of 3-cyanophenylsulfonyl chloride with 2-methylalanine under covnentional conditions gives 2-(3-cyanophenylsulfonylamino)-2-methylpropionic acid.

[0405] The following compounds are obtained analogously

[0406] 1-(3-cyanophenylsulfonylamino)cyclopentanecarboxylic acid,

[0407] 1-(3-cyanophenylsulfonylamino)cyclohexanecarboxylic acid,

[0408] mono-tert-butyl 4-(3-cyanophenylsulfonylamino)piperidine-1,4-dicarboxylate,

[0409] 4-(3-cyanophenylsulfonylamino)tetrahydropyran-4-carboxylic acid,

[0410] 4-(3-cyanophenylsulfonylamino)tetrahydrothiopyran4-carboxylic acid,

[0411] 4-(3-cyanophenylsulfonylamino)-1,1-dioxotetrahydrothiopyran-4-carboxylic acid.

[0412] Analogously to Example 3, 5, 6 and 7, these give the compounds

[0413] N-(2′-sulfamoylbiphenyl-4-yl)-2-(3-amidinophenylsulfonylamino)-2-methylpropionamide,

[0414] N-(2′-sulfamoylbiphenyl-4-yl)-1-(3-amidinophenylsulfonylamino)cyclopentanecarboxamide,

[0415] N-(2′-sulfamoylbiphenyl-4-yl)-1-(3-amidinophenylsulfonylamino)cyclohexanecarboxamide,

[0416] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylsulfonylamino)piperidine-4-carboxamide,

[0417] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylsulfonylamino)tetrahydropyran-4-carboxamide,

[0418] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylsulfonylamino)tetrahydrothiopyran-4-carboxamide,

[0419] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylsulfonylamino)-1,1-dioxotetrahydrothiopyran-4-carboxamide.

[0420] The following compounds are obtained analogously starting from 3-cyanobenzoyl chloride

[0421] N-(2′-sulfamoylbiphenyl-4-yl)-2-(3-amidinophenylcarbonylamino)-2-methylpropionamide,

[0422] N-(2′-sulfamoylbiphenyl-4-yl)-1-(3-amidinophenylcarbonylamino)cyclopentanecarboxamide,

[0423] N-(2′-sulfamoylbiphenyl-4-yl)-1-(3-amidinophenylcarbonylamino)cyclohexanecarboxamide,

[0424] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylcarbonylamino)-piperidine-4-carboxamide,

[0425] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylcarbonylamino)tetrahydropyran-4-carboxamide,

[0426] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylcarbonylamino)tetrahydrothiopyran-4-carboxamide,

[0427] N-(2′-sulfamoylbiphenyl-4-yl)-4-(3-amidinophenylcarbonylamino)-1,1-dioxotetrahydrothiopyran-4-carboxamide.

[0428] The examples below relate to pharmaceutical preparations:

EXAMPLE A

[0429] Injection Vials

[0430] A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.

EXAMPLE B

[0431] Suppositories

[0432] A mixture of 20 g of an active ingredient of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredient.

EXAMPLE C

[0433] Solution

[0434] A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH2PO4·2 H2O, 28.48 g of Na2HPO4·12 H2O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 l and sterilised by irradiation. This solution can be used in the form of eye drops.

EXAMPLE D

[0435] Ointment

[0436] 500 mg of an active ingredient of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.

EXAMPLE E

[0437] Tablets

[0438] A mixture of 1 kg of active ingredient of the formula 1, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed to give tablets in a conventional manner in such a way that each tablet contains 10 mg of active ingredient.

EXAMPLE F

[0439] Coated Tablets

[0440] Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

EXAMPLE G

[0441] Capsules

[0442] 2 kg of active ingredient of the formula I are introduced into hard gelatine capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ingredient.

EXAMPLE H

[0443] Ampoules

[0444] A solution of 1 kg of active ingredient of the formula I in 60 l of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Claims

1. Compounds of the formula I
2. Compounds according to claim 1, in which R1 is Cl, F, NH2, NHCOA, NHCOOA, NH—(CH2)n—Ar, CN, CONH2, CSNH2, C(═NH)SA, C(═NH)NH2, C(═NH—OH)—NH2, C(═NH—O—COA)-NH2, C(═NH—O—COAr)—NH2, C(═NH—O—COHet)-NH2, C(═NH)NH—COOA, C(═NH)NH—COA, C(═NH)NH—COO—(CH2)m—Ar, C(═NH)NH—COO—(CH2)m-Het, NH—C(═NH)NH—COOA, NHC(═NH)NH—COO—(CH2)m—Ar, 17and their pharmaceutically tolerated salts, solvates and stereo-isomers.
3. Compounds according to claim 1, in which R1 is F, NH2, NHCOA, NHCOOA, NH—(CH2)n—Ar, CN, CONH2, CSNH2, C(═NH)SA, C(═NH)NH2, C(═NH—OH)—NH2, C(═NH—O—COA)—NH2, C(═NH—O—COAr)—NH2, C(═NH)NH—COOA, C(═NH)NH—COA, C(═NH)NH—COO—(CH2)m—Ar, NH—C(═NH)NH—COOA, NHC(═NH)NH—COO—(CH2)m—Ar, 18Ar is phenyl, and their pharmaceutically tolerated salts, solvates and stereo-isomers.
4. Compounds according to claim 1, in which R1 is F, NH2, NHCOA, NHCOOA, NH—(CH2)n—Ar, CN, CONH2, CSNH2, C(═NH)SA, C(═NH)NH2, C(═NH—OH)—NH2, C(═NH—O—COA)-NH2, C(═NH—O—COAr)—NH2, C(═NH)NH—COOA, C(═NH)NH—COA, C(═NH)NH—COO—(CH2)m—Ar, NH—C(═NH)NH—COOA, NHC(═NH)NH—COO—(CH2)m—Ar, 19R2, R2′ and R2″ are each, independently of one another, H or F, Ar is phenyl, and their pharmaceutically tolerated salts, solvates and stereo-isomers.
5. Compounds according to claim 1, in which R1 is F, NH2, NHCOA, NHCOOA, NH—(CH2)n—Ar, CN, CONH2, CSNH2, C(═NH)SA, C(═NH)NH2, C(═NH—OH)—NH2, C(═NH—O—COA)-NH2, C(═NH—O—COAr)—NH2, C(═NH)NH—COOA, C(═NH)NH—COA, C(═NH)NH—COO—(CH2)m—Ar, NH—C(═NH)NH—COOA, NHC(═NH)NH—COO—(CH2)m—Ar, 20R2, R2′ and R2″ are each, independently of one another, H or F, Ar is phenyl, R3 is alkyl having 1, 2, 3 or 4 carbon atoms, R4 is alkyl having 1, 2, 3 or 4 carbon atoms, R3 and R4 together are alternatively (CH2)4, (CH2)5, (CH2)2NHCH2, (CH2)2NH(CH2)2, (CH2)—N(COOA)-CH2, (CH2)—N(CH2COOA)-CH2, (CH2)—N(CH2COOH)—CH2, (CH2)—N(CH2COOA)-(CH2)2, (CH2)—N(CH2COOH)—(CH2)2, COOCH(A)-, (CH2)2—S(O)m—(CH2)2 or (CH2)2—O—(CH2)2, where A is alkyl having 1, 2, 3 or 4 carbon atoms, and their pharmaceutically tolerated salts, solvates and stereo-isomers.
6. Compounds according to claim 1, in which R1 is F, NH2, NHCOA, NHCOOA, NH—(CH2)n—Ar, CN, CONH2, CSNH2, C(═NH)SA, C(═NH)NH2, C(═NH—OH)—NH2, C(═NH—O—COA)-NH2, C(═NH—O—COAr)—NH2, C(═NH)NH—COOA, C(═NH)NH—COA, C(═NH)NH—COO—(CH2)m—Ar, NH—C(═NH)NH—COOA, NHC(═NH)NH—COO—(CH2)m—Ar, 21R2 R2′ and R2″ are each, independently of one another, H or F, Ar is phenyl, R3 is alkyl having 1, 2, 3 or 4 carbon atoms, R4 is alkyl having 1, 2, 3 or 4 carbon atoms, R3 and R4 together are alternatively (CH2)4, (CH2)5, (CH2)2NHCH2, (CH2)2NH(CH2)2, (CH2)—N(COOA)-CH2, (CH2)—N(CH2COOA)-CH2, (CH2)—N(CH2COOH)—CH2, (CH2)—N(CH2COOA)-(CH2)2, (CH2)—N(CH2COOH)—(CH2)2, COOCH(A)-, (CH2)2—S(O)m—(CH2)2 or (CH2)2—O—(CH2)2, where A is alkyl having 1, 2, 3 or 4 carbon atoms, R5 is SO2NH2, SO2NHA, CH2COOH, phenyl which is monosubstituted by SO2NHA, SO2NH2 or SO2A, where A is alkyl having 1, 2, 3 or 4 carbon atoms, or unsubstituted 4-pyridyl, R5′, R5″, R5′″and R5″″ are H, and their pharmaceutically tolerated salts, solvates and stereo-isomers.
7. Compounds according to claim 1, in which R1 is H, Cl, F, NH2, NHCOA, NHCOOA, NH—(CH2)n—Ar, CN, CONH2, CSNH2, C(═NH)SA, C(═NH)NH2, C(═NH—OH)—NH2, C(═NH—O—COA)-NH2, C(═NH—O—COAr)—NH2, C(═NH)—OA, C(═NH)NHNH2, C(═NH)NHNHA, C(═NH)NH—COOA, C(═NH)NH—COA, C(═NH)NH—COO—(CH2)m—Ar, NH—C(═NH)NH2, NH—C(═NH)NH—COOA, NHC(═NH)NH—COO—(CH2)m—Ar, 22R2, R2′ and R2″ are each, independently of one another, H or F, R3 is alkyl having 1, 2, 3 or 4 carbon atoms, R4 is alkyl having 1, 2, 3 or 4 carbon atoms, R3 and R4 together are alternatively (CH2)4, (CH2)5, (CH2)2NHCH2, (CH2)2NH(CH2)2, (CH2)—N(COOA)-CH2, (CH2)—N(CH2COOA)-CH2, (CH2)—N(CH2COOH)—CH2, (CH2)—N(CH2COOA)-(CH2)2, (CH2)—N(CH2COOH)—(CH2)2, COOCH(A)-, (CH2)2—S(O)m—(CH2)2 or (CH2)2—O—(CH2)2, where A is alkyl having 1, 2, 3 or 4 carbon atoms, R5 is SO2NH2, SO2NHA, CH2COOH, phenyl which is mono-substituted by SO2NHA, SO2NH2 or SO2A or unsubstituted 4-pyridyl, R5′, R5″, R5′″and R5″″ are H, R6 is OH, A or Ar, R7 is H, A or Ar, R8 is H, (CH2)n—COOH, (CH2)m—COOA, (CH2)m—COO—(CH2)n—Ar, (CH2)m—CONH2, (CH2)m—CONHA or (CH2)m—CONA2, R9 is H, A or benzyl, U is CO, V is NH, W is absent, X is CH or N, Y is absent, A is alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms or CF3, Ar is phenyl, n is 1 or 2, m is 0, 1 or 2, p is4 or5, and their pharmaceutically tolerated salts, solvates and stereo-isomers
8. Compounds according to claim 1, in which R1 is F, NH2, NH—(CH2)n—Ar, CN, CSNH2, C(═NH)SA, C(═NH)NH2 or C(═NH—OH)—NH2, R2, R2′ and R2″ are each, independently of one another, H or F, R3 is alkyl having 1, 2, 3 or 4 carbon atoms, R4 is alkyl having 1, 2, 3 or 4 carbon atoms, R3 and R4 together are alternatively (CH2)4, (CH2)5, (CH2)2NHCH2, (CH2)2NH(CH2)2, (CH2)—N(COOA)-CH2, (CH2)—N(CH2COOA)-CH2, (CH2)—N(CH2COOH)—CH2, (CH2)—N(CH2COOA)-(CH2)2, (CH2)—N(CH2COOH)—(CH2)2, (CH2)2—S(O)m—(CH2)2 or (CH2)2—O—(CH2)2, where A is alkyl having 1, 2, 3 or 4 carbon atoms, R5 is SO2NH2, SO2NHA, CH2COOH, phenyl which is monosubstituted by SO2NHA, SO2NH2 or SO2A or unsubstituted 4-pyridyl, R5′, R5″ R5′″and R5″″ are H, R7 is H, A or Ar, R8 is (CH2)n—COOH, (CH2)m—COOA, (CH2)m—COO—(CH2)n—Ar, (CH2)m—COO—(CH2)n-Het, (CH2)m—CONH2, (CH2)m—CONHA or (CH2)m—CONA2, R9 is H, A or benzyl, U is CO, V is NH, W is absent, X is CH, Y is absent, A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF3, Ar is phenyl, n is 1 or 2, m is 0, 1 or 2, p is 4 or 5, and their pharmaceutically tolerated salts, solvates and stereo-isomers.
9. Compounds according to claim 1, in which R1 is H, R2 is CH2NH2, CH2NHCOA or CH2NHCOOA, R2′ and R2″ are each, independently of one another, H, R3 is alkyl having 1, 2, 3 or 4 carbon atoms, R4 is alkyl having 1, 2, 3 or 4 carbon atoms, R3 and R4 together are alternatively (CH2)4, (CH2)5, (CH2)2NHCH2, (CH2)2NH(CH2)2, (CH2)—N(COOA)-CH2, (CH2)—N(CH2COOA)-CH2, (CH2)—N(CH2COOH)—CH2, (CH2)—N(CH2COOA)-(CH2)2, (CH2)—N(CH2COOH)—(CH2)2, (CH2)2—S(O)m—(CH2)2 or (CH2)2—O—(CH2)2, where A is alkyl having 1, 2, 3 or 4 carbon atoms, R5 is SO2NH2, SO2NHA, CH2COOH, phenyl which is monosubstituted by SO2NHA, SO2NH2 or SO2A, or unsubstituted 4-pyridyl, R5′ is F, R5″, R5′″and R5″″ are H, R7 is H, A or Ar, R8 is H, (CH2)n—COOH, (CH2)m—COOA, (CH2)m—COO—(CH2)n—Ar, (CH2)m—COO—(CH2)n-Het, (CH2)m—CONH2, (CH2)m—CONHA or (CH2)m—CONA2, R9 is H, A or benzyl, U is CO, V is NH, W is absent, X is CH, Y is absent, A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF3, Ar is phenyl, n is 1 or 2, m is 0, 1 or 2, p is 4 or 5, and their pharmaceutically tolerated salts, solvates and stereoisomers.
10. Compounds according to claim 1, in which R1 is CN, C(═NH)NH2, C(═NH—OH)—NH2 23R2, R2′ and R2″ are H, R3 is alkyl having 1, 2, 3 or 4 carbon atoms, R4 is alkyl having 1, 2, 3 or 4 carbon atoms, R3 and R4 together are alternatively (CH2)4, (CH2)5, (CH2)2NHCH2, (CH2)2NH(CH2)2, (CH2)—N(COOA)-CH2, (CH2)—N(CH2COOA)-CH2, (CH2)—N(CH2COOH)—CH2, (CH2)—N(CH2COOA)-(CH2)2, (CH2)—N(CH2COOH)—(CH2)2, (CH2)2—S(O)m—(CH2)2 or (CH2)2—O—(CH2)2, where A is alkyl having 1, 2, 3 or 4 carbon atoms, R5 is SO2NH2, SO2NHA, CH2COOH, phenyl which is monosubstituted by SO2NHA, SO2NH2 or SO2A, or unsubstituted 4-pyridyl, R5′, R5″, R5′″and R5″″ are H, R6 is methyl, R7 is H, A or Ar, R8 is (CH2)n—COOH, (CH2)m—COOA, (CH2)m—COO—(CH2)n—Ar, (OCH2)m—COO—(CH2)n-Het, (CH2)m—CONH2, (CH2)m—CONHA or (CH2)m—CONA2, R9 is H, A or benzyl, U is CO, V is NH, W is absent, X is CH or N, Y is absent, A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF3, Ar is phenyl, n is 1 or 2, m is 0, 1 or 2, p is 4 or 5, and their pharmaceutically tolerated salts, solvates and stereoisomers.
11. Compounds according to claim 1, in which R1 is CN, C(═NH)NH2, C(═NH—OH)—NH2 24R2, R2′ and R2″ are H, R3 is alkyl having 1, 2, 3 or 4 carbon atoms, R4 is alkyl having 1, 2, 3 or 4 carbon atoms, R3 and R4 together are alternatively (CH2)4, (CH2)5, (CH2)2NHCH2, (CH2)2NH(CH2)2, (CH2)—N(COOA)-CH2, (CH2)—N(CH2COOA)-CH2, (CH2)—N(CH2COOH)—CH2, (CH2)—N(CH2COOA)-(CH2)2, (CH2)—N(CH2COOH)—(CH2)2, (CH2)2—S(O)m—(CH2)2 or (CH2)2—O—(CH2)2, where A is alkyl having 1, 2, 3 or 4 carbon atoms, R5 is SO2NH2, SO2NHA, CH2COOH, phenyl which is monosubstituted by SO2NHA, SO2NH2 or SO2A, or unsubstituted 4-pyridyl, R5′, R5″, R5′″and R5″″ are H, R6 is methyl, R7 is H, A or Ar, R8 is (CH2)n—COOH, (CH2)m—COOA, (CH2)m—COO—(CH2)n—Ar, (CH2)m—COO—(CH2)n-Het, (CH2)m—CONH2, (CH2)m—CONHA or (CH2)m—CONA2, R9 is H, A or benzyl, U is CO, V is NH, W is absent, X is CH or N, Y is absent or is SO2 or CO, A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF3, Ar is phenyl, n is 1 or 2, m is 0, 1 or 2, p is4 or5, and their pharmaceutically tolerated salts, solvates and stereoisomers.
12. Compounds according to claim 1:a) 2-[3-(N-hydroxyamidino)phenylamino]-N-(2′-sulfamoylbiphenyl-4-yl)-2-methylpropionamide; b) 2-(3-amidinophenylamino)-N-(2′-tert-butylsulfamoylbiphenyl-4-yl)-2-methylpropionamide; c) 1-[3-(N-hydroxyamidino)phenylamino]-N-(2′-sulfamoylbiphenyl-4-yl)cyclopentanecarboxamide; d) 1-(3-amidinophenylamino)-N-(2′-tert-butylsulfamoylbiphenyl-4-yl )cyclopentanecarboxamide; e) 2-(3-amidinophenylamino)-N-(2′-sulfamoylbiphenyl-4-yl)-2-methylpropionamide; f) 1-(3-amidinophenylamino)-N-(2′-sulfamoylbiphenyl-4-yl)cyclopentanecarboxamide; g) N-(2′-sulfamoylbiphenyl-4-yl)-1-(3-amidinophenylamino)cyclohexanecarboxamide; and their pharmaceutically tolerated salts, solvates and stereoisomers.
13. Process for the preparation of compounds of the formula I according to claim 1 and their salts, characterised in that they are liberated from one of their functional derivatives by treatment with a solvolysing and/or hydrogenolysing agent by i) liberating an amidino group from their oxadiazole derivative or oxazolidinone derivative by hydrogenolysis or solvolysis, ii) replacing a conventional amino-protecting group with hydrogen by treatment with a solvolysing or hydrogenolysing agent or liberating an amino group protected by a conventional protecting group, and/or converting a base or acid of the formula I into one of its salts.
14. Compounds of the formula I according to claims 1 to 12 and their physiologically acceptable salts and solvates as medicaments.
15. Medicaments according to claim 14 as inhibitors of coagulation factor Xa.
16. Medicaments according to claim 14 as inhibitors of coagulation factor VIIa.
17. Medicaments according to claim 14, 15 or 16 for the treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris, restenosis after angioplasty, claudicatio intermittens, tumours, tumour illnesses and/or tumour metastases.
18. Pharmaceutical preparation comprising at least one medicament according to one of claims 14 to 17 and optionally excipients and/or assistants and optionally other active ingredients.
19. Use of compounds according to claims 1 to 12 and/or their physiologically acceptable salts and solvates for the preparation of a medicament for the treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris, restenosis after angioplasty, claudicatio intermittens, tumours, tumour illnesses and/or tumour metastases.

Priority Claims (1)

Number	Date	Country	Kind
100 36 121.8	Jul 2000	DE

PCT Information

Filing Document	Filing Date	Country	Kind
PCT/EP01/07596	7/3/2001	WO

N-substituted 1-amino-1,1-dialkylcarboxylic acid derivatives

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CPC

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Priority Claims (1)

PCT Information