CA2382850A1 - Novel inhibitors of the integrin .alpha.v.beta.3 - Google Patents
Novel inhibitors of the integrin .alpha.v.beta.3 Download PDFInfo
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- CA2382850A1 CA2382850A1 CA002382850A CA2382850A CA2382850A1 CA 2382850 A1 CA2382850 A1 CA 2382850A1 CA 002382850 A CA002382850 A CA 002382850A CA 2382850 A CA2382850 A CA 2382850A CA 2382850 A1 CA2382850 A1 CA 2382850A1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/44—Nitrogen atoms not forming part of a nitro radical
- C07D233/48—Nitrogen atoms not forming part of a nitro radical with acyclic hydrocarbon or substituted acyclic hydrocarbon radicals, attached to said nitrogen atoms
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/88—Nitrogen atoms, e.g. allantoin
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Abstract
The invention relates to novel compounds of formula (I) which are biological ly active when present as ligands of the integrin .alpha.v.beta.3: X-Y-Z-R1-CH2 - R2(R4)-CH2-CO-R5 wherein the meaning of X, Y, Z, R1, R2, R4 and R5 is given in Claim 1. The invention also relates to the physiologically acceptable salts and solvates of said compounds.
Description
Novel inhibitors of the integrin a"(33 The invention relates to novel compounds of the formula I
X-Y-Z-R1-CHz-R2 (R4) -CHz-CO-RS I
in which ' X is H2N-C (=NH) -, HZN-C (=NH) -NH-, A-C (=NH) -NH-, Hetl-or Hetl-NH-, where the primary amino groups can also be provided with conventional amino protective groups, Y is \
-(CH2)n- ~ -(CHZ)rt, tC~"'~2)0-in which one, two, three or four methylene groups can be replaced by N, 0 and/or S, Z is absent, -O-, -NH-, -NA-, -CH(OH)-, -CH(OA)-, -CHA-, -CAZ- or -S-, R1 is phenylene which is unsubstituted or mono-, di-or trisubstituted by F, Cl, Br, A, OA, OCF3 or CN, Rz is N, CH or CA, R3 is H, F, C1, Br, A, OA or OCF3, R4 is phenyl, naphthyl or Het2, mono- or poly-substituted by F, Cl, Br, A, aryl, OA, SA, CO-A, CN, COOA, CONHZ , CONHA, CONA2 or N02 , RS is OH, OA, NH2, NHA or NA2, Hetl is a mono- or binuclear heterocycle having 1 to 4 N atoms, which can be unsubstituted or mono- or disubstituted by NHz, Hetz is an aromatic mono- or binuclear heterocycle having 1 to 3 N, O and/or S atoms, which can be unsubstituted or mono- or disubstituted by F, C1, Br, A, OA, SA, OCF3, -CO-A, CN, COOA, CONHz, CONHA, CONAZ or NOZ , aryl is phenyl or naphthyl, unsubstituted or mono- or polysubstituted by Hal, A, OA, OH, CO-A, CN, COOA, COOH, CONHz , CONHA, CONA2 or N02 , A is alkyl having 1-12 C atoms, n is 1, 2, 3, 4, 5 or 6, m, o in each case independently of one another are 0, l, 2, 3, 4, 5 or 6, with the proviso that R4 ~ a phenyl or naphthyl radical monosubstituted by A or aryl, and their physiologically acceptable salts and solvates.
The invention was based on the object of discovering novel compounds having valuable properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I
and their salts have very valuable pharmacological properties, together with good tolerability. They act especially as integrin inhibitors, in particular inhibiting the interactions of the a~ integrin receptors with ligands. The compounds exhibit particular activity in the case of the integrins oc"~33 and a"(35. The compounds are very particularly active as adhesion receptor antagonists for the receptor oc~,(33.
This action can be demonstrated by the method which is described by J.W. Smith et al., in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).
The inhibition of vitronectin binding to the receptor a~(33 was confirmed experimentally for 3- (4-fluoro-phenyl)-4-f4-[3-(pyridin-2-ylamino)propoxy]phenyl)-butyric acid.
In Curr. Opin. Cell. Biol. 5, 864 (1993), B. Felding-Habermann and D.A. Cheresh describe the importance of the integrins as adhesion receptors for a wide variety of phenomena and syndromes, especially with respect to the receptor av(33.
Other inhibitors of the integrin av(33 are described in EP 0820988. Vitronectin receptor antagonists are also described in WO 97/24124 and in EP 0820991.
The dependence of the origin of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins is described by P.C. Brooks, R.A. Clark and D.A. Cheresh in Science 264, 569-71 (1994).
The possibility of the inhibition of this interaction and thus for the initiation of apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide is described by P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T.-Hu, G. Klier and D.A. Cheresh in Cell 79, 1157-64 (1994).
The experimental proof that the compounds according to the invention also prevent the adhesion of living cells to the corresponding matrix proteins and accordingly also the adhesion of tumour cells to matrix proteins can be furnished in a cell adhesion test which is carried out analogously to the method of F. Mitjans et al., J. Cell Science 108, 2825-2838 (1995).
X-Y-Z-R1-CHz-R2 (R4) -CHz-CO-RS I
in which ' X is H2N-C (=NH) -, HZN-C (=NH) -NH-, A-C (=NH) -NH-, Hetl-or Hetl-NH-, where the primary amino groups can also be provided with conventional amino protective groups, Y is \
-(CH2)n- ~ -(CHZ)rt, tC~"'~2)0-in which one, two, three or four methylene groups can be replaced by N, 0 and/or S, Z is absent, -O-, -NH-, -NA-, -CH(OH)-, -CH(OA)-, -CHA-, -CAZ- or -S-, R1 is phenylene which is unsubstituted or mono-, di-or trisubstituted by F, Cl, Br, A, OA, OCF3 or CN, Rz is N, CH or CA, R3 is H, F, C1, Br, A, OA or OCF3, R4 is phenyl, naphthyl or Het2, mono- or poly-substituted by F, Cl, Br, A, aryl, OA, SA, CO-A, CN, COOA, CONHZ , CONHA, CONA2 or N02 , RS is OH, OA, NH2, NHA or NA2, Hetl is a mono- or binuclear heterocycle having 1 to 4 N atoms, which can be unsubstituted or mono- or disubstituted by NHz, Hetz is an aromatic mono- or binuclear heterocycle having 1 to 3 N, O and/or S atoms, which can be unsubstituted or mono- or disubstituted by F, C1, Br, A, OA, SA, OCF3, -CO-A, CN, COOA, CONHz, CONHA, CONAZ or NOZ , aryl is phenyl or naphthyl, unsubstituted or mono- or polysubstituted by Hal, A, OA, OH, CO-A, CN, COOA, COOH, CONHz , CONHA, CONA2 or N02 , A is alkyl having 1-12 C atoms, n is 1, 2, 3, 4, 5 or 6, m, o in each case independently of one another are 0, l, 2, 3, 4, 5 or 6, with the proviso that R4 ~ a phenyl or naphthyl radical monosubstituted by A or aryl, and their physiologically acceptable salts and solvates.
The invention was based on the object of discovering novel compounds having valuable properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I
and their salts have very valuable pharmacological properties, together with good tolerability. They act especially as integrin inhibitors, in particular inhibiting the interactions of the a~ integrin receptors with ligands. The compounds exhibit particular activity in the case of the integrins oc"~33 and a"(35. The compounds are very particularly active as adhesion receptor antagonists for the receptor oc~,(33.
This action can be demonstrated by the method which is described by J.W. Smith et al., in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).
The inhibition of vitronectin binding to the receptor a~(33 was confirmed experimentally for 3- (4-fluoro-phenyl)-4-f4-[3-(pyridin-2-ylamino)propoxy]phenyl)-butyric acid.
In Curr. Opin. Cell. Biol. 5, 864 (1993), B. Felding-Habermann and D.A. Cheresh describe the importance of the integrins as adhesion receptors for a wide variety of phenomena and syndromes, especially with respect to the receptor av(33.
Other inhibitors of the integrin av(33 are described in EP 0820988. Vitronectin receptor antagonists are also described in WO 97/24124 and in EP 0820991.
The dependence of the origin of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins is described by P.C. Brooks, R.A. Clark and D.A. Cheresh in Science 264, 569-71 (1994).
The possibility of the inhibition of this interaction and thus for the initiation of apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide is described by P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T.-Hu, G. Klier and D.A. Cheresh in Cell 79, 1157-64 (1994).
The experimental proof that the compounds according to the invention also prevent the adhesion of living cells to the corresponding matrix proteins and accordingly also the adhesion of tumour cells to matrix proteins can be furnished in a cell adhesion test which is carried out analogously to the method of F. Mitjans et al., J. Cell Science 108, 2825-2838 (1995).
In J. Clin. Invest. 96, 1815-1822 (1995), P.C. Brooks et al. describe oc~,(33 antagonists for the control of cancer and for the treatment of tumour-induced angiogenic diseases.
The compounds of the formula I according to the invention can therefore be employed as pharmaceutical active compounds, in particular for the treatment of oncoses, osteoporosis, osteolytic disorders and for the suppression of angiogenesis.
Compounds of the formula I which block the interaction of integrin receptors and ligands, such as, for example, of fibrinogen, on the fibrinogen receptor (glycoprotein IIb/IIIa), prevent, as GPIIb/IIIa antagonists, the spread of tumour cells by metastasis.
This is confirmed by the following observations:
The spread of tumour cells from a local tumour into the vascular system takes place through the formation of microaggregates (microthrombi) by interaction of the tumour cells with blood platelets. The tumour cells are screened by the protection in the microaggregate and are not recognized by the cells of the immune system.
The microaggregates can attach to vessel walls, owing to which further penetration of tumour cells into the tissue is facilitated. Since the formation of the microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on the activated blood platelets, the GPIIb/IIIa antagonists can be regarded as effective metastasis inhibitors.
In addition to the binding of fibrinogen, fibronectin and of the von Willebrand factor to the fibrinogen receptor of the blood platelets, compounds of the formula I also inhibit the binding of further adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. In particular, they prevent the formation of blood platelet thrombi and can therefore be employed for the treatment of thromboses, apoplexy, cardiac infarct, inflammation and arteriosclerosis.
The properties of the compounds can also be demonstrated by methods which are described in EP-A1-0 462 960. The inhibition of fibrinogen binding to the fibrinogen receptor can be demonstrated by the method which is given in EP-Al-0 381 033.
The platelet aggregation-inhibiting action can be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962). The inhibition of bone resorption by the compounds of the invention can be confirmed with the aid of a osteoclast resorption test analogously to WO 95/32710.
The invention accordingly relates to the compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts for the production of a medicament for use as an integrin inhibitor. The invention relates in particular to compounds of the formula I according to Claim 1 and/or their acceptable salts for the production of a medicament for the control of pathologically angiogenic disorders, tumours, osteoporosis, inflammations and infections.
The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine, for the prophylaxis and/or therapy of thrombosis, myocardial infarct, arteriosclerosis, inflammation, apoplexy, angina pectoris, oncoses, osteolytic diseases such as osteoporosis, hypercalcaemia, pathologically angiogenic diseases such as, for example, inflammation, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, viral infection, bacterial infection, fungal infection, in acute kidney failure and in wound healing for assisting the healing processes.
The compounds of the formula I can be employed as antimicrobially active substances in operations where biomaterials, implants, catheters or heart pacemakers are used. They have an antiseptic action here. The efficacy of the antimicrobial activity can be demonstrated by the process described by P. Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988).
The invention also relates to the hydrates and solvates, e.g. alcoholates, of these compounds.
The invention further relates to a process for the preparation of compounds of the formula I according to Claim 1, and their salts, characterized in that a) a compound of the formula I is set free from its functional derivatives by treating with a solvolysing, reducing or hydrogenolysing agent, or b) a radical X and/or RS is converted into another radical X and/or R5, by, for example, i) converting an amino group into a guanidino group by reaction with an amidinating agent, ii) hydrolysing an ester, iii) converting a hydroxyamidine into an amidine by hydrogenation, and/or converting a base or acid of the formula I into one of its salts.
_ 7 _ The compounds of the formula I can have a chiral centre and can therefore occur in a number of stereoisomeric forms. All these forms (e. g. D and L forms) and their mixtures (e.g. the DL forms) are included in the formula I.
So-called prodrug derivatives are also included in the compounds according to the invention, i.e. compounds of the formula I modified with, for example, alkyl or acyl groups, sugars or oligopeptides, which are rapidly cleaved in the body to the active compounds according to the invention.
The abbreviations mentioned above and below stand for:
Ac acetyl BOC tert-butoxycarbonyl CBZ or Z benzyloxycarbonyl DCCI dicyclohexylcarbodiimide DMF dimethylformamide EDCI N-ethyl-N,N'-(dimethylaminopropyl)carbo-diimide Et ethyl Fmoc 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole Me methyl Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl HONSu N-hydroxysuccinimide OBut tert-butyl ester Oct octanoyl OMe methyl ester OEt ethyl ester POA phenoxyacetyl TFA trifluoroacetic acid Trt trityl (triphenylmethyl).
It applies to the whole invention that all radicals which occur a number of times, such as, for example, A, can be identical or different, i.e. are independent of one another.
A is alkyl and has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 C atoms and is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, additionally 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-, 1,2,2-trimethylpropyl, heptyl, octyl, nonyl or decyl, undecyl or docecyl. A is also alkyl substituted by halogen, preferably CF3.
X is preferably, for example, pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino, 2-aminoimidazol-5-ylamino, 2-aminopyridin-6-ylamino, 2-aminoimidazol-5-yl or 2-aminopyridin-6-yl.
Y is preferably, for example, ethylene, propylene or butylene.
Z is preferably, for example, O.
R1 is preferably, for example, 1,4-phenylene.
R2 is preferably, for example, CH or N, very particularly CH.
R4 is preferably, for example, phenyl mono- or polysubstituted by F.
RS is preferably, for example, OH.
Hetl is preferably 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, unsubstituted or mono- or disubstituted by A, NHA and/or NH2, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 3-, 4-, 5-, 6-, 7-_ g _ or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, 1H-imidazo[4,5-b]pyridin-2-yl or 1,8-naphthyridin-7-yl.
The heterocyclic radicals can also be partially or completely hydrogenated.
Hetl can thus, for example, also be 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, tetra-hydro-1-, -2- or -4-imidazolyl, 4,5-dihydroimidazol-2-yl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 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 or 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl.
Hydrogenated or partially hydrogenated Hetl radicals can additionally be substituted by =NH or carbonyl oxygen.
Het2 is preferably 2,3-, 2,4-, 2,5- or 3,4-thienyl, 2,3-, 2,4-, 2,5- or 3,4-pyrrolyl, 2,4-, 2,5- or 4,5-imidazolyl, 2,3-, 2,4-, 2,6- or 3,5-pyridyl, 2,4-, 2,5-, 2,6-, 4,5- or 5,6-pyrimidinyl, unsubstituted or monosubstituted by F, Cl, Br, A, OA or OCF3.
n is preferably 2, 3, 4, 5 or 6, very particularly preferably n is 3, 4 or 5.
m and o are preferably, in each case independently of one another, 0, 1 or 2, very particularly preferably they are 0.
Substituted "one or more times" means mono-, di-, tri-or tetrasubstituted.
Aryl is phenyl which is unsubstituted, preferably - as indicated - monosubstituted, specifically preferably phenyl, o-, m- or p-tolyl, 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-cyanophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m-or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methylthiophenyl, o-, m- or p-methylsulfinylphenyl, o-, m- or p-methylsulfonyl phenyl, o-, m- or p-aminophenyl, o-, m- or p-methyl aminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- or p-nitrophenyl, o-, m- or p-acetylphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-aminocarbonyl phenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3-methyl-, 2-chloro-4-methyl-, 2-chloro-5-methyl-, 2-chloro-6-methyl-, 2-methyl-3-chloro-, 2-methyl-4-chloro-, 2-methyl-5-chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl- or 3-methyl-4-chlorophenyl, 2-bromo-3-methyl-, 2-bromo-4-methyl-, 2-bromo-5-methyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-, 2-methyl-4-bromo-, 2-methyl-5-bromo-, 2-methyl-6-bromo-, 3-bromo-4-methyl-, 3-bromo-5-methyl- or 3-methyl-4-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichloro-phenyl, 2,4,6-tri-tert-butylphenyl, 2,5-dimethylphenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro-3,5-di methylphenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro 4-bromophenyl, 2,4-dichloro-5-methylphenyl, 3-bromo 6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 2-methoxy 5-methylphenyl, 2,4,6-triisopropylphenyl.
Amino protective group is preferably formyl, acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxy-carbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("carbo-benzoxy"), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl.
Accordingly, the present 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 subformulae Ia to Im, which correspond to the formula I
and in which the radicals not designated in greater detail have the meaning indicated in the formula I, but in which in a) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino, 4,5-di-hydroimidazol-2-ylamino, 2-amino-imidazol-5-ylamino, 2-aminopyridin-6-ylamino, 2-aminoimidazol-5-yl or 2-aminopyridin-6-yl;
in b) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CHZ) n-, n is 2, 3 or 4;
in c) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y 1S - (CH2) n-.
n is 2, 3 or 4;
in d) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CH2) n-.
n is 2, 3 or 4, Z is O;
in e) X is pyrimidin-2-ylamino, pyridin-2-yl amino, imidazol-1-yl, imidazol-2-yl amino, benzimidazol-2-ylamino or 4,5-di hydroimidazol-2-ylamino, Y 1 S - ( CH2 ) n- , n is 2, 3 or 4, Z is O, R2 is N or CH;
in f) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CH2) n-, n is 2, 3 or 4, Z is O, R2 is N or CH, R4 is phenyl which is mono- or poly substituted by F, Cl, Br, OA, OCF3, -CO-A, CN, COOA, CONHz or NO2;
in g) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CH2) n-, n is 2, 3 or 4, Z is O, RZ is N or CH, R4 is phenyl which is mono- or poly-substituted by F, Cl, Br, OA or OCF3;
RS is OA or OH;
in h) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CHZ) n- i n is 2, 3 or 4, Z is O, R2 is N or CH, R4 is phenyl which is mono- or poly-substituted by F, RS is OA or OH;
in i) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CH2)n-, n is 2, 3 or 4, Z is O, R2 is N or CH, R4 is phenyl which is mono- or poly-substituted by Hal, A or aryl, RS is OA or OH
with the proviso that R4 is not equal to a phenyl or naphthyl radical monosubstituted by A
or aryl;
in k) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CH2)n-, n is 2, 3 or 4, Z is O, R2 is N or CH, R4 is phenyl which is substituted by Hal and aryl, RS is OA or OH
with the proviso that R4 is not equal to a phenyl or naphthyl radical monosubstituted by A
or aryl;
in 1) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CHZ) n-.
n is 2, 3 or 4, Z is O, R2 is N or CH, R4 is phenyl which is substituted by Hal and aryl, RS is OA or OH, aryl is phenyl which is mono-, di- or trisubstituted by Hal, A, OA, CF3, CN
or with t he proviso that R4 is not equal to a phenyl or naphthyl radical monosubstituted by A
or aryl;
in m) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino, 4,5-di-hydroimidazol-2-ylamino, 2-amino-imidazol-5-ylamino, 2-aminopyridin-6-yl-amino, 2-aminoimidazol-5-yl or 2-amino-pyridin-6-yl, Y iS - (CHZ) n-, n is 2, 3 or 4, Z is O, R2 is N or CH, R4 is phenyl which is mono- or poly-substituted by Hal, A or aryl, RS is OA or OH
with t he proviso that R4 is not equal to a phenyl or naphthyl radical monosubstituted by A
or aryl.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made in this case of variants which are known per se, but not mentioned here in greater detail.
If desired, the starting substances can also be formed in situ, such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
Compounds of the formula I can preferably be obtained by liberating compounds of the formula I from one of their functional derivatives by treating with a solvolysing or hydrogenolysing agent.
Preferred starting substances for the 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 linked to an N atom, carry an amino protective group, in particular those which, instead of an HN group, carry an R' N group in which R' is an amino protective group, and/or those which, instead of the H atom of a hydroxyl group, carry a hydroxyl protective group, e.g. those which correspond to the formula I, but instead of a group -COOH carry a group -COOR", in which R" is a hydroxyl protective group.
It is also possible for a number of - identical or different - protected amino and/or hydroxyl groups to be present in the molecule of the starting substances.
If the protective groups present are different from one another, in many cases they can be removed selectively.
The expression "amino protective group" is generally known and relates to groups which are suitable for protecting (or blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. Typical groups of this type are, in particular, unsubstituted or substituted aryl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size is otherwise not critical; however, those having 1-20, in particular 1-8, C atoms are preferred. The expression "aryl group" is to be interpreted in the widest 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 acyl groups of this type are formyl or alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenyl acetyl; aroyl such as benzoyl or toluyl;
aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxy-carbonyl, BOC, 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxy-carbonyl, Fmoc; arylsulfonyl such as Mtr. Preferred amino protective groups are BOC and Mtr, additionally CBZ, Fmoc, benzyl, formyl and acetyl.
The removal of the amino protective group takes place -depending on the protective group used - e.g. using strong acids, expediently 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 not always necessary. Suitable inert solvents are preferably organic solvents, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, additionally also alcohols such as methanol, ethanol or isopropanol, and also water. Mixtures of the above-mentioned solvents are additionally suitable. TFA is preferably used in an excess without addition of a further solvent, perchloric acid 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 expediently between approximately 0 and approximately 50°; the reaction is preferably carried out at between 15 and 30° (room temperature).
The groups BOC, OBut and Mtr can preferably be removed, for example, using TFA in dichloromethane or using approximately 3 to 5N HC1 in dioxane at 15-30°, the Fmoc group using an approximately 5 to 50% strength solution of secondary amines such as dimethylamine, diethylamine or piperidine in DMF at 15-30°.
Hydrogenolytically removable protective groups (e. g.
CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst (e . g . of a noble metal catalyst such as palladium, expediently 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. As a rule, the hydrogenolysis is carried out at temperatures between approximately 0 and 100° and pressures between approximately 1 and 200 bar, preferably at 20-30° and 1-10 bar. Hydrogenolysis of the CBZ group takes place 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°.
Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloro-ethylene, 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); 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, water or mixtures of the solvents mentioned.
It is furthermore possible to hydrolyse an ester of the formula I. Expediently, this is carried out by solvolysis or hydrogenolysis, as indicated above, e.g.
using LiOH in methanol, NaOH or KOH in dioxane/water at temperatures between 0 and 60°C, preferably between 10 and 40°C.
The conversion of a cyano group into an amidino group is carried out by reaction with, for example, hydroxyl-amine and subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as, for example, Pd/C.
It is furthermore possible to replace a conventional amino protective group by hydrogen by removing the protective group, as described above, solvolytically or hydrogenolytically or by liberating an amino group protected by a conventional protective group by solvolysis or hydrogenolysis.
For the preparation of compounds of the formula I in which X is HzN-C(=NH)-NH-, an appropriate amino compound can be treated with an amidinating agent. A
preferred amidinating agent is 1-amidino-3,5-di-methylpyrazole (DPFN), which is particularly employed in the form of its nitrate. The reaction is expediently carried out with addition of a base such as tri-ethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, e.g. water/dioxane at temperatures between 0 and 120°C, preferably between 60 and 120°C.
For the preparation of an amidine of the formula I
(X = -C (=NH) -NH2) , ammonia can be added to a nitrile of the formula I (X = CN). The addition is preferably carried out in a number of stages by a) converting the nitrile in a manner known per se using HzS into a thioamide, which is converted using an alkylating agent, e.g. CH3I, into the corresponding S-alkyl-imidothioester, which for its part reacts with NH3 to give the amidine, b) converting the nitrile using an alcohol , a . g . ethanol in the presence of HCl , into the corresponding imidoester and treating this with ammonia, or c) reacting the nitrile with lithium bis-(trimethylsilyl)amide and then hydrolysing the product.
The release of the compounds of the formula I from an oxidized precursor, by, for example, reducing an oxy-heterocycle using a reducing agent such as, for example, phosphorus trichloride in an inert solvent, is furthermore preferred.
Furthermore, free amino groups can be acylated in the customary manner using an acid chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, expediently 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 reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation. For this reaction, suitable acids are in particular those which yield physiologically acceptable salts. Thus inorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, in addition organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g.
formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malefic 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, laurylsulfuric acid. Salts with physiologically unacceptable acids, e.9. picrates, can be used for the isolation and/or purification of the compounds of the formula I.
On the other hand, an acid of the formula I can be converted into one of its physiologically acceptable metal or ammonium salts by reaction with a base.
Possible salts here are, in particular, the sodium, potassium, magnesium, calcium and ammonium salts, in addition substituted ammonium salts, e.g. the dimethyl-, diethyl- or diisopropylammonium salts, monoethanol-, diethanol- or diisopropylammonium salts, cyclohexyl-, dicyclohexylammonium salts, dibenzyl-ethylenediammonium salts, furthermore, for example, salts with arginine or lysine.
The compounds of the formula I contain one or more chiral centres and can therefore be present in racemic or in optically active form. Racemates obtained can be separated into the enantiomers mechanically or chemically by methods known per se. Preferably, diastereomers are formed from the racemic mixture by reaction with an optically active resolving agent.
Suitable resolving agents are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as (3-camphorsulfonic acid. Resolution of enantiomers with the aid of a column packed with an optically active resolving agent (e.g. dinitrobenzoylphenylglycine) is also advantageous; a suitable eluent is, for example, a mixture of hexane/isopropanol/acetonitrile, e.g. in the volume ratio 82:15:3.
Of course, it is also possible to obtain optically active compounds of the formula I according to the methods described above, by using starting substances which are already optically active.
The invention includes not only the compounds mentioned but also mixtures and preparations which, in addition to these compounds according to the invention, also contain other pharmacological active compounds or adjuvants which can influence the primary pharmacological action of the compounds according to the invention in the desired manner. These can be used as therapeutics, diagnostics or as reagents. They can be given to man or animals locally or systemically, orally, intravenously, intraperitoneally, intramuscularly, subcutaneously, transdermally, nasally, buccally, or iontophoretically, which includes formulations in suspensions, emulsions or solutions, liposomes, ointments, pastes, biodegradable polymers or as nanoparticles, tablets, capsules or pills, granules or powders, as an aerosol for inhaling, as intranasal drops or sprays. A combination of the novel products with other techniques, such as surgery, irradiation, diagnosis, radiotherapy, photodynamic therapy and gene therapy, as well as with other medicaments is also possible. Such medicaments can originate, for example, from the cardiovascular, central nervous system or oncology fields. They can be tumour agents, such as angiogenesis inhibitors or cytostatics, chemotherapeutics of the groups alkylating agents, antibiotics, antimetabolites, biologicals and immunomodulators, hormones and their antagonists, mustard gas derivatives, alkaloids and others, where these substances can be of low molecular weight or high molecular weight. They can be lipids, carbohydrates or proteins. Also included amongst these are cytokines, toxins, fusion proteins, monoclonal antibodies and vaccines.
The invention accordingly relates to compounds of the formulae defined above and below and also in the claims, including their physiologically acceptable salts, as medicaments, diagnostics or reagents.
The invention relates in particular to corresponding medicaments as inhibitors for the control of disorders which are based indirectly or directly on expression of the a,~(33 integrin receptor, thus in particular in the case of pathologically angiogenic disorders, thromboses, cardiac infarcts, coronary heart disorders, arteriosclerosis, tumours, osteoporosis, inflammations, infections and also for influencing wound-healing processes.
The invention also relates to corresponding pharmaceutical preparations which contain at least one medicament of the formula I and, if appropriate, vehicles and/or excipients.
The invention furthermore relates to the use of the compounds and/or their physiologically acceptable salts according to the claims and the description for the production of a medicament for the control of disorders which are based indirectly or directly on expression of the a"(33 integrin receptor, thus in particular in the case of pathologically angiogenic disorders, thromboses, cardiac infarcts, coronary heart disorders, arteriosclerosis, tumours, osteoporosis, inflammations, infections and for influencing wound-healing processes.
The medicaments according to the invention or pharmaceutical preparations comprising them can be used as medicaments in human or veterinary medicine.
Suitable vehicles are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application or for application in the form of an inhalation spray and do not react with the novel 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, coated tablets, capsules, powders, granules, syrups, juices or drops are used for oral administration, suppositories are used, in particular, for rectal administration, solutions, preferably oily or aqueous solutions, in addition suspensions, emulsions or implants, are used for parenteral administration and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. The preparations indicated can be sterilized and/or can contain excipients such as glidants, preservatives, stabilizing and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colourants, flavourings and/or one or more further active compounds, e.g. one or more vitamins.
For administration as an inhalation spray, sprays can be used which contain the active compound either dissolved or suspended in a propellant or propellant mixture (e. g. COZ or chlorofluorohydrocarbons).
Expediently, the active compound is used here in micronized form, it being possible for one or more additional physiologically tolerable solvents to be present, e.g. ethanol. Inhalation solutions can be administered with the aid of customary inhalers.
As a rule, the substances according to the invention can be administered in analogy to other known, commercially available preparations (e.g. described in US-A-4 472 305), preferably in doses between approximately 0.05 and 500 mg, in particular between 0.5 and 100 mg, per dose unit. The daily dose is preferably between approximately 0.01 and 20 mg/kg of body weight. The specific dose for each patient depends, however, on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health and sex, on the diet, on the time and route of administration, and on the excretion rate, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Parenteral administration is preferred.
Above and below, all temperatures are given in °C.
The HPLC analyses (retention time Rt) were carried out in the following systems:
column 3 ~m silica rod with a 210 second gradient of 20 to 100% water/acetonitrile/0.01% trifluoroacetic acid, at 2.2 ml/min flow and detection at 220 nm.
Mass spectrometry (MS): EI (electron impact ionization) M+
FAB (fast atom bombardment) (M+H)+
Example 1 Synthesis of 3- (4-fluorophenyl) -4-{4- [3- (pyridin-2-ylamino)propoxy]phenyl~butyric acid 835 mg of Mg are suspended in 5 ml of abs. THF. A
solution of 2.0 g of 4-benzyloxybenzyl chloride in 5 ml of abs. tetrahydrofuran is then added dropwise. After addition is complete, the turbid solution is stirred at room temperature for 1 hour, then a solution of 1.73 g of ethyl 2-cyano-3-(4-fluorophenyl)acrylate in 10 ml of abs. toluene is added and the mixture is refluxed for 16 hours. The solvent is removed and, after customary working up, ethyl 4-(4-benzyloxyphenyl)-2-cyano 3-(4-fluorophenyl)butyrate ("AA") is obtained.
8.27 g of "AA" are suspended in a mixture of 80 ml of acetic acid and 80 ml of cons. HCl and the mixture is then refluxed for 16 hours. After customary working up, 4-(4-hydroxyphenyl)-3-(4-fluorophenyl)butyric acid ("AB") is obtained.
A solution of 1.0 g of "AB" in 10 ml of abs. methanol is treated with 0.4 ml of thionyl chloride and stirred at room temperature for 16 hours. After customary working up, methyl 4-(4-hydroxyphenyl)-3-(4-fluoro-phenyl)butyrate ("AC") is obtained.
0.62 ml of diethyl azodicarboxylate is added dropwise to a suspension of 0.4 g of "AC", 0.5 g of 3-(1-oxy-pyridin-2-ylamino)propan-1-of and 1.23 g of polymer-bound triphenylphosphine (loading about 3 mmol/g) in 17 ml of abs. THF and the mixture is subsequently stirred for 16 hours. After filtration and removal of the solvent, the residue is purified by means of HPLC.
Methyl 3-(4-fluorophenyl)-4-{4-[3-(1-oxypyridin-2-yl-amino)propoxy]phenyl~butyrate ("AD") is obtained.
A solution of 0.45 g of "AD" in 30 ml of chloroform is treated with 0.59 g of phosphorus trichloride, and stirred for 2 hours at room temperature and for a further 2 hours under reflux. After customary working up, the residue is treated in 15 ml of methanol with 0.2 g of lithium hydroxide and stirred at room temperature for 16 hours. After removal of the solvent, the residue is treated with 0.66 ml of trifluoroacetic acid and purified by means of HPLC. 3-(4-Fluorophenyl)-4-{4-[3-pyridin-2-ylamino)propoxy]phenyl}butyric acid, trifluoroacetate, is obtained H
N N
OH
Test results of the a,V~3 inhibition by 3-4-fluoro-phenyl)-4-{4-[3-pyridin-2-ylamino)propoxy]phenyl~-butyric acid The ICso value, i.e. the concentration in nmol/litre which inhibits 50% of the vitronectin binding to the corresponding isolated receptor, is given for the vitronectin binding test (method of Smith et al., J.
Biol. Chem. 265, 12267-71, 1990).
ICso 0c"(33: 10.
The pharmacological data confirm the antagonistic activity of the compound according to the invention for the receptor a"(33.
The compounds below were obtained analogously to the synthesis scheme described above 3- (4-fluorophenyl) -4-{4- [2- (pyrimidin-2-ylamino) -ethoxy]phenyl~butyric acid, trifluoroacetate;
3-(4-fluorophenyl)-4-{4-[3-(pyrimidin-2-ylamino)-propoxy]phenyl~butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4-{4- [4- (pyrimidin-2-ylamino) -butoxy]phenyl~butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4-{4- [2- (pyridin-2-ylamino) ethoxy] -phenyl)butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4-{4- [4- (pyridin-2-ylamino)butoxy] -phenyl}butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4-{4- [3- (imidazol-1-yl)propoxy] -phenyl~butyric acid;
3-(4-fluorophenyl)-4-{4-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propoxy]phenyl}butyric acid;
3- (4-fluorophenyl) -4-{4- [3- (imidazol-2-ylamino) -propoxy]phenyl~butyric acid;
3-(4-fluorophenyl)-4-{4-[3-(benzimidazol-2-ylamino)-propoxy]phenyl~butyric acid;
3-(4-fluorophenyl)-4-{4-[3-(2-aminopyridin-6-ylamino)-propoxy]phenyl)butyric acid, 3-(4-fluorophenyl)-4-{4-[3-(2-aminoimidazol-5-ylamino)-propoxy]phenyl}butyric acid.
Example 2 Synthesis of (4-fluorophenyl-{4-[3-(pyridin-2-ylamino)-propoxy]benzyl~amino)acetic acid 40.0 g of 4-hydroxybenzaldehyde are dissolved in 400 ml of abs. THF under a protective gas atmosphere, and the solution is treated with 55.1 g of dihydropyran and 13.7 g of pyridinium p-toluenesulfonate and stirred at room temperature overnight. The solvent is removed on a rotary evaporator, the residue is worked up in the customary manner and 4-(tetrahydropyran-2-yloxy)-benzaldehyde ("BA") is obtained as a colourless oil.
A solution of 2.0 g of "BA" in 20 ml of abs. methanol is treated with 1.17 g of 4-fluoroaniline and stirred at 60° for 3 hours. 0.79 g of sodium cyanoborohydride are added at room temperature, and the reaction soluion is refluxed for 16 hours. After removal of the solvent, customary working up and purification by chromatography, 4-fluorophenyl-[4-(tetrahydropyran-2-yloxy)benzyl]amine ("BB") is obtained as a colourless liquid.
8.0 g of "BB" and 10.36 g of methyl bromoacetate are dissolved in 100 ml of abs. THF under an Nz atmosphere, treated with 12.0 g of potassium carbonate and refluxed for 16 hours. After removal of the solvent, customary working up and purification by chromatography, methyl ( [4-fluorophenyl] - [4- (tetrahydropryan-2-yloxy) benzyl] -amino}acetate ("BC") is obtained as a colourless solid.
A solution of 0.5 g of "BC" in 25 ml of methanol and 5 ml of dichloromethane is treated with 2.76 ml of conc. HCl and stirred at room temperature for 5 minutes. After removal of the solvents and customary working up, the residue is dissolved in 16 ml of abs.
THF together with 0.47 g of 3-(1-oxypyridin-2-yl-amino)propan-1-of and then treated with 1.17 g of polymeric triphenylphosphine (loading about 3 mmol/g).
0.62 ml of diethyl azodicarboxylate is then added dropwise. The suspension is then stirred at room temperature for 16 hours. After filtration and removal of the solvent, the residue is purified by means of HPLC. Methyl (~4-[3-(1-oxypyridin-2-ylamino)propoxy]-benzyl}-(4-fluorophenyl)amino)acetate ("BD") is obtained.
A solution of 0.44 g of "BD" in 30 ml of chloroform is treated with 0.57 g of phosphorus trichloride, and stirred for 2 hours at room temperature and for a further 2 hours under reflux. After customary working up, the residue is treated in 15 ml of methanol with 0.27 g of lithium hydroxide and stirred at room temperature for 16 hours. After removal of the solvent, 0.66 ml of trifluoroacetic acid is added and the mixture is purified by means of HPLC. ((4-Fluoro-phenyl)-{4-[3-(pyridin-2-ylamino)propoxy]benzyl~amino)-acetic acid, bistrifluoroacetate is obtained F
N N.~.-~.O .~ ( ~ O
p t ~ .
N OH
The compounds below are obtained analogously ((4-fluorophenyl)-~4-[2-(pyrimidin-2-ylamino)ethoxy]-benzyl~amino)acetic acid, ((4-fluorophenyl)-~4-[3-(pyrimidin-2-ylamino)propoxy]-benzyl}amino)acetic acid, ( (4-fluorophenyl) -{4- [4- (pyrimidin-2-ylamino) butoxy] -benzyl~amino)acetic acid, ( (4-fluorophenyl) -~4- [2- (pyridin-2-ylamino) ethoxy] -benzyl~amino)acetic acid, ( (4-fluorophenyl) -{4- [4- (pyridin-2-ylamino) butoxy] -benzyl~amino)acetic acid, ((4-fluorophenyl)-f4-[3-(imidazol-1-yl)propoxy]benzyl~-amino)acetic acid, ((4-fluorophenyl)-{4-[3-(4,5-dihydro-1H-imidazol-2-yl-amino)propoxy]benzyl}amino)acetic acid, ( (4-fluorophenyl) -{4- [3- (imidazol-2-ylamino)propoxy] -benzyl}amino)-acetic acid, ( (4-fluorophenyl) -{4- [3- (benzimidazol-2-ylamino) -propoxy]benzyl}amino)acetic acid.
Example 3 The compounds below are obtained analogously to Example 1 3-(3-chloro-4-phenyl)phenyl)-4-{4-[3-(pyridin-2-yl-amino)propoxy]phenyl}butyric acid, H
N\ NCO
OH
3-(2-bromo-phenyl)-4-{4-[3-(pyridin-2-ylamino)propoxy]-phenyl}butyric acid, 3-(3,4-dichloro-phenyl)-4-{4-[3-(pyridin-2-yl-amino)propoxy]phenyl}butyric acid, 3-(4-bromo-phenyl)-4-{4-[3-(pyridin-2-ylamino)propoxy]-phenyl}butyric acid, 3-(2,3-dichloro-phenyl)-4-{4-[3-(pyridin-2-yl-amino)propoxy]phenyl}butyric acid, 3-(2,4-dichloro-phenyl)-4-{4-[3-(pyridin-2-yl-amino)propoxy]phenyl~butyric acid, 3-(3-bromo-phenyl)-4-{4-[3-(pyridin-2-ylamino)propoxy]-phenyl}butyric acid, 3-(2,6-difluoro-phenyl)-4-{4-[3-(pyridin-2-yl-amino)propoxy]phenyl}butyric acid, 3-(3,5-dichloro-phenyl)-4-{4-[3-(pyridin-2-yl-amino)propoxy]phenyl}butyric acid.
The following examples relate to pharmaceutical preparations:
Example A: Injection vials A solution of 100 g of 3-(4-fluorophenyl)-4-{4-[3-(pyridin-2-ylamino)propoxy]phenyl~butyric acid and 5 g of disodium hydrogenphosphate is adjusted to pH
6.5 in 3 1 of double-distilled water using 2 N
hydrochloric acid, sterile-filtered, filled into injection vials, lyophilized under sterile conditions and aseptically sealed. Each injection vial contains 5 mg of active compound.
Example B: Suppositories A mixture of 20 g of 3-(4-fluorophenyl)-4-{4-[3-(pyridin-2-ylamino)propoxy]phenyl~butyric acid is fused with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool.
Each suppository contains 20 mg of active compound.
Example C: Solution A solution is prepared from 1 g of 3- (4-fluorophenyl) -4-{4-[3-(pyridin-2-ylamino)propoxy]phenyl~butyric acid, 9.38 g of NaH2P04 ~ 2 H20, 28.48 g of Na2HP04 ~ 12 HZO
and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. The solution is adjusted to pH 6.8, made up to 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops.
Example D: Ointment 500 mg of 3- (4-fluorophenyl) -4-{4- [3- (pyridin-2-yl amino)propoxy]phenyl~butyric acid are mixed with 99.5 g of petroleum jelly under aseptic conditions.
Example E: Tablets A mixture of 1 kg of 3-(4-fluorophenyl) 4-{4-[3-(pyridin-2-ylamino)propoxy]phenyl~butyric acid, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a customary manner to give tablets such that each tablet contains 10 mg of active compound.
Example F: Coated tablets Analogously to Example E, tablets are pressed and are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and colourant.
Example G: Capsules 2 kg of 3-(4-fluorophenyl)-4-~4-[3-(pyridin-2-ylamino)-propoxy]phenyl}butyric acid are filled into hard gelatin capsules in a customary manner such that each capsule contains 20 mg of the active compound.
Example H: Ampoules A solution of 1 kg of 3-(4-fluorophenyl)-4-f4-[3-(pyridin-2-ylamino)propoxy]phenyl}butyric acid in 60 1 of double-distilled water is sterile-filtered, filled into ampoules, lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 10 mg of active compound.
Example I: Inhalation spray 14 g of 3-(4-fluorophenyl)-4-{4-[3-(pyridin-2-yl-amino)propoxy]phenyl~butyric acid are dissolved in 10 1 of isotonic NaCl solution and the solution is filled into commercially available spray containers having a pump mechanism. The solution can be sprayed into the mouth or nose. One puff of spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.
The compounds of the formula I according to the invention can therefore be employed as pharmaceutical active compounds, in particular for the treatment of oncoses, osteoporosis, osteolytic disorders and for the suppression of angiogenesis.
Compounds of the formula I which block the interaction of integrin receptors and ligands, such as, for example, of fibrinogen, on the fibrinogen receptor (glycoprotein IIb/IIIa), prevent, as GPIIb/IIIa antagonists, the spread of tumour cells by metastasis.
This is confirmed by the following observations:
The spread of tumour cells from a local tumour into the vascular system takes place through the formation of microaggregates (microthrombi) by interaction of the tumour cells with blood platelets. The tumour cells are screened by the protection in the microaggregate and are not recognized by the cells of the immune system.
The microaggregates can attach to vessel walls, owing to which further penetration of tumour cells into the tissue is facilitated. Since the formation of the microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on the activated blood platelets, the GPIIb/IIIa antagonists can be regarded as effective metastasis inhibitors.
In addition to the binding of fibrinogen, fibronectin and of the von Willebrand factor to the fibrinogen receptor of the blood platelets, compounds of the formula I also inhibit the binding of further adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. In particular, they prevent the formation of blood platelet thrombi and can therefore be employed for the treatment of thromboses, apoplexy, cardiac infarct, inflammation and arteriosclerosis.
The properties of the compounds can also be demonstrated by methods which are described in EP-A1-0 462 960. The inhibition of fibrinogen binding to the fibrinogen receptor can be demonstrated by the method which is given in EP-Al-0 381 033.
The platelet aggregation-inhibiting action can be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962). The inhibition of bone resorption by the compounds of the invention can be confirmed with the aid of a osteoclast resorption test analogously to WO 95/32710.
The invention accordingly relates to the compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts for the production of a medicament for use as an integrin inhibitor. The invention relates in particular to compounds of the formula I according to Claim 1 and/or their acceptable salts for the production of a medicament for the control of pathologically angiogenic disorders, tumours, osteoporosis, inflammations and infections.
The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine, for the prophylaxis and/or therapy of thrombosis, myocardial infarct, arteriosclerosis, inflammation, apoplexy, angina pectoris, oncoses, osteolytic diseases such as osteoporosis, hypercalcaemia, pathologically angiogenic diseases such as, for example, inflammation, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, viral infection, bacterial infection, fungal infection, in acute kidney failure and in wound healing for assisting the healing processes.
The compounds of the formula I can be employed as antimicrobially active substances in operations where biomaterials, implants, catheters or heart pacemakers are used. They have an antiseptic action here. The efficacy of the antimicrobial activity can be demonstrated by the process described by P. Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988).
The invention also relates to the hydrates and solvates, e.g. alcoholates, of these compounds.
The invention further relates to a process for the preparation of compounds of the formula I according to Claim 1, and their salts, characterized in that a) a compound of the formula I is set free from its functional derivatives by treating with a solvolysing, reducing or hydrogenolysing agent, or b) a radical X and/or RS is converted into another radical X and/or R5, by, for example, i) converting an amino group into a guanidino group by reaction with an amidinating agent, ii) hydrolysing an ester, iii) converting a hydroxyamidine into an amidine by hydrogenation, and/or converting a base or acid of the formula I into one of its salts.
_ 7 _ The compounds of the formula I can have a chiral centre and can therefore occur in a number of stereoisomeric forms. All these forms (e. g. D and L forms) and their mixtures (e.g. the DL forms) are included in the formula I.
So-called prodrug derivatives are also included in the compounds according to the invention, i.e. compounds of the formula I modified with, for example, alkyl or acyl groups, sugars or oligopeptides, which are rapidly cleaved in the body to the active compounds according to the invention.
The abbreviations mentioned above and below stand for:
Ac acetyl BOC tert-butoxycarbonyl CBZ or Z benzyloxycarbonyl DCCI dicyclohexylcarbodiimide DMF dimethylformamide EDCI N-ethyl-N,N'-(dimethylaminopropyl)carbo-diimide Et ethyl Fmoc 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole Me methyl Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl HONSu N-hydroxysuccinimide OBut tert-butyl ester Oct octanoyl OMe methyl ester OEt ethyl ester POA phenoxyacetyl TFA trifluoroacetic acid Trt trityl (triphenylmethyl).
It applies to the whole invention that all radicals which occur a number of times, such as, for example, A, can be identical or different, i.e. are independent of one another.
A is alkyl and has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 C atoms and is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, additionally 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-, 1,2,2-trimethylpropyl, heptyl, octyl, nonyl or decyl, undecyl or docecyl. A is also alkyl substituted by halogen, preferably CF3.
X is preferably, for example, pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino, 2-aminoimidazol-5-ylamino, 2-aminopyridin-6-ylamino, 2-aminoimidazol-5-yl or 2-aminopyridin-6-yl.
Y is preferably, for example, ethylene, propylene or butylene.
Z is preferably, for example, O.
R1 is preferably, for example, 1,4-phenylene.
R2 is preferably, for example, CH or N, very particularly CH.
R4 is preferably, for example, phenyl mono- or polysubstituted by F.
RS is preferably, for example, OH.
Hetl is preferably 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, unsubstituted or mono- or disubstituted by A, NHA and/or NH2, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 3-, 4-, 5-, 6-, 7-_ g _ or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, 1H-imidazo[4,5-b]pyridin-2-yl or 1,8-naphthyridin-7-yl.
The heterocyclic radicals can also be partially or completely hydrogenated.
Hetl can thus, for example, also be 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, tetra-hydro-1-, -2- or -4-imidazolyl, 4,5-dihydroimidazol-2-yl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 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 or 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl.
Hydrogenated or partially hydrogenated Hetl radicals can additionally be substituted by =NH or carbonyl oxygen.
Het2 is preferably 2,3-, 2,4-, 2,5- or 3,4-thienyl, 2,3-, 2,4-, 2,5- or 3,4-pyrrolyl, 2,4-, 2,5- or 4,5-imidazolyl, 2,3-, 2,4-, 2,6- or 3,5-pyridyl, 2,4-, 2,5-, 2,6-, 4,5- or 5,6-pyrimidinyl, unsubstituted or monosubstituted by F, Cl, Br, A, OA or OCF3.
n is preferably 2, 3, 4, 5 or 6, very particularly preferably n is 3, 4 or 5.
m and o are preferably, in each case independently of one another, 0, 1 or 2, very particularly preferably they are 0.
Substituted "one or more times" means mono-, di-, tri-or tetrasubstituted.
Aryl is phenyl which is unsubstituted, preferably - as indicated - monosubstituted, specifically preferably phenyl, o-, m- or p-tolyl, 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-cyanophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m-or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methylthiophenyl, o-, m- or p-methylsulfinylphenyl, o-, m- or p-methylsulfonyl phenyl, o-, m- or p-aminophenyl, o-, m- or p-methyl aminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- or p-nitrophenyl, o-, m- or p-acetylphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-aminocarbonyl phenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3-methyl-, 2-chloro-4-methyl-, 2-chloro-5-methyl-, 2-chloro-6-methyl-, 2-methyl-3-chloro-, 2-methyl-4-chloro-, 2-methyl-5-chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl- or 3-methyl-4-chlorophenyl, 2-bromo-3-methyl-, 2-bromo-4-methyl-, 2-bromo-5-methyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-, 2-methyl-4-bromo-, 2-methyl-5-bromo-, 2-methyl-6-bromo-, 3-bromo-4-methyl-, 3-bromo-5-methyl- or 3-methyl-4-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichloro-phenyl, 2,4,6-tri-tert-butylphenyl, 2,5-dimethylphenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro-3,5-di methylphenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro 4-bromophenyl, 2,4-dichloro-5-methylphenyl, 3-bromo 6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 2-methoxy 5-methylphenyl, 2,4,6-triisopropylphenyl.
Amino protective group is preferably formyl, acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxy-carbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("carbo-benzoxy"), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl.
Accordingly, the present 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 subformulae Ia to Im, which correspond to the formula I
and in which the radicals not designated in greater detail have the meaning indicated in the formula I, but in which in a) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino, 4,5-di-hydroimidazol-2-ylamino, 2-amino-imidazol-5-ylamino, 2-aminopyridin-6-ylamino, 2-aminoimidazol-5-yl or 2-aminopyridin-6-yl;
in b) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CHZ) n-, n is 2, 3 or 4;
in c) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y 1S - (CH2) n-.
n is 2, 3 or 4;
in d) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CH2) n-.
n is 2, 3 or 4, Z is O;
in e) X is pyrimidin-2-ylamino, pyridin-2-yl amino, imidazol-1-yl, imidazol-2-yl amino, benzimidazol-2-ylamino or 4,5-di hydroimidazol-2-ylamino, Y 1 S - ( CH2 ) n- , n is 2, 3 or 4, Z is O, R2 is N or CH;
in f) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CH2) n-, n is 2, 3 or 4, Z is O, R2 is N or CH, R4 is phenyl which is mono- or poly substituted by F, Cl, Br, OA, OCF3, -CO-A, CN, COOA, CONHz or NO2;
in g) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CH2) n-, n is 2, 3 or 4, Z is O, RZ is N or CH, R4 is phenyl which is mono- or poly-substituted by F, Cl, Br, OA or OCF3;
RS is OA or OH;
in h) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CHZ) n- i n is 2, 3 or 4, Z is O, R2 is N or CH, R4 is phenyl which is mono- or poly-substituted by F, RS is OA or OH;
in i) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CH2)n-, n is 2, 3 or 4, Z is O, R2 is N or CH, R4 is phenyl which is mono- or poly-substituted by Hal, A or aryl, RS is OA or OH
with the proviso that R4 is not equal to a phenyl or naphthyl radical monosubstituted by A
or aryl;
in k) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CH2)n-, n is 2, 3 or 4, Z is O, R2 is N or CH, R4 is phenyl which is substituted by Hal and aryl, RS is OA or OH
with the proviso that R4 is not equal to a phenyl or naphthyl radical monosubstituted by A
or aryl;
in 1) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino or 4,5-di-hydroimidazol-2-ylamino, Y is - (CHZ) n-.
n is 2, 3 or 4, Z is O, R2 is N or CH, R4 is phenyl which is substituted by Hal and aryl, RS is OA or OH, aryl is phenyl which is mono-, di- or trisubstituted by Hal, A, OA, CF3, CN
or with t he proviso that R4 is not equal to a phenyl or naphthyl radical monosubstituted by A
or aryl;
in m) X is pyrimidin-2-ylamino, pyridin-2-yl-amino, imidazol-1-yl, imidazol-2-yl-amino, benzimidazol-2-ylamino, 4,5-di-hydroimidazol-2-ylamino, 2-amino-imidazol-5-ylamino, 2-aminopyridin-6-yl-amino, 2-aminoimidazol-5-yl or 2-amino-pyridin-6-yl, Y iS - (CHZ) n-, n is 2, 3 or 4, Z is O, R2 is N or CH, R4 is phenyl which is mono- or poly-substituted by Hal, A or aryl, RS is OA or OH
with t he proviso that R4 is not equal to a phenyl or naphthyl radical monosubstituted by A
or aryl.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made in this case of variants which are known per se, but not mentioned here in greater detail.
If desired, the starting substances can also be formed in situ, such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
Compounds of the formula I can preferably be obtained by liberating compounds of the formula I from one of their functional derivatives by treating with a solvolysing or hydrogenolysing agent.
Preferred starting substances for the 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 linked to an N atom, carry an amino protective group, in particular those which, instead of an HN group, carry an R' N group in which R' is an amino protective group, and/or those which, instead of the H atom of a hydroxyl group, carry a hydroxyl protective group, e.g. those which correspond to the formula I, but instead of a group -COOH carry a group -COOR", in which R" is a hydroxyl protective group.
It is also possible for a number of - identical or different - protected amino and/or hydroxyl groups to be present in the molecule of the starting substances.
If the protective groups present are different from one another, in many cases they can be removed selectively.
The expression "amino protective group" is generally known and relates to groups which are suitable for protecting (or blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. Typical groups of this type are, in particular, unsubstituted or substituted aryl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size is otherwise not critical; however, those having 1-20, in particular 1-8, C atoms are preferred. The expression "aryl group" is to be interpreted in the widest 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 acyl groups of this type are formyl or alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenyl acetyl; aroyl such as benzoyl or toluyl;
aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxy-carbonyl, BOC, 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxy-carbonyl, Fmoc; arylsulfonyl such as Mtr. Preferred amino protective groups are BOC and Mtr, additionally CBZ, Fmoc, benzyl, formyl and acetyl.
The removal of the amino protective group takes place -depending on the protective group used - e.g. using strong acids, expediently 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 not always necessary. Suitable inert solvents are preferably organic solvents, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, additionally also alcohols such as methanol, ethanol or isopropanol, and also water. Mixtures of the above-mentioned solvents are additionally suitable. TFA is preferably used in an excess without addition of a further solvent, perchloric acid 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 expediently between approximately 0 and approximately 50°; the reaction is preferably carried out at between 15 and 30° (room temperature).
The groups BOC, OBut and Mtr can preferably be removed, for example, using TFA in dichloromethane or using approximately 3 to 5N HC1 in dioxane at 15-30°, the Fmoc group using an approximately 5 to 50% strength solution of secondary amines such as dimethylamine, diethylamine or piperidine in DMF at 15-30°.
Hydrogenolytically removable protective groups (e. g.
CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst (e . g . of a noble metal catalyst such as palladium, expediently 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. As a rule, the hydrogenolysis is carried out at temperatures between approximately 0 and 100° and pressures between approximately 1 and 200 bar, preferably at 20-30° and 1-10 bar. Hydrogenolysis of the CBZ group takes place 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°.
Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloro-ethylene, 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); 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, water or mixtures of the solvents mentioned.
It is furthermore possible to hydrolyse an ester of the formula I. Expediently, this is carried out by solvolysis or hydrogenolysis, as indicated above, e.g.
using LiOH in methanol, NaOH or KOH in dioxane/water at temperatures between 0 and 60°C, preferably between 10 and 40°C.
The conversion of a cyano group into an amidino group is carried out by reaction with, for example, hydroxyl-amine and subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as, for example, Pd/C.
It is furthermore possible to replace a conventional amino protective group by hydrogen by removing the protective group, as described above, solvolytically or hydrogenolytically or by liberating an amino group protected by a conventional protective group by solvolysis or hydrogenolysis.
For the preparation of compounds of the formula I in which X is HzN-C(=NH)-NH-, an appropriate amino compound can be treated with an amidinating agent. A
preferred amidinating agent is 1-amidino-3,5-di-methylpyrazole (DPFN), which is particularly employed in the form of its nitrate. The reaction is expediently carried out with addition of a base such as tri-ethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, e.g. water/dioxane at temperatures between 0 and 120°C, preferably between 60 and 120°C.
For the preparation of an amidine of the formula I
(X = -C (=NH) -NH2) , ammonia can be added to a nitrile of the formula I (X = CN). The addition is preferably carried out in a number of stages by a) converting the nitrile in a manner known per se using HzS into a thioamide, which is converted using an alkylating agent, e.g. CH3I, into the corresponding S-alkyl-imidothioester, which for its part reacts with NH3 to give the amidine, b) converting the nitrile using an alcohol , a . g . ethanol in the presence of HCl , into the corresponding imidoester and treating this with ammonia, or c) reacting the nitrile with lithium bis-(trimethylsilyl)amide and then hydrolysing the product.
The release of the compounds of the formula I from an oxidized precursor, by, for example, reducing an oxy-heterocycle using a reducing agent such as, for example, phosphorus trichloride in an inert solvent, is furthermore preferred.
Furthermore, free amino groups can be acylated in the customary manner using an acid chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, expediently 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 reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation. For this reaction, suitable acids are in particular those which yield physiologically acceptable salts. Thus inorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, in addition organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g.
formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malefic 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, laurylsulfuric acid. Salts with physiologically unacceptable acids, e.9. picrates, can be used for the isolation and/or purification of the compounds of the formula I.
On the other hand, an acid of the formula I can be converted into one of its physiologically acceptable metal or ammonium salts by reaction with a base.
Possible salts here are, in particular, the sodium, potassium, magnesium, calcium and ammonium salts, in addition substituted ammonium salts, e.g. the dimethyl-, diethyl- or diisopropylammonium salts, monoethanol-, diethanol- or diisopropylammonium salts, cyclohexyl-, dicyclohexylammonium salts, dibenzyl-ethylenediammonium salts, furthermore, for example, salts with arginine or lysine.
The compounds of the formula I contain one or more chiral centres and can therefore be present in racemic or in optically active form. Racemates obtained can be separated into the enantiomers mechanically or chemically by methods known per se. Preferably, diastereomers are formed from the racemic mixture by reaction with an optically active resolving agent.
Suitable resolving agents are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as (3-camphorsulfonic acid. Resolution of enantiomers with the aid of a column packed with an optically active resolving agent (e.g. dinitrobenzoylphenylglycine) is also advantageous; a suitable eluent is, for example, a mixture of hexane/isopropanol/acetonitrile, e.g. in the volume ratio 82:15:3.
Of course, it is also possible to obtain optically active compounds of the formula I according to the methods described above, by using starting substances which are already optically active.
The invention includes not only the compounds mentioned but also mixtures and preparations which, in addition to these compounds according to the invention, also contain other pharmacological active compounds or adjuvants which can influence the primary pharmacological action of the compounds according to the invention in the desired manner. These can be used as therapeutics, diagnostics or as reagents. They can be given to man or animals locally or systemically, orally, intravenously, intraperitoneally, intramuscularly, subcutaneously, transdermally, nasally, buccally, or iontophoretically, which includes formulations in suspensions, emulsions or solutions, liposomes, ointments, pastes, biodegradable polymers or as nanoparticles, tablets, capsules or pills, granules or powders, as an aerosol for inhaling, as intranasal drops or sprays. A combination of the novel products with other techniques, such as surgery, irradiation, diagnosis, radiotherapy, photodynamic therapy and gene therapy, as well as with other medicaments is also possible. Such medicaments can originate, for example, from the cardiovascular, central nervous system or oncology fields. They can be tumour agents, such as angiogenesis inhibitors or cytostatics, chemotherapeutics of the groups alkylating agents, antibiotics, antimetabolites, biologicals and immunomodulators, hormones and their antagonists, mustard gas derivatives, alkaloids and others, where these substances can be of low molecular weight or high molecular weight. They can be lipids, carbohydrates or proteins. Also included amongst these are cytokines, toxins, fusion proteins, monoclonal antibodies and vaccines.
The invention accordingly relates to compounds of the formulae defined above and below and also in the claims, including their physiologically acceptable salts, as medicaments, diagnostics or reagents.
The invention relates in particular to corresponding medicaments as inhibitors for the control of disorders which are based indirectly or directly on expression of the a,~(33 integrin receptor, thus in particular in the case of pathologically angiogenic disorders, thromboses, cardiac infarcts, coronary heart disorders, arteriosclerosis, tumours, osteoporosis, inflammations, infections and also for influencing wound-healing processes.
The invention also relates to corresponding pharmaceutical preparations which contain at least one medicament of the formula I and, if appropriate, vehicles and/or excipients.
The invention furthermore relates to the use of the compounds and/or their physiologically acceptable salts according to the claims and the description for the production of a medicament for the control of disorders which are based indirectly or directly on expression of the a"(33 integrin receptor, thus in particular in the case of pathologically angiogenic disorders, thromboses, cardiac infarcts, coronary heart disorders, arteriosclerosis, tumours, osteoporosis, inflammations, infections and for influencing wound-healing processes.
The medicaments according to the invention or pharmaceutical preparations comprising them can be used as medicaments in human or veterinary medicine.
Suitable vehicles are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application or for application in the form of an inhalation spray and do not react with the novel 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, coated tablets, capsules, powders, granules, syrups, juices or drops are used for oral administration, suppositories are used, in particular, for rectal administration, solutions, preferably oily or aqueous solutions, in addition suspensions, emulsions or implants, are used for parenteral administration and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. The preparations indicated can be sterilized and/or can contain excipients such as glidants, preservatives, stabilizing and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colourants, flavourings and/or one or more further active compounds, e.g. one or more vitamins.
For administration as an inhalation spray, sprays can be used which contain the active compound either dissolved or suspended in a propellant or propellant mixture (e. g. COZ or chlorofluorohydrocarbons).
Expediently, the active compound is used here in micronized form, it being possible for one or more additional physiologically tolerable solvents to be present, e.g. ethanol. Inhalation solutions can be administered with the aid of customary inhalers.
As a rule, the substances according to the invention can be administered in analogy to other known, commercially available preparations (e.g. described in US-A-4 472 305), preferably in doses between approximately 0.05 and 500 mg, in particular between 0.5 and 100 mg, per dose unit. The daily dose is preferably between approximately 0.01 and 20 mg/kg of body weight. The specific dose for each patient depends, however, on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health and sex, on the diet, on the time and route of administration, and on the excretion rate, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Parenteral administration is preferred.
Above and below, all temperatures are given in °C.
The HPLC analyses (retention time Rt) were carried out in the following systems:
column 3 ~m silica rod with a 210 second gradient of 20 to 100% water/acetonitrile/0.01% trifluoroacetic acid, at 2.2 ml/min flow and detection at 220 nm.
Mass spectrometry (MS): EI (electron impact ionization) M+
FAB (fast atom bombardment) (M+H)+
Example 1 Synthesis of 3- (4-fluorophenyl) -4-{4- [3- (pyridin-2-ylamino)propoxy]phenyl~butyric acid 835 mg of Mg are suspended in 5 ml of abs. THF. A
solution of 2.0 g of 4-benzyloxybenzyl chloride in 5 ml of abs. tetrahydrofuran is then added dropwise. After addition is complete, the turbid solution is stirred at room temperature for 1 hour, then a solution of 1.73 g of ethyl 2-cyano-3-(4-fluorophenyl)acrylate in 10 ml of abs. toluene is added and the mixture is refluxed for 16 hours. The solvent is removed and, after customary working up, ethyl 4-(4-benzyloxyphenyl)-2-cyano 3-(4-fluorophenyl)butyrate ("AA") is obtained.
8.27 g of "AA" are suspended in a mixture of 80 ml of acetic acid and 80 ml of cons. HCl and the mixture is then refluxed for 16 hours. After customary working up, 4-(4-hydroxyphenyl)-3-(4-fluorophenyl)butyric acid ("AB") is obtained.
A solution of 1.0 g of "AB" in 10 ml of abs. methanol is treated with 0.4 ml of thionyl chloride and stirred at room temperature for 16 hours. After customary working up, methyl 4-(4-hydroxyphenyl)-3-(4-fluoro-phenyl)butyrate ("AC") is obtained.
0.62 ml of diethyl azodicarboxylate is added dropwise to a suspension of 0.4 g of "AC", 0.5 g of 3-(1-oxy-pyridin-2-ylamino)propan-1-of and 1.23 g of polymer-bound triphenylphosphine (loading about 3 mmol/g) in 17 ml of abs. THF and the mixture is subsequently stirred for 16 hours. After filtration and removal of the solvent, the residue is purified by means of HPLC.
Methyl 3-(4-fluorophenyl)-4-{4-[3-(1-oxypyridin-2-yl-amino)propoxy]phenyl~butyrate ("AD") is obtained.
A solution of 0.45 g of "AD" in 30 ml of chloroform is treated with 0.59 g of phosphorus trichloride, and stirred for 2 hours at room temperature and for a further 2 hours under reflux. After customary working up, the residue is treated in 15 ml of methanol with 0.2 g of lithium hydroxide and stirred at room temperature for 16 hours. After removal of the solvent, the residue is treated with 0.66 ml of trifluoroacetic acid and purified by means of HPLC. 3-(4-Fluorophenyl)-4-{4-[3-pyridin-2-ylamino)propoxy]phenyl}butyric acid, trifluoroacetate, is obtained H
N N
OH
Test results of the a,V~3 inhibition by 3-4-fluoro-phenyl)-4-{4-[3-pyridin-2-ylamino)propoxy]phenyl~-butyric acid The ICso value, i.e. the concentration in nmol/litre which inhibits 50% of the vitronectin binding to the corresponding isolated receptor, is given for the vitronectin binding test (method of Smith et al., J.
Biol. Chem. 265, 12267-71, 1990).
ICso 0c"(33: 10.
The pharmacological data confirm the antagonistic activity of the compound according to the invention for the receptor a"(33.
The compounds below were obtained analogously to the synthesis scheme described above 3- (4-fluorophenyl) -4-{4- [2- (pyrimidin-2-ylamino) -ethoxy]phenyl~butyric acid, trifluoroacetate;
3-(4-fluorophenyl)-4-{4-[3-(pyrimidin-2-ylamino)-propoxy]phenyl~butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4-{4- [4- (pyrimidin-2-ylamino) -butoxy]phenyl~butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4-{4- [2- (pyridin-2-ylamino) ethoxy] -phenyl)butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4-{4- [4- (pyridin-2-ylamino)butoxy] -phenyl}butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4-{4- [3- (imidazol-1-yl)propoxy] -phenyl~butyric acid;
3-(4-fluorophenyl)-4-{4-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propoxy]phenyl}butyric acid;
3- (4-fluorophenyl) -4-{4- [3- (imidazol-2-ylamino) -propoxy]phenyl~butyric acid;
3-(4-fluorophenyl)-4-{4-[3-(benzimidazol-2-ylamino)-propoxy]phenyl~butyric acid;
3-(4-fluorophenyl)-4-{4-[3-(2-aminopyridin-6-ylamino)-propoxy]phenyl)butyric acid, 3-(4-fluorophenyl)-4-{4-[3-(2-aminoimidazol-5-ylamino)-propoxy]phenyl}butyric acid.
Example 2 Synthesis of (4-fluorophenyl-{4-[3-(pyridin-2-ylamino)-propoxy]benzyl~amino)acetic acid 40.0 g of 4-hydroxybenzaldehyde are dissolved in 400 ml of abs. THF under a protective gas atmosphere, and the solution is treated with 55.1 g of dihydropyran and 13.7 g of pyridinium p-toluenesulfonate and stirred at room temperature overnight. The solvent is removed on a rotary evaporator, the residue is worked up in the customary manner and 4-(tetrahydropyran-2-yloxy)-benzaldehyde ("BA") is obtained as a colourless oil.
A solution of 2.0 g of "BA" in 20 ml of abs. methanol is treated with 1.17 g of 4-fluoroaniline and stirred at 60° for 3 hours. 0.79 g of sodium cyanoborohydride are added at room temperature, and the reaction soluion is refluxed for 16 hours. After removal of the solvent, customary working up and purification by chromatography, 4-fluorophenyl-[4-(tetrahydropyran-2-yloxy)benzyl]amine ("BB") is obtained as a colourless liquid.
8.0 g of "BB" and 10.36 g of methyl bromoacetate are dissolved in 100 ml of abs. THF under an Nz atmosphere, treated with 12.0 g of potassium carbonate and refluxed for 16 hours. After removal of the solvent, customary working up and purification by chromatography, methyl ( [4-fluorophenyl] - [4- (tetrahydropryan-2-yloxy) benzyl] -amino}acetate ("BC") is obtained as a colourless solid.
A solution of 0.5 g of "BC" in 25 ml of methanol and 5 ml of dichloromethane is treated with 2.76 ml of conc. HCl and stirred at room temperature for 5 minutes. After removal of the solvents and customary working up, the residue is dissolved in 16 ml of abs.
THF together with 0.47 g of 3-(1-oxypyridin-2-yl-amino)propan-1-of and then treated with 1.17 g of polymeric triphenylphosphine (loading about 3 mmol/g).
0.62 ml of diethyl azodicarboxylate is then added dropwise. The suspension is then stirred at room temperature for 16 hours. After filtration and removal of the solvent, the residue is purified by means of HPLC. Methyl (~4-[3-(1-oxypyridin-2-ylamino)propoxy]-benzyl}-(4-fluorophenyl)amino)acetate ("BD") is obtained.
A solution of 0.44 g of "BD" in 30 ml of chloroform is treated with 0.57 g of phosphorus trichloride, and stirred for 2 hours at room temperature and for a further 2 hours under reflux. After customary working up, the residue is treated in 15 ml of methanol with 0.27 g of lithium hydroxide and stirred at room temperature for 16 hours. After removal of the solvent, 0.66 ml of trifluoroacetic acid is added and the mixture is purified by means of HPLC. ((4-Fluoro-phenyl)-{4-[3-(pyridin-2-ylamino)propoxy]benzyl~amino)-acetic acid, bistrifluoroacetate is obtained F
N N.~.-~.O .~ ( ~ O
p t ~ .
N OH
The compounds below are obtained analogously ((4-fluorophenyl)-~4-[2-(pyrimidin-2-ylamino)ethoxy]-benzyl~amino)acetic acid, ((4-fluorophenyl)-~4-[3-(pyrimidin-2-ylamino)propoxy]-benzyl}amino)acetic acid, ( (4-fluorophenyl) -{4- [4- (pyrimidin-2-ylamino) butoxy] -benzyl~amino)acetic acid, ( (4-fluorophenyl) -~4- [2- (pyridin-2-ylamino) ethoxy] -benzyl~amino)acetic acid, ( (4-fluorophenyl) -{4- [4- (pyridin-2-ylamino) butoxy] -benzyl~amino)acetic acid, ((4-fluorophenyl)-f4-[3-(imidazol-1-yl)propoxy]benzyl~-amino)acetic acid, ((4-fluorophenyl)-{4-[3-(4,5-dihydro-1H-imidazol-2-yl-amino)propoxy]benzyl}amino)acetic acid, ( (4-fluorophenyl) -{4- [3- (imidazol-2-ylamino)propoxy] -benzyl}amino)-acetic acid, ( (4-fluorophenyl) -{4- [3- (benzimidazol-2-ylamino) -propoxy]benzyl}amino)acetic acid.
Example 3 The compounds below are obtained analogously to Example 1 3-(3-chloro-4-phenyl)phenyl)-4-{4-[3-(pyridin-2-yl-amino)propoxy]phenyl}butyric acid, H
N\ NCO
OH
3-(2-bromo-phenyl)-4-{4-[3-(pyridin-2-ylamino)propoxy]-phenyl}butyric acid, 3-(3,4-dichloro-phenyl)-4-{4-[3-(pyridin-2-yl-amino)propoxy]phenyl}butyric acid, 3-(4-bromo-phenyl)-4-{4-[3-(pyridin-2-ylamino)propoxy]-phenyl}butyric acid, 3-(2,3-dichloro-phenyl)-4-{4-[3-(pyridin-2-yl-amino)propoxy]phenyl}butyric acid, 3-(2,4-dichloro-phenyl)-4-{4-[3-(pyridin-2-yl-amino)propoxy]phenyl~butyric acid, 3-(3-bromo-phenyl)-4-{4-[3-(pyridin-2-ylamino)propoxy]-phenyl}butyric acid, 3-(2,6-difluoro-phenyl)-4-{4-[3-(pyridin-2-yl-amino)propoxy]phenyl}butyric acid, 3-(3,5-dichloro-phenyl)-4-{4-[3-(pyridin-2-yl-amino)propoxy]phenyl}butyric acid.
The following examples relate to pharmaceutical preparations:
Example A: Injection vials A solution of 100 g of 3-(4-fluorophenyl)-4-{4-[3-(pyridin-2-ylamino)propoxy]phenyl~butyric acid and 5 g of disodium hydrogenphosphate is adjusted to pH
6.5 in 3 1 of double-distilled water using 2 N
hydrochloric acid, sterile-filtered, filled into injection vials, lyophilized under sterile conditions and aseptically sealed. Each injection vial contains 5 mg of active compound.
Example B: Suppositories A mixture of 20 g of 3-(4-fluorophenyl)-4-{4-[3-(pyridin-2-ylamino)propoxy]phenyl~butyric acid is fused with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool.
Each suppository contains 20 mg of active compound.
Example C: Solution A solution is prepared from 1 g of 3- (4-fluorophenyl) -4-{4-[3-(pyridin-2-ylamino)propoxy]phenyl~butyric acid, 9.38 g of NaH2P04 ~ 2 H20, 28.48 g of Na2HP04 ~ 12 HZO
and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. The solution is adjusted to pH 6.8, made up to 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops.
Example D: Ointment 500 mg of 3- (4-fluorophenyl) -4-{4- [3- (pyridin-2-yl amino)propoxy]phenyl~butyric acid are mixed with 99.5 g of petroleum jelly under aseptic conditions.
Example E: Tablets A mixture of 1 kg of 3-(4-fluorophenyl) 4-{4-[3-(pyridin-2-ylamino)propoxy]phenyl~butyric acid, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a customary manner to give tablets such that each tablet contains 10 mg of active compound.
Example F: Coated tablets Analogously to Example E, tablets are pressed and are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and colourant.
Example G: Capsules 2 kg of 3-(4-fluorophenyl)-4-~4-[3-(pyridin-2-ylamino)-propoxy]phenyl}butyric acid are filled into hard gelatin capsules in a customary manner such that each capsule contains 20 mg of the active compound.
Example H: Ampoules A solution of 1 kg of 3-(4-fluorophenyl)-4-f4-[3-(pyridin-2-ylamino)propoxy]phenyl}butyric acid in 60 1 of double-distilled water is sterile-filtered, filled into ampoules, lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 10 mg of active compound.
Example I: Inhalation spray 14 g of 3-(4-fluorophenyl)-4-{4-[3-(pyridin-2-yl-amino)propoxy]phenyl~butyric acid are dissolved in 10 1 of isotonic NaCl solution and the solution is filled into commercially available spray containers having a pump mechanism. The solution can be sprayed into the mouth or nose. One puff of spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.
Claims (10)
1. Compounds of the formula I
X-Y-Z-R1-CH2-R2(R4)-CH2-CO-R5~ I
in which X is H2N-C(=NH)-, H2N-C(=NH)-NH-, A-C(=NH)-NH-, Het1- or Het1-NH-, where the primary amino groups can also be provided with conventional amino protective groups, Y is in which one, two, three or four methylene groups can be replaced by N, O and/or S, Z is absent, -O-, -NH-, -NA-, -CH(OH)-, -CH(OA)-, -CHA-, -CA2- or -S-, R1 is phenylene which is unsubstituted or mono-, di- or trisubstituted by F, Cl, Br, A, OA, OCF3 or CN, R2 is N, CH or CA, R3 is H, F, Cl, Br, A, OA or OCF3, R4 is phenyl, naphthyl or Het2, mono- or poly-substituted by F, Cl, Br, A, aryl, OA, SA, CO-A, CN, COOA, CONH2, CONHA, CONA2 or NO2, R5 is OH, OA, NH2, NHA or NA2, Het1 is a mono- or binuclear heterocycle having 1 to 4 N atoms, which can be unsubstituted or mono- or disubstituted by NH2, Het2 is an aromatic mono- or binuclear heterocycle having 1 to 3 N, O and/or S atoms, which can be unsubstituted or mono- or disubstituted by F, Cl, Br, A, OA, SA, OCF3, -CO-A, CN, COOA, CONH2, CONHA, CONA2 or NO2, aryl is phenyl or naphthyl, unsubstituted or mono-or polysubstituted by Hal, A, OA, OH, CO-A, CN, COOA, COOH, CONH2, CONHA, CONA2 or NO2, A is alkyl having 1-12 C atoms, n is 1, 2, 3, 4, 5 or 6, m, o in each case independently of one another are 0, 1, 2, 3, 4, 5 or 6, with the proviso that R4 is not equal to a phenyl or naphthyl radical monosubstituted by A or aryl, and their physiologically acceptable salts and solvates.
X-Y-Z-R1-CH2-R2(R4)-CH2-CO-R5~ I
in which X is H2N-C(=NH)-, H2N-C(=NH)-NH-, A-C(=NH)-NH-, Het1- or Het1-NH-, where the primary amino groups can also be provided with conventional amino protective groups, Y is in which one, two, three or four methylene groups can be replaced by N, O and/or S, Z is absent, -O-, -NH-, -NA-, -CH(OH)-, -CH(OA)-, -CHA-, -CA2- or -S-, R1 is phenylene which is unsubstituted or mono-, di- or trisubstituted by F, Cl, Br, A, OA, OCF3 or CN, R2 is N, CH or CA, R3 is H, F, Cl, Br, A, OA or OCF3, R4 is phenyl, naphthyl or Het2, mono- or poly-substituted by F, Cl, Br, A, aryl, OA, SA, CO-A, CN, COOA, CONH2, CONHA, CONA2 or NO2, R5 is OH, OA, NH2, NHA or NA2, Het1 is a mono- or binuclear heterocycle having 1 to 4 N atoms, which can be unsubstituted or mono- or disubstituted by NH2, Het2 is an aromatic mono- or binuclear heterocycle having 1 to 3 N, O and/or S atoms, which can be unsubstituted or mono- or disubstituted by F, Cl, Br, A, OA, SA, OCF3, -CO-A, CN, COOA, CONH2, CONHA, CONA2 or NO2, aryl is phenyl or naphthyl, unsubstituted or mono-or polysubstituted by Hal, A, OA, OH, CO-A, CN, COOA, COOH, CONH2, CONHA, CONA2 or NO2, A is alkyl having 1-12 C atoms, n is 1, 2, 3, 4, 5 or 6, m, o in each case independently of one another are 0, 1, 2, 3, 4, 5 or 6, with the proviso that R4 is not equal to a phenyl or naphthyl radical monosubstituted by A or aryl, and their physiologically acceptable salts and solvates.
2. Compounds according to Claim 1 a) 3-(4-fluorophenyl)-4-(4-[3-(pyridin-2-ylamino)-propoxy]phenyl}butyric acid, b) 3-(4-fluorophenyl)-4-{4-[3-(2-aminopyridin-6-ylamino)propoxy]phenyl}butyric acid, c) 3-(4-fluorophenyl)-4-{4-[3-(2-aminoimidazol-5-ylamino)propoxy]phenyl}butyric acid, and their physiologically acceptable salts and solvates.
3. Process for the preparation of compounds of the formula I according to Claim 1 and their salts, characterized in that a) a compound of the formula I is set free from its functional derivatives by treating with a solvolysing, reducing or hydrogenolysing agent, or b) a radical X and/or R5 is converted into another radical X and/or R5, by, for example, i) converting an amino group into a guanidino group by reaction with an amidinating agent, ii) hydrolysing an ester, iii) converting a hydroxyamidine into an amidine by hydrogenation, and/or converting a base or acid of the formula I
into one of its salts.
into one of its salts.
4. Compounds of the formula I according to Claim 1 and the compounds according to Claim 2, and their physiologically acceptable salts and solvates as medicaments.
5. Medicament according to Claim 4 as an inhibitor for the control of disorders which are based on expression and pathological function of .alpha.v.beta.3 integrin receptors.
6. Medicament according to Claim 5 for the control of thromboses, cardiac infarcts, coronary heart disorders, arteriosclerosis, tumours, osteoporosis, fibroses, inflammation, infections, psoriasis and also for influencing wound-healing processes.
7. Pharmaceutical preparation, comprising at least one medicament according to one of Claims 5 and 6 and, if appropriate, vehicles and/or excipients and, if appropriate, other active compounds.
8. Use of compounds according to Claims 1 and 2 and/or their physiologically acceptable salts for the production of a medicament for the control of disorders which are based on expression and pathological function of .alpha.v.beta.3 integrin receptors.
9. Use according to Claim 8 for the production of a medicament for the control of pathological processes which are supported or propagated by angiogenesis.
10. Use according to Claim 8 for the production of a medicament for the control of thromboses, cardiac infarcts, coronary heart disorders, arteriosclerosis, tumours, osteoporosis, fibroses, inflammation, infections, psoriasis and for influencing wound-healing processes.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19939981.6 | 1999-08-24 | ||
| DE19939981A DE19939981A1 (en) | 1999-08-24 | 1999-08-24 | New inhibitors of the integrin alphavß3 |
| PCT/EP2000/007591 WO2001014338A1 (en) | 1999-08-24 | 2000-08-04 | NOVEL INTEGRIN αVβ3 INHIBITORS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2382850A1 true CA2382850A1 (en) | 2001-03-01 |
Family
ID=7919343
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002382850A Abandoned CA2382850A1 (en) | 1999-08-24 | 2000-08-04 | Novel inhibitors of the integrin .alpha.v.beta.3 |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP1206454A1 (en) |
| JP (1) | JP2003507458A (en) |
| KR (1) | KR20020016651A (en) |
| CN (1) | CN1370147A (en) |
| AU (1) | AU6570500A (en) |
| BR (1) | BR0013504A (en) |
| CA (1) | CA2382850A1 (en) |
| CZ (1) | CZ2002523A3 (en) |
| DE (1) | DE19939981A1 (en) |
| HK (1) | HK1049666A1 (en) |
| HU (1) | HUP0203697A3 (en) |
| MX (1) | MXPA02001861A (en) |
| NO (1) | NO20020886D0 (en) |
| PL (1) | PL352989A1 (en) |
| SK (1) | SK2282002A3 (en) |
| WO (1) | WO2001014338A1 (en) |
| ZA (1) | ZA200202287B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PE20020665A1 (en) | 2000-06-15 | 2002-08-14 | Pharmacia Corp | CYCLOALKYL PHENYL ALCANOIC ACID AS ANTAGONIST OF INTEGRINS OVß3 |
| US6531494B1 (en) | 2001-08-29 | 2003-03-11 | Pharmacia Corporation | Gem-substituted αvβ3 antagonists |
| ES2436170T3 (en) * | 2003-12-03 | 2013-12-27 | The Scripps Research Institute | Antibodies and peptides specific for integrin alfa II beta3 |
| EP1802618A1 (en) * | 2004-10-14 | 2007-07-04 | Pharmacia Corporation | Biphenyl integrin antagonists |
| US10717736B2 (en) * | 2016-11-08 | 2020-07-21 | Bristol-Myers Squibb Company | Pyrrole amides as alpha V integrin inhibitors |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08325264A (en) * | 1995-05-31 | 1996-12-10 | Sumitomo Metal Ind Ltd | New 2-aromatic ring-substituted-3-phenylpropionic acid or acrylic acid derivative |
| AU717283B2 (en) * | 1996-10-30 | 2000-03-23 | Merck & Co., Inc. | Integrin antagonists |
| EP1061921A4 (en) * | 1998-03-10 | 2005-03-30 | Smithkline Beecham Corp | Vitronectin receptor antagonists |
-
1999
- 1999-08-24 DE DE19939981A patent/DE19939981A1/en not_active Withdrawn
-
2000
- 2000-08-04 WO PCT/EP2000/007591 patent/WO2001014338A1/en not_active Application Discontinuation
- 2000-08-04 CZ CZ2002523A patent/CZ2002523A3/en unknown
- 2000-08-04 EP EP00953158A patent/EP1206454A1/en not_active Withdrawn
- 2000-08-04 CN CN00811950A patent/CN1370147A/en active Pending
- 2000-08-04 PL PL00352989A patent/PL352989A1/en unknown
- 2000-08-04 MX MXPA02001861A patent/MXPA02001861A/en unknown
- 2000-08-04 SK SK228-2002A patent/SK2282002A3/en unknown
- 2000-08-04 CA CA002382850A patent/CA2382850A1/en not_active Abandoned
- 2000-08-04 AU AU65705/00A patent/AU6570500A/en not_active Abandoned
- 2000-08-04 JP JP2001518427A patent/JP2003507458A/en active Pending
- 2000-08-04 HU HU0203697A patent/HUP0203697A3/en unknown
- 2000-08-04 KR KR1020027001419A patent/KR20020016651A/en not_active Application Discontinuation
- 2000-08-04 BR BR0013504-6A patent/BR0013504A/en not_active IP Right Cessation
-
2002
- 2002-02-22 NO NO20020886A patent/NO20020886D0/en not_active Application Discontinuation
- 2002-03-20 ZA ZA200202287A patent/ZA200202287B/en unknown
-
2003
- 2003-03-12 HK HK03101785.4A patent/HK1049666A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO20020886L (en) | 2002-02-22 |
| EP1206454A1 (en) | 2002-05-22 |
| KR20020016651A (en) | 2002-03-04 |
| CZ2002523A3 (en) | 2002-05-15 |
| HUP0203697A3 (en) | 2004-04-28 |
| HUP0203697A2 (en) | 2003-03-28 |
| WO2001014338A1 (en) | 2001-03-01 |
| DE19939981A1 (en) | 2001-03-01 |
| SK2282002A3 (en) | 2002-06-04 |
| BR0013504A (en) | 2002-05-07 |
| CN1370147A (en) | 2002-09-18 |
| JP2003507458A (en) | 2003-02-25 |
| ZA200202287B (en) | 2003-08-27 |
| NO20020886D0 (en) | 2002-02-22 |
| AU6570500A (en) | 2001-03-19 |
| PL352989A1 (en) | 2003-09-22 |
| MXPA02001861A (en) | 2004-09-06 |
| HK1049666A1 (en) | 2003-05-23 |
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Legal Events
| Date | Code | Title | Description |
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| FZDE | Discontinued |