CA2380981A1 - Fluorene derivatives - Google Patents
Fluorene derivatives Download PDFInfo
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- CA2380981A1 CA2380981A1 CA002380981A CA2380981A CA2380981A1 CA 2380981 A1 CA2380981 A1 CA 2380981A1 CA 002380981 A CA002380981 A CA 002380981A CA 2380981 A CA2380981 A CA 2380981A CA 2380981 A1 CA2380981 A1 CA 2380981A1
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- 0 CC(C*(C)=CC)N Chemical compound CC(C*(C)=CC)N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
Abstract
The invention relates to compounds of formula (I) wherein R1, R2, R3, R4, R5 , m and n have the meaning given in Claim 1, and to their physiologically acceptable salts and solvates, which can be used as integrin inhibitors, especially for the prophylaxis and treatment of blood circulation disorders, thrombosis, myocardial infarction, coronary disorders, arteriosclerosis, osteoporosis, pathological processes which are maintained or propagated through angiogenesis, as well as in tumour therapy.
Description
Fluorene derivatives The invention relates to compounds of the formula I
R3-(CH2)n R' I
(CHZ)m _0 in which R1 i s OR' , NHR~ or NA" z , Rz i s H, CO-R~ , CO-OR' , CONHR~ , CONA" z or SOzR~ , R4, RS in each case independently of one another are H, Hal, NOz, NHR~, NA"z, OR', -CO-R', S03R~, SOzR~
or SR' , R3 i s NHz , -C ( =NH ) -NHz , -NH-C ( =NH ) -NHz or -C ( =0 ) -N=C ( NHz ) 2 , ~Ny H N ' N -=-C
which is unsubstituted or monosubstituted by -COA, -COOA, -OH or by a conventional amino protective group, or R6-NH-, R6 is a mono- or binuclear heterocycle having 1 to 4 N, 0 and/or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A" , -CO-A' , OA' , CN, COOA' , CONHz, NOz, =NH or =0, v t _ _ R' is H, A, Ar or aralk, A is alkyl having 1-15 C atoms or cycloalkyl having 3-15 C atoms, which is unsubstituted or mono-, di- or trisubstituted by Ra and in which one, two or three methylene groups can be replaced by N, O and/or S, R8 is Hal, N02, NHA', NA"2, OA', phenoxy, CO-A', S03A' , CN, NHCOA' , CODA' , CONA' 2 or S02A' , A' is H or alkyl having 1-6 C atoms, A" is alkyl having 1-6 C atoms, Ar is a mono- or binuclear aromatic ring system having 0, 1, 2, 3 or 4 N, 0 and/or S atoms, which is unsubstituted or mono-, di- or trisubstituted by alkyl having 1-6 C atoms and/or R8, aralk is aralkylene having 7-14 C atoms, which is unsubstituted or mono-, di- or trisubstituted by Re and in which one, two or three methylene groups can be replaced by N, 0 and/or S, Hal is F, C1, Br or I, m, n in each case independently of one another are 0, 1, 2, 3 or 4, and their physiologically acceptable salts and solvates.
Other vitronectin antagonists are disclosed in WO 97/24124. Bicyclic fibrinogen antagonists are described, for example, in WO 96/18602.
_ 3 _ 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 and solvates have very valuable pharmacological properties, together with good tolerability. They act especially as integrin inhibitors, in particular inhibiting the interactions of the oc~, integrin receptors with ligands. The compounds exhibit particular activity in the case of the integrins ot"(33 and oc~,(35. The compounds are very particularly active as adhesion receptor antagonists for the oc~,(33 receptor. This action can be demonstrated, for example, by the method which is described in J.W.
Smith et al., in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).
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 oc"(33.
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 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~,~i3 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 interactin 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 mediates 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 binding of fibrinogen, fibronectin and of the [lacuna] 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 methoxy which is given in EP-A1-0 381 033.
The platelet aggregation-inhibiting action an be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962).
The invention accordingly relates to the compounds of the formula I and their physiologically acceptable salts and solvates as medicament.
The invention furthermore relates to said medicaments as inhibitors for the control of disorders which are based on an expression and pathological function of oc"~i3 and oc"(35 integrin receptors. The invention also relates to medicaments as GPIIb/IIIa antagonists for the control of thromboses, cardiac infarct, coronary heart diseases and arteriosclerosis, and the medicaments as oc" integrin inhibitors for the control of pathologically angiogenic diseases, thromboses, cardiac infarcts, coronary heart diseases, arteriosclerosis, tumours, osteoporosis and rheumatoid arthritis.
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, patho-. CA 02380981 2002-02-05 ' _ logically 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 angio-plasty, 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 demon-strated by the process described by P. Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988).
The invention further relates to a process for the preparation of compounds of the formula I according to Claim 1 and their salts and solvates, 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 R1, RZ and/or R3 is converted into another radical R1, R2 and/or R3, 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.
The invention furthermore relates to a process for the preparation of compounds of the formula I according to Claim 1 in which R1 is OH and R2, R3, R4, R5, m and n have the meanings indicated in Claim 1, and their salts and solvates, characterized in that a compound of the formula II
R3-(CH2)" -~ 1 R~
R~ II
R4 ~CH2)m ~O
O
R~
in which R1 is 0-alkyl having 1-6 C atoms and R2, R3, R4, R5, m and n have the meanings indicated in Claim 1, is hydrolysed and then decarboxylated.
The compounds of the formula I have at least one 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.
Solvates of the compounds are also included in the compounds according to the invention. These are under-stood as meaning addition compounds with, for example, . CA 02380981 2002-02-05 -water (hydrates) or alcohols such as methanol or ethanol.
The abbreviations mentioned above and below stand for:
Ac acetyl BOC tert-butoxycarbonyl CBZ or Z benzyloxycarbonyl DCCI dicyclohexylcarbodiimide DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DMF dimethylformamide DOPA (3,4-dihydroxyphenyl)alanine DPFN 3,5-dimethylpyrazole-1-formamidinium nitrate DMAP dimethylaminopyridine EDCI N-ethyl-N,N'-(dimethylaminopropyl)carbo-diimide Et ethyl Fmoc 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole Me methyl MTB ether methyl tert-butyl ether Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl HONSu N-hydroxysuccinimide Np neopentyl OBn benzyl ester OBut tert-butyl ester Oct octanoyl OMe methyl ester OEt ethyl ester Orn ornithine POA phenoxyacetyl TBTU 0-(benzotriazol-1-yl)-N,N,N,N-tetramethyl-uronium tetrafluoroborate TFA trifluoroacetic acid pTSS salt para-toluenesulfonic acid salt Trt trityl (triphenylmethyl) Z or CBZ benzyloxycarbonyl.
- g _ It applies to the whole invention that all radicals which occur a number of times, can be identical or different, i.e. are independent of one another.
Preferred compounds of the formula I are those in which the radical -(CHZ)n-R3 substitutes the 2-position and the radical -(CH2)m-CH(NHRZ)-COR1 the 7-position of the fluorene ring system.
Alkyl 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, and also, for example, trifluoromethyl or pentafluoroethyl.
A' is preferably H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.
A" is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl or 3-menthyl.
Alkylene is preferably methylene, ethylene, propylene, butylene, pentylene, preferably hexylene, heptylene, octylene, nonylene or decylene. Aralk is aralkylene and is preferably alkylenephenyl and is, for example, preferably benzyl or phenethyl.
A is very particularly preferably methyl, ethyl, propyl, isopropyl, butyl or tert-butyl.
v CO-A' is alkanoyl or cycloalkanoyl and is preferably formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl or octadecanoyl.
Preferred substituents RB for alkyl, Ar, cycloalkyl and aralk are preferably, for example, Hal, NO2, NH2, NHA" , such as methylamino, NA"a., such as, for example, dimethylamino, methoxy, phenoxy, acyl, such as, for example, formyl or acetyl, CN, NHCOA', such as, for example, acetamido, COOA', such as, for example, COOH
or methoxycarbonyl, CONA'2 or SOzA', in particular, for example, F, C1, hydroxyl, methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, methyl-sulfonyl or phenylsulfonyl.
In the radicals alkyl, alkylene and cycloalkyl, one, two or three methylene groups can in each case be replaced by N, 0 and/or S.
Ar-Co is aroyl and is preferably benzoyl or naphthoyl.
Ar 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, 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 ' - 11 -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, naphthyl, 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, benzo thiadiazol-5-yl or benzoxadiazol-5-yl.
Ar is further preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, particularly preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3-or 4-4-H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-' - 12 -2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.
R6 is a mono- or binuclear heterocycle, preferably 2-or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, particularly preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxa-diazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4-H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5- 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzo-pyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisooxazolyl, 2-, 4-, 5-, 6- or 7-benzo-thiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-Benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-iso-quinolyl, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.
The heterocyclic radicals can also be partially or completely hydrogenated.
R5 can thus, for example, also be 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-' - 13 -tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetra-hydro-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.
The heterocyclic rings mentioned can also be mono-, di-or trisubstituted by Hal, A, -CO-A, OH, CN, COOH, CODA, CONH2, N02, =NH or =0.
R6 is very particularly preferably 1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-2-yl, 5-oxo-4,5-dihydro-1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazol-2-yl, 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidin-4-on-5-yl, 1-alkyl-1,5-dihydroimidazol-4-on-2-yl, pyridin-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydro-pyrimidin-2-yl.
R1 is in particular, for example, hydroxyl, methoxy, ethoxy, NH2, NHMe, NHEt, NMe2 or NEt2.
R1 is very particularly preferably OH or OEt.
R2 is preferably, for example, H, acetyl, propionyl, aminocarbonyl, N,N-dimethylaminocarbonyl, alkoxy-carbonyl such as, for example, pentyloxycarbonyl, alkylsulfonyl such as, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, isobutyl-sulfonyl, 2,2-dimethylpropylsulfonyl, phenylsulfonyl or benzylsulfonyl.
R2 is very particularly preferably 2,2-dimethylpropoxy-carbonyl or butylsulfonyl.
R3 is preferably, for example, H2N-C (=NH) , H2N (C=NH) -NH, 1H-imidazol-2-ylamino, 4,5-dihydro-1H-imidazol-2-yl-amino, 5-oxo-4,5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2-ylamino, 2H-pyrazol-2-ylamino, 2-iminoimidazolidin-4-on-5-ylamino, 1-methyl-1,5 dihydroimidazol-4-on-2-ylamino, pyridin-2-ylamino, pyrimidin-2-ylamino or 1,4,5,6-tetrahydropyrimidin 2-ylamino.
R4 and RS are very particularly preferably H.
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 Ih, 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 Ia) R1 is OH;
in Ib) R1 is OH and R2 i s CO-OR' or SOzR' ;
in Ic) R1 is OH, R2 i s CO-OR' or SOzR' and R3 i s HZN-C ( =NH ) , HZN- ( C=NH ) -NH, 1H-imidazol-2-ylamino, 4,5-dihydro-1H-imidazol-2-ylamino, 5-oxo-4,5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2-ylamino, 2H-pyrazol-2-ylamino, 2-iminoimidazolidin-4-on-5-ylamino, 1-methyl-1,5-dihydroimidazol-4-on-2-ylamino, pyridin-2-ylamino, pyrimidin-2-ylamino or 1,4,5,6-tetra-hydropyrimidin-2-ylamino;
in Id) m is 1;
in Ie) m is 1 and R1 is OH;
in If) R1 is OH, RZ is CO-OR' or SOZR' and m is 1;
in Ig) R1 is OH, R2 i s CO-OR' or S02R' and R' is alkyl having 1-6 C atoms and m is 1;
in Ih) R1 is OH, R2 i s CO-OR' or S02R' , R' is alkyl having 1-6 C atoms, R3 i s H2N-C ( =NH ) . H2N- ( C=NH ) -NH
, 1H-imidazol-2-ylamino, 4,5-dihydro-1H-imidazol-2-ylamino, 5-oxo-4,5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2-ylamino, 2H-pyrazol-2-ylamino, 2-iminoimidazolidin-4-on-5-ylamino, 1-methyl-1,5-dihydroimidazol-4-on-2-ylamino, pyridin-2-ylamino, pyrimidin-2-ylamino or 1,4,5,6-tetra-hydropyrimidin-2-ylamino;
R4 , RS i s H , m is 1 and n is 2,3 or 4;
and their physiologically acceptable salts and solvates.
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.
Preferred starting substances are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.
The amidino group can be liberated from its oxadiazole derivative, for example, by treating with hydrogen in the presence of a catalyst (e. g. Raney nickel).
Suitable solvents are those indicated below, in particular alcohols such as methanol or ethanol, organic acids such as acetic acid or propionic acid or mixtures thereof. 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° (room temperature) and 1-10 bar.
The introduction of the oxadiazole group is possible, for example, by reaction of the cyano compounds with hydroxylamine and reaction with phosgene, dialkyl a carbonate [sic], chloroformic acid esters, N,N'-carbonyldiimidazole or acetic anhydride.
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 acyl, 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 "acyl 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 alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl;
aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-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 is possible -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 approxi-mately 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 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 convert a radical R1, RZ
and/or R3 into another radical R1, Rz and/or R3.
In particular, a carboxylic acid ester can be converted into a carboxylic acid.
Thus it is possible to hydrolyse an ester of the formula I. Expediently, this is carried out by solvolysis or hydrogenolysis, as indicated above, e.g.
using 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 R3 is H2N-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
(R3 - -C (=NH) -NHZ) , ammonia can be added to a nitrile of the formula I (R3 - CN). The addition is preferably carried out in a number of stages by a) converting the nitrile in a manner known per se using H2S 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, e.g. ethanol in the presence of HC1, into the corresponding imidoester and treating this with ammonia, or c) reacting the nitrile with lithium bis-(trimethylsilyl)amide and then hydrolysing the product.
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 physio-logically 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 hetero-cyclic 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 ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethane-sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and disulfonic acids, lauryl-sulfuric acid. Salts with physiologically unacceptable acids, e.g. 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 further relates to the use of the compounds of the formula I and/or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular in a non-chemical manner.
In this connection, they can be brought into a suitable dose form together with at least one solid, liquid and/or semiliquid vehicle or excipient and, if appropriate, in combination with one or more further active compounds.
~
The invention furthermore relates to pharmaceutical preparations comprising at least one medicament, comprising at least one compound of the formula I
and/or one of its physiologically acceptable salts, and also, if appropriate, vehicles and/or excipients and optionally other active compounds.
These preparations can be used 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 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, colorants, 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. C02 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.
The invention thus also relates to the use of compounds of the formula I and/or their physiologically acceptable salts and solvates for the production of a medicament for the control of disorders which are based on an expression and pathological function of oc"~i3 and oc"(35 integrin receptors .
The invention furthermore relates to the use of compounds of the formula I and/or their physiologically acceptable salts and solvates for the production of a medicament for the control of pathologically angiogenic diseases, thromboses, cardiac infarct, coronary heart diseases, arteriosclerosis, tumours, osteoporosis, rheumatoid arthritis, restenoses and diabetic retinopathy.
As a rule, the substances according to the invention can be administered here in analogy to other known, commercially available integrin inhibitors, but in particular in analogy to the compounds described in US-A-4 472 305, preferably in doses between approxi-mately 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 2 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. In the following examples, "customary working up" means:
~
if necessary, water is added, the pH is adjusted, if necessary, depending on the constitution of the final product, to a pH of between 2 and 10, the mixture is extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallization.
Mass spectrometry (MS): EI (electron impact ionization) M+
FAB (fast atom bombardment) (M+H)+
EM/MS (electron spray MS) (M + H)+
The Rf values indicated were determined by thin-layer chromatography using TLC films, silica gel 60 F25a.
Example 1 3-i7-[2-(4,5-Dihydro-ix-imidazol-2-ylamino)ethyl]-9X-fluoren-2-yl~-2-(2,2-dimethylpropoxycarbonyl-amino)propionic acid:
A solution of 19.8 g of 2,7-di(bromomethyl)fluorene, 16.3 g of diethyl 2-(2,2-dimethylpropoxycarbonyl-amino)malonate and 15.6 g of potassium carbonate in 300 ml of acetonitrile is stirred for 4 hours at 90°
and for 16 hours at room temperature. After filtration and removal of the solvent, the crude product is chromatographed on silica gel (petroleum ether/dichloromethane 4:1). 5.1 g of diethyl 2-(7-bromomethyl-9H-fluoren-2-ylmethyl)-2-(2,2-di methylpropoxycarbonylamino)malonate ("AB") are obtained, Rf 0.45.
A solution of 5.1 g of "AB" and 0.8 g of sodium cyanide in 30 ml of DMF is stirred for 1 hour at 90°. After customary working up, 4.1 g of diethyl 2-(7-cyano-methyl-9H-fluoren-2-ylmethyl)-2-(2,2-dimethylpropoxy-carbonylamino)malonate ("AC") are obtained, Rf 0.18 (petroleum ether/ethyl acetate 4:1).
' CA 02380981 2002-02-05 A solution of 4.1 g of "AC" in 50 ml of methanol and 4.6 ml of glacial acetic acid is treated with 1.05 g of cobalt(II) chloride. 3.06 g of sodium borohydride is [sic] added with stirring and cooling and the mixture is subsequently stirred for 16 hours. It is worked up in the customary manner, chromatographed on silica gel (ethyl acetate/methanol 4:1) and 2.0 g of diethyl 2-(7-aminoethyl-9H-fluoren-2-ylmethyl)-2-(2,2-dimethyl propoxycarbonylamino)malonate ("AD") are obtained, Rf 0.14 (methanol).
A solution of 0.6 g of "AD", 1 g of 2-(3,5-dimethyl-pyrazolyl)-4,5-dihydroimidazole and 1 ml of triethyl-amine in 30 ml of DMF is stirred for 16 hours at 100° .
After removal of the solvent and purification by means of HPLC, 220 mg of diethyl 2-(7-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethyl]-9H-fluoren-2-ylmethyl}-2-(2,2-dimethylpropoxycarbonylamino)malonate ("AE") are obtained, Rf 0.69 (ethyl acetate/methanol 1:1) ~N O O
r~
N~ I ~ ~ N
O O .. ,.
O O AE
A solution of 0.22 g of "AE" and 50 mg of potassium hydroxide in 20 ml of ethylene glycol monoethyl ether is stirred for 4 days at room temperature. After removal of the solvent, the residue is dissolved in 20 ml of 1N HCl and 5 ml of acetonitrile and stirred for 2 days at 100°. After removal of the solvent, the residue is purified by means of HPLC. 100 mg of 3-{7-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethyl]-9H-fluoren-2-yl]-2-(2,2-dimethylpropoxycarbonylamino)-propionic acid are obtained.
~
~_N ~
N~ J ~ ~ N
H H \ O
--O
OH O
ES/MS 479.3.
The compounds below are obtained analogously 3-{7-[2-benzimidazol-2-ylamino)ethyl]-9H-fluoren-2-yl}-2-(2,2-dimethylpropoxycarbonylamino)propionic acid, EM/MS 527;
3-{7-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethyl]-9H-fluoren-2-yl}-2-butylsulfonamidopropionic acid, 3-{7-[2-(benzimidazol-2-ylamino)ethyl]-9H-fluoren-2-yl}-2-butylsulfonamidopropionic acid.
The following examples relate to pharmaceutical preparations:
Example A: Injection vials A solution of 100 g of an active compound of the formula I 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 an active compound of the formula I 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 an active compound of the formula NaH2P04 ~ 2 H20, 28.48 of I, 9.38 g of g Na2HP04 ~ 12 H20 and 0.1 g in of benzalkonium chloride 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 an be used in the form of c eye drops.
Example D: Ointment 500 mg of an active compound of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
Example E: Tablets A mixture of 1 kg of an active compound of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed 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 colorant.
Example G: Capsules 2 kg of an active compound of the formula I 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 an active compound of the formula I 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.
Exaa:ple I: Inhalation spray 14 g of an active compound of the formula I 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.
R3-(CH2)n R' I
(CHZ)m _0 in which R1 i s OR' , NHR~ or NA" z , Rz i s H, CO-R~ , CO-OR' , CONHR~ , CONA" z or SOzR~ , R4, RS in each case independently of one another are H, Hal, NOz, NHR~, NA"z, OR', -CO-R', S03R~, SOzR~
or SR' , R3 i s NHz , -C ( =NH ) -NHz , -NH-C ( =NH ) -NHz or -C ( =0 ) -N=C ( NHz ) 2 , ~Ny H N ' N -=-C
which is unsubstituted or monosubstituted by -COA, -COOA, -OH or by a conventional amino protective group, or R6-NH-, R6 is a mono- or binuclear heterocycle having 1 to 4 N, 0 and/or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A" , -CO-A' , OA' , CN, COOA' , CONHz, NOz, =NH or =0, v t _ _ R' is H, A, Ar or aralk, A is alkyl having 1-15 C atoms or cycloalkyl having 3-15 C atoms, which is unsubstituted or mono-, di- or trisubstituted by Ra and in which one, two or three methylene groups can be replaced by N, O and/or S, R8 is Hal, N02, NHA', NA"2, OA', phenoxy, CO-A', S03A' , CN, NHCOA' , CODA' , CONA' 2 or S02A' , A' is H or alkyl having 1-6 C atoms, A" is alkyl having 1-6 C atoms, Ar is a mono- or binuclear aromatic ring system having 0, 1, 2, 3 or 4 N, 0 and/or S atoms, which is unsubstituted or mono-, di- or trisubstituted by alkyl having 1-6 C atoms and/or R8, aralk is aralkylene having 7-14 C atoms, which is unsubstituted or mono-, di- or trisubstituted by Re and in which one, two or three methylene groups can be replaced by N, 0 and/or S, Hal is F, C1, Br or I, m, n in each case independently of one another are 0, 1, 2, 3 or 4, and their physiologically acceptable salts and solvates.
Other vitronectin antagonists are disclosed in WO 97/24124. Bicyclic fibrinogen antagonists are described, for example, in WO 96/18602.
_ 3 _ 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 and solvates have very valuable pharmacological properties, together with good tolerability. They act especially as integrin inhibitors, in particular inhibiting the interactions of the oc~, integrin receptors with ligands. The compounds exhibit particular activity in the case of the integrins ot"(33 and oc~,(35. The compounds are very particularly active as adhesion receptor antagonists for the oc~,(33 receptor. This action can be demonstrated, for example, by the method which is described in J.W.
Smith et al., in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).
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 oc"(33.
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 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~,~i3 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 interactin 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 mediates 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 binding of fibrinogen, fibronectin and of the [lacuna] 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 methoxy which is given in EP-A1-0 381 033.
The platelet aggregation-inhibiting action an be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962).
The invention accordingly relates to the compounds of the formula I and their physiologically acceptable salts and solvates as medicament.
The invention furthermore relates to said medicaments as inhibitors for the control of disorders which are based on an expression and pathological function of oc"~i3 and oc"(35 integrin receptors. The invention also relates to medicaments as GPIIb/IIIa antagonists for the control of thromboses, cardiac infarct, coronary heart diseases and arteriosclerosis, and the medicaments as oc" integrin inhibitors for the control of pathologically angiogenic diseases, thromboses, cardiac infarcts, coronary heart diseases, arteriosclerosis, tumours, osteoporosis and rheumatoid arthritis.
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, patho-. CA 02380981 2002-02-05 ' _ logically 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 angio-plasty, 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 demon-strated by the process described by P. Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988).
The invention further relates to a process for the preparation of compounds of the formula I according to Claim 1 and their salts and solvates, 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 R1, RZ and/or R3 is converted into another radical R1, R2 and/or R3, 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.
The invention furthermore relates to a process for the preparation of compounds of the formula I according to Claim 1 in which R1 is OH and R2, R3, R4, R5, m and n have the meanings indicated in Claim 1, and their salts and solvates, characterized in that a compound of the formula II
R3-(CH2)" -~ 1 R~
R~ II
R4 ~CH2)m ~O
O
R~
in which R1 is 0-alkyl having 1-6 C atoms and R2, R3, R4, R5, m and n have the meanings indicated in Claim 1, is hydrolysed and then decarboxylated.
The compounds of the formula I have at least one 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.
Solvates of the compounds are also included in the compounds according to the invention. These are under-stood as meaning addition compounds with, for example, . CA 02380981 2002-02-05 -water (hydrates) or alcohols such as methanol or ethanol.
The abbreviations mentioned above and below stand for:
Ac acetyl BOC tert-butoxycarbonyl CBZ or Z benzyloxycarbonyl DCCI dicyclohexylcarbodiimide DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DMF dimethylformamide DOPA (3,4-dihydroxyphenyl)alanine DPFN 3,5-dimethylpyrazole-1-formamidinium nitrate DMAP dimethylaminopyridine EDCI N-ethyl-N,N'-(dimethylaminopropyl)carbo-diimide Et ethyl Fmoc 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole Me methyl MTB ether methyl tert-butyl ether Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl HONSu N-hydroxysuccinimide Np neopentyl OBn benzyl ester OBut tert-butyl ester Oct octanoyl OMe methyl ester OEt ethyl ester Orn ornithine POA phenoxyacetyl TBTU 0-(benzotriazol-1-yl)-N,N,N,N-tetramethyl-uronium tetrafluoroborate TFA trifluoroacetic acid pTSS salt para-toluenesulfonic acid salt Trt trityl (triphenylmethyl) Z or CBZ benzyloxycarbonyl.
- g _ It applies to the whole invention that all radicals which occur a number of times, can be identical or different, i.e. are independent of one another.
Preferred compounds of the formula I are those in which the radical -(CHZ)n-R3 substitutes the 2-position and the radical -(CH2)m-CH(NHRZ)-COR1 the 7-position of the fluorene ring system.
Alkyl 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, and also, for example, trifluoromethyl or pentafluoroethyl.
A' is preferably H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.
A" is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl or 3-menthyl.
Alkylene is preferably methylene, ethylene, propylene, butylene, pentylene, preferably hexylene, heptylene, octylene, nonylene or decylene. Aralk is aralkylene and is preferably alkylenephenyl and is, for example, preferably benzyl or phenethyl.
A is very particularly preferably methyl, ethyl, propyl, isopropyl, butyl or tert-butyl.
v CO-A' is alkanoyl or cycloalkanoyl and is preferably formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl or octadecanoyl.
Preferred substituents RB for alkyl, Ar, cycloalkyl and aralk are preferably, for example, Hal, NO2, NH2, NHA" , such as methylamino, NA"a., such as, for example, dimethylamino, methoxy, phenoxy, acyl, such as, for example, formyl or acetyl, CN, NHCOA', such as, for example, acetamido, COOA', such as, for example, COOH
or methoxycarbonyl, CONA'2 or SOzA', in particular, for example, F, C1, hydroxyl, methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, methyl-sulfonyl or phenylsulfonyl.
In the radicals alkyl, alkylene and cycloalkyl, one, two or three methylene groups can in each case be replaced by N, 0 and/or S.
Ar-Co is aroyl and is preferably benzoyl or naphthoyl.
Ar 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, 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 ' - 11 -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, naphthyl, 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, benzo thiadiazol-5-yl or benzoxadiazol-5-yl.
Ar is further preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, particularly preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3-or 4-4-H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-' - 12 -2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.
R6 is a mono- or binuclear heterocycle, preferably 2-or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, particularly preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxa-diazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4-H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5- 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzo-pyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisooxazolyl, 2-, 4-, 5-, 6- or 7-benzo-thiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-Benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-iso-quinolyl, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.
The heterocyclic radicals can also be partially or completely hydrogenated.
R5 can thus, for example, also be 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-' - 13 -tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetra-hydro-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.
The heterocyclic rings mentioned can also be mono-, di-or trisubstituted by Hal, A, -CO-A, OH, CN, COOH, CODA, CONH2, N02, =NH or =0.
R6 is very particularly preferably 1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-2-yl, 5-oxo-4,5-dihydro-1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazol-2-yl, 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidin-4-on-5-yl, 1-alkyl-1,5-dihydroimidazol-4-on-2-yl, pyridin-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydro-pyrimidin-2-yl.
R1 is in particular, for example, hydroxyl, methoxy, ethoxy, NH2, NHMe, NHEt, NMe2 or NEt2.
R1 is very particularly preferably OH or OEt.
R2 is preferably, for example, H, acetyl, propionyl, aminocarbonyl, N,N-dimethylaminocarbonyl, alkoxy-carbonyl such as, for example, pentyloxycarbonyl, alkylsulfonyl such as, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, isobutyl-sulfonyl, 2,2-dimethylpropylsulfonyl, phenylsulfonyl or benzylsulfonyl.
R2 is very particularly preferably 2,2-dimethylpropoxy-carbonyl or butylsulfonyl.
R3 is preferably, for example, H2N-C (=NH) , H2N (C=NH) -NH, 1H-imidazol-2-ylamino, 4,5-dihydro-1H-imidazol-2-yl-amino, 5-oxo-4,5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2-ylamino, 2H-pyrazol-2-ylamino, 2-iminoimidazolidin-4-on-5-ylamino, 1-methyl-1,5 dihydroimidazol-4-on-2-ylamino, pyridin-2-ylamino, pyrimidin-2-ylamino or 1,4,5,6-tetrahydropyrimidin 2-ylamino.
R4 and RS are very particularly preferably H.
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 Ih, 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 Ia) R1 is OH;
in Ib) R1 is OH and R2 i s CO-OR' or SOzR' ;
in Ic) R1 is OH, R2 i s CO-OR' or SOzR' and R3 i s HZN-C ( =NH ) , HZN- ( C=NH ) -NH, 1H-imidazol-2-ylamino, 4,5-dihydro-1H-imidazol-2-ylamino, 5-oxo-4,5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2-ylamino, 2H-pyrazol-2-ylamino, 2-iminoimidazolidin-4-on-5-ylamino, 1-methyl-1,5-dihydroimidazol-4-on-2-ylamino, pyridin-2-ylamino, pyrimidin-2-ylamino or 1,4,5,6-tetra-hydropyrimidin-2-ylamino;
in Id) m is 1;
in Ie) m is 1 and R1 is OH;
in If) R1 is OH, RZ is CO-OR' or SOZR' and m is 1;
in Ig) R1 is OH, R2 i s CO-OR' or S02R' and R' is alkyl having 1-6 C atoms and m is 1;
in Ih) R1 is OH, R2 i s CO-OR' or S02R' , R' is alkyl having 1-6 C atoms, R3 i s H2N-C ( =NH ) . H2N- ( C=NH ) -NH
, 1H-imidazol-2-ylamino, 4,5-dihydro-1H-imidazol-2-ylamino, 5-oxo-4,5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2-ylamino, 2H-pyrazol-2-ylamino, 2-iminoimidazolidin-4-on-5-ylamino, 1-methyl-1,5-dihydroimidazol-4-on-2-ylamino, pyridin-2-ylamino, pyrimidin-2-ylamino or 1,4,5,6-tetra-hydropyrimidin-2-ylamino;
R4 , RS i s H , m is 1 and n is 2,3 or 4;
and their physiologically acceptable salts and solvates.
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.
Preferred starting substances are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.
The amidino group can be liberated from its oxadiazole derivative, for example, by treating with hydrogen in the presence of a catalyst (e. g. Raney nickel).
Suitable solvents are those indicated below, in particular alcohols such as methanol or ethanol, organic acids such as acetic acid or propionic acid or mixtures thereof. 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° (room temperature) and 1-10 bar.
The introduction of the oxadiazole group is possible, for example, by reaction of the cyano compounds with hydroxylamine and reaction with phosgene, dialkyl a carbonate [sic], chloroformic acid esters, N,N'-carbonyldiimidazole or acetic anhydride.
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 acyl, 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 "acyl 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 alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl;
aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-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 is possible -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 approxi-mately 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 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 convert a radical R1, RZ
and/or R3 into another radical R1, Rz and/or R3.
In particular, a carboxylic acid ester can be converted into a carboxylic acid.
Thus it is possible to hydrolyse an ester of the formula I. Expediently, this is carried out by solvolysis or hydrogenolysis, as indicated above, e.g.
using 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 R3 is H2N-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
(R3 - -C (=NH) -NHZ) , ammonia can be added to a nitrile of the formula I (R3 - CN). The addition is preferably carried out in a number of stages by a) converting the nitrile in a manner known per se using H2S 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, e.g. ethanol in the presence of HC1, into the corresponding imidoester and treating this with ammonia, or c) reacting the nitrile with lithium bis-(trimethylsilyl)amide and then hydrolysing the product.
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 physio-logically 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 hetero-cyclic 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 ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethane-sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and disulfonic acids, lauryl-sulfuric acid. Salts with physiologically unacceptable acids, e.g. 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 further relates to the use of the compounds of the formula I and/or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular in a non-chemical manner.
In this connection, they can be brought into a suitable dose form together with at least one solid, liquid and/or semiliquid vehicle or excipient and, if appropriate, in combination with one or more further active compounds.
~
The invention furthermore relates to pharmaceutical preparations comprising at least one medicament, comprising at least one compound of the formula I
and/or one of its physiologically acceptable salts, and also, if appropriate, vehicles and/or excipients and optionally other active compounds.
These preparations can be used 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 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, colorants, 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. C02 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.
The invention thus also relates to the use of compounds of the formula I and/or their physiologically acceptable salts and solvates for the production of a medicament for the control of disorders which are based on an expression and pathological function of oc"~i3 and oc"(35 integrin receptors .
The invention furthermore relates to the use of compounds of the formula I and/or their physiologically acceptable salts and solvates for the production of a medicament for the control of pathologically angiogenic diseases, thromboses, cardiac infarct, coronary heart diseases, arteriosclerosis, tumours, osteoporosis, rheumatoid arthritis, restenoses and diabetic retinopathy.
As a rule, the substances according to the invention can be administered here in analogy to other known, commercially available integrin inhibitors, but in particular in analogy to the compounds described in US-A-4 472 305, preferably in doses between approxi-mately 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 2 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. In the following examples, "customary working up" means:
~
if necessary, water is added, the pH is adjusted, if necessary, depending on the constitution of the final product, to a pH of between 2 and 10, the mixture is extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallization.
Mass spectrometry (MS): EI (electron impact ionization) M+
FAB (fast atom bombardment) (M+H)+
EM/MS (electron spray MS) (M + H)+
The Rf values indicated were determined by thin-layer chromatography using TLC films, silica gel 60 F25a.
Example 1 3-i7-[2-(4,5-Dihydro-ix-imidazol-2-ylamino)ethyl]-9X-fluoren-2-yl~-2-(2,2-dimethylpropoxycarbonyl-amino)propionic acid:
A solution of 19.8 g of 2,7-di(bromomethyl)fluorene, 16.3 g of diethyl 2-(2,2-dimethylpropoxycarbonyl-amino)malonate and 15.6 g of potassium carbonate in 300 ml of acetonitrile is stirred for 4 hours at 90°
and for 16 hours at room temperature. After filtration and removal of the solvent, the crude product is chromatographed on silica gel (petroleum ether/dichloromethane 4:1). 5.1 g of diethyl 2-(7-bromomethyl-9H-fluoren-2-ylmethyl)-2-(2,2-di methylpropoxycarbonylamino)malonate ("AB") are obtained, Rf 0.45.
A solution of 5.1 g of "AB" and 0.8 g of sodium cyanide in 30 ml of DMF is stirred for 1 hour at 90°. After customary working up, 4.1 g of diethyl 2-(7-cyano-methyl-9H-fluoren-2-ylmethyl)-2-(2,2-dimethylpropoxy-carbonylamino)malonate ("AC") are obtained, Rf 0.18 (petroleum ether/ethyl acetate 4:1).
' CA 02380981 2002-02-05 A solution of 4.1 g of "AC" in 50 ml of methanol and 4.6 ml of glacial acetic acid is treated with 1.05 g of cobalt(II) chloride. 3.06 g of sodium borohydride is [sic] added with stirring and cooling and the mixture is subsequently stirred for 16 hours. It is worked up in the customary manner, chromatographed on silica gel (ethyl acetate/methanol 4:1) and 2.0 g of diethyl 2-(7-aminoethyl-9H-fluoren-2-ylmethyl)-2-(2,2-dimethyl propoxycarbonylamino)malonate ("AD") are obtained, Rf 0.14 (methanol).
A solution of 0.6 g of "AD", 1 g of 2-(3,5-dimethyl-pyrazolyl)-4,5-dihydroimidazole and 1 ml of triethyl-amine in 30 ml of DMF is stirred for 16 hours at 100° .
After removal of the solvent and purification by means of HPLC, 220 mg of diethyl 2-(7-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethyl]-9H-fluoren-2-ylmethyl}-2-(2,2-dimethylpropoxycarbonylamino)malonate ("AE") are obtained, Rf 0.69 (ethyl acetate/methanol 1:1) ~N O O
r~
N~ I ~ ~ N
O O .. ,.
O O AE
A solution of 0.22 g of "AE" and 50 mg of potassium hydroxide in 20 ml of ethylene glycol monoethyl ether is stirred for 4 days at room temperature. After removal of the solvent, the residue is dissolved in 20 ml of 1N HCl and 5 ml of acetonitrile and stirred for 2 days at 100°. After removal of the solvent, the residue is purified by means of HPLC. 100 mg of 3-{7-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethyl]-9H-fluoren-2-yl]-2-(2,2-dimethylpropoxycarbonylamino)-propionic acid are obtained.
~
~_N ~
N~ J ~ ~ N
H H \ O
--O
OH O
ES/MS 479.3.
The compounds below are obtained analogously 3-{7-[2-benzimidazol-2-ylamino)ethyl]-9H-fluoren-2-yl}-2-(2,2-dimethylpropoxycarbonylamino)propionic acid, EM/MS 527;
3-{7-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethyl]-9H-fluoren-2-yl}-2-butylsulfonamidopropionic acid, 3-{7-[2-(benzimidazol-2-ylamino)ethyl]-9H-fluoren-2-yl}-2-butylsulfonamidopropionic acid.
The following examples relate to pharmaceutical preparations:
Example A: Injection vials A solution of 100 g of an active compound of the formula I 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 an active compound of the formula I 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 an active compound of the formula NaH2P04 ~ 2 H20, 28.48 of I, 9.38 g of g Na2HP04 ~ 12 H20 and 0.1 g in of benzalkonium chloride 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 an be used in the form of c eye drops.
Example D: Ointment 500 mg of an active compound of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
Example E: Tablets A mixture of 1 kg of an active compound of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed 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 colorant.
Example G: Capsules 2 kg of an active compound of the formula I 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 an active compound of the formula I 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.
Exaa:ple I: Inhalation spray 14 g of an active compound of the formula I 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 (12)
1. Compounds of the formula I
in which R1 is OR7, NHR7 or NA"2, R2 is H, CO-R7, CO-OR7, CONHR7, CONA"2 or SO2R7, R4, R5 in each case independently of one another are H, Hal, NO2, NHR7, NA"2, OR7, -CO-R7, SO3R7, SO2R7 or SR7, R3 is NH2, -C (=NH)-NH2 , -NH-C(=NH)-NH2 or -C(=0)-N=C(NH2)2, which is unsubstituted or mono-substituted by -COA, -COOA, -OH or by a conventional amino protective group, or R6-NH-, R6 is a mono- or binuclear heterocycle having 1 to 4 N, O and/or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A", -CO-A', OA', CN, COOA', CONH2, NO2, =NH or =O, R7 is H, A, Ar or aralk, A is alkyl having 1-15 C atoms or cycloalkyl having 3-15 C atoms, which is unsubstituted or mono-, di- or trisubstituted by R8 and in which one, two or three methylene groups can be replaced by N, O and/or S, R8 is Hal, NO2, NHA', NA"2, OA', phenoxy, CO-A', SO3A', CN, NHCOA', COOA', CONA'2 or SO2A', A' is H or alkyl having 1-6 C atoms, A" is alkyl having 1-6 C atoms, Ar is a mono- or binuclear aromatic ring system having 0, 1, 2, 3 or 4 N, O
and/or S atoms, which is unsubstituted or mono-, di- or trisubstituted by alkyl having 1-6 C atoms and/or R8, aralk is aralkylene having 7-14 C atoms, which is unsubstituted or mono-, di- or tri-substituted by R8 and in which one, two or three methylene groups can be replaced by N, O and/or S, Hal is F, Cl, Br or I, m, n in each case independently of one another are 0, 1, 2, 3 or 4, and their physiologically acceptable salts and solvates.
in which R1 is OR7, NHR7 or NA"2, R2 is H, CO-R7, CO-OR7, CONHR7, CONA"2 or SO2R7, R4, R5 in each case independently of one another are H, Hal, NO2, NHR7, NA"2, OR7, -CO-R7, SO3R7, SO2R7 or SR7, R3 is NH2, -C (=NH)-NH2 , -NH-C(=NH)-NH2 or -C(=0)-N=C(NH2)2, which is unsubstituted or mono-substituted by -COA, -COOA, -OH or by a conventional amino protective group, or R6-NH-, R6 is a mono- or binuclear heterocycle having 1 to 4 N, O and/or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A", -CO-A', OA', CN, COOA', CONH2, NO2, =NH or =O, R7 is H, A, Ar or aralk, A is alkyl having 1-15 C atoms or cycloalkyl having 3-15 C atoms, which is unsubstituted or mono-, di- or trisubstituted by R8 and in which one, two or three methylene groups can be replaced by N, O and/or S, R8 is Hal, NO2, NHA', NA"2, OA', phenoxy, CO-A', SO3A', CN, NHCOA', COOA', CONA'2 or SO2A', A' is H or alkyl having 1-6 C atoms, A" is alkyl having 1-6 C atoms, Ar is a mono- or binuclear aromatic ring system having 0, 1, 2, 3 or 4 N, O
and/or S atoms, which is unsubstituted or mono-, di- or trisubstituted by alkyl having 1-6 C atoms and/or R8, aralk is aralkylene having 7-14 C atoms, which is unsubstituted or mono-, di- or tri-substituted by R8 and in which one, two or three methylene groups can be replaced by N, O and/or S, Hal is F, Cl, Br or I, m, n in each case independently of one another are 0, 1, 2, 3 or 4, and their physiologically acceptable salts and solvates.
2. Enantiomers or diastereomers of the compounds of the formula I according to Claim 1.
3. Compounds of the formula I according to Claim 1 a) 3-{7-[2-(4,5-dihydro-1H-imidazol-2-ylamino)-ethyl]-9H-fluoren-2-yl}-2-(2,2-dimethyl-propoxycarbonylamino)propionic acid;
b) 3-{7-[2-(4,5-dihydro-1H-imidazol-2-ylamino)-ethyl]-9H-fluoren-2-yl}-2-butylsulfonamido propionic acid;
and their physiologically acceptable salts and solvates.
b) 3-{7-[2-(4,5-dihydro-1H-imidazol-2-ylamino)-ethyl]-9H-fluoren-2-yl}-2-butylsulfonamido propionic acid;
and their physiologically acceptable salts and solvates.
4. 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 R1, R2 and/or R3 is converted into another radical R1, R2 and/or R3, by, for example, i) converting an amino group into a guanidine 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.
5. Process for the preparation of compounds of the formula I according to Claim 1, in which R1 is OH
and R2, R3, R4, R5, m and n have the meanings indicated in Claim 1, and their salts and solvates, characterized in that a compound of the formula II
in which R1 is O-alkyl having 1-6 C atoms and R2, R3, R4, R5, m and n have the meanings indicated in Claim 1, is hydrolysed and then decarboxylated.
and R2, R3, R4, R5, m and n have the meanings indicated in Claim 1, and their salts and solvates, characterized in that a compound of the formula II
in which R1 is O-alkyl having 1-6 C atoms and R2, R3, R4, R5, m and n have the meanings indicated in Claim 1, is hydrolysed and then decarboxylated.
6. Compounds of the formula I according to Claims 1-2 and the compounds according to Claim 3, and their physiologically acceptable salts and solvates as medicaments.
7. Medicament according to Claim 6 as an inhibitor for the control of disorders which are based on expression and pathological function of .alpha.v.beta.3 and .alpha.v.beta.5 integrin receptors.
8. Medicament according to Claim 6 as GPIIb/IIIa antagonists for the control of thromboses, cardiac infarct, coronary heart disorders and arteriosclerosis.
9. Medicament according to Claim 7 as .alpha.v integrin inhibitors for the control of pathologically angiogenic diseases, thromboses, cardiac infarct, coronary heart diseases, arteriosclerosis, tumours, osteoporosis and rheumatoid arthritis.
10. Pharmaceutical preparation, comprising at least one medicament according to one of Claims 7 to 9 and, if appropriate, vehicles and/or excipients and, if appropriate, other active compounds.
11. Use of compounds according to Claims 1 to 3 and/or their physiologically acceptable salts and solvates for the production of a medicament for the control of disorders which are based on expression and pathological function of .alpha.v.beta.3 and .alpha.v.beta.5 integrin receptors.
12. Use of compounds according to Claims 1 to 3 and/or their physiologically acceptable salts and solvates for the production of a medicament for the control of pathologically angiogenic diseases, thromboses, cardiac infarct, coronary heart disorders, arteriosclerosis, tumours, osteoporosis, rheumatoid arthritis, restenoses and diabetic retinopathy.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19937394.9 | 1999-08-07 | ||
| DE19937394A DE19937394A1 (en) | 1999-08-07 | 1999-08-07 | Fluorene derivatives |
| PCT/EP2000/007153 WO2001010841A2 (en) | 1999-08-07 | 2000-07-26 | Fluorene derivatives as integrin inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2380981A1 true CA2380981A1 (en) | 2001-02-15 |
Family
ID=7917613
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| CA002380981A Abandoned CA2380981A1 (en) | 1999-08-07 | 2000-07-26 | Fluorene derivatives |
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| EP (1) | EP1208088A2 (en) |
| JP (1) | JP2003506439A (en) |
| KR (1) | KR20020012631A (en) |
| CN (1) | CN1368962A (en) |
| AR (1) | AR025042A1 (en) |
| AU (1) | AU6828600A (en) |
| BR (1) | BR0013083A (en) |
| CA (1) | CA2380981A1 (en) |
| CZ (1) | CZ2002298A3 (en) |
| DE (1) | DE19937394A1 (en) |
| HK (1) | HK1049006A1 (en) |
| HU (1) | HUP0202464A3 (en) |
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| NO (1) | NO20020592L (en) |
| PL (1) | PL353054A1 (en) |
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| US8574899B2 (en) | 2010-12-22 | 2013-11-05 | Vladimir B Serikov | Methods for augmentation collection of placental hematopoietic stem cells and uses thereof |
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| CA2058925A1 (en) * | 1989-06-22 | 1990-12-23 | Moshe Weitzberg | Pharmaceutical compositions and methods for treating inflammation |
| IL113196A0 (en) * | 1994-03-31 | 1995-06-29 | Bristol Myers Squibb Co | Imidazole derivatives and pharmaceutical compositions containing the same |
| WO1997036862A1 (en) * | 1996-03-29 | 1997-10-09 | G.D. Searle & Co. | META-SUBSTITUTED PHENYLENE DERIVATIVES AND THEIR USE AS ALPHAvBETA3 INTEGRIN ANTAGONISTS OR INHIBITORS |
| DE19654483A1 (en) * | 1996-06-28 | 1998-01-02 | Merck Patent Gmbh | Phenylalanine derivatives |
| CA2214931A1 (en) * | 1996-09-26 | 1998-03-26 | Henry Uhlman Bryant | Tetrahydrobenzo-a-fluorene compounds and method of use |
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1999
- 1999-08-07 DE DE19937394A patent/DE19937394A1/en not_active Withdrawn
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2000
- 2000-07-26 SK SK140-2002A patent/SK1402002A3/en unknown
- 2000-07-26 MX MXPA02001297A patent/MXPA02001297A/en not_active Application Discontinuation
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- 2000-07-26 CA CA002380981A patent/CA2380981A1/en not_active Abandoned
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- 2000-07-26 WO PCT/EP2000/007153 patent/WO2001010841A2/en not_active Application Discontinuation
- 2000-07-26 AU AU68286/00A patent/AU6828600A/en not_active Abandoned
- 2000-07-26 CZ CZ2002298A patent/CZ2002298A3/en unknown
- 2000-07-26 EP EP00956284A patent/EP1208088A2/en not_active Withdrawn
- 2000-07-26 HU HU0202464A patent/HUP0202464A3/en unknown
- 2000-07-26 BR BR0013083-4A patent/BR0013083A/en not_active Application Discontinuation
- 2000-07-26 CN CN00811476A patent/CN1368962A/en active Pending
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| WO2001010841A2 (en) | 2001-02-15 |
| SK1402002A3 (en) | 2002-06-04 |
| NO20020592L (en) | 2002-04-04 |
| DE19937394A1 (en) | 2001-02-08 |
| HUP0202464A3 (en) | 2003-02-28 |
| PL353054A1 (en) | 2003-10-06 |
| EP1208088A2 (en) | 2002-05-29 |
| KR20020012631A (en) | 2002-02-16 |
| AU6828600A (en) | 2001-03-05 |
| CZ2002298A3 (en) | 2002-04-17 |
| MXPA02001297A (en) | 2004-07-16 |
| JP2003506439A (en) | 2003-02-18 |
| NO20020592D0 (en) | 2002-02-06 |
| HUP0202464A2 (en) | 2002-12-28 |
| HK1049006A1 (en) | 2003-04-25 |
| AR025042A1 (en) | 2002-11-06 |
| BR0013083A (en) | 2002-04-23 |
| CN1368962A (en) | 2002-09-11 |
| ZA200201873B (en) | 2003-08-27 |
| WO2001010841A3 (en) | 2001-09-07 |
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