CA2259224A1 - Phenylalamine derivatives as integrin inhibitors - Google Patents

Phenylalamine derivatives as integrin inhibitors Download PDF

Info

Publication number
CA2259224A1
CA2259224A1 CA002259224A CA2259224A CA2259224A1 CA 2259224 A1 CA2259224 A1 CA 2259224A1 CA 002259224 A CA002259224 A CA 002259224A CA 2259224 A CA2259224 A CA 2259224A CA 2259224 A1 CA2259224 A1 CA 2259224A1
Authority
CA
Canada
Prior art keywords
phenyl
formula
compounds
tert
propionate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002259224A
Other languages
French (fr)
Inventor
Beate Diefenbach
Claus Fittschen
Simon Goodman
Joachim Marz
Peter Raddatz
Matthias Wiesner
Soheila Anzali
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE19654483A external-priority patent/DE19654483A1/en
Application filed by Individual filed Critical Individual
Publication of CA2259224A1 publication Critical patent/CA2259224A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/14—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with 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
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • 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
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Abstract

Compounds of formula (I) wherein X, Y, Z, R1, R2, R3 and R4 have the meaning stated in claim 1, with the proviso that at least one element chosen from the group X, Y, Z must be CH2, as well as their physiologically harmless salts, can be used as integrin inhibitors, particularly for prophylaxis and treatment of circulatory diseases, in case of thrombosis, heart infarct, coronary heart diseases, arteriosclerosis, osteoporosis, in pathological processes which are maintained or propagated by angiogenesis, and in tumor therapy.

Description

CA 022~9224 1998-12-24 f~f ~S
~' FILL'~ ''''; f'''''' '' ' ' 7 "''- ~ ~St ~o~J

Phenylalanine derivatives The invention relates to compounds of the formula I

R1 ~ X Z ~ ~2 in which X is absent, or is alkylene, arylene, cyclo-alkyLene having 4-8 carbon atoms, or hetero-cycloalkylene having from 1 to 3 N, O and/or S atoms which is unsubstituted or substituted once, twice or three times by A, oxo and/or R4, Y and Z are, in each case, independently of each other, absent, or are alkylene, O, S, NH, C(=O), CONH, NHCO, C(=S), SO2NH, CA=CA' or -C_C-, 20 Rl is E~2N-C(=NH) or H2N(C=NH)-NH, where the prima.ry amino groups can also be provided with conventional amino protecting groups or can be substituted once, twice or three times by A, Ar or R5, R2 is A, Ar or aralkylene, R3 is H or A, 30 R4 is H, Hal, OA, NHA, NAA', CN, NO2, SA, SOA, SO2A, SO2Ar or SO3H, CA 022~9224 1998-12-24 Rs is ~lkanoyl or cycloalkanoyl having 1-18 carbon atoms, in which one, two or three methylene groups can be replaced with N, O
and/or S, Ar-C()- or Ar-alkylene-CO-, A and A' are, in each case, independently of each other, H, or alkyl or cycloalkyl having 1-15 carbon atoms which is unsubstituted or sub-stituted once, twice or three times by R4 and in which one, two or three methylene groups can be replaced with N, O and/or S, Ar is a mononuclear or binuclear aromatic ring system having 0, 1, 2, 3 or 4 N, O and/or S
atoms which is unsubstituted or substituted once, twice or three times by A and/or R4, Hal is F, Cl, Br or I, with the proviso that at least one element selected from the group X, Y and Z must be CH2, and the physiologically harmless salts thereof.
Similar compounds are known, for example, from EP 0 478 363, EP 0 478 328, WO 94/12181 and WO 95/32710.

The underlying object of the invention was to discover novel compounds possessing valuable properties, in par-ticular such compounds as can be used to prepare pharmaceuticals.

It has been found that the compounds of the formula I, and their salt~, possess very valuable pharmacological properties whi:Le being well tolerated. In particular, they act as integrin inhibitors, in connection with which they inhibit, in particular, the interactions of , ' CA 022~9224 1998-12-24 , the av integrin receptors with ligands. The compounds exhibit parti~ular activity in the case of the integrins av~3 and av~s~ The compounds are very particularly active as adhesion receptor antagonists for the vitronectin receptor av~3. This effect can be demonstrated, for example, using the method which is described by J.W. Smith et al. in J. Biol. Chem. 265, 11008-11013 ancl 12267-12271 (1990).

The ability oE some representative compounds of the formula I to inhibit the binding of vitronectin to receptors was proven experimentally. The pharmaco-logical test data are summarized in Table I.

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 very wide range of phenomena and syndromes, especially in relation to the vitronectin receptor av~3.
The dependence of the development of angiogenesis on the interaction between vascular integrins and extra-cellular matrix proteins is described by P.C. Brooks, R.A. Clark an~ D.A. Cheresh in Science 264 569-71 25 (1994).

The possibility of using a cyclic peptide to inhibit this interact:ion and thereby institute apoptosis (programmed cell death) of angiogenic vascular cells is reported 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 demonstration that the novel compounds also prevent adherence of living cells to the corres-ponding matrix proteins, and accordingly also prevent adherence of tumour cells to matrix proteins, can be provided in a cell adhesion test, which is carried out CA 022~9224 1998-12-24 in analogy wit:h the method of F. Mitjans et al., J.
Cell Science 108, 2825-2838 (1995).

In J. Clin. Invest. _, 1815-1822 (1995), P.C. Brooks et al. describ~ av~3 antagonists for controlling cancer and for treating tumour-induced angiogenic diseases.
The novel compounds of the formula I can therefore be employed as pharmaceutical active compounds, in par-ticular for treating tumour diseases, osteoporoses and osteolytic d seases, and also for suppressing angiogenesis.

Compounds of the formula I which block the interaction of integrin receptors and ligands, for example of fibrinogen to (sic) the fibrinogen receptor (glycoprotein IIb/IIIa), prevent, as GPIIb/IIIa antagonists, the dissemination of tumour cells by means of metastasis. This is substantiated by the following observations:
Tumour cells are spread into the vascular system from a local tumour by the formation of microaggregates (microthrombi) as a result of interaction of the tumour cells with b]ood platelets. The tumour cells are shielded by being protected in the microaggregate and are not recognized by the cells of the immune system.
The microaggregates can become attached to vessel walls, thereby facilitating further penetration of tumour cells into the tissue. Since the formation of the microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on activated blood platelets, GPIIa/IIIb anl:agonists can be regarded as being effective metastasis inhibitors.

In addition to inhibiting the binding of fibrinogen, fibronectin and the Willebrand factor to the fibrinogen receptor of the blood platelets, compounds of the formula I also inhibit the binding of other adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of different .. . . ..

CA 022~9224 1998-12-24 cell types. They prevent, in particular, the develop-ment of blood platelet thrombi and can therefore be employed for treating thromboses, stroke, cardiac infarction, inflammations and arteriosclerosis.

The properties of the compounds can also be demon-strated using methods which are described in EP-A1-0 462 960. The inhlbition of the binding of fibrinogen to the fibrinogen receptor can be demon-10 strated by the method which is given inEP-A1-0 381 033.
The experimental (sic) fact that the novel compounds, too, block inhibition of the binding of fibrinogen to the corresponding receptors was demonstrated 15 experimentally in the case of some representative compounds of the formula I. The pharmacological test data are summarized in Table II.

The thrombocyte aggregation-inhibiting effect can be 20 demonstrated ir vitro using the method of Born (Nature 4832, 927-929, 1962).

Accordingly, the invention relates to compounds of the formula I ac:cording to Claim 1, and/or their 25 physiologically harmless salts, for preparing a pharmaceutical for use as integrin inhibitors [sic].
The invention relates, in particular, to compounds of the formula I according to Claim 1, and/or their harmless salts, in which R2 has the meaning of camphor-30 10-yl, for preparing a pharmaceutical for controlling pathologically angiogenic diseases, tumours, osteoporosis, inflammations and infections.

The compounds of the formula I may be employed, as 35 pharmaceutical active compounds in humans and veterinary medicine, for the prophylaxis and/or therapy of thrombosis, myocardial infarction, arteriosclerosis, inflammations, stroke, angina pectoris, tumour dis-eases, osteolytic diseases such as osteoporosis, patho-, CA 022~9224 1998-12-24 logically angiogenic diseases such as inflammations, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid ,~rthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, viral infection, bacterial infection, fungal infection, in acute renal failure and in wound healing, to support the healing processes.
The compounds of the formula I may be employed as anti-microbial substances in operations where biomaterials, implants, catheters or cardiac pacemakers are used. In this context, lhey have an antiseptic effect. The anti-microbial activity can be demonstrated by the methoddescribed by F. Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988).

The invention furthermore relates to a process for preparing compounds of the formula I according to Claim 1, and also their salts, which process is characterized in that a) a compound of the formula I is liberated from one of its functional derivatives by treating the derivative with a solvolysing or hydrogenolysing agent, or b) a compouncl of the formula II

O i J ~ O~ 11 in which R1, R3, R4, X, Y and Z have the meanings given in Claim 1, is reacted with a compound of the formula III

CA 022~9224 1998-12-24 in which R2 has the meaning given in Claim 1 and L is C1, Br, I, OH or an OH group which has been esterified to make it capable of reacting, or - c) an ester of the formula I is hydrolysed, or d) a radica] R1 and/or R3 is/are converted into another radical Rl and/or R3, and/or e) a basic or acidic compound of the formula I is converted into one of its salts by treating it with an ac:id or base.

The compounds of the formula I possess at least one chiral centre and can therefore occur in several stereoisomeric forms. All these forms (e.g. D and L
forms) and their mixtures (e.g. the DL forms) are included in formula I.
So-called prodrug derivatives, i.e. compounds of the formula I which are modified with, for example, alkyl or acyl groups sugars or oligopeptides, and which are rapidly cleaved in the organism to form the active novel compouncls, are also included in the novel compounds.

The abbreviations which are listed above and in that which follows have the following meanings:

CA 022~9224 1998-12-24 ,, .

Ac acety:L
BOC tert-butoxycarbonyl CBZ or Z benzyloxycarbonyl DCCl dicyc:lohexylcarbodiimide 5 DMF dimethylformamide EDCl N-ethyl-N,N'-(dimethylaminopropyl)carbodiimide Et ethyl Fmoc 9-fluorenylmethoxycarbonyl HOBt 1-hyd:roxybenzotriazole 10 Me methyl Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl HONSu N-hyd:roxysuccinimide OBut tert-butyl ester Oct octanoyl 15 OMe methy:L ester OEt ethyl ester POA phenoxyacetyl TFA trifluoroacetic acid Trt trity:L(triphenylmethyl).
For the whole invention, it holds that all the radicals which occur several times, such as A and A', can be identical or different, i.e. are independent of each other.
In the above formulae, alkyl is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, heptyl, octyl, nonyl or decyl.

Cycloalkyl is preferably cyclopropyl, cyclobutyl, cylopentyl [sic], cyclohexyl, cycloheptyl or 3-menthyl. Cycloalkyl is, in particular, the radical of a bicyclic terpene; the camphor-10-yl radical is very particularly preferred.

CA 022~9224 1998-12-24 Alkylene is preferably methylene, ethylene, propylene, butylene or pentylene, and also hexylene, heptylene, ocytylene [sic], nonylene or decylene. Aralkylene is preferably aLkylenephenyl and is, for example, preferably benzyl or phenethyl.

Cycloalkylene is preferably cyclopropylene, 1,2- or 1,3-cyclobutylene, 1,2- or 1,3-cyclopentylene or 1,2-, 1,3- or 1,4-cyclohexylene, and also 1,2-, 1,3- or 1,4-cycloheptylene Alkanoyl is preferably formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, dec:anoyl, undecanoyl, dodecanoyl, tri-decanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl or octadecanoyl.

Preferred substltuents for alkyl, alkylene, cycloalkyl, cycloalkylene, alkanoyl and cycloalkanoyl are, for example, Hal, OA, NHA, NAA', CN, NO2, SA, SOA, SO2A, SO2Ar and/or SO3H, in particular, for example, F, Cl, hydroxyl, met:hoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, methylsulfonyl or phenyl-sulfonyl.

Preferred subctituents for Ar and arylene are, forexample, A and/or Hal, OA, NHA, NAA', CN, NO2, SA, SOA, SO2A, SO2Ar and/or SO3H, in particular, for example, F, Cl, hydroxyl, methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, methylsulfonyl or phenyl-sulfonyl.

In the radicals alkyl, alkylene, cycloalkyl, cyclo-alkylene, alkanoyl and cycloalkanoyl, one, two or threemethylene groups can in each case be replaced with N, O
and/or S.

Ar-CO is aroyl and is preferably benzoyl or naphthoyl.

CA 022~9224 1998-12-24 .

Ar is unsubsti_uted, preferably - as indicated - mono-substituted phenyl, preferably and specifically 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 or o-, m-or p-nitrophenyl, and also, preferably, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3-methyl-, 2-chloro-4-methyl-, 2-chloro-5-methyl-, 2-chloro-6-methyl-, 2-methyl-3-chloro-, 2-methyl-4-chloro-, 2-methyl-5-chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl.- or 3-methyl-4-chlorophenyl, 2-bromo-3-methyl-, 2-bromo-4-methyl-, 2-bromo-5-methyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-, 2-methyl-4-bromo-, 2-methyl-5-bromo-, 2-methyl-6-bromo-, 3-bromo-4-methyl-, 3-bromo-5-methyl- or 3-methyl-4-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-tri-tert-butylphenyl, 2,5-dimethylphenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro-3,5-dimethylphenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 2,4-dichloro-5-methylphenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-meth.oxyphenyl, 2-methoxy-5-methylphenyl, 2,4,6-triisopropylphenyl, naphthyl, 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, benzothiadiazol-5-yl or benzoxadiazol-5-yl.
In addition, Ar is 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 CA 022~9224 1998-12-24 .

S-thiazolyl, :3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl or :7-, 4-, 5- or 6-pyrimidinyl, and also, preferably, 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-tri-azol-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 [sic], 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-benz-imidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benz-isoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazo]yl, 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-cinnolinyl or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.
Arylene has the same meanings as given for Ar, with the proviso that a further bond of the aromatic system is linked to the nearest bonding neighbour.

Heterocycloalkylene is preferably 1,2-, 2,3- or 1,3-pyrrolidinyl, 1,2-, 2,4-, 4,5- or 1,5-imidazolidinyl, 1,2-, 2,3- or 1,3-pyrazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-oxazolidin~l, 1,2-, 2,3-, 3,4- or 1,4-isoxazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-thiazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-isothiazolidinyl, 1,2-, 2,3-, 3,4- or 1,4-pi.peridinyl, 1,4- or 1,2-piperazinyl, and also, preferab;y, 1,2,3-tetrahydrotriazol-1,2- or -1,4-yl, 1,2,4-tetrahydrotriazol-1,2- or -3,5-yl, 1,2- or 2,5-tetrahydrot:etrazolyl, 1,2,3-tetrahydrooxadiazol-2,3-, -3,4-, -4,5- or -1,5-yl, 1,2,4-tetrahydrooxadi.azol-2,3-, -3,4- or -4,5-yl, 1,3,4-tetrahydrothiacliazol-2,3-, -3,4-, -4,5- or -1,5-yl, 1,2,4-tetrahydrothiadiazol-2,3-, -3,4-, -4,5- or -1,5-yl, 1,2,3-thiadiazol-2,3-, -3,4-, -4,5- or -1,5-yl, CA 022~9224 1998-12-24 2,3- or 3,4-morpholinyl or 2,3-, 3,4- or 2,4-thiomorpholinyl..

Amino protecting group is preferably acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ
("carbobenzoxy'), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl.
Correspondingl~, the invention relates, in particular, to those compounds of the formula I in which at least one of the said radicals has one of the abovementioned preferred meanings. Some preferred groups of compounds can be expressed by the following part formulae Ia to Ie, which cor.form to formula I and in which the radicals which are not designated more precisely have the meaning given in formula I, but in which in a) R is H2N-C(=NH) X is alkylene having 1-6 carbon atoms, y is O, R2 is A, R3 and R4 are H;

in b) R1 is H2N-(C=NH)-NH, X alkylene having 1-6 carbon atoms, Y 0, R2 A, R3 and R4 are H;

in c) X is alkylene having 1-6 carbon atoms, Y is absent, R3 and E~4 are H, and R2 is aryl;

in d) R is H2N-(C=NH)-NH, X is alkylene having 1-6 carbon atoms, Y is CONH, CA 022~9224 1998-12-24 , R3 and R4 are H, and R2 is A;

in e) X is alkylene having 1-6 carbon atoms, Y is O or CO-NH, Z is absent, R2 is camphor-10-yl, R3 is H or A, and R4 is H.

The compounds of the formula I, and also the starting compounds for l:heir preparation, are otherwise prepared in accordance with methods known per se and as described in the literature (for example in the standard work, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart;), using reaction conditions whi-h are known and suitable for the said reactions. In this context, use can also be made of variants which are known per se but which are not mentioned in detail here.

If desired, the starting compounds can also be formed lS in situ, so that they are not isolated from the reaction mixture but immediately subjected to further reaction to form 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 means of treating the latter with a solvolysing or hydrogenolysing agent.

Starting compounds which are preferred for the solvo-lysis or hydrogenolysis are those which conform to theformula I except that, instead of one or more free amino groups and/or hydroxyl groups, they contain corresponding, protected amino groups and/or hydroxyl groups, preferably those starting compounds which carry an amino protecting group instead of an H atom which is .... . . . . . . . .

CA 022~9224 1998-12-24 , linked to a N atom, in particular those starting com-pounds which c:arry an R'-N group, in which R' is an amino protecting group, instead of an HN group, and/or those starting compounds which carry a hydroxyl pro-tecting group instead of the H atom of a hydroxylgroup, for example those starting compounds which conform to the formula I except that they carry a -COOR" group, in which R" is a hydroxyl protecting group, instead of a -COOH group.
Several - identical or different - protected amino groups and/or hydroxyl groups can also be present in the molecule of the starting compound. If the protect-ing groups which are present differ from each other, they can in many cases be eliminated selectively.

The expression "amino protecting group" is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions but which can readily be removed after the desired chemical reaction has been carried out at other sites in the molecule. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are, in particular, typical of such groups. Since the amino protecting groups are removed after the desired reaction (or sequence of reactions), their nature and size is otherwise not criticali however, those having 1-20, in particular 1-8, carbon atoms are preferred. In connection with the present process, the expression "acyl group" is to be understood in the widest sense.
It encompasses acyl groups which are derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and also, in par-ticular, alkoxycarbonyl, aryloxycarbonyl and, especially, ar-Llkoxycarbonyl groups. Examples of acyl groups of this nature are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenyl-acetyl; aroyl, such as benzoyl or toluyl;
aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as . _ _ CA 022~9224 1998-12-24 methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, BOC and 2-iodoethoxycarbonyl; aralkyl-oxycarbonyl, such as CBZ ("carbobenzoxy"), 4-methoxy-benzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr. Amino protecting groups which are preferred are BOC and Mtr ancl also CBZ, Fmoc, benzyl and acetyl.

Depending on the protecting group which is used, the amino protecting group is eliminated, for example, with strong acids, expediently with TFA or perchloric acid, or else with other strong inorganic acids, such as hydrochloric acid or sulfuric acid, or strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid. It is possible, but not always necessary, for an additional inert solvent to be present. Suitable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, or halogenated hydrocarbons, such as dichloromethane, and also alcohols, such as methanol, ethanol or isopropanol, and also water.
Mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without the addition of any further solvent while perchloric acid is used in the form of a mixture of acetic acid and 70%
perchloric acid in a ratio of 9:1. Expediently, the reaction temperatures for the cleavage are between about 0 and about 50~, preferably between 15 and 30~
(room temperature).

The BOC, OBut and Mtr groups can be eliminated, for example, preferably with TFA in dichloromethane or with from about 3 to 5N HCl in dioxane, at 15-30~, while the FMOC group can be eliminated with an approximately 5 to 50% solution of dimethylamine, diethylamine or piperi-dine in DMF at 15-30~.

CA 022~9224 1998-12-24 Protecting groups which can be removed by hydrogeno-lysis (for example CBZ or benzyl) can be eliminated, for example, by treatment with hydrogen in the presence of a catalyst (for example a precious metal catalyst such as palladium, expediently on a support such as charcoal). The abovementioned solvents, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF, are suitable as solvents in this context. As a rule, the hydrogenolysis is carried out at temperatures of between about 0 and 100~ and under pressures of between about 1 and 200 bar, preferably at 20-30~ and under 1-10 bar. The CBZ group is hydrogenolysed satisfactorily on, for example, 5 to 10%
Pd/C in methanol or with ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30~.

Compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III. As a rule, the starting compounds of the formula II and III are novel. However, they can be prepared us:Lng methods which are known per se.

In the compounds of the formula III, L is preferably Cl, Br, I or an OH group which has been modified so as to make it capable of reaction, such as alkyl-sulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolyl-sulfonyloxy).
As a rule, the compounds of the formula II are reacted in an inert solvent and in the presence of an acid-binding agent, preferably an organic base such as tri-ethylamine, dimethylaniline, pyridine or quinoline.
It can also be advantageous to add an alkali metal or alkaline earth metal hydroxide, carbonate or bicar-bonate or another salt of a weak acid of (sic) alkali metals or alkaline earth metals, preferably potassium, sodium, calciun- or caesium.

CA 022~9224 1998-12-24 Depending on the conditions which are used, the reaction time is between a few minutes and 14 days, while the reac:tion temperature is between about -30~
and 140~, norm~lly between -10~ and 90~, in particular between about ()~ and about 70~.

Examples of suitable inert solvents are 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-butano.l; ethers, such as diethyl ether, diiso-propyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl ether or ethylene glyco:L monoethyl ether (methyl glycol or ethyl glycol), or et:hylene glycol dimethyl ether (diglyme);
ketones, such as acetone or butanone; amides, such as acetamide, d.imethylacetamide 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 a.s ethyl acetate, or water, or mixtures of the said solvents.

It is furthermore possible to hydrolyse an ester of the formula I. Th.is is expediently effected by means of solvolysis or hydrogenolysis, as indicated above, for example using NaOH or KOH in dioxane/water at temperatures of between 0 and 60~C, preferably of between 10 and 40~C.

It is also po.ssible to convert a radical R1 and/or R3 into another radical R1 and/or R3.
In particular, a carboxylic acid can be converted into a carboxylic e;ter.
A cyano group is converted into an amidino group by reaction, for example, with hydroxylamine and subse-CA 022~9224 1998-12-24 .

quent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as Pd/C.
It is also possible to replace a conventional amino protecting group with hydrogen by eliminating the pro-tecting group solvolytically or hydrogenolytically, asdescribed above, or for an amino group which is pro-tected by a conventional protecting group to be libe-rated by solvo:Lysis or hydrogenolysis.

A base of the formula I can be converted with an acid into the associated acid addition salt, for example by reacting equiv~lent quantities of the base and the acid in an inert solvent, such as ethanol, and then concentrating by evaporation. Acids which yield physio-logically harmless salts are particularly suitable forthis reaction. Thus, inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, or sulfamic acid can be used, ~s can organic acids, in particular ali-phatic, alicyclic, araliphatic, aromatic or hetero-cyclic monobacic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethane-sulfonic acil~, ethanedisulfonic acid, 2-hydroxy-ethanesulfonic acid, benzenesulfonic acid, p-toluene-sulfonic acid, naphthalenemono- and disulfonic acids, or laurylsulfuric acid. Salts with acids which are not physiologically harmless, for example picrates, can be used for isolating and/or purifying the compounds of the formula I.

On the other hand, an acid of the formula I can be con-verted into one of its physiologically harmless metal salts or ammonium salts by reaction with a base.

CA 022~9224 1998-12-24 .

Suitable salts in this context are, in particular, the sodium, potassium, magnesium, calcium and ammonium salts, and also substituted ammonium salts, for example the dimethyl-, diethyl- or diisopropylammonium salts, monoethanol-, diethanol- or diisopropylammonium salts, cyclohexyl- or dicyclohexylammonium salts or dibenzyl-ethylenediammonium salts, and also, 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 form or in optically active form. Racemates which have been obtained can be resolved mechanically or chemi-cally into the enantiomers using methods which are known per se. Preferably, diastereomers are formed from the racemic mixture by means of reaction with an opti-cally active separating agent. Examples of suitable separating agents are optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyLtartaric acid, mandelic acid, malic acid or lactic acid, or the different optically active camphorsulfonic acids, such as ~-camphorsulfonic acid.
Enantiomer resolution using a column which is filled with an optically active separating agent (for example dinitrobenzoylphenylglycine) is also advantageous; a suitable mokile phase is, for example, a hexane/isopropanol/acetonitrile mixture, for example in a volume ratio of 82:15:3.

Naturally, it is also possible to use the above des-cribed methods to obtain optically active compounds of the formula I by employing starting compounds which are already optica:Lly active.

The test results obtained for av~3 and av~5 inhibitions with some representative compounds of the formula I are summarized in Table I below. The table gives the IC50 values, i.e. the concentrations in nmol/litre which inhibit 50~ of the binding of vitronectin to the CA 022~9224 1998-12-24 corresponding isolated receptor, for the vitronectin binding tests.

Tabl- I

ICso values (ccncentrations in nmol/litre which inhibit 50% of the binding of vitronectin to the isolated receptor) of representative compounds of the formula I, which were obtained in analogy with the method of Smith et al., J. Biol. Chem. 265, 12267-71 (1990), and the measured FAB values of the substances.

RS ~H ~ ~ 2 (1) Butyl H Propyl 0 471 6.5 55 H Butyl H Propyl 0 429 1.1 2.1 (2) Butyl H Propyl 0 563 92 (2) (A) H Propyl 0 657 61 136 H (A) H Propyl 0 523 0.13 0.16 H (A) Ethyl Propyl 0 551 16 13 EthylButyl H Propyl 0 457 0.81 (2) (A) H Butyl 0 671 252 H4-Tolyl H Butyl 0 477 4.6 H Butyl H Butyl 0 443 6.2 H (A) H Butyl 0 537 0.45 (1) = acetyl; (2) = benzyloxycarbonyl;
(A) = (S)-camphor-10-yl , CA 022~9224 l998-l2-24 The pharmacological data provide proof of the antago-nistic activit~ of the novel compounds of the formula I
for the av~3 and av~5 vitronectin receptors.

The results obtained for GPIIb/IIIa inhibition with some representative compounds of formula I are summarized in rable II below. The table gives the ICso values, i.e. the concentrations in nmol/litre which inhibit 50% of the binding of fibrinogen to the corresponding isolated receptor.

Table II

ICso values (ccncentrations in nmol/litre which isolate [sic] 50% of the binding of fibrinogen to the isolated receptor) of representative compounds of the formula I, and the FAB va]ues which were measured.

NH ~ O R2 _~L
(1) Butyl H Propyl O 471 1860 H Butyl H Propyl O 429 16 (2)Butyl H Propyl O 563 5600 (2) (A) H Propyl O 657 167 H (A) H Propyl O 523 1.3 H (A) Ethyl Propyl O 551 78 (1) = acetyl; (2) = benzyloxycarbonyl;
(A) = (S)-camphor-10-yl CA 022~9224 1998-12-24 .

The pharmacological data provide proof of the antago-nistic activity of the novel compounds of the formula I
for the GPIIb/]:IIa fibrinogen receptor.

The invention furthermore relates to the use of the compounds of the formula I, and/or their physio-logically harmless salts, for producing pharmaceutical preparations, :.n particular by a non-chemical route. In this context, they can be brought into a suitable dosage form together with at least one solid, liquid and/or semiliquid carrier substance or auxiliary sub-stance and, where appropriate, in combination with one or more additional active compounds.

The invention furthermore relates to pharmaceutical preparations which comprise at least one compound of the formula I and/or one of its physiologically harmless salts These preparations can be used as pharmaceuticals in human or veterinary medicine. Suitable carrier sub-stances are organic or inorganic substances which are appropriate for enteral (e.g. oral), parenteral or topical administration, or for administration in the form of an inhalation spray, and which 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 or vaseline. For oral applications, use is made, in par-ticular, of tablets, pills, coated tablets, capsules, powders, granulates, syrups, juices or drops, for rectal applications, of suppositories, for parenteral applications, of solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants, and for topical applications, of ointments, creams or powders. The novel compounds can also be lyophilized and the resulting lyophilizates used, for example, for producing preparations for injection. The indicated CA 022~9224 1998-12-24 preparations can be sterilized and/or comprise auxiliary substances such as glidants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffering sub-stances, dyes, flavorings and/or several additionalactive compouncls, for example one or more vitamins.

For administration as an inhalation spray, sprays can be used which comprise the active compound either dis-solved or suspended in a propellant gas or propellantgas mixture (for example CO2 or fluorochloro-hydrocarbons). In this context, the active compound is expediently used in micronized form, with it being pos-sible for one or more additional physiologically tolerated solvents, for example ethanol, to be present.
Solutions for inhalation can be administered using customary inha]ers.

The compounds of the formula I, and their physio-logically harn-less salts, can be used as integrin inhibitors in the control of diseases, in particular of pathologically angiogenic diseases, thromboses, cardiac infarction, coronary heart diseases, arteriosclerosis, tumours, inflammations and infections.
For controlling pathologically angiogenic diseases, tumours, osteoporosis, inflammations and infections, preference is given to using compounds of the formula I
according to Claim 1, and/or their harmless salts, in which R2 has the meaning camphor-10-yl.
In this context, the novel substances can as a rule be administered iIl analogy with other known peptides which are on the market, in particular, however, in analogy with the compounds described in US-A-4 472 305, pre-ferably in doses of between about 0.05 and 500 mg, inparticular between 0.5 and 100 mg, per dose unit. The daily dose is preferably between about 0.01 and 2 mg/kg of body weight. However, the particular dose for each patient depend, on a very wide variety of factors, for CA 022~9224 1998-12-24 , example on the activity of the particular compound employed, on the age, bodyweight, general state of health and sex, on the diet, on the time and route of administration, on the speed of excretion, on the drug combination and on the severity of the particular disease to which the therapy applies. Parenteral administration is preferred.

Both above and in that which follows, all the tempe-ratures are given in C. In the following examples,"customary working-up" denotes: water is, if necessary, added, the pH is, if necessary, adjusted to values of between 2 and 10, depending on the constitution of the end product, extraction takes place with ethyl acetate or dichloromet:hane, the phases are separated, the organic phase is dried over sodium sulfate and evapo-rated, and purification takes place by means of chromatography on silica gel and/or by means of crystallization.
Mass spectrometry (MS):
EI (electron impact ionization) M+
FAB (fast atom bombardment) (M+H)+

Example 1 A solution of 25 g of benzyloxycarbonyl-L-tyrosine tert-butyl est:er, 29 ml of ethyl 4-bromobutyrate, 18.7 g of potassium carbonate and 1.8 g of 18-Crown-6 in 300 ml of loluene is stirred at 85~ for 12 hours.
Following customary working-up, 25.3 g of tert-butyl (2S)-2-benzyloxycarboxamido-3-[4-(4-ethoxy-4-oxobutyl-oxy)phenyl]propionate ("A") are obtained as acolourless syrup; FAB 486.
1 g of 10% palladium on active charcoal is added to a solution of 10 g of "A" in 70 ml of ethyl acetate, 20 ml of methanol, 10 ml of water us [sic] 2 ml of TFA
and the mixture is hydrogenated with hydrogen at room temperature for 4 hours. After the catalyst has been . . _ .

CA 022~9224 1998-12-24 , removed, and after customary working-up, 8.8 g of tert-butyl (2S)-2-amino-3-[4-(4-ethoxy-4-oxobutyloxy)-phenyl]propiona.te, trifluoroacetate ("B") are obtained;
FAB 352.
5 5.5 ml of triethylamine and 3.9 ml of 1-butanesulfonyl chloride are added, at room temperature, to a solution of 8.8 g of "E~" in 100 ml of dichloromethane and the whole is stirred for 5 hours. Following customary working-up, 7.9 g of tert-butyl (2S)-2-butyl-sulfonamido-3-[4-(4-ethoxy-4-oxobutyloxy)phenyl]-propionate are obtained; FAB 472.

The following are obtained in an analogous manner by reacting "B"
with (S)-(+)-camphor-10-sulfonyl chloride, tert-butyl. (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-ethoxy-4-oxobutyloxy)phenyl]propionate; FAB 566 with 4-tolylsul.fonyl chloride, tert-butyl. (2S)-2-tolylsulfonamido-3-[4-(4-ethoxy-4-oxobutyloxy)phenyl]propionate; FAB 506.

A solution of 7.9 g of tert-butyl (2S)-2-butyl-sulfonamido-3-14-(4-ethoxy-4-oxobutyloxy)phenyl]-propionate and 10 ml of 2 N sodium hydroxide solution in 75 ml of melhanol is stirred at room temperature for 12 hours. Following customary working-up, tert-butyl (2S)-2-butylsul.fonamido-3-[4-(3-carboxypropyloxy)-phenyl]propionate is obtained as a colourless syrup;FAB 444.

The following are obtained in an analogous manner by cleaving the et:hyl ester:
from tert-butyl (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-ethoxy-4-oxobutyloxy)phenyl]propionate, tert-butyl. (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(3-carboxypropyloxy)phenyl]propionate; FAB 538, and CA 022~9224 1998-12-24 from tert-buty: (2S)-2-tolylsulfonamido-3-[4-(4-ethoxy-4-oxobutyloxy)Fhenyl]propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(3-carboxypropyloxy)phenyl]propionate; FAB 478.

1.1 g of 2-chloro-1-methylpyridinium iodide, 3.9 ml of ethyl diisopropylamine and 2.8 g of Z-guanidine are added to a solution of 1.3 g of tert-butyl (2S)-2-butylsulfonamico-3-[4-(3-carboxypropyloxy)phenyl]-propionate in 15 ml of DMF and the mixture is stirredat room temperature for 12 hours. Following customary working-up, ]..0 g of tert-butyl (2S)-2-butyl-sulfonamido-3-[4-(4-N-benzyloxycarbonylguanidino-4-oxobutyloxy)phenyl]propionate is obtained; FAB 619.
The following 2re obtained in an analogous manner:

from tert-butyl (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(3-carboxypropyloxy)phenyl]propionate, tert-butyl (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-N-benzyloxycarbonylguanidino-4-oxobutyloxy)-phenyl]propionate; FAB 713 and from tert-butyl (2S)-2-tolylsulfonamido-3-[4-(3-carboxypropyloxy)phenyl]propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(4-N-benzyloxycarbonylguanidino-4-oxobutyloxy)phenyl]-propionate; FAEi 653.

Example 2 250 mg of pall~dium (10% on active charcoal) are added to a solution of 1 g of tert-butyl (2S)-2-butyl-sulfonamido-3-[4-(4-N-benzyloxycarbonylguanidino-4-oxobutyloxy)phenyl]propionate in 18 ml of dioxane and 2 ml of water and the mixture is hydrogenated at room temperature fcr 3 hours. After separating off the catalyst and after customary working-up, 0.78 g of tert-butyl (2S)-2-butylsulfonamido-3-[4-(4-guanidino-4-oxobutyloxy)phenyl]propionate is obtained; FAB 485.

CA 022~9224 1998-12-24 The following are obtained in an analogous manner:

from tert-butyl (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-N-benzyloxycarbonylguanidino-4-oxobutyloxy)-phenyl]propionate, tert-buty]. (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-guanidino-4-oxobutyloxy)phenyl]propionate;

and from tert--butyl (2s)-2-tolylsulfonamido-3-[4-(4-N
benzyloxycarbonylguanidino-4-oxobutyloxy)phenyl]-propionate, tert-buty] (2S)-2-tolylsulfonamido-3-[4-(4-guani-dino-4-oxobuty]oxy)phenyl]propionate; FAB 519.
Example 3 2 ml of TFA are added to a solution of 0.78 g of tert-butyl (2S)-2-butylsulfonamido-3-[4-(4-guanidino-4-oxo-butyloxy)phenyL]propionate in 20 ml of dichloromethaneand the mixture is stirred for 12 hours. Following customary wor.;ing-up and freeze drying, 0.87 g of (2S)-2-butylsu fonamido-3-[4-(4-guanidino-4-oxobutyl-oxy)phenyl]propionic acid, trifluoroacetate is obtained as a white amorphous powder; FAB 429.

The following are obtained in an analogous manner:

from tert-butyl (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-guanidino-4-oxobutyloxy)phenyl]propionate, (2S)-2-[(',)-camphor-10-sulfonamido]-3-[4-(4-guani-dino-4-oxobuty:oxy)phenyl]propionic acid, trifluoro-acetate; FAB 523 and from tert-butyl (2S)-2-tolylsulfonamido-3-[4-(4-guanidino-4-oxobutyloxy)phenyl]propionate, (2S)-2-to:ylsulfonamido-3-[4-(4-guanidino-4-oxo-butyloxy)pheny:]propionic acid, trifluoroacetate;
FAB 463.

CA 022~9224 1998-12-24 Example 4 ul of acetyl chloride are added, at 0~, to a solution of 50 mg of (2S)-2-butylsulfonamido-3-[4-(4-guanidino-4-oxobutyloxy)phenyl]propionic acid, tri-fluoroaceate, in 5 ml of pyridine and the mixture is stirred for 2 hours. Following customary working-up, 0.027 g of (2S)-2-butylsulfonamido-3-[4-(4-N-acetyl-guanidino-4-oxobutyloxy)phenyl]propionic acid is obtained; FAB 471.

The following are obtained in an analogous manner:

from (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-guanidino-4-oxobutyloxy)phenyl]propionic acid, tri-fluoroacetate, (2S)-2-[(';)-camphor-10-sulfonamido]-3-[4-(4-N-acetylguanidino-4-oxobutyloxy)phenyl]propionic acid;

and from (2S)-2-tolylsulfonamido-3-[4-(4-guanidino-4-oxobutyloxy)phenyl]propionic acid, trifluoroacetate, (2S)-2-toLylsulfonamido-3-[4-(4-N-acetylguanidino-4-oxobutyloxy)phenyl]propionic acid; FAB 505.
Example 5 1 ml of TFA is added to a solution of 0.05 g of tert-butyl (2S)-2-butylsulfonamido-3-[4-(4-N-benzyloxy-carbonylguanidino-4-oxobutyloxy)phenyl]propionate in 5 ml of dichloromethane and the mixture is stirred at room temperature for 12 hours. Following customary working-up, 0.()45 g of (2S)-2-butylsulfonamido-3-[4-(4-N-benzyloxycarbonylguanidino-4-oxobutyloxy)phenyl]-propionic acid is obtained; FAB 563.The following are obtained in an analogous manner:

CA 022~9224 1998-12-24 from tert-buty.l (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-N-benzyloxycarbonylguanidino-4-oxobutyloxy)-phenyl]propionate, (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-N-benzyloxycarbonylguanidino-4-oxobutyloxy)phenyl]-propionic acid; FAB 657 and from tert-butyl (2S)-2-tolylsulfonamido-3-[4-(4-N-benzyloxycarbon.ylguanidino-4-oxobutyloxy)phenyl]-propionate, (2S)-2-tol.ylsulfonamido-3-[4-(4-N-benzyloxy-carbonylguanidi.no-4-oxobutyloxy)phenyl]propionic acid;
FAB 597.

Example 6 5 mg of p-toluenesulfonic acid are added to a solution of 0.1 g of (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-guanidino-4-oxobutyloxy)phenyl]propionic acid, tri-fluoroacetate, in 10 ml of ethanol and the mixture isstirred at room temperature for 72 hours. Following customary wor~:ing-up and freeze drying, 0.055 mg of ethyl (2';)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-guanidino-4-oxobutyloxy)phenyl]propionic acid is obtained; FAB 551.

~ The following are obtained in an analogous manner:

from (2S)-2-butylsulfonamido-3-[4-(4-guanidino-4-oxo-butyloxy)phenyl]propioniç acid, trifluoroacetate, ethyl (2S)-2-butylsulfonamido-3-[4-(4-guanidino-4-oxobutyloxy)phenyl]propionic acid; FAB 457 and from (2S)-2-tolylsulfonamido-3-[4-(4-guanidino-4-oxobutyloxy)phenyl]propionic acid, trifluoroacetate, ethyl (2S)-2-tolylsulfonamido-3-[4-(4-guanidino-4-oxobutyloxy)ph.enyl]propionic acid; FAB 491.

CA 022~9224 1998-12-24 ..

Example 7 The compound t:ert-butyl (2S)-2-benzyloxycarboxamido-3-[4-(3-ethoxy-3-oxopropylcarboxamido)phenyl]propionate is obtained in an analogous manner by reacting benzyl-oxycarbonyl-L-p-aminophenylalanine tert-butyl ester and l-chloro-4-ethoxybutane-1,4-dione. Tert-butyl (2S)-2-amino-3-[4-(3-ethoxy-3-oxopropylcarboxamido)phenyl]-propionate ("C") is obtained by eliminating the Z
protecting group.

The following are obtained by the subsequent reaction of "C"

with l-butanesulfonyl chloride, tert-butyl. (2S)-2-butylsulfonamido-3-[4-(3-ethoxy-3-oxopropylcarboxamido)phenyl]propionate, with 4-tolylsul.fonyl chloride, tert-butyl. (2S)-2-tolylsulfonamido-3-[4-(3-ethoxy-3-oxopropylcarboxamido)phenyl]propionate, and with (S)-(~)-camphor-10-sulfonyl chloride, tert-butyl. (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(3-ethoxy-3-oxopropylcarboxamido)phenyl]propionate.

The following are obtained from the above by cleaving the ethyl ester:

tert-butyl (2S)-2-butylsulfonamido-3-[4-(2-carboxy-ethylcarboxamiclo)phenyl]propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(2-carboxy-ethylcarboxamiclo)phenyl]propionate, and tert-buty:L (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(2-carboxyet.hylcarboxamido]phenyl]propionate.

In analogy with Example 1, the following are obtained from these by reaction with Z-guanidine:

tert-butyl (2S)-2-butylsulfonamido-3-[4-(3-N-benzyl-oxycarbonylguan.idino-3-oxopropylcarboxamido)phenyl]-propionate, tert-bu_yl (2S)-2-tolylsulfonamido-3-[4-(3-N-benzyl-oxycarbonylguanidino-3-oxopropylcarboxamido)phenyl]-propionate, and tert-buty:L (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(3-N-benzyloxycarbonylguanidino-3-oxopropylcarbox-amido)phenyl]propionate.
The Z protecting group is eliminated in analogy with Example 2, and the following compounds are obtained:

tert-butyl (2S)-2-butylsulfonamido-3-[4-(3-guanidino-3-oxopropylcarboxamido)phenyl]propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(3-guanidino-3-oxopropylcarboxamido)phenyl]propionate, and tert-buty:L (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(3-guanidino-3-oxopropylcarboxamido)phenyl]-propionate.

In analogy with Example 3, the tert-butyl ester is cleaved with TEA, and the following are obtained;

(2S)-2-butylsulfonamido-3-[4-(3-guanidino-3-oxopropyl-carboxamido)phenyl]propionic acid, trifluoroacetate, (2S)-2-tolylsulfonamido-3-[4-(3-guanidino-3-oxopropyl-carboxamido)phenyl]propionic acid, trifluoroacetate CA 022~9224 1998-12-24 , and (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(3-guani-dino-3-oxopropylcarboxamldo)phenyl]propionic acid, tri-fluoroacetate.

In analogy wit:h Example 4, the following compounds are obtained form t:hese by reaction with acetyl chloride:

(2S)-2-butylsulfonamido-3-[4-(3-N-acetylguanidino-3-oxopropylcarboxamido)phenyl]propionic acid, (2S)-2-tolylsulfonamido-3-[4-(3-N-acetylguanidino-3-oxopropylcarboxamido)phenyl]propionic acid, and (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(3-N-acetylguanidino-3-oxopropylcarboxamido)phenyl]propionic acid.

In analogy with Example 5, treatment with TFA converts tert-butyl (2S)-2-butylsulfonamido-3-[4-(3-N-benzyl-oxycarbonylguanidino-3-oxopropylcarboxamido)phenyl]-propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(3-N-benzyl-oxycarbonylguanidino-3-oxopropylcarboxamido)phenyl]-propionate, and tert-buty.l (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(3-N-benzyloxycarbonylguanidino-3-oxopropylcarbox-amido)phenyl]propionate into the following compounds (2S)-2-butylsul.fonamido-3-[4-(3-N-benzyloxycarbonyl-guanidino-3-oxopropylcarboxamido)phenyl]propionic acid, (2S)-2-tolylsul.fonamido-3-[4-(3-N-benzyloxycarbonyl-guanidino-3-oxopropylcarboxamido)phenyl]propionic acid, CA 022~9224 1998-12-24 , and (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(3-N-benzyloxycarbonylguanidino-3-oxopropylcarboxamido)-phenyl]propionic acid.

Example 8 The compound t:ert-butyl (2S)-2-benzyloxycarboxamido-3-[4-(4-ethoxy-4-oxobutylcarboxamido)phenyl]propionate is obtained, in analogy with Example 1, by reacting benzyloxycarbonyl-L-p-aminophenylalanine tert-butyl ester and 1--chloro-5-ethoxypentane-1,5-dione. Tert-butyl (2S)-2-amino-3-[4-(4-ethoxy-4-oxobutylcarbox-amido)phenyl]propionate ("D") is obtained by eliminat-ing the Z protecting group.
The following are obtained by the subsequent reaction of "D"

with 1-butanesulfonyl chloride, tert-butyl (2S)-2-butylsulfonamido-3-[4-(4-ethoxy-4-oxobutylcarboxamido)phenyl]propionate, with 4-tolylsu]fonyl chloride, tert-buty] (2S)-2-tolylsulfonamido-3-[4-(4-ethoxy-4-oxobutylcarboxamido)phenyl]propionate and with (S)-(~-)-camphor-10-sulfonyl chloride, tert-buty] (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-ethoxy-4--oxobutylcarboxamido)phenyl]propionate.
The following are obtained from these by cleaving the ethyl ester:

tert-butyl (2S)-2-butylsulfonamido-3-[4-(3-carboxy-propylcarboxamido)phenyl]propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(3-carboxy-propylcarboxam do)phenyl]propionate CA 022~9224 1998-12-24 and tert-butyl (2S)-2-[(S)-camphor-10-sulfonamido-3-[4-(3-carboxypropylcarboxamido)phenyl]propionate.

In analogy with Example 1, the following are obtained from these by reaction with Z guanidine:

tert-butyl (2S)-2-butylsulfonamido-3-[4-(4-N-benzyl-oxycarbonylguan.idino-4-oxobutylcarboxamido)phenyl]-propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(4-N-benzyl-oxycarbonylguan.idino-4-oxobutylcarboxamido)phenyl]-propionate and tert-buty:L (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-N-benzyloxycarbonylguanidino-4-oxobutyl-carboxamido)phenyl]propionate.

The Z protecting group is eliminated in analogy with Example 2, and the following compounds are obtained:

tert-butyl (2S)-2-butylsulfonamido-3-[4-(4-guanidino-4-oxobutylcarboxa.mido)phenyl]propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(4-guanidino-4-oxobutylcarboxa.mido)phenyl]propionate and tert-buty:L (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-guanidinc,-4-oxobutylcarboxamido)phenyl]-propionate.

In analogy with Example 3, the tert-butyl ester is cleaved with TEA, and the following are obtained:

(2S)-2-butylsulfonamido-3-[4-(4-guanidino-4-oxobutyl-carboxamido)phenyl]propionic acld, trifluoroacetate, (2S)-2-tolylsulfonamido-3-[4-(4-guanidino-4-oxobutyl-carboxamido)phenyl]propionic acid, trifluoroacetate CA 022~9224 1998-12-24 and (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-guanidino-4-oxobutylcarboxamido)phenyl]propionic acid, trifluoroacetat:e.

In analogy with Example 4, the following compounds are obtained from t:hese by reaction with acetyl chloride:

(2S)-2-butylsulfonamido-3-[4-(4-N-acetylguanidino-4-oxobutylcarboxamido)phenyl]propionic acid, (2S)-2-tolylsuLfonamido-3-[4-(4- N-acetylguanidino-4-oxobutylcarboxamido)phenyl]propionic acid, and (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-N-acetylguanidino-4-oxobutylcarboxamido)phenyl]propionic acid.

In analogy with Example 5, treatment with TFA converts tert-butyl (2S)-2-butylsulfonamido-3-[4-(4-N-benzyl-oxycarbonylguanidino-4-oxobutylcarboxamido)phenyl]-propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(4-N-benzyl-oxycarbonylguanidino-4-oxobutylcarboxamido)phenyl]-propionate, and tert-buty.l (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-N-benzyloxycarbonylguanidino-4-oxobutyl-carboxamido)phenyl]propionate into the following compounds (2S)-2-butylsul.fonamido-3-[4-(4-N-benzyloxycarbonyl-guanidino-4-oxobutylcarboxamido)phenyl]proponic acid, (2S)-2-tolylsul.fonamido-3-[4-(4-N-benzyloxycarbonyl-guanidino-4-oxobutylcarboxamido)phenyl]proponic acid CA 022~9224 1998-12-24 and (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-N-benzyloxycarbon.ylguanidino-4-oxobutylcarboxamido)-phenyl]propionic acid.

Example 9 The compound t:ert-butyl (2S)-2-benzyloxycarboxamido-3-[4-(2-ethoxy-2-oxoethylcarboxamido)phenyl]propionate is obtained, in analogy with Example 1, by reacting benzyloxycarbonyl-L-p-aminophenylalanine tert-butyl ester and 1-chloro-3-ethoxypropane-1,3-dione. Tert-butyl (2S)-2-amino-3-[4-(2-ethoxy-2-oxobutylcarbox-amido)phenyl]propionate ("E") is obtained by eliminating the Z protecting group.
The following are obtained by subsequent reaction of "E"

with 1-butanesulfonyl chloride, tert-butyl (2S)-2-butylsulfonamido-3-[4-(2-ethoxy-2-oxoethylcarboxamido)phenyl]propionate, with 4-tolylsulfonyl chloride, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(2-ethoxy-2-oxoethylcarbc,xamido)phenyl]propionate and with (S)-(~)-camphor-10-sulfonyl chloride, tert-butyl (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(2-ethoxy-2-oxoethylcarboxamido)phenyl]propionate.
The following are obtained from these by cleaving the ethyl ester:

tert-butyl (2S)-2-butylsulfonamido-3-[4-(carboxy-methylcarboxamido)phenyl]propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(carboxy-methylcarboxamido)phenyl]propionate, CA 022~9224 1998-12-24 , and tert-buty.L (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(carboxymethylcarboxamido)phenyl]propionate.

In analogy with Example 1, the following are obtained from these by reaction with Z-guanidine:

tert-butyl (2S)-2-butylsulfonamido-3-[4-(2-N-benzyl-oxycarbonylguanidino-2-oxoethylcarboxamido)phenyl]-propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(2-N-benzyl-oxycarbonylguanidino-2-oxoethylcarboxamido)phenyl]-propionate, and tert-buty.l (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(2-N-benzyloxycarbonylguanidino-2-oxoethyl-carboxamido)phenyl]propionate.

The Z protecti.ng group is eliminated in analogy with Example 2, and the following compounds are obtained:

tert-butyl (2S)-2-butylsulfonamido-3-[4-(2-guanidino-2-oxoethylcarboxamido)phenyl]propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(2-guanidino-2-oxoethylcarboxamido)phenyl]propionate and tert-buty:l (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(2-guanidino-2-oxoethylcarboxamido)phenyl]-propionate.

In analogy with Example 3, the tert-butyl ester is cleaved with TEA, and the following are obtained:

35 (2S)-2-butylsul.fonamido-3-[4-(2-guanidino-2-oxoethyl-carboxamido)phenyl]propionic acid, trifluoroacetate, (2S)-2-tolylsul.fonamido-3-[4-(2-guanidino-2-oxoethyl-carboxamido)phenyl]propionic acid, trifluoroacetate CA 022~9224 1998-12-24 and (2S)-2-[('i)-camphor-10-sulfonamido]-3-[q-(2-guani-dino-2-oxoethylcarboxamido)phenyl]propionic acid, tri-fluoroacetate.

In analogy with Example 4, the following compounds are obtained from these by reaction with acetyl chloride:

(2S)-2-butylsulfonamido-3-[4-(2-N-acetylguanidino-2-oxoethylcarboxamido)phenyl]propionic acid, (2S)-2-tolylsulfonamido-3-[4-(2-N-acetylguanidino-2-oxoethylcarboxamido)phenyl]propionic acid, and (2S)-.2-[(S)-camphor-10-sulfonamido]-3-[4-(2-N-acetylguanidino-2-oxoethylcarboxamido)phenyl]propionic acid.

In analogy with Example 5, treatment with TFA converts tert-butyl (2S)-2-butylsulfonamido-3-[4-(2-N-benzyl-oxycarbonylguanidino-2-oxoethylcarboxamido)phenyl]-propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(2-N-benzyl-oxycarbonylguanidino-2-oxoethylcarboxamido)phenyl]-propionate, and tert-buty] (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(2-N-benzylcxycarbonylguanidino-2-oxoethyl-carboxamido)phenyl]propionate into the following compounds (2S)-2-butylsulfonamido-3-[4-(2-N-benzyloxycarbonyl-guanidino-2-oxcethylcarboxamido)phenyl]propionic acid, (2S)-2-tolylsulfonamido-3-[4-(2-N-benzyloxycarbonyl-guanidino-2-oxcethylcarboxamido)phenyl]propionic acid CA 022~9224 1998-12-24 and (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(2-N-benzyloxycarbonylguanidino-2-oxoethylcarboxamido)-phenyl]propionic acid.

Example 10 The compound tert-butyl (2S)-2-benzyloxycarboxamido-3-[4-(5-ethoxy-5-oxopentyloxy)phenyl]propionate is obtained, in analogy with Example 1, by reacting benzyloxycarbonyl-L-tyrosine tert-butyl ester and ethyl 5-bromovalerate. Tert-butyl (2S)-2-amino-3-[4-(5-ethoxy-5-oxopentyloxy)phenyl]propionate ("F") is obtained by el:Lminating the Z protecting group.

The following are obtained by subsequent reaction of "F"

with 1-butanesulfonyl chloride, tert-buty:L (2S)-2-butylsulfonamido-3-[4-(5-ethoxy-5-oxopentyloxylphenyl]propionate, with 4-tolylsu:Lfonyl chloride, tert-buty:L (2S)-2-tolylsulfonamido-3-[4-(5-ethoxy-5-oxopentyloxy'lphenyl]propionate and with (S)-(-~)-camphor-10-sulfonyl chloride, tert-buty:L (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(5-ethoxy-5--oxopentyloxy)phenyl]propionate.

The following are obtained from these by cleaving the ethyl ester:

tert-butyl (2S)-2-butylsulfonamido-3-[4-(4-carboxy-butyloxy)pheny:L]propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(4-carboxy-butyloxy)pheny:]propionate, ' CA 022~9224 1998-12-24 ..

and tert-buty] (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-carboxybutyloxy)phenyl]propionate.

In analogy wit:h Example 1, the following are obtained from these by reaction with Z-guanidine:

tert-butyl (2S)-2-butylsulfonamido-3-[4-(5-N-benzyl-oxycarbonylguanidino-5-oxopentyloxy)phenyl]propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(5-N-benzyl-oxycarbonylguanidino-5-oxopentyloxy)phenyl]propionate and tert-buty:L (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(5-N-benzylcxycarbonylguanidino-5-oxopentyloxy)-phenyl]propionate.

The Z protecting group is eliminated in analogy withExample 2, and the following compounds are obtained:

tert-butyl (2S)-2-butylsulfonamido-3-[4-(5-guanidino-5-oxopentyloxy)phenyl]propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(5-guanidino-5-oxopentyloxy)phenyl]propionate, and tert-buty] (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(5-guanidinc-5-oxopentyloxy)phenyl]propionate.

In analogy wil:h Example 3, the tert-butyl ester is cleaved with TFA, and the following compounds are obtained:

(2S)-2-butylsulfonamido-3-[4-(5-guanidino-5-oxopentyl-oxy)phenyl]propionic acid, trifluoroacetate; FAB 443 (2S)-2-tolylsulfonamido-3-[4-(5-guanidino-5-oxopentyl-oxy)phenyl]propionic acid, trifluoroacetate; FAB 477 CA 022~9224 1998-12-24 .

and (2S)-2-[(~)-camphor-10-sulfonamido]-3-[4-(5-guani-dino-5-oxopentyloxy)phenyl]propionic acid, trifluoro-acetate; FAB 537.

In analogy with Example 4, the following compounds are obtained from these by reaction with acetyl chloride:

(2S)-2-butylsulfonamido-3-[4-(5-N-acetylguanidino-5-oxopentyloxy)phenyl]propionic acid, (2S)-2-tolylsulfonamido-3-[4-(2-N-acetylguanidino-2-oxoethylcarboxamido)phenyl]propionic acid, and (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(5-N-acetylguanidino-5-oxopentyloxy)phenyl]propionic acid.

In analogy with. Example 5, treatment with TFA converts tert-butyl (2S)-2-butylsulfonamido-3-[4-(5-N-benzyl-oxycarbonylguan.idino-5-oxopentyloxy)phenyl]propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(5-N-benzyl-oxycarbonylguan.idino-5-oxopentyloxy)phenyl]propionate and tert-buty:L (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(5-N-benzyloxycarbonylguanidino-5-oxopentyloxy)-phenyl]propiona.te into the following compounds (2S)-2-butylsul.fonamido-3-[4-(5-N-benzyloxycarbonyl-guanidino-5-oxopentyloxy)phenyl]propionic acid; FAB 577 (2S)-2-tolylsul.fonamido-3-[4-(5-N-benzyloxycarbonyl-guanidino-5-oxopentyloxy)phenyl]propionic acid and (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(5-N-benzyloxycarbonylguanidino-5-oxopentyloxy)phenyl]-propionic acid; FAB 671.

CA 022~9224 1998-12-24 Example 11 The compound t:ert-butyl (2S)-2-benzyloxycarboxamido-3-[4-(4-cyano-4-oxobutyloxy)phenyl]propionate is obtained, in analogy with Example 1, by reacting benzyloxycarbonyl-L-tyrosine tert-butyl ester with 5-bromo-2-oxovaleronitrile.

The compound tert-butyl (2S)-2-amino-3-[4-(4-cyano-4-oxobutyloxy)phenyl]propionate ("G") is obtained byeliminating the Z protecting group.
Tert-butyl (2S)-2-butylsulfonamido-3-[4-(4-cyano-4-oxobutyloxy)phenyl]propionate ("H") is obtained by reacting "G" with 1-butanesulfonyl chloride.
A solution of "H" and equimolar quantities of hydroxylamine hydrochloride and sodium hydrogen carbonate in isopropanol/water 6:1 is heated under reflux for 12 hours. Following customary working-up, tert-butyl (2S)-2-butylsulfonamido-3-[4-(5-amino-5-N-hydroxylimino-4-oxopentyloXy)phenyl]propionate ("J") is obtained.

A solution of "J" in acetic acid is hydrogenated, at room temperature for 2 hours and under standard pressure, with palladium catalyst (10% on active charcoal). After separating off the catalyst, and after customary working-up, (2S)-2-butylsulfonamido-3-[4-(4-amidino-4-oxobutyloxy)phenyl]propionic acid is obtained.

Example 12 In analogy with Example 1, the following are obtained by reacting N-benzyloxycarbonyl-N-ethylguanidine with tert-butyl (2S)-2-butylsulfonamido-3-[4-(3-carboxypropyloxy)phenyl]propionate, CA 022~9224 1998-12-24 tert-butyl (2S)-2-butylsulfonamido-3-[4-(4-N-benzyloxycarbonyl-N-ethylguanidino-4-oxobutyloxy)-phenyl]propionate; FAB 647 with tert-butyl (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(3-carboxypropyloxy)phenyl]propionate, tert-butyl (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-N-benzyloxycarbonyl-N-ethylguanidino-4-oxobutyl-oxy)phenyl]propionate; FAB 741 and with tert:-butyl (2S)-2-tolylsulfonamido-3-[4-(3-carboxypropyloxy)phenyl]propionate, tert-butyl (2S)-2-tolylsulfonamido-3-[4-(4-N-benzyloxycarbonyl-N-ethylguanidino-4-oxobutyloxy)-phenyl]propionate; FAB 681.

The Z protecting group is eliminated in analogy with Example 2, and the following compounds are obtained:

tert-butyl (2S)-2-butylsulfonamido-3-[4-(4-N-ethyl-guanidino-4-oxobutyloxy)phenyl]propionate; FAB 513 tert-butyl (2S)-2-[(S)-camphor-10-sulfonamido]-3-[4-(4-N-ethylguanidino-4-oxobutyloxy)phenyl]propionate;

and tert-but:yl (2S)-2-tolylsulfonamido-3-[4-(4-N-ethylguanidino-4-oxobutyloxy)phenyl]propionate;
FAB 547.
In analogy with Example 3, the following compounds are obtained from these by cleaving the tert-butyl ester with TFA:

(2S)-2-butylsulfonamido-3-[4-(4-N-ethylguanidino-4-oxo-butyloxy)phenyl]propionic acid, trifluoroacetate;

CA 022~9224 1998-12-24 , (2S)-2-[(S)-camphor-10-sulfonamido-3-[4-(4-N-ethyl-guanidino-4-oxobutyloxy)phenyl]propionic acid, tri-fluoroacetate; FAB 551 and (2S)-2-tolylsulfonamido-3-[4-(4-N-ethylguanidino-4-oxobutyloxy)phenyl]propionic acid, trifluoroacetate;
FAB 491.

The following examples relate to pharmaceutical preparations:

Exampl- A: Inje~ction vial.~

A solution of 100 g of an active compound of the formula I and 'i g of disodium hydrogen phosphate in 3 l of double dist.illed water, is adjusted to a pH of 6.5 with 2 N hydrochloric acid, sterilized by filtration and aliquoted into injection vials; the solution is then lyophilized, and the vials sealed, under sterile conditions. Each injection vial comprises 5 mg of active compound..

Example B: Supp~o~itorie~

A mixture of 2() g of an active compound of the formula I with 100 g of soybean lecithin and 1400 g of cocoa butter is melt:ed, poured into moulds and allowed to cool. Each suppository comprises 20 mg of active compound.
Example C: Solution A solution of 1 g of an active compound of formula I, 9.38 g of NaH2PO4 2H2O, 28.48 g of Na2HPO4 12H2O and 0.1 g of benzalkonium chloride in 940 ml of double distilled water is prepared. It is adjusted to pH 6.8, made up to 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops.

CA 022~9224 1998-12-24 Example D: Ointment 500 mg of an active compound of the formula I is mixed with 99.5 g of vaseline under aseptic conditions.

Example E: Tablets A mixture of 1 kg of 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 into tablets in the customary manner such that each tablet comprises 10 mg of active compound.

Example F: Coated tablets Tablets are compressed in analogy with Example E and are then coated, in a customary manner, with a coating of sucrose, potato starch, talc, tragacanth and dye Example G: Capsules 2 kg of active compound of the formula I is aliquoted, in a customary manner, into hard gelatin capsules such that each capsule comprises 20 mg of the active compound.

Example ~: Ampaule~

A solution of :L kg of active compound of the formula I
in 60 l of double distilled water is sterilized by filtration and aliquoted into ampoules; the solution is then lyophilized, and the vials sealed, under sterile conditions. Each ampoule comprises 10 mg of active compound.
Example I: T~halation spray 14 g of active compound of the formula I are dissolved in 10 l of isotonic NaCl solution, and the solution is aliquoted intc commercial spraying vessels having a pump mechanism. The solution can be sprayed into the mouth or nose. One spray pulse (approximately 0.1 ml) corresponds to a dose of about 0.14 mg.

Claims (11)

Patent claims
1. Compounds of the formula I

in which X is absent, or is alkylene, arylene, cycloalkylene having 4-8 carbon atoms, or heterocycloalkylene having from 1 to 3 N, O and/or S atoms which is unsubstituted or substituted once, twice or three times by A, oxo and/or R4, Y and Z are, in each case, independently of each other, absent, or are alkylene, O, S, NH, C(=O), CONH, NHCO, C(=S), SO2NH, CA=CA' or -C~C-, R1 is H2N-C(=NH) or H2N(C=NH)-NH, where the primary amino groups can also be provided with conventional amino protecting groups or can be substituted once, twice or three times by A, Ar or R5, R2 is A, Ar or aralkylene, R3 is H or A, R4 is H, Hal, OA, NHA, NAA', CN, NO2, SA, SOA, SO2A, SO2Ar or SO3H, R5 is alkanoyl or cycloalkanoyl having 1-18 carbon atoms, in which one, two or three methylene groups can be replaced with N, O and/or S, Ar-CO- or Ar-alkylene-CO-, A and A' are, in each case, independently of each other, H, or alkyl or cycloalkyl having 1-15 carbon atoms which is unsubstituted or substituted once, twice or three times by R4 and in which one, two or three methylene groups can be replaced with N, O and/or S, Ar is a mononuclear or binuclear aromatic ring system having 0, 1, 2, 3 or 4 N, O
and/or S atoms which is unsubstituted or substituted once, twice or three times by A and/or R4, Hal is F, Cl, Br or I, with the proviso that at least one element selected from the group X, Y and Z must be CH2, and the physiologically harmless salts thereof.
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) (2S)-2-butylsulfonamido-3-[4-(4-N-acetyl-guanidino-4-oxobutoxy)phenyl]propionic acid;

b) (2S)-2-butylsulfonamido-3-[4-(4-guanidino-4-oxobutyloxy) phenyl]propionic acid;

c) (2S)-2-(camphor-10-sulfonamido)-3-[4-(4-N-ethylguanidino-4-oxobutoxy)phenyl]propionic acid;

d) (2S)-2-(camphor-10-sulfonamido)-3-[4-(4-N-benzyloxycarbonylguanidino-4-oxobutoxy)-phenyl]propionic acid;

e) (2S)-2-(camphor-10-sulfonamido)-3-[4-(4-guanidino-4-oxobutoxy)phenyl]propionic acid;

f) ethyl (2S)-2-(camphor-10-sulfonamido)-3-[4-(4-guanidino-4-oxobutoxy)phenyl]propionate;

g) (2S)-2-butylsulfonamido-3-[4-(4-N-ethylguani-dino-4-oxobutoxy)phenyl]propionic acid;

h) (2S)-2-butylsulfonamido-3-[4-(5-guanidino-5-oxopentoxy)phenyl]propionic acid;

i) (2S)-2-(camphor-10-sulfonamido)-3-[4-(5-guanidino-5-oxopentoxy)phenyl]propionic acid;

and the physiologically harmless salts thereof.
4. Process for preparing compounds of the formula I
according to Claim 1, and their salts, characterized in that a) a compound of the formula I is liberated from one of its functional derivatives by treating the derivative with a solvolysing or hydrogenolysing agent, or b) a compound of the formula II

in which R1 R3 R4 X Y and Z ha the meanings given in Claim 1, is reacted with a compound of the formula III

in which R2 has the meaning given in Claim 1 and L is Cl, Br, I, OH or an OH group which has been esterified to make it capable of reacting, or c) an ester of the formula I is hydrolysed, or d) a radical R1 and/or R3 is/are converted into another radical R1 and/or R3, and/or e) a basic or acidic compound of the formula I is converted into one of its salts by treating it with an acid or base.
5. Process for producing a pharmaceutical preparation, characterized in that a compound of the formula I according to Claim 1, and/or one of its physiological [sic] harmless salts, is brought into a suitable dosage form together with at least one solid, liquid or semiliquid carrier substance or auxiliary substance.
6. Pharmaceutical preparation, characterized by a content of at least one compound of the formula I
according to Claim 1 and/or one of its physiologically harmless salts.
7. Compounds of the formula I according to Claim 1, and their physiologically harmless salts, as GPIIb/IIIa antagonists for controlling thromboses, cardiac infarction, coronary heart diseases and arteriosclerosis.
8. Compounds of the formula I according to Claim 1, and their physiologically harmless salts, as .alpha. v integrin inhibitors for controlling pathologically angiogenic diseases, tumours, osteoporosis, inflammations and infections.
9. Compounds of the formula I according to Claim 1, and their physiologically harmless salts, in which R2 has the meaning camphor-10-yl, as .alpha. v integrin inhibitors for controlling pathologically angiogenic diseases, tumours, osteoporosis, inflammations and infections.
10. Use of compounds of the formula I according to Claim 1, and/or their physiologically harmless salts, for preparing a pharmaceutical.
11. Compounds of the formula I according to Claim 1, and/or their physiologically harmless salts, for preparing a pharmaceutical for use as an .alpha. v integrin inhibitor.
CA002259224A 1996-06-28 1997-06-23 Phenylalamine derivatives as integrin inhibitors Abandoned CA2259224A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19625929.0 1996-06-28
DE19625929 1996-06-28
DE19654483.1 1996-12-27
DE19654483A DE19654483A1 (en) 1996-06-28 1996-12-27 Phenylalanine derivatives

Publications (1)

Publication Number Publication Date
CA2259224A1 true CA2259224A1 (en) 1998-01-08

Family

ID=26027004

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002259224A Abandoned CA2259224A1 (en) 1996-06-28 1997-06-23 Phenylalamine derivatives as integrin inhibitors

Country Status (10)

Country Link
EP (1) EP0907637A1 (en)
JP (1) JP2000516575A (en)
KR (1) KR20000022190A (en)
AU (1) AU3343097A (en)
CA (1) CA2259224A1 (en)
CZ (1) CZ424998A3 (en)
NO (1) NO986090L (en)
PL (1) PL330915A1 (en)
SK (1) SK176898A3 (en)
WO (1) WO1998000395A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6436904B1 (en) 1999-01-25 2002-08-20 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6479492B1 (en) 1999-01-22 2002-11-12 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US7452912B2 (en) 1999-01-22 2008-11-18 Elan Pharmaceuticals, Inc. Fused ring heteroaryl and heterocyclic compounds which inhibit leukocyte adhesion mediated by VLA-4
US7579466B2 (en) 2006-02-27 2009-08-25 Elan Pharmaceuticals, Inc. Pyrimidinyl sulfonamide compounds which inhibit leukocyte adhesion mediated by VLA-4
US7727996B2 (en) 2005-09-29 2010-06-01 Elan Pharmaceuticals, Inc. Carbamate compounds which inhibit leukocyte adhesion mediated by VLA-4
US7763632B2 (en) 2005-09-29 2010-07-27 Elan Pharmaceuticals, Inc. Pyrimidinyl amide compounds which inhibit leukocyte adhesion mediated by VLA-4
US8367836B2 (en) 2009-04-27 2013-02-05 Elan Pharmaceuticals, Inc. Pyridinone antagonists of alpha-4 integrins

Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040063790A1 (en) * 1996-05-31 2004-04-01 The Scripps Research Institute Methods for inhibition of angiogenesis
DE19705450A1 (en) * 1997-02-13 1998-08-20 Merck Patent Gmbh Bicyclic aromatic amino acids
US6197794B1 (en) 1998-01-08 2001-03-06 Celltech Therapeutics Limited Phenylalanine derivatives
US6313119B1 (en) 1998-01-23 2001-11-06 Adventis Pharma Deutschland Gmbh Sulfonamide derivatives as inhibitors of bone resorption and as inhibitors of cell adhesion
US6329372B1 (en) 1998-01-27 2001-12-11 Celltech Therapeutics Limited Phenylalanine derivatives
US6555562B1 (en) 1998-02-26 2003-04-29 Celltech R&D Limited Phenylalanine derivatives
GB9805655D0 (en) 1998-03-16 1998-05-13 Celltech Therapeutics Ltd Chemical compounds
US6521626B1 (en) 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
GB9811159D0 (en) 1998-05-22 1998-07-22 Celltech Therapeutics Ltd Chemical compounds
GB9811969D0 (en) * 1998-06-03 1998-07-29 Celltech Therapeutics Ltd Chemical compounds
GB9812088D0 (en) * 1998-06-05 1998-08-05 Celltech Therapeutics Ltd Chemical compounds
GB9814414D0 (en) 1998-07-03 1998-09-02 Celltech Therapeutics Ltd Chemical compounds
GB9821061D0 (en) 1998-09-28 1998-11-18 Celltech Therapeutics Ltd Chemical compounds
GB9821222D0 (en) 1998-09-30 1998-11-25 Celltech Therapeutics Ltd Chemical compounds
GB9825652D0 (en) 1998-11-23 1999-01-13 Celltech Therapeutics Ltd Chemical compounds
GB9826174D0 (en) * 1998-11-30 1999-01-20 Celltech Therapeutics Ltd Chemical compounds
CA2355161A1 (en) * 1998-12-16 2000-06-22 Bayer Aktiengesellschaft Biphenyl and biphenyl-analogous compounds as integrin antagonists
US6677360B2 (en) 1998-12-16 2004-01-13 Bayer Aktiengesellschaft Biphenyl and biphenyl-analogous compounds as integrin antagonists
US6291503B1 (en) 1999-01-15 2001-09-18 Bayer Aktiengesellschaft β-phenylalanine derivatives as integrin antagonists
US6344484B1 (en) 1999-02-12 2002-02-05 3-Dimensional Pharmaceuticals, Inc. Tyrosine alkoxyguanidines as integrin inhibitors
EP1028114A1 (en) * 1999-02-13 2000-08-16 Aventis Pharma Deutschland GmbH Novel guanidine derivatives as inhibitors of cell adhesion
EP1161416B1 (en) 1999-03-01 2004-04-14 Elan Pharmaceuticals, Inc. Alpha-aminoacetic acid derivatives useful as alpha 4 beta 7 - receptor antagonists
WO2000061551A2 (en) 1999-04-13 2000-10-19 Basf Aktiengesellschaft Pyrimidine-2-one derivatives as integrin receptor ligands
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
WO2001047874A1 (en) * 1999-12-24 2001-07-05 Smithkline Beecham P.L.C. (hetero)bicyclymethanesulfonylamino-substituted hydroxamic acid derivatives
DE60130910T2 (en) 2000-04-17 2008-07-10 Ucb Pharma, S.A. ENAMINE DERIVATIVES AS CELL ADHESION MOLECULES
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
AU2001267753A1 (en) 2000-07-07 2002-01-21 Celltech R And D Limited Squaric acid derivatives containing a bicyclic heteroaromatic ring as integrin antagonists
CA2417059A1 (en) 2000-08-02 2002-02-07 Celltech R&D Limited 3-substituted isoquinolin-1-yl derivatives
US20020037897A1 (en) * 2000-08-07 2002-03-28 3-Dimensional Pharmaceuticals, Inc. Tetrahydroisoquinoline-3-carboxylic acid alkoxyguanidines as integrin antagonists
US6486174B2 (en) 2000-08-07 2002-11-26 3-Dimensional Pharmaceuticals, Inc. Tetrahydroisoquinoline-3-carboxylic acid alkoxyguanidines as integrin antagonists
ES2376161T3 (en) 2001-01-29 2012-03-09 Janssen Pharmaceuticals, Inc. SUBSTITUTE INDOLES AND THEIR USE AS AN INTEGRINE ANTAGONISTS.
US6872730B2 (en) 2001-04-27 2005-03-29 3-Dimensional Pharmaceuticals, Inc. Substituted benzofurans and benzothiophenes, methods of making and methods of use as integrin antagonists
TWI281470B (en) 2002-05-24 2007-05-21 Elan Pharm Inc Heterocyclic compounds which inhibit leukocyte adhesion mediated by alpha4 integrins
TW200307671A (en) 2002-05-24 2003-12-16 Elan Pharm Inc Heteroaryl compounds which inhibit leukocyte adhesion mediated by α 4 integrins
FR2847254B1 (en) 2002-11-19 2005-01-28 Aventis Pharma Sa NOVEL VITRONECTIN RECEPTOR ANTAGONIST DERIVATIVES, PROCESS FOR PREPARING THEM, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS REFLECTING THEM
FR2870541B1 (en) 2004-05-18 2006-07-14 Proskelia Sas ANTIGONISTIC PYRIMIDINE DERIVATIVES OF VITRONECTIN RECEPTOR
UA87854C2 (en) 2004-06-07 2009-08-25 Мерк Энд Ко., Инк. N-(2-benzyl)-2-phenylbutanamides as androgen receptor modulators
DE102006059317A1 (en) * 2006-07-04 2008-01-10 Evonik Degussa Gmbh Process for the preparation of β-amino-α-hydroxy-carboxylic acid amides
CA2950390C (en) 2014-05-30 2020-09-22 Pfizer Inc. Carbonitrile derivatives as selective androgen receptor modulators
WO2023275715A1 (en) 2021-06-30 2023-01-05 Pfizer Inc. Metabolites of selective androgen receptor modulators

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0673247A4 (en) * 1992-12-01 1996-05-01 Merck & Co Inc Fibrinogen receptor antagonists.
JPH10501222A (en) * 1994-05-27 1998-02-03 メルク エンド カンパニー インコーポレーテッド Compounds for inhibiting osteoclast-mediated bone resorption

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7741328B2 (en) 1999-01-22 2010-06-22 Elan Pharmaceuticals, Inc. Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4
US6479492B1 (en) 1999-01-22 2002-11-12 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6492372B1 (en) 1999-01-22 2002-12-10 Elan Pharmaceuticals, Inc. Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4
US6903088B2 (en) 1999-01-22 2005-06-07 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6911439B2 (en) 1999-01-22 2005-06-28 Elan Pharmaceuticals, Inc. Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4
US7973044B2 (en) 1999-01-22 2011-07-05 Elan Pharmaceuticals, Inc. Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4
US7005433B2 (en) 1999-01-22 2006-02-28 Elan Pharmaceuticals, Inc. Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4
US7049306B2 (en) 1999-01-22 2006-05-23 Elan Pharmaceuticals, Inc. Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4.
US7378529B2 (en) 1999-01-22 2008-05-27 Wyeth Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4
US7452912B2 (en) 1999-01-22 2008-11-18 Elan Pharmaceuticals, Inc. Fused ring heteroaryl and heterocyclic compounds which inhibit leukocyte adhesion mediated by VLA-4
US7538215B2 (en) 1999-01-22 2009-05-26 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US7968547B2 (en) 1999-01-22 2011-06-28 Elan Pharmaceuticals, Inc. Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4
US6949570B2 (en) 1999-01-25 2005-09-27 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6436904B1 (en) 1999-01-25 2002-08-20 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US7727996B2 (en) 2005-09-29 2010-06-01 Elan Pharmaceuticals, Inc. Carbamate compounds which inhibit leukocyte adhesion mediated by VLA-4
US7763632B2 (en) 2005-09-29 2010-07-27 Elan Pharmaceuticals, Inc. Pyrimidinyl amide compounds which inhibit leukocyte adhesion mediated by VLA-4
US8158642B2 (en) 2005-09-29 2012-04-17 Elan Pharmaceuticals, Inc. Carbamate compounds which inhibit leukocyte adhesion mediated by VLA-4
US8367688B2 (en) 2005-09-29 2013-02-05 Elan Pharmaceuticals, Inc. Carbamate compounds which inhibit leukocyte adhesion mediated by VLA-4
US7820687B2 (en) 2006-02-27 2010-10-26 Elan Pharmaceuticals, Inc. Pyrimidinyl sulfonamide compounds which inhibit leukocyte adhesion mediated by VLA-4
US7579466B2 (en) 2006-02-27 2009-08-25 Elan Pharmaceuticals, Inc. Pyrimidinyl sulfonamide compounds which inhibit leukocyte adhesion mediated by VLA-4
US8367836B2 (en) 2009-04-27 2013-02-05 Elan Pharmaceuticals, Inc. Pyridinone antagonists of alpha-4 integrins

Also Published As

Publication number Publication date
AU3343097A (en) 1998-01-21
JP2000516575A (en) 2000-12-12
KR20000022190A (en) 2000-04-25
NO986090D0 (en) 1998-12-23
PL330915A1 (en) 1999-06-07
CZ424998A3 (en) 1999-03-17
WO1998000395A1 (en) 1998-01-08
EP0907637A1 (en) 1999-04-14
NO986090L (en) 1998-12-23
SK176898A3 (en) 1999-05-07

Similar Documents

Publication Publication Date Title
CA2259224A1 (en) Phenylalamine derivatives as integrin inhibitors
AU735313B2 (en) Bicyclic aromatic amino acids
US6559144B2 (en) Bicyclic amino acids
SK412001A3 (en) Diacylhydrazine derivatives as integrin inhibitors
RU2234505C2 (en) Derivatives of chromenone and chromanone as integrin inhibitors
US6576637B1 (en) β-alanine derivatives
US20030171304A1 (en) Pyridine-2-yl-aminoalkyl carbonyl glycyl-$g(b)-alanine and derivatives thereof
EP1343764A1 (en) Urea and urethane derivatives as integrin inhibitors
KR20030022418A (en) Biphenyl derivatives and the use thereof as integrin inhibitors
CZ20033000A3 (en) Inhibitors of a(v)B6 integrins
MXPA01010294A (en) Dibenzoazulene derivatives for treating thrombosis, osteoporosis, arteriosclerosis.
JP2003507458A (en) Novel integrin αvβ3 inhibitor
US20030187289A1 (en) Biphenyl derivatives and the use thereof as integrin inhibitors
AU6828600A (en) Fluorene derivatives
MXPA98010586A (en) Phenylalanin derivatives as laintegr inhibitors
MXPA99007464A (en) Bicyclic amino acids
MXPA01004272A (en) Chromenone and chromanone derivatives as integrin inhibitors
CZ2001141A3 (en) Diacylhydrazine derivative functioning as integrin inhibitor, process of its preparation, its use and pharmaceutical preparation in which it is comprised

Legal Events

Date Code Title Description
FZDE Discontinued