WO1997044333A1

WO1997044333A1 - 1,2,4-oxadiazoles as adhesion-receptor antagonists

Info

Publication number: WO1997044333A1
Application number: PCT/EP1997/002555
Authority: WO
Inventors: Horst Juraszyk; Joachim Gante; Hanns Wurziger; Sabine Bernotat-Danielowski; Guido Melzer
Original assignee: Merck Patent Gmbh
Priority date: 1996-05-17
Filing date: 1997-05-20
Publication date: 1997-11-27
Also published as: DE19620041A1; AR007160A1; AU2957997A; ZA974234B

Abstract

The invention concerns novel compounds of formula (I), in which R?1, R2, R2', R3¿, U, V, W, X, Y, Ar, m, n, n', p and q have the meanings given in claim 1, and their salts. These compounds and their salts inhibit the bonding of fibrinogen to the corresponding receptor and can be used in the treatment of thrombosis, osteoporosis, tumour diseases, apoplexy, cardiac infarction, ischaemia, inflammations, arteriosclerosis and osteolytic diseases.

Description

1,2,4-OXADIAZOLE AS ADHESION RECEPTOR ANTAGONISTS

The invention relates to compounds of the formula I.

wherein

R ¹ NH ₂ , -C (= NH) -NH ₂ , H ₂ NC (= NH) -NH-, one simply

-C (= NH) -NH ₂ substituted phenyl, an unsubstituted or simply substituted by NH ₂ pyrimidinyl, tetrahydropyrimidinyl, pyridyl or tetrahydropyridyl, an unsubstituted or simply substituted by pyridyl

Piperazinyl or piperidinyl, where NH, NH _2l -C (= NH) -NH ₂ and H ₂ NC (= NH) -NH- also simply by A-CO, Ar-alk-CO, AO-CO, Ar-alk -O-CO or can be substituted by a conventional amino protecting group,

R ² , R ² each independently of one another are H, A-CO, AO-CO, A-sulfonyl, an unsubstituted or mono-, di- or triple by shark, A, AO, AO-CO, CONH ₂ , NH ₂ or NO ₂ substituted benzoyl, heteroaroyl or phenylsulfonyl radical,

R ³ OH, AO, NH-COOR ⁴ , an amino acid residue selected from a group consisting of Ala, β-Ala, 3-amino-3-alkylpropionic acid, 3-amino-3-alkynylpropionic acid, 3-amino-3-phenyl - propionic acid, aminomalonic acid, Asn, Asp, Arg, Cys, Gin, Glu, Gly, His, lle, Leu, Lys, Met, Phe, Pro, Sar, Ser, Thr, Trp, Taurin, Tyr, Val,

.CONFIRMATION COPY 7- where the amino acids mentioned can also be derivatized, and the amino acid residues are linked to the residue W via the amino group,

R ⁴ A or Ar-alk,

U is a bond or O,

V is a bond, O, CONH or S (O) _k ,

W CO or if V is a bond and n, p and q are zero, also SO ₂ ,

X, Y are each independently N or O, where X ≠ Y,

Ar unsubstituted or single, double or triple by shark, A,

AO, AO-CO, CONH ₂ , NH ₂ or NO ₂ substituted phenyl,

^' Shark F, Cl, Br or I,

A alkyl with 1-6 C atoms,

alk alkylene with 1-6 C atoms,

m 0, 1, 2, 3 or 4,

n, n ', q each independently of one another 0 or 1,

k, p are each independently 0, 1 or 2

mean,

where, as far as residues of optically active amino acids and amino acid derivatives are concerned, both the D and the L forms are included, as well as their salts.

Similar compounds are known from EP-A1-0 381 033.

The object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.

It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. Above all, they act as integrin inhibitors, in particular inhibiting the interactions of the αv integrin receptors with ligands. The compounds show particular effectiveness in the case of the integrins _αv p ₃ and α _v ßs. The compounds are particularly effective as adhesion receptor antagonists for the vitronectin receptor αvß _3. This effect can be demonstrated, for example, by the method described by JW Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).

B. Felding-Habermann and DA Cheresh describe in Curr. Opin. Cell. Biol. 5, 864 (1993) the meanings of integrins as adhesion receptors for a wide variety of phenomena and clinical pictures, especially with regard to the vitronectin receptor αvß ₃ -

The dependence of the development of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins is described by P.C. Brooks, R.A. Clark and D.A. Cheresh in Science 264, 569-71 (1994).

The possibility of inhibiting this interaction and thus inducing apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide is from PC Brooks, AM Montgomery, M. Rosenfeld, RA Reisfeld, T.-Hu, G. Klier and DA Cheresh in Cell 79, 1157-64 (1994). The experimental proof that the compounds according to the invention also prevent the attachment of living cells to the corresponding matrix proteins and accordingly also prevent the attachment of tumor cells to matrix proteins can be carried out in a cell adhesion test analogous to the method by F. Mitjans et al., J Cell Science 108, 2825-

2838 (1995).

P.C. Brooks et al. describe in J. Clin. Invest. 96, 1815-1822 (1995) αvß3 antagonists for combating cancer and for treating tumor-induced angiogenic diseases.

The compounds of the formula I according to the invention can therefore be used as active pharmaceutical ingredients, in particular for the treatment of tumor diseases, osteoporoses, osteolytic diseases and for suppressing angiogenesis in the pathological environment of the organism.

Compounds of formula I, the interaction of integrin receptors and ligands, such as. B. from fibrinogen to the fibrinogen receptor (glycoprotein llb / llla) prevent GPIIb / llla antagonists from spreading tumor cells through metastasis. This is evidenced by the following observations:

The spread of tumor cells from a local tumor into the vascular system takes place through the formation of micro-aggregates (micro thrombi) through interaction of the tumor cells with platelets. The tumor cells are shielded by the protection in the micro-aggregate and are not recognized by the cells of the immune system. The micro-aggregates can attach themselves to the vessel walls, which facilitates further penetration of tumor cells into the tissue. Since the formation of the microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on activated platelets, the GPIIa / IIIb antagonists can be regarded as effective metastasis inhibitors.

In addition to the binding of fibrinogen, fibronectin and the Willebrand factor to the fibrinogen receptor of the platelets, compounds of the formula I also inhibit the binding of other adhesive proteins, such as vitro- nectin, collagen and laminin, to the corresponding receptors on the surface of different cell types. In particular, they prevent the formation of platelet thrombi and can therefore be used to treat thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis.

The properties of the compounds can also be demonstrated by methods which are described in EP-A1-0462 960. The inhibition of fibrinogen binding to the fibrinogen receptor can be demonstrated by the method specified in EP-A1-0 381 033. The antiplatelet effect can be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962).

The invention accordingly relates to compounds of the formula I according to claim 1 and / or their physiologically acceptable salts for the preparation of a medicament for use as integrin inhibitors.

The compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, for the prophylaxis and / or therapy of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, tumor diseases, osteolytic diseases such as osteoporosis, pathologically angiogenic diseases such as B. inflammation, ophthalmic diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative coiitis, Crohn's disease, atherosclerosis, psoriasis, restenosis, viral infection, biosafety, biosafety in acute kidney failure and in wound healing to support the healing processes.

The compounds of formula I can be used as antimicrobial substances in operations where biomaterials, implants, catheters or pacemakers are used. They have an antiseptic effect. The effectiveness of the antimicrobial activity can be by P.Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988).

The invention relates to the compounds of the formula I and their salts and to a process for the preparation of these compounds and theirs

Salts, characterized in

(a) liberating a compound of the formula I from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent,

or,

(b) that a compound of formula II

in which R ¹ , U, R ² , m and n 'have the meanings given in claim 1 and L is Cl, Br, I, OH or a reactive esterified OH group or a nucleophilically substitutable leaving group,

with a compound of formula III

wherein V, W, R ² , R ³ , Ar, n, p and q are those specified in claim 1

Have meanings

implements, or (c) that for the preparation of compounds of the formula I in which n 'is zero, a compound of the formula IV

where n '0, and

R ¹ , R ³ , U, V, W, X, Y, Ar, m, n, p and q are those specified in claim 1

Have meanings

with a compound of formula V

R ² LV

where L is Cl, Br, I, OH or a reactive esterified OH group or a nucleophilically substitutable leaving group,

implements, or

(d) converting an amino group into a guanidino group by reaction with an amidinizing agent,

or,

(e) converting an R ³ radical into another R ³ radical by saponifying an ester of the formula I or esterifying a carboxylic acid of the formula I,

or,

(f) converting a methylsulfinimidoyl group to an amidine group, - «-

and / or converts a base or acid of the formula I into one of its salts.

For all residues or parameters that occur several times, such as B. n or R ² , applies that their meanings are independent of each other.

Compounds of formula I which have one or more centers of chirality can occur in various enantiomeric forms. All of these forms (e.g. R and S forms) and their mixtures (e.g. the RS forms) are included in Formula I.

The abbreviations of amino acid residues listed above and below stand for the residues of the following amino acids:

Ala alanine

Asn asparagine

Asp aspartic acid

Arg arginine

Cys cysteine

Gin glutamine

Glu glutamic acid

Gly glycine isoleucine

Leu leucine

Lys lysine

With methionine

Phe phenylalanine

Per proline

Sar Sarcosine

Ser Serin

Thr threonine

Trp tryptophan

Tyr tyrosine

Val valine. - 7 -

Furthermore, below mean:

BOC tert-butoxycarbonyl

CBZ benzyloxycarbonyl

DCCI dicyclohexylcarbodiimide

DMF dimethylformamide

Et ethyl

Fmoc 9-fluorenylmethoxycarbonyl

HOBt 1 -hydroxybenzotriazole

Me methyl

MBHA 4-methyl-benzhydrylamine

Mtr 4-methoxy-2,3,6-trimethylphenyl sulfonyl

OBut tert-butyl ester

OMe methyl ester

OEt ethyl ester

POA phenoxyacetyl

TFA trifluoroacetic acid

Trt trityl (triphenylmethyl).

If the above-mentioned amino acids can occur in several enantiomeric forms, then above and below, for. B. as a component of the compounds of the formula I, including all these forms and also their mixtures (for example the DL forms). Furthermore, the amino acids, e.g. B. as part of compounds of formula I, provided with corresponding protective groups known per se.

In the above formulas, alkyl has 1 to 6, preferably 1, 2, 3 or 4, carbon atoms. Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert. -Butyl, also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4- Methylpentyl, 1, 1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1- Ethyl-2-methylpropyl, 1, 1,2- or 1,2,2-trimethylpropyl. - to-

Furthermore, alkyl means cyclobutyl, methylene cyclobutyl, cyclopentyl, methylene cyclopentyl, cyclohexyl or methylene cyclohexyl, methylene cyclopropyl or cyclopropyl.

Alkylene preferably means methylene, ethylene, propylene, but also butylene, pentylene or hexylene.

Alkynyl is preferably ethynyl, propynyl, butynyl, pentynyl or hexynyl.

Alkanoyl preferably means formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, furthermore nonanoyl or decanoyl.

Ar is phenyl, preferably - as indicated - monosubstituted phenyl, in particular preferably phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-aminophenyl, o-, m- or p-aminocarbonylphenyl, o-, m- or p-nitrophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p- Chlorophenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-ethoxycarbonylphenyl, more 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- Bromine-4-methyl, 3-bromo-5-methyl or 3-methyl-4-bromophenyl, 2,5- or 3,4-dimethoxyphenyl.

Aralkanoyl is preferably benzoyl, unsubstituted, preferably - as indicated - monosubstituted phenylacetyl, in particular preferably phenylacetyl, o-, m- or p-methoxyphenylacetyl, o-, m- or p-ethoxyphenylacetyl, o-, m- or p-fluorophenylacetyl, o-, m- or p- - ι ι -

Bromophenylacetyl, o-, m- or p-chlorophenylacetyl, o-, m- or p-methylphenyiacetyl, o-, m- or p-ethylphenylacetyl, o-, m- or p-aminophenylacetyl, o-, m - or p-nitrophenylacetyl, o-, m- or p-aminocarbonyi-phenylacetyl, o-, m- or p-methoxycarbonylphenylacetyl, more preferably 3-phenylpropionyl, 4-phenylbutyryl, 5-phenylpentanoyl or 6-phenylhexanoyl.

Alkoxycarbonyl preferably means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, further also isopropoxycarbonyl, tert-butoxycarbonyl or hexyloxycarbonyl.

Alkylsulfonyl preferably means methylsulfonyl, furthermore ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl or tert. -Butylsulfonyl, also pentylsulfonyl or 1-, 2- or 3-methylbutylsulfonyl.

Heteroaroyl is preferably furan-2- or 3-carbonyl, thiophene-2-or 3-carbonyl, pyrrole-1-, 2- or 3-carbonyl, imidazole-1-, 2-, 4- or 5-carbonyl, pyrazole- 1-, 3-, 4- or 5-carbonyl, oxazole-2-, 4- or 5-carbonyl, isoxazole-3-, 4- or 5-carbonyl, thiazole-2-, 4- or 5-carbonyl, isothiazole -3-, 4- or 5-carbonyl, pyridine-2-, 3- or 4-carbonyl, pyrimidine-2-, 4-, 5- or 6-carbonyl, further preferably 1, 2,3-triazole-1- , -4- or -5-carbonyl, 1,2,4-triazole-1-, -3- or 5-carbonyl, tetrazole-1- or 5-carbonyl, 1,2,3-oxadiazole-4- or - 5-carbonyl, 1, 2,4-oxadiazole-3- or -5-carbonyl, 1, 3,4-thiadiazole-2- or -5-carbonyl, 1, 2,4-thiadiazole-3- or -5- carbonyl, 1, 2,3-thiadiazole-4- or -5-carbonyl, pyridazin-3- or 4-carbonyl, pyrazine-carbonyl, benzofuran-2-, 3-, 4-, 5-, 6- or 7- carbonyl, indole-1-, 2-, 3-, 4-, 5-, 6- or 7-carbonyl, benzimidazole-1-, 2-, 4- or 5-carbonyl or quinolinyl-2-, 3-, 4 -, 5-, 6-, 7- or 8-carbonyl.

R ¹ is preferably NH ₂ , -C (= NH) -NH ₂ , H ₂ NC (= NH) -NH-

Piperazinyl, 4- (4-pyridyl) -piperazin-1-yl, more preferably a phenyl radical substituted by -C (= NH) -NH ₂ , 5-pyrimidinyl or 2-amino-5-pyrimidinyl, 1, 4, 5,6-tetrahydropyrimidinyl or 2-amino-1,4,5,6-tetra-hydropyrimidinyl, 2-amino-3,4,5,6-tetrahydropyridin-4- or 5-yl, 3- or 4- Piperidinyl or 1- (4-pyridyl) -piperidin-3- or 4-yl, furthermore 2-, 3- or 4-pyridyl or 2-amino-4- or 5-pyridyl.

R ² is preferably H, alkanoyl, alkoxycarbonyl, alkylsulfonyl, unsubstituted benzoyl, heteroaroyl or alkylsulphonyl, preferably - as indicated - monosubstituted benzoyl, in particular preferably benzoyl, o-, m- or p-methylbenzoyl, o-, m- or p- Ethylbenzoyl, o-, m- or p-propylbenzoyl, o-, m- or p- isopropylbenzoyl, o-, m- or p-tert-butylbenzoyl, o-, m- or p-aminobenzoyl, o-, m- or p-aminocarbonyl benzoyl, o-, m- or p-nitrobenzoyl, o-, m- or p-methoxybenzoyl, o-, m- or p-ethoxybenzoyl, o-, m- or p-fluorobenzoyl, o-, m - or p-bromobenzoyl, o-, m- or p-chlorobenzoyl, o-, m- or p-methoxycarbonyl-benzoyl, o-, m- or p-ethoxycarbonylbenzoyl, more preferably 2,3-, 2,4 -, 2,5-, 2,6-, 3,4- or 3,5-difluorobenzoyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3, 5- dichlorobenzoyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromobenzoyl, 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-chlorobenzoyl, 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-bromobenzoyl, 2,5- or 3,4-dimethoxybenzoyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, Butylsulfonyl, phenylsulfonyl or p-tolylsulfonyl.

The amino acids and amino acid residues mentioned for R ³ can also be derivatized, the N-methyl, N-ethyl, N-propyl, N-benzyl, N-phenethyl or C _α -methyl derivatives being preferred are.

R ³ very particularly preferably denotes hydroxy, alkoxy, Ala, β-Ala, 3-amino-3-alkylpropionic acid, 3-amino-3-alkynylpropionic acid, 3-amino-3-phenylpropionic acid, Asn, Asp, Gly, Pro, Sar, Ser, N-benzylglycine, N-phenethylglycine, N-benzyl-ß-alanine, N-phenethyl-ß-alanine, aminomalonic acid, and the alkyl esters, especially the methyl or ethyl esters of the above amino acids or amino acid derivatives. Alkoxy preferably means methoxy, ethoxy, propoxy, butoxy or tert-butoxy.

The propyl, butyl, tert-butyl, neopentyl or benzyl esters of the carboxy groups are further preferred.

Furthermore, the derivatives of Asp and Glu are preferred, in particular the methyl, ethyl, propyl, butyl, tert-butyl, neopentyl or benzyl esters of the side chain carboxy groups, and also derivatives of Arg which is located on the -NH-C (= NH) -NH ₂ group can be substituted with an acetyl, benzoyl, methoxycarbonyl or ethoxycarbonyl radical.

Amino protecting group preferably means acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl.

Shark preferably means F, Cl or Br, but also I.

if in the compounds of the formula I the parameter n ', n or q is zero, the remainder NHR ^2' , NHR ² or q is also missing. The meaning of X is always not the same as that of Y.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Ig, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which

WV

u is a bond, m, n, n ', p and q 0, XO,

Y N,

V is a bond and w is CO;

WV

u is a bond, m, n and n '0,

X O,

Y N,

V O,

P 1 or 2 and

W is CO;

u is a bond, n, n 'and p 0,

X O,

Y N,

V is a bond and w is CO;

U is a bond, m, n, n ', p and q 0, X O,

Y N,

V represents a bond and W SO ₂ ;

^<>

U is a bond, n, n 'and p 0,

X 0,

Y N,

V a bond and

W is CO;

in lf R ¹ a simply substituted by -C (= NH) -NH ₂

Phenyl radical, 4-piperidyl or 4-pyridyl,

R ³ OH or ß-Ala,

U a bond,

V is a bond or O, w CO,

X 0,

Y N, m 0, 1, 2 or 3, n, n 'O and

P 1;

u is a bond, m and n '0,

X O,

Y N,

V O or CONH,

P 1, n 1 and w represent CO;

The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) are described, under reaction conditions that are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.

The compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis or by hydrogenolysis.

Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, preferably those which instead of an H atom, which is connected to an N atom carry an amino protective group, in particular those which carry an R'-N group instead of an HN group, in which R ^! represents an amino protective group, and / or those which carry a hydroxyl protective group instead of the H atom of a hydroxyl group, for example those which correspond to the formula I, but carry a group -COOR "instead of a group -COOH, where R" denotes a hydroxyl protective group.

Several - identical or different - protected amino and / or hydroxy groups can also be present in the molecule of the starting material. If the existing protective groups are different from one another, they can in many cases be split off selectively.

The term "amino protecting group" is generally known and refers to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other locations in the molecule is. Typical of such groups are special unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term "acyl group" is to be understood in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are

Alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred

Amino protecting groups are BOC and Mtr, also CBZ, Fmoc, benzyl and acetyl.

The term "hydroxyl protecting group" is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the unsubstituted or substituted aryl, aralkyl or acyl groups mentioned above, and also alkyl groups. The nature and size of the hydroxyl protective groups is not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred. Examples of hydroxy protecting groups include Benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred. The COOH groups in aspartic acid and glutamic acid are preferably protected in the form of their tert-butyl esters (eg Asp (OBut)).

The liberation of the compounds of formula I from their functional derivatives succeeds - depending on the protective group used - z. B. with strong acids, suitably with TFA or perchloric acid, but also with -1 * 9- other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).

The groups BOC, OBut and Mtr can e.g. B. preferably with TFA in dichloromethane or with about 3 to 5N HCl in dioxane at 15-30 °, the FMOC group with an about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15 -30 °.

The trityl group is used to protect the amino acids histidine, asparagine, glutamine and cysteine. Depending on the desired end product, the cleavage takes place with TFA / 10% thiophenol, the trityl group being cleaved from all of the amino acids mentioned

Use of TFA / anisole or TFA / thioanisole only cleaves the trityl group from His, Asn and Gin, whereas it remains on the Cys side chain.

Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) can e.g. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal). Suitable solvents are the above, especially z. B. alcohols such as methanol or ethanol or amides such as DMF. Hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° and pressure between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds e.g. B. good on 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °.

Compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III. The starting compounds of the formula II and III are generally new. However, they can be produced by methods known per se.

In the compounds of formula II L is preferably Cl, Br, I or a reactively modified OH group such as e.g. an activated ester or an imidazolide, which are commonly used in the various peptide coupling methods.

The reaction is usually carried out in an inert solvent, in the presence of an acid-binding agent, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metal or alkaline earth metal, preferably potassium, sodium, calcium or cesium. The addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the amide component of the formula II or the alkylation derivative of the formula III can also be favorable. Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature is between about 0 ° and 150 °, normally between 20 ° and 130 °.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Sulfur carbon; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

The reaction of the compounds of formula IV with compounds of formula V is preferably carried out in an inert solvent, with the addition of a base and at temperatures as indicated above.

In the compounds of formula V, L is preferably Cl or Br.

Derivatives with a free primary or secondary amino group are expediently implemented in protected form. The aforementioned groups can be used as protective groups.

To prepare compounds of the formula I in which R ^{1 is} H ₂ NC (= NH) -NH-, a corresponding aminophenyl compound can be treated with an amidinating agent. 1-Amidino-3,5-dimethylpyrazole (DPFN), which is used in particular in the form of its nitrate, is preferred as the amidizing agent. It is advantageous to work with the addition of a base such as triethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, for example water / dioxane, at temperatures between 0 and 120 ° C., preferably between 60 and 120 ° C.

For the esterification, an acid of the formula I (R 3 = OH) can be treated with an excess of an alcohol (R ³ = alkoxy or benzyl), advantageously in the presence of a strong acid such as hydrochloric acid or sulfuric acid at temperatures between 0 and 100 ° C, preferably between 20 and 50 ° C.

Conversely, an ester of the formula I (R ³ = alkoxy or benzyl) can be converted into the corresponding acid of the formula I (R ³ = OH), advantageously by solvolysis using one of the methods given above, for example using NaOH or KOH in water dioxane at temperatures between 0 and 40 ° C, preferably between 10 and 30 ° C. To produce an amidine of the formula I (R ¹ = -C (= NH) -NH ₂ ), ammonia can be added to a nitrile of the formula I (R ¹ = CN). The addition is preferably carried out in several stages by, in a manner known per se, a) converting the nitrile with H ₂ S into a thioamide, which is converted into the corresponding S-alkylimidothioester using an alkylating agent, for example CH ₃ I, which in turn, reacts with NH ₃ to form the amidine, b) converting the nitrile with an alcohol, for example ethanol in the presence of HCl, into the corresponding imidoester and treating it with ammonia, or c) reacting the nitrile with lithium bis (trimethylsilyl) amide and the product then hydrolyzed.

Furthermore, free amino groups can be acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between 60 and + 30 °.

A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. Thus, inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polycarbonate, sulfone - or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isoniconic acid sulfonic acid, methane acid sulfonic acid, methane acid 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.

On the other hand, compounds of formula I with bases (e.g. sodium or potassium hydroxide or carbonate) can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salts.

The invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.

The invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.

These preparations can be used as medicinal products in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used in particular for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants for which are used for parenteral use topical application ointments, creams or powder. The new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables. The specified preparations can be sterilized and / or auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active ingredients, for example one or more vitamins.

The compounds of formula I and their physiologically acceptable

Salts can be used to combat diseases, particularly hypertension and heart failure.

The substances according to the invention are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg / kg body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, and on the rate of excretion , Drug combination and severity of the respective disease to which the therapy applies. Oral application is preferred.

All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, dried organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel, the isomers described below also being separated and / or by crystallization. Rf values on silica gel; Mobile solvent: ethyl acetate / methanol 9: 1.

The 4- (carboxyethylaminocarbonyl) phenyl radical occurring in the examples below means

is the 4- (sulfoethylaminocarbonyl) phenyl radical

example 1

A solution of 14.7 g of 3-cyanobenzoic acid, 21.5 g of hydroxylamine hydrochloride and 58 g of potassium carbonate in 600 ml of methanol and 25 ml of water is heated under reflux. It is worked up as usual, the residue is dissolved in water, acidified and obtained after the

16.8 g of 3- [amino- (hydroxyimino) methyl-] benzoic acid, F.

220 °.

A solution of 13.3 g of 3- [amino- (hydroxyimino) methyl-] benzoic acid

("C") and 12.23 g of 4-cyanobenzoyl chloride in 150 ml of glacial acetic acid are heated under reflux. The mixture is worked up in the customary manner, recrystallized from DMF, and 3- [5- (4-cyanophenyl) -1, 2,4-oxadiazol-3-yl] benzoic acid, mp> 300 ° is obtained. A solution of 2.0 g of 3- [5- (4-cyanophenyl) -1, 2,4-oxadiazol-3-yl] benzoic acid, 1.25 g of β-alanine tert-butyl ester hydrochloride, 1st , 2 g of HOBt, 1.45 g of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride and 1.53 g of N-methylmorpholine in 25 ml of DMF are stirred for one hour at room temperature. The mixture is worked up in the customary manner and 2.86 g of 5-p-cyanophenyl-3- [3- (tert-butoxycarbonyl-ethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole, mp 188-190 ° are obtained.

2.8 of this compound is saturated with hydrogen sulfide in a mixture of 40 ml of pyridine, 5 ml of triethylamine and 5 ml of DMF with ice cooling. The solvents are removed in vacuo and 2.96 g of 5-p-thiocarbamoylphenyl-3- [3- (tert-butoxycarbonyl-ethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole, m.p. 178 °.

2.9 g of the last-mentioned compound are suspended in 100 ml of acetone and stirred with 16.9 ml of methyl iodide at room temperature. The mixture is worked up as usual and 3.71 g of 5-p-methylsulfinirnidoy! Phenyl-3- [3- (tert-butoxycarbonyl-ethylaminocarbonyl) phenylj-1, 2,4-oxadiazole, hydroiodide, mp 183-185 ° (dec.).

A solution of 3.6 g of 5-p-methylsulfonimidoylphenyl-3- [3- (tert-butoxycarbonylethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole, hydroiodide and 5.6 g of ammonium acetate in 300 ml Methanol is stirred at room temperature.

After customary working up, 1.8 g of 5-p-amidino-phenyl-3- [3- (tert-butoxycarbonyl-ethylaminocarbonyl) -phenyl] -1, 2,4-oxadiazole, mp 298-302 ° (dec .). 1.0 g of 5-p-amidino-phenyl-3- [3- (tert-butoxycarbonyl-ethylaminocarbonyl) phenyl] -1,2,4-oxadiazole is added in 12 ml of HCl-saturated dioxane with the addition of 2.4 ml of water stirred at room temperature. After usual working up, 0.86 g of 5-p-amidino-phenyl-3- [3- (carboxyethylamino-carbonyl) -phenyl] -1, 2,4-oxadiazole, hydrochloride, mp 291-292 °.

One obtains analogously by ester hydrolysis

of 5-p-amidino-phenyl-3- [4- (tert-butoxycarbonyl-ethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole

5-p-Amidino-phenyl-3- [4- (carboxyethylaminocarbonyl) phenyl] - ^' 1, 2,4-oxadiazole, mp 293 °.

Example 2

Analogously to Example 1, starting from 3-cyanophenol and hydroxylamine hydrochloride, the 3- [amino- (hydroxyimino) methyl-] phenol is obtained,

Hydrochloride, mp 220 °.

Subsequent reaction with 4-cyanbenzoyl chloride gives 3-

[5- (4-cyanophenyl) -1,2,4-oxadiazol-3-yl] phenol, mp 212-217 °.

With bromoacetic acid tert-butyl ester, this product gives 5-p-cyano-phenyl-3- [3- (tert-butoxycarbonyl-methoxy) -phenyl] -1, 2,4-oxadiazole, F.

118-123 °.

By reaction analogous to Example 1, 5-p-amidino-phenyl

3- [3- (tert-butoxycarbonyl-methoxy) phenyl] -1, 2,4-oxadiazole.

Ester splitting gives 5-p-amidino-phenyl-3- [3- (carboxymethoxy) phenyl) -1,2,4-oxadiazole, hydrochloride, mp 288-290 °. One obtains analogously by ester hydrolysis

of 5-p-amidino-phenyl-3- [4- (tert-butoxycarbonyl-methoxy) -phenyl] -1, 2,4-oxadiazole 5-p-amidino-phenyl-3- [4- (carboxymethoxy) - phenyl] -1, 2,4-oxadiazole, hydrochloride, mp 288 ° (dec.).

Example 3

A solution of 3.25 g of 4- (1-BOC-piperidin-4-yl) butyric acid and 2.43 g of 1,1'-carbonyldiimidazole in 60 ml of THF is heated under reflux for 1.5 hours. In addition, 2.16 g of 4- [amino- (hydroxyimino) methyl] benzoic acid ("A") are dissolved in 60 ml of water with the addition of 4.1 ml of 2N sodium hydroxide solution. The solution of the butyric acid imidazolide derivative is dropped into this solution. The mixture is stirred for one hour, worked up as usual and 4- [4- (1- BOC-piperidin-4-yl) butyrylamino (hydroxyimino) methyl] benzoic acid, mp 157-159 °, is obtained.

2.6 g thereof are cyclized in pyridine at 100 ° C. After customary work-up, 2.3 g of 5- (BOC-piperidin-4-ylpropyl) -3- (4-carboxyphenyl) -1, 2,4-oxadiazole, mp 192-194 °.

By reacting 1.86 g of the above compound with 0.82 g of β-alanine tert-butyl ester ("B"), 5- (BOC-piperidin-4-ylpropyl) -3- [4- (tert-butoxycarbonyl-ethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole as an oil, which is then stirred in diethyl ether saturated with HCl. After customary working up, 0.45 g of 5- (piperidin-4-yl-propyl) -3- [4- (carboxyethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole, hydrochloride, mp 196 ° (dec. ).

Analogously, by gradually implementing and splitting off the protective groups, as described above,

of 1-BOC-piperidine-4-carboxylic acid with "A" and "B"

5- (piperidin-4-yl) -3- [4- (carboxyethylaminocarbonyl) phenyl] -1,2,4-oxadiazole, hydrochloride, mp 249-251 °;

of 1-BOC-piperidine-4-carboxylic acid with "C" and "B" - 2) -

5- (piperidin-4-yl) -3- [3- (carboxyethylaminocarbonyl) phenyl] -1,2,4-oxadiazole;

of 2- (1-BOC-piperidin-4-yl) acetic acid with "A" and "B" 5- (piperidin-4-ylmethyl) -3- [4- (carboxyethylaminocarbonyl) phenyl] -

1, 2,4-oxadiazole, hydrochloride, mp 92 ° (dec.);

of 2- (1-BOC-piperidin-4-yl) acetic acid with "C" and "B"

5- (piperidin-4-yimethyl) -3- [3- (carboxyethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole, hydrochloride, mp 154 ° (dec.);

of 4- (pyridin-4-yl) butyric acid with "A"

5- (pyridin-4-ylpropyl) -3- (4-carboxyphenyl) -1, 2,4-oxadiazole, mp 256-258 °;

of 3- (1-BOC-piperidin-4-yl) propionic acid with "A"

5- (piperidin-4-ylethyl) -3- (4-carboxy-phenyl) -1, 2,4-oxadiazole, hydrochloride, melting point> 290 ° and subsequent reaction with "B"

5- (piperidin-4-ylethyl) -3- [4- (carboxyethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole, hydrochloride, mp 264-265 °;

of 4- (pyridin-4-yl) butyric acid with "A" and "B"

5- (pyridin-4-ylpropyl) -3- [4- (carboxyethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole, hydrochloride, mp 244-245 °;

of 3- (1-BOC-piperidin-4-yl) propionic acid with "C"

5- (piperidin-4-ylethyl) -3- (3-carboxyphenyl) -1, 2,4-oxadiazoI, hydrochloride, mp 281 °;

of 1-BOC-piperidine-4-carboxylic acid with "C" and "B"

5- (piperidin-4-yl) -3- [3- (carboxyethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole, hydrochloride, mp 220-224 ° (dec.);

of 3- (1-BOC-piperidin-4-yl) propionic acid with "C" and "B" 5- (piperidin-4-ylethyl) -3- [3- (carboxyethylaminocarbonyl) phenyl] -

1, 2,4-oxadiazole, hydrochloride, mp 120 °; ~ 2 <P-

on 4- (1-BOC-piperidin-4-yl) butyric acid with "C" and "B"

5- (piperidin-4-ylpropyl) -3- [3- (carboxyethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole, hydrochloride, mp 85 ° (dec.);

on 4- (4-pyridyl) butyric acid with "C"

3- [Amino- (4- (4-pyridyl) butyryloxyimino) methyl] benzoic acid, mp 199 ° and therefrom by cyclization in pyridine at 100 °

5- (pyridin-4-ylpropyl) -3- (3-carboxyphenyl) -1, 2,4-oxadiazole, hydrochloride, mp 186-188 °;

of pyridine-4-carboxylic acid with "C" and "B"

5- (pyridin-4-yl) -3- [3- (carboxyethylaminocarbonyl) phenyl] -1,2,4-oxadiazole, hydrochloride, mp 225-226 °;

of pyridine-4-carboxylic acid with "A" and "B"

5- (pyridin-4-yl) -3- [4- (carboxyethylaminocarbonyl) phenyl] -1,2,4-oxadiazole, hydrochloride, mp 283-287 °;

of 4- (pyridin-4-yl) butyric acid with "C" and "B"

5- (pyridin-4-ylpropyl) -3- [3- (carboxyethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole, hydrochloride, mp 177-179 °;

After splitting off the BOC group from 5- (BOC-piperidin-4-ylpropyl) -3- (4-carboxy-phenyl) -1, 2,4-oxadiazole and usual work-up, 5- (piperidin-4-ylpropyl) is obtained. -3- (4-carboxyphenyl) -1, 2,4-oxadiazole, hydrochloride, mp 291-293 °.

Analogously, one obtains by conversion, removal of the protective groups and customary workup

of 4- (1-BOC-piperidin-4-yl) butyric acid with p- [amino- (hydroxyimino) methylj-phenylacetic acid

5- (piperidin-4-yl-propyl) -3- (p-carboxymethylphenyl) -1, 2,4-oxadiazole, hydrochloride, mp 256-258 °; of (S) -2,6-di- (BOC-amino) -hexanoic acid with "C" and "B"

(S) -5- (1,5-diaminopent-1-yl) -3- [3- (carboxyethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole;

of (S) -2-butylsulfonylamino-6-BOC-amino-hexanoic acid with "C" and "B"

(S) -5- (1-butylsulfonylamino-5-amino-1-pentyl) -3- [3- (carboxyethylaminocarbonyl) phenyl] -1,2,4-oxadiazole;

of 1-BOC-piperidine-4-carboxylic acid with (S) -O- [4- (amino- (hydroxyimino) methyl) phenyl] -N- (butylsulfonyl) serine

(S) -3- [4- (5- (4-piperidyl) -1,2,4-oxadiazol-3-yl -) phenoxy] -2- (butylsulfonylamino) propionic acid;

of 1-BOC-piperidine-4-carboxylic acid with "A" and (S) -2- (butylsulfonylamino) -ß-alanine tert-butyl ester

(S) -3- [4- (5- (4-Piperidyl) -1, 2,4-oxadiazol-3-yl) benzamido] -2- (butylsulfonylamino) propionic acid.

Analogously, the reaction of 1-BOC-Pipeπ ^' din-4-carboxylic acid with "C" and 3-amino-3-phenyl-propionic acid tert-butyl ester with subsequent removal of the protective groups

5- (piperidin-4-yl) -3- [3- (carboxy- (2-phenyl) ethylaminocarbonyl) phenyl] -1,2,4-oxadiazole, hydrochloride, mp 168 °;

Example 4

Analogously to Example 1, starting from 3-cyanophenol and hydroxylamine hydrochloride, the 3- [amino- (hydroxyimino) methyl-] phenol, hydrochloride, melting point 220 ° is obtained. Subsequent reaction with 4- (1-BOC-piperidin-4-yl) butyric acid analogously to Example 3 gives 3- [5- (1-BOC-piperidin-4-ylpropyl) -1, 2,4-oxadiazol-3 -yl] phenol.

With bromoacetic acid tert-butyl ester, this product gives 5- (1-BOC-piperidin-4-ylpropyl) -3- [3- (tert-butoxycarbonyl-methoxy) phenyl] -1, 2,4-oxadiazole. - 3o-

Splitting off the BOC and ester groups gives 5- (piperidin-4-ylpropyl) -3- [3- (carboxymethoxy) phenyl] -1, 2,4-oxadiazole, mp 241-245 °.

Analogously, 5- (1-BOC-piperidin-4-ylpropyl) -3- [4- (tert-butoxycarbonyl-methoxy) -phenyl] -1, 2,4-oxadiazole is obtained

5- (piperidin-4-ylpropyl) -3- [4- (carboxymethoxy) phenyl] -1, 2,4-oxadiazole.

Example 5

Analogously to Example 3, 1-BOC-piperidine-4-carboxylic acid and 3- [3- (amino- (hydroxyimino) methyl) benzene sulfonamido] propionic acid ("D", mp 139 °; obtainable by reacting 3 - (3-Cyanobenzenesulfonamido) propionic acid with hydroxylamine hydrochloride) the compound 3- [3- (amino- (1 -BOC-4-piperidinyl-carbonyloxyimino) methyl) -benzenesulfonamido] - propionic acid.

Cyclization in glacial acetic acid and cleavage of the BOC group give 5- (4-piperidinyl) -3- [3- (carboxyethylaminosulfonyl) phenyl] -1, 2,4-oxadiazole.

Analogue one gets through implementation

of 1-BOC-piperidine-4-carboxylic acid with 3- [4- (amino (hydroxyimino) methyl) benzenesulfonamido] propionic acid ("E") 5- (4-piperidinyl) -3- [4- (carboxyethylaminosulfonyl ) -phenyl] -1,2,4-oxadiazole, acetate, mp 253-260 ° (dec.);

of 2- (1-BOC-piperidin-4-yl) acetic acid with 'Ε "

5- (piperidin-4-ylmethyl) -3- [4- (carboxyethylaminosulfonyl) phenyl] -1, 2,4-oxadiazole;

of 2- (1-BOC-piperidin-4-yl) acetic acid with "D"

5- (piperidin-4-ylmethyl) -3- [3- (carboxyethylaminosulfonyl) phenyl] -1, 2,4-oxadiazole;

of 3- (1-BOC-piperidin-4-yl) propionic acid with 'Ε " - 3) -

5- (piperidin-4-ylethyl) -3- [4- (carboxyethylaminosulfonyl) phenylj-1, 2,4-oxadiazole;

on 4- (pyridin-4-yl) butyric acid with "E" 5- (pyridin-4-ylpropyl) -3- [4- (carboxyethylaminosulfonyl) phenyl] -

1, 2,4-oxadiazole;

of 3- (1-BOC-piperidin-4-yl) propionic acid with "D"

5- (piperidin-4-ylethyl) -3- [3- (carboxyethylaminosulfonyl) phenyl] -1, 2,4-oxadiazole;

of 4- (1-BOC-piperidin-4-yl) butyric acid with "D"

5- (piperidin-4-ylpropyl) -3- [3- (carboxyethylaminosulfonyl) phenyl] -1, 2,4-oxadiazole;

of pyridine-4-carboxylic acid with "D"

5- (pyridin-4-yl) -3- [3- (carboxyethylaminosulfonyl) phenyl] -1,2,4-oxadiazole;

of pyridine-4-carboxylic acid with "E"

5- (pyridin-4-yl) -3- [4- (carboxyethylaminosulfonyl) phenyl] -1,2,4-oxadiazole;

of 4- (pyridin-4-yl) butyric acid with "D" 5- (pyridin-4-ylpropyl) -3- [3- (carboxyethylaminosulfonyl) phenyl] -1, 2,4-oxadiazole.

Example 6

Analogously to Example 5, 1-BOC-piperidine-4-carboxylic acid and 3- [3- (amino- (hydroxyimino) methyl) -benzenesulfonamido] -ethanesulfonic acid are used to obtain the compound 3- [3- (amino- (1-BOC- 4-piperidinyl-carbonyloxyimino) methyl) benzenesulfonamidoj-ethanesulfonic acid. Cyclization in glacial acetic acid and cleavage of the BOC group give 5- (4-piperidinyl) -3- [3- (sulfoethylaminosulfonyl) phenyl] -1,2,4-oxadiazole. Analogue one gets through implementation

of 1-BOC-piperidine-4-carboxylic acid with 3- [4- (amino (hydroxyimino) methyl) benzenesulfonamido] ethanesulfonic acid

5- (4-piperidinyl) -3- [4- (sulfoethylaminosulfonyl) phenyl] -1, 2,4-oxadiazole;

of 1-BOC-piperidine-4-carboxylic acid with 3- [4- (amino- (hydroxyimino) methyl) benzamido] ethanesulfonic acid

5- (4-piperidinyl) -3- [4- (sulfoethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole;

of 1-BOC-piperidine-4-carboxylic acid with (2S) -2-benzenesulfonylamino-3- [4- (amino- (hydroxyimino) methyl) -benzoylaminoj-propionic acid, methyl ester

(2S) -2-benzenesulfonylamino-3- [4- (5-piperidin-4-yl- [1,2,4] oxadiazole-

3-yl) -benzoylamino] -propionic acid methyl ester, hydrochloride, mp 141 °, and subsequent ester cleavage (2S) -2-benzenesulfonylamino-3- [4- (5-piperidin-4-yl- [1,2,4] oxadiazole -

3-yl) benzoylamino] propionic acid, hydrochloride, mp 154 °;

of 1-BOC-piperidine-4-carboxylic acid with (2S) -2 - [(4-tolyl) sulfonylamino] -3- [4- (amino- (hydroxyimino) methyl) benzoylamino] propionic acid methyl ester

(2S) -2 - [(4-toyl) sulfonylamino] -3- [4- (5-piperidin-4-yl- [1, 2,4] oxadiazol-3-yl) benzoylamino] propionic acid methyl ester and subsequent Ester cleavage

(2S) -2 - [(4-toyl) sulfonylamino] -3- [4- (5-piperidin-4-yl- [1, 2,4] oxadiazol-3-yl) benzoylamino] propionic acid, hydrochloride , FAB 514.

Example 7

Analogously to Example 3, reaction of 3-nitropropionic acid with 3- [3- (amino- (hydroxyimino) methyl) benzene sulfonamido] propionic acid is obtained - 3T> -

("D") the compound 5- (2-nitroethyl) -3- [3- (carboxyethylaminosulfonyl) phenyl] -1, 2,4-oxadiazole.

By hydrogenation on palladium on activated carbon, 5- (2-

Aminoethyl) -3- [3- (carboxyethylaminosulfonyl) phenyl] -1, 2,4-oxadiazole.

Subsequent reaction with 3,5-dimethylpyrazole-1-form amidinium nitrate (DPFN) gives 5- (2-guanidinoethyl) -3- [3- (carboxyethylaminosulfonyl) phenyl] -1, 2,4- oxadiazole.

Example 8

Analogously to Example 1, the compound is obtained from 4-cyanobenzoyl chloride and 3- [3- (amino- (hydroxyimino) methyl) benzene sulfonamido] propionic acid ("D")

5- (4-Cyanophenyl) -3- [3- (carboxyethylaminosulfonyl) phenyl] -1, 2,4-oxadiazole.

Subsequent reaction with H ₂ S, subsequent methylation and reaction with ammonium acetate give 5-p-amidino-phenyl-3- [3- (carboxyethylaminosulfonyl) phenyl] -1, 2,4-oxadiazole.

Example 9

To a solution of (S) -3- [4- (5- (1-BOC-piperidin-4-yl) -1, 2,4-oxadiazol-3-yl) benzamido] -2-aminopropionic acid ( "F") in DMF, equimolar amounts of methylsulfonyl chloride and cesium carbonate are added. The mixture is stirred for one hour, worked up as usual and (S) -3- [4- (5- (1-BOC-piperidin-4-yl) -1,2,4-oxadiazol-3-yl) benzamido] is obtained. -2- (methylsulfonylamino) propionic acid.

Analogously, "F" and p-toluenesulfonyl chloride (S) -3- [4- (5- (1-BOC-piperidin-4-yl) -1, 2,4-oxadiazol-3-yl) benzamido] -

2- (p-tolylsulfonylamino) propionic acid.

By splitting off the BOC group you get from

(S) -3- [4- (5- (1-BOC-Piperidin-4-yl) -1,2,4-oxadiazol-3-yl) benzamido] -2- (methylsulfonylamino) propionic acid (S) -3- [4- (5- (Piperidin-4-yl) -1, 2,4-oxadiazol-3-yl) benzamido] -2- (methylsulfonylamino) propionic acid and from

(S) -3- [4- (5- (1-BOC-Piperidin-4-yl) -1, 2,4-oxadiazol-3-yl) -benzamidoj-2- (p-tolylsulfonylamino) propionic acid

(S) -3- [4- (5- (Piperidin-4-yl) -1, 2,4-oxadiazol-3-yl) benzamido] -2- (p-tolylsulfonylamino) propionic acid.

Example 10

Esterification with methanol gives 5- (piperidin-4-yl-propyl) -3- (p-carboxymethylphenyl) -1,2,4-oxadiazole

5- (Piperidin-4-yl-propyl) -3- (p-methoxycarbonylmethylphenyl) -1, 2,4-oxadiazole, acetate, mp 183 ° and

from 5- (piperidin-4-yl) -3- [3- (carboxyethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole

5- (Piperidin-4-yl) -3- [3- (methoxycarbonylethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole, hydrochloride, mp 190-191 °

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile . Each injection glass contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient. - 3s- - Example C: solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH ₂ PO ₄ .2H ₂ O, 28.48 g of Na ₂ HPO ₄ ^.12H ₂ O and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient .

Example F: coated tablets

Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G: capsules

2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.

Example H: ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, under sterile conditions. -34- lyophilized and sterile sealed. Each ampoule contains 10 mg of active ingredient.

Claims

claims

1. Compounds of formula I.

wherein

R ¹ NH ₂ , -C (= NH) -NH ₂ , H ₂ NC (= NH) -NH-, a phenyl radical which is simply substituted by -C (= NH) -NH ₂ , an unsubstituted or simply substituted by NH ₂ pyrimidinyl -, Tetrahydropyrimidinyl, pyridyl or tetrahydropyridyl radical, an unsubstituted or simply substituted by pyridyl piperazinyl or piperidinyl radical, whereby NH, NH ₂ , -C (= NH) -NH ₂ and H ₂ NC (= NH) -NH- also simple can be substituted by A-CO, Ar-alk-CO, AO-CO, Ar-alk-O-CO or by a conventional amino protecting group,

R ² , R ² each independently of one another H, A-CO, AO-CO,

A-sulfonyl, an unsubstituted or mono-, di- or trisubstituted by shark, alkyl, alkoxy, alkoxycarbonyl, CONH ₂ , NH ₂ or NO ₂ substituted benzoyl, heteroaroyl or phenylsulfonyl radical,

R ³ OH, AO, NH-COOR ⁴ , an amino acid residue selected from a group consisting of Ala, β-Ala, 3-amino-3-alkylpropionic acid, 3-amino-3-alkynylpropionic acid, 3-amino-3-phenylpropionic acid , Aminomalonic acid, Asn, Asp, Arg, Cys, Gin, Glu, Gly, - 3 * ~

His, Ile, Leu, Lys, Met, Phe, Pro, Sar, Ser, Thr, Trp, Taurine, Tyr, Val, where the amino acids mentioned can also be derivatized, and the amino acid residues are linked to the rest W via the amino group are,

R ⁴ A or Ar-alk,

U is a bond or O,

V is a bond, O, CONH or S (O) _k ,

W CO or if V is a bond and n, p and q are zero, too

SO ₂ ,

X, Y are each independently N or O, where X ≠ Y,

Ar unsubstituted or single, double or triple through

Shark, A, AO, AO-CO, CONH ₂ , NH ₂ or NO ₂ substituted phenyl,

Shark F, Cl, Br or I,

A alkyl with 1-6 C atoms,

alk alkylene with 1-6 C atoms,

_m 0, 1, 2, 3 or 4,

n, n ', q each independently of one another 0 or 1,

k, p are each independently 0, 1 or 2

mean, where, in the case of residues of optically active amino acids and amino acid derivatives, both the D and the L forms are included,

as well as their salts.

2. Compounds of formula I according to claim 1

a) 5-p-Amidino-phenyl-3- [3- (carboxyethylaminocarbonyl) phenyl] -

1,2,4-oxadiazole;

b) 5-p-amidino-phenyl-3- [3- (carboxymethoxy) phenyl] -1, 2,4-oxadiazole;

c) 5- (4-piperidinyl) -3- [4- (carboxyethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole;

d) 5- (piperidin-4-ylpropyl) -3- [4- (carboxyethylaminocarbonyl) phenyl] -1,2,4-oxadiazole;

e) 5- (pyridin-4-ylpropyl) -3- (3-carboxyphenyl) -1, 2,4-oxadiazole;

f) 5- (4-pyridinyl) -3- [4- (carboxyethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole;

g) 5- (4-piperidinyl) -3- [4- (carboxyethylaminosulfonyl) phenyl] -1,2,4-oxadiazole;

h) 5- (4-piperidinyl) -3- [4- (sulfoethylaminocarbonyl) phenyl] -1, 2,4-oxadiazole;

and their physiologically acceptable salts.

3. A process for the preparation of compounds of the formula I as claimed in claim 1 and their salts, characterized in that (a) liberating a compound of formula I from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent,

or,

(b) that a compound of formula II

with a compound of formula III

wherein V, W, R ² , R ³ , Ar, n, p and q are those specified in claim 1

Have meanings

implements, or

(c) that for the preparation of compounds of the formula I in which n 'is zero, a compound of the formula I. ~ <1 year -

where n '0, and

R ¹ , R ³ , U, V, W, X, Y, Ar, m, n, p and q have the meanings given in Claim 1,

with a compound of formula V

R ² LV

implements, or

or,

(e) converting a radical R into another radical R by saponifying an ester of the formula I or esterifying a carboxylic acid of the formula I,

or,

(f) converting a methylsulfinimidoyl group to an amidine group,

and / or converts a base or acid of the formula I into one of its salts.

4. A process for the preparation of pharmaceutical preparations, characterized in that a compound of the formula I according to Claim 1 and / or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid carrier or auxiliary.

5. Pharmaceutical preparation, characterized in that it contains at least one compound of the formula I as claimed in claim 1 and / or one of its physiologically acceptable salts.

6. Compounds of formula I according to claim 1 and their physiologically acceptable salts as GPIIb / llla antagonists for combating thrombosis, heart attack, coronary heart disease and

Arteriosclerosis.

7. Compounds of the formula I according to claim 1 and their physiologically acceptable salts as αv-integrin inhibitors for combating pathologically angiogenic diseases, tumors, osteoporosis,

Inflammation and infection.

8. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the manufacture of a medicament.

9. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts in the fight against thromboses, heart attacks, coronary heart diseases, arteriosclerosis, apoplexy, tumors, osteoporosis,

Inflammation and infection.