DE19620041A1 - Adhesion receptor antagonists - Google Patents

Description

The invention relates to compounds of the formula I.

wherein
R¹ NH₂, -C (= NH) -NH₂, H₂N-C (= NH) -NH-, a phenyl radical substituted simply by -C (= NH) -NH₂, an unsubstituted or simply substituted by NH₂ pyrimidinyl, tetrahydro pyrimidinyl- , Pyridyl or tetrahydropyridyl radical, an unsubstituted or simply substituted by pyridyl piperazinyl or piperidinyl radical,
where NH, NH₂, -C (= NH) -NH₂ and H₂N-C (= NH) -NH- also simply by A-CO, Ar-alk-CO, AO-CO, Ar-alk-O-CO or by a conventional amino protecting group can be substituted,
R², R ^{2 '} each independently of one another H, A-CO, AO-CO, A-sulfonyl, an unsubstituted or mono-, di- or trisubstituted by Hal, A, AO, AO-CO, CONH₂, NH₂ or NO₂ substituted benzoyl -, heteroaroyl or phenylsulfonyl,
R³ OH, AO, NH-COOR⁴, 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, His, Ile, Leu, Lys, Met, Phe, Pro, Sar, Ser, Thr, Trp, Taurin, Tyr, Val,
wherein the amino acids mentioned can also be derivatized and the amino acid residues are linked to the residue W via the amino group,
R⁴ 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 and p are zero, also SO₂,
X, Y are each independently N or O, where X ≠ Y,
Ar unsubstituted or mono-, di- or trisubstituted by Hal, A, AO, AO-CO, CONH₂, NH₂ or NO₂,
Hal 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 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 L forms are included,
as well as their salts.

Similar compounds are known from EP 0 381 033 A1.

The invention was based on the object, new compounds with value to find full properties, especially those that are manufactured medication can be used.

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 α _v integrin receptors with ligands. The compounds show particular effectiveness in the case of the integrins α _v β₃ and α _v β₅. The compounds are particularly effective as adhesion receptor antagonists for the vitronectin receptor α _v β₃. This effect can e.g. B. can be detected 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 in relation to the vitronectin receptor α _v β₃.

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

The possibility of inhibiting this interaction and thus to Initiation of apoptosis (programmed cell death) angiogenic vascular Cells by a cyclic peptide is from P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T.-Hu, G. Klier and D.A. Cheresh at 79 Gell, 1157-64 (1994).  

The experimental evidence that the verb the attachment of living cells to the corresponding Prevent matrix proteins and, accordingly, the attachment of Preventing tumor cells from matrix proteins can result in cell adhesion test analogous to the method of F. Mitjans et al., J. Cell Science 108, 2825-2838 (1995).

PC Brooks et al. describe in J. Clin. Invest. 96, 1815-1822 (1995) α _v β₃ antagonists for combating cancer and for treating tumor-induced angiogenic diseases.

The compounds of formula I according to the invention can therefore as Active pharmaceutical ingredients, in particular for the treatment of tumor cranes kung, osteoporosis, osteolytic diseases as well as under oppression of angiogenesis in the pathological environment of the organism be used.

Compounds of formula I, the interactions of integrin receptors and ligands, such as. B. from fibrinogen to the fibrinogen receptor (glycoprotein IIb / IIIa) prevent GPIIb / IIIa 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 occurs through the formation of microaggregates (micro thrombi) through the 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 stick to the walls of the vessel, causing further penetration of tumor cells into the tissue is facilitated. Since the formation of the microthrombi by fibrinogen binding to the fibri nogenreceptors mediated on activated platelets, can GPIIa / IIIb antagonists regarded as effective metastasis inhibitors will.

Compounds of the formula I inhibit the binding of fibrinogen, Fibronectin and the Willebrand factor to the fibrinogen receptor Platelets also bind other adhesive proteins, such as Vitro  nectin, collagen and laminin, to the appropriate receptors on the Surface of different cell types. In particular, they prevent that Formation of platelet thrombi and can therefore be used for treatment of thrombosis, apoplexy, heart attack, inflammation and arterio sclerosis can be used.

The properties of the compounds can also be determined by methods can be detected, which are described in EP 0 462 960 A1. The Inhibition of fibrinogen binding to the fibrinogen receptor can occur after the method can be demonstrated, which is in EP 0 381 033 A1 is specified. The antiplatelet effect has in vitro using the Born method (Nature 4832, 927-929, 1962) to prove.

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

The compounds of formula I can be used as active pharmaceutical ingredients in the Human and veterinary medicine are used for prophylaxis and / or Therapy of thrombosis, myocardial infarction, arteriosclerosis, inflammation exercises, apoplexy, angina pectoris, tumor diseases, osteolytic Diseases such as osteoporosis, pathologically angiogenic diseases such as e.g. B. inflammation, ophthalmic diseases, diabetic Retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic glaucoma, ulcerative Colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angio plastic, viral infection, bacterial infection, fungal infection, in acute Kidney failure and wound healing to support healing processes.

The compounds of formula I can act as antimicrobial sub punches are used in operations where biomaterials, implants, Catheters or pacemakers can be used. They work here antiseptic. The effectiveness of the antimicrobial activity can be  by P. Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988) described methods can be detected.

The invention relates to the compounds of formula I and their Salts and a process for the preparation of these compounds as well of their salts, characterized in

• (a) that a compound of formula I from one of its functional derivatives by treatment with a solvolysing or sets hydrogenolysing agents free,

or,

• (b) that a compound of formula II wherein R¹, 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 easily nucleophilically substitutable leaving group,

with a compound of formula III

wherein
V, W, R², R³, n and p have the meanings given in Claim 1,
implements, or

• (c) that for the preparation of compounds of formula I, wherein n 'is zero, a compound of formula IV wherein

n ′ 0, and
R¹, R³, U, V, W, X, Y, m, n and p have the meanings given in claim 1,
with a compound of formula V

R²-L V

wherein
L denotes Cl, Br, I, OH or a reactive esterified OH group or easily nucleophilically substitutable leaving group,
implements, or

• (d) that an amino group by reaction with a converts amidinating agents into a guanidino group,

or,

• (e) converting one R³ residue into another R³ residue, by saponifying an ester of formula I, or a carboxylic acid Formula I esterified

or,

• (f) that a methylsulfinimidoyl group into an amidine group convicted,

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

For all residues or parameters that occur several times, such as B. n or R², applies that their meanings are independent of each other.

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

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

Ala alanine
Asn asparagine
Asp aspartic acid
Arg arginine
Cys cysteine
Gln glutamine
Glu glutamic acid
Gly glycine
Ile isoleucine
Leu leucine
Lys lysine
With methionine
Phe phenylalanine
Per proline
Sar Sarcosine
Ser Serin
Thr threonine
Trp tryptophan
Tyr tyrosine
Val valine

Furthermore, below mean:

BOC tert-butoxycarbonyl
CBZ benzyloxycarbonyl
DCCl 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)

Provided the above amino acids in several enantiomers Shapes can occur, are above and below, z. B. as Be Part of the compounds of formula I, all of these forms and theirs Mixtures (e.g. the DL forms) included. Furthermore, the Amino acids, e.g. B. as part of compounds of formula I 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 preferably means methyl, furthermore 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.

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

Alkylene preferably means methylene, ethylene, propylene, and also also Butylene, pentylene or hexylene.

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

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-methoxy phenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methoxycarbonyl phenyl, 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-bromo-4-methyl, 3-bromo-5-methyl- or 3-methyl-4-bromophenyl, 2,5- or 3,4-dimethoxy phenyl.

Aralkanoyl preferably means benzoyl, unsubstituted, preferably wise - as indicated - monosubstituted phenylacetyl, in detail preferably phenylacetyl, o-, m- or p-methoxyphenylacetyl, o-, o-, m- or p-ethoxyphenylacetyl, o-, m- or p-fluorophenylacetyl, o-, m- or p- Bromophenylacetyl, o-, m- or p-chlorophenylacetyl, o-, m- or p-methyl phenylacetyl, o-, m- or p-ethylphenylacetyl, o-, m- or p-aminophenyl acetyl, o-, m- or p-nitrophenylacetyl, o-, m- or p-aminocarbonyl  phenylacetyl, o-, m- or p-methoxycarbonylphenylacetyl further ahead adds 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 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-thiadiazol-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 Quinolyl-2-, 3-, 4-, 5-, 6-, 7- or 8-carbonyl.

R¹ is preferably NH₂, -C (= NH) -NH₂, H₂N-C (= NH) -NH-, 4- Piperazinyl, 4- (4-pyridyl) -piperazin-1-yl, more preferably one by one -C (= NH) -NH₂ para-substituted phenyl, 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-tetrahydrnpyridin-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.  

R² is preferably H, alkanoyl, alkoxycarbonyl, alkylsulfonyl, unsubstituted benzoyl, heteroaroyl or alkylsulphonyl, preferably - as indicated - monosubstituted benzoyl, preferred in particular 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-, in- 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-bromo benzoyl, 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 R³ can also be derivatized, the N-methyl, N-ethyl, N-propyl, N-benzyl, N-phenethyl or C _α -methyl derivatives being preferred.

R³ very particularly preferably denotes hydroxyl, 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-β-alanine, N-phenethyl-β-alanine, aminomalon acid, and the alkyl esters, especially the methyl or ethyl esters Above amino acids or amino acid derivatives.

Alkoxy preferably means methoxy, ethoxy, propoxy, or butoxy tert-butoxy.  

The propyl, butyl, tert-butyl, neopentyl or Benzyl ester of the carboxy groups.

Also preferred are the derivatives of Asp and Glu, especially those Methyl, ethyl, propyl, butyl, tert-butyl, neopentyl or benzyl ester Side chain carboxy groups, also derivatives of Arg, which on the -NH-C (= NH) -NH₂ group with an acetyl, benzoyl, methoxycarbonyl or ethoxycarbonyl radical can be substituted.

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

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

If in the compounds of the formula I the parameter n ′ or n is zero, the remainder NHR ^{2 ′} or NHR² is also missing.

The meaning of X is always not the same as that of Y.

Accordingly, the invention relates in particular to those gene compounds of formula I in which at least one of the above Radicals has one of the preferred meanings given above. Some preferred groups of compounds can follow through the sub-formulas Ia to Ig are expressed, that of the formula I ent speak and in which the unspecified radicals that in the formula I have given meaning, however

The compounds of formula I and also the starting materials for their manufacture position are otherwise produced by methods known per se, as described in literature (e.g. in standard works such as Houben-Weyl, Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) are described, and under reaction conditions that for the mentioned implementations are known and suitable. You can  also of variants known per se, not mentioned here in more detail Make use.

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

The compounds of formula I can be obtained by using them from their functional derivatives by solvolysis, especially hydro lysis or released by hydrogenolysis.

Preferred starting materials for solvolysis or hydrogenolysis are those that otherwise correspond to formula I, but instead of an or corresponding to several free amino and / or hydroxy groups contain protected amino and / or hydroxy groups, preferably those that, instead of an H atom connected to an N atom, carry an amino protecting group, especially those that replace one Hn group carry an R'-N group, where R 'is an amino protecting group means, and / or those instead of the H atom of a hydroxy group carry a hydroxy protecting group, e.g. B. those of the formula I correspond, but instead of a group -COOH a group -COOR ′ ′ wear, wherein R '' is a hydroxy protecting group.

Several - identical or different - protected amino and / or hydroxyl groups present in the molecule of the starting material be. If the existing protecting groups are different from each other they can be split off selectively in many cases.

The term "amino protecting group" is well known and refers to on groups that are suitable, an amino group before chemical order to protect (block) settlements that are easily removable, after the desired chemical reaction elsewhere in the Molecule has been carried out. Typical of such groups are ins special unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protecting groups according to the desired Reaction (or sequence of reactions) to be removed is their type and size  the rest not critical; however, preference is given to those with 1-20, in particular special 1-8 carbon atoms. The term "acyl group" is related with the present procedure in the broadest sense. He around includes aliphatic, araliphatic, aromatic or hetero cyclic carboxylic acids or sulfonic acid derived acyl groups 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 like 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 "hydroxy protecting group" is also well known and refers to groups that are suitable for a hydroxy group protect chemical reactions that are easily removable, after the desired chemical reaction elsewhere in the Molecule has been carried out. They are typical of such groups unsubstituted or substituted aryl, aralkyl or Acyl groups, also alkyl groups. The nature and size of the hydroxy Protecting groups are not critical as they are chemical-based Reaction or sequence of reactions are removed again; are preferred Groups with 1-20, especially 1-10 carbon atoms. Examples of hydroxy protecting groups are a. 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 before protected in the form of their tert-butyl esters (e.g. Asp (OBut)).

The liberation of the compounds of formula I from their radio tional derivatives succeed - depending on the protective group used - e.g. B. with strong acids, suitably with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfur acid, strong organic carboxylic acids such as trichloroacetic acid or Sulfonic acids such as benzene or p-toluenesulfonic acid. The presence  an additional inert solvent is possible, but not always required. 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 carbons Hydrogen such as dichloromethane, also alcohols such as methanol, Ethanol or isopropanol, as well as water. There are also mixtures of aforementioned solvents in question. TFA is preferred in over shot used without the addition of another solvent, perchlor acid in the form of a mixture of acetic acid and 70% perchlorine acid in the ratio 9: 1. The reaction temperatures for the cleavage are expediently between about = and about 50 °, preferably working one between 15 and 30 ° (room temperature).

The groups BOC, OBut and Mtr can e.g. B. preferably with TFA in Di chloromethane or with about 3 to 5N HCl in dioxane at 15-30 ° be the FMOC group with an approximately 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 are used. The separation takes place depending on desired end product, with TFA / 10% thiophenol, the Trityl group is split off from all of the amino acids mentioned Only the trityl group is used with TFA / anisole or TFA / thioanisole split off from His, Asn and Gin, whereas on the Cys side chain remains.

Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) can e.g. B. by treatment with hydrogen in the presence of a catalyst (e.g. a noble metal catalyst such as palladium, expedient on a carrier such as coal). As a solvent are the above, especially z. B. alcohols such as Methanol or ethanol or amides such as DMF. The hydrogenolysis is in usually at temperatures between about 0 and 100 ° and printing between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar guided. Hydrogenolysis of the CBZ group succeeds e.g. B. good at 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 formula I can preferably be obtained by reacting compounds of formula II with compounds of formula III. The starting compounds of the formula II and III are generally new. she but can be prepared 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 B. an activated ester or an imidazolide, commonly found in the various peptides coupling methods are used.

The reaction is usually carried out in an inert solvent Presence of an acid-binding agent, preferably an alkali or Alkaline earth metal hydroxides, carbonates or bicarbonates or one other weak acid salt of the alkali or alkaline earth metals, preferably potassium, sodium, calcium or cesium. Also 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 be favorable. The Response time is between depending on the conditions used a few minutes and 14 days, the reaction temperature between about 0 ° and 150 °, usually between 20 ° and 130 °.

Suitable inert solvents are, for. B. 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; Nitrover  bonds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or Mixtures of the solvents mentioned.

Derivatives with a free primary or secondary amino group appropriately implemented in a protected form. Come as protection groups the aforementioned in question.

For the preparation of compounds of the formula I in which R¹ is H₂N-C (= NH) -NH- means you can use a corresponding aminophenyl compound treat an amidinating agent. The amidizing agent is 1- Amidino-3,5-dimethylpyrazole (DPFN) is preferred, especially in the form its nitrate is used. One works expediently with addition a base such as triethylamine or ethyl diisopropylamine in an inert Solvent or solvent mixture, e.g. B. water / dioxane Temperatures between 0 and 120 ° C, preferably between 60 and 120 ° C.

For the esterification, an acid of the formula I (R³ = OH) with a Treat excess alcohol (R³ = alkoxy or benzyl) moderately 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 formula I (R³ = alkoxy or benzyl) in the corresponding acid of formula I (R³ = OH) are converted, expediently by solvolysis according to one of the above Methods, e.g. B. with NaOH or KOH in water-dioxane at temperatures between 0 and 40 ° C, preferably between 10 and 30 ° C.

To produce an amidine of formula I (R¹ = -C (= NH) -NH₂) you can add ammonia to a nitrile of the formula I (R 1 = CN). The attachment is preferably carried out in several stages by, in a manner known per se: converts the nitrile with H₂S into a thioamide with an alkylation medium, e.g. B. CH₃I, converted into the corresponding S-alkyl imidothioester is, which in turn reacts with NH₃ to the amidine, b) the nitrile with an alcohol, e.g. B. ethanol in the presence of HCl in the corresponding Converts imidoesters and treats them with ammonia, or c) that  Nitrile with lithium bis (trimethylsilyl) amide and the product then hydrolyzed.

You can also free amino groups in the usual way with an acid chloride or anhydride or with an unsubstituted or Alkylate substituted alkyl halide, advantageously in an inert Solvents such as dichloromethane or THF and / or in the presence of one Base such as triethylamine or pyridine at temperatures between -60 and + 30 °.

A base of formula I can with an acid in the associated acid addition salt can be transferred, for example by reaction equi valent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. For this implementation In particular acids are considered, the physiologically harmless Deliver salts. So inorganic acids can be used, e.g. B. Sulfuric acid, nitric acid, hydrohalic acids such as chlorine hydrochloric acid or hydrobromic acid, phosphoric acids such as ortho phosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic Iische mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. B. Formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malein acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, Ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfone acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfone acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. B. Picrates, can be used to isolate and / or purify the compounds of formula I can be used.

On the other hand, compounds of the formula I with bases (e.g. sodium or potassium hydroxide or carbonate) in the corresponding metal, ins special alkali metal or alkaline earth metal, or in the corresponding Ammonium salts are converted.  

The invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for Manufacture of pharmaceutical preparations, especially not chemical way. You can do this together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and optionally in combination with one or more others Active ingredients are brought into a suitable dosage form.

The invention furthermore relates to pharmaceutical preparations, containing at least one compound of formula I and / or one of them physiologically acceptable salts.

These preparations can be used as medicinal products in human or Veterinary medicine can be used. Organic come as carriers or inorganic substances that are suitable for enteral (e.g. oral), parenteral or topical application and with the new Compounds do not react, e.g. water, vegetable oils, Benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, Gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, Vaseline. Tablets, pills, Dragees, capsules, powders, granules, syrups, juices or drops, for rectal application suppositories, for parenteral application solutions gene, preferably oily or aqueous solutions, further suspensions, Emulsions or implants, for topical use, ointments, creams or powder. The new compounds can also be lyophilized and the obtained lyophilisates z. B. for the production of injectables be used. The specified preparations can be sterilized be and / or auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmo table pressure, buffer substances, color, taste and / or contain several other active ingredients, e.g. B. one or more vitamins.

The compounds of formula I and their physiologically acceptable Salts can help fight diseases, especially those of Hypertension and heart failure can be used.  

The substances according to the invention are generally preferred wise in dosages between about 1 and 500 mg, in particular administered 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 the various factors, for example the effectiveness of used special connection, of age, body weight, general my state of health, gender, food, enjoyment time and route of excretion, Drug combination and severity of the disease, which the therapy applies. Oral application is preferred.

All temperatures above and below are given in ° C. In the The following examples mean "customary workup": If there is required to add water, if necessary, depending on constitution of the end product to pH values between 2 and 10, extracted with Ethyl acetate or dichloromethane, separates, dries the organic phase over sodium sulfate, evaporated and purified by chromatography Silica gel, with a separation of those described below Isomer takes place, and / or by crystallization. Rf values on silica gel; Mobile solvent: ethyl acetate / methanol 9: 1.

The one found in the examples below 4- (carboxyethylaminocarbonyl) phenyl radical 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 Water is heated under reflux. You work up as usual, solve it Residue in water, acidifies and receives after separation of the Precipitation 16.8 g 3 - [(amino-hydroxyimino) methyl-] benzoic acid, F. 220 °.

A solution of 13.3 g of 3 - [(amino-hydroxylmino) methyl-] benzoic acid ("C") and 12.23 g of 4-cyanobenzoyl chloride in 150 ml of glacial acetic acid is added Reflux heated. You work up as usual, recrystallize from DMF, and obtains 3- [5- (4-cyanophenyl) -1,2,4-oxadiazol-3-yl] benzoic acid, F. < 300 °.

A solution of 2.0 g of 3- [5- (4-cyanophenyl) -1,2,4-oxadiazol-3-yl] benzoin acid, 1.25 g β-alanine tert-butyl ester hydrochloride, 1.2 g HOBt, 1.45 g N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride and 1.53 g N- Methylmorpholine in 25 ml DMF is one hour at room temperature touched. The mixture is worked up in the customary manner and 2.86 g of 5-p-cyanophenyl-3- are obtained. [3- (tert-butoxycarbonyl-ethylaminocarbonyl) phenyl] -1,2,4-oxadiazole-, F. 188-190 °.

2.8 of this compound is in a mixture of 40 ml of pyridine, 5 ml Triethylamine and 5 ml DMF with ice cooling with hydrogen sulfide saturated. The solvents are removed in vacuo and is obtained after customary working up 2.96 g of 5-p-thiocarbamoylphenyl-3- (3- (tert. butoxycarbonyl-ethylaminocarbonyl) phenyl] -1,2,4-oxadiazole, mp 173-178 °. 2.9 g of the last-mentioned compound are suspended in 100 ml of acetone dated and stirred with 16.9 ml of methyl iodide at room temperature. Man works up as usual and receives 3.71 g of 5-p-methylsulfinimidoylphenyl-3- [3- (tert-butoxycarbonyl-ethylaminocarbonyl) phenyl] -1,2,4-oxadiazole-, Hydroiodide, mp 183-185 ° (dec.).

A solution of 3.6 g of 5-p-methylsulfinimidoylphenyl-3- [3- (tert-butoxy carbonyl-ethylaminocarbonyl) phenyl] -1,2,4-oxadiazole, hydroiodide and 5.6 g of ammonium acetate in 300 ml of 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 5-p-amidino-phenyl-3- [3- (tert-butoxycarbonyl-ethylaminocarbonyl) - phenyl] -1,2,4-oxadiazole is added in 12 ml HCl-saturated dioxane stirred by 2.4 ml of water at room temperature. After usual work tion, 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-hydroxylmino) methyl-] phenol, 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 tert-butyl bromoacetate, this product gives 5-p-cyan 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 cleavage gives 5-p-amidino-phenyl-3- [3- (carboxy methoxy) 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 1,1'-carbonyldiimidazole in 60 ml of THF is heated under reflux for 1.5 h In addition, 2.16 g of 4 - [(amino-hydroxylmino) methyl] benzoic acid ("A") dissolved in 60 ml of water with the addition of 4.1 ml of 2N sodium hydroxide solution. In this solution becomes the solution of the butyrimidazolide derivative dripped. You stir for one hour, work up as usual and get 4-4- (1- BOC-piperidin-4-yl) -butyrylamino- (hydroxylmino) methyl] -benzoic acid, F. 1579 °.

2.6 g thereof are cyclized in pyridine at 100 ° C. After usual opening Work gives 2.3 g of 5- (BOC-piperidin-4-ylpropyl) -3- (4-carboxy phenyl) -1,2,4-oxadiazole, mp 192-194 °.

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

Analogously, through step-by-step implementation, 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 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-ylmethyl) -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 256-268 °;
of 3- (1-BOC-piperidin-4-yl) propionic acid with "A"
5- (piperidin-4-ylethyl) -3- (4-carboxy-phenyl) -1,2,4-oxadiazole, hydrochloride, mp <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-oxadiazole, 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 °;
of 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.);
of 4- (4-pyridyl) butyric acid with "C"
3- [Amino- (4- (4-pyridyl) butyryloxylmino) 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, m.p. 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 gives 5- (Piperidin-4-ylpropyl) -3- (4-carboxyphenyl) -1,2,4-oxadiazole, hydrochloride, F. 291-293 °.

Analogously, one obtains by conversion, removal of the protective groups and customary workup
of 4- (1-BOC-piperazin-4-yl) butyric acid with p - [(aminohydroxylmino) methyl] phenylacetic acid
5- (piperidin-4-yl-propyl) -3- (p-phenylacetic acid) -1,2,4-oxadiazole;
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) -3- [3- (carboxyethylamino carbonyl) phenyl] -1,2,4-oxadiazole;
of 1-BOC-piperidine-4-carboxylic acid with (S) -O- [4 - ((amino-hydroxylmino) 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) -β-alanine tert-butyl ester
(S) -3- (4- (5- (4-Piperidyl) -1,2,4-oxadiazol-3-yl) benzamido] -2- (butylsulfonylamino) propionic acid.

Example 4

Analogously to Example 1, 3-cyanophenol and hydroxyl are obtained amine hydrochloride the 3 - [(amino-hydroxylmino) methyl-] phenol, hydro chloride, mp 220 °.

By subsequent reaction with 4- (1-BOC-piperidin-4-yl) butyric acid Analogously to Example 3, 3- [5- (1-BOC-piperidin-4-ylpropyl) -1,2,4- oxadiazol-3-yl] phenol.

With tert-butyl bromoacetate, this product gives the 5- (1-BOC- Piperidin-4-ylpropyl) -3- [3- (tert-butoxycarbonyl-methoxy) -phenyl] -1, -2,4- oxadiazole.

By splitting off the BOC and ester groups, 5- (piperidine-4- ylpropyl) -3- [3- (carboxymethoxy) phenyl] -1,2,4-oxadiazole.

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 (hydroxylmino) methyl) benzenesulfonamido] propionic acid ("D", F. 139 °; obtainable by reaction of 3- (3-cyanobenzenesulfonamido) - propionic acid with hydroxylamine hydrochloride) the compound 3- [3- (amino- (1-BOC-4-piperidinyl-carbonyloxylmino) methyl) benzene sulfonamido] - propionic acid.

By cyclization in glacial acetic acid and splitting off the BOC group 5- (4-piperidinyl) -3- [3- (carboxyethylaminosulfonyl) phenyl] - 1,2,4-oxadiazole.  

Analogue one gets through implementation
1-BOC-piperidine-4-carboxylic acid with 3- [4- (amino- (hydroxylmino) 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 "E"
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 "E"
5- (piperidin-4-ylethyl) -3- [4- (carboxyethylaminosulfonyl) phenyl] -1,2,4-oxadiazole;
of 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- (carboxyethylaminosuifonyl) 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-p- (carboxyethylaminosulfonyl) phenyl] -1,2,4-- oxadiazole.

Example 6

Analogously to Example 5, 1-BOC-piperidine-4-carboxylic acid and 3- [3- (Amino- (hydroxylmino) methyl) benzenesulfonamido] ethanesulfonic acid - the compound 3- [3- (amino- (1-BOC-4-piperidinyl-carbonyloxylmino) - methyl) -benzenesulfonamido] -ethanesulfonic acid.

By cyclization in glacial acetic acid and splitting off the BOC group 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 (hydroxylmino) 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- (hydroxylmino) methyl) benzamido] ethanesulfonic acid
5- (4-Piperidinyl) -3- [4- (sulfoethylaminocarbonyl) phenyl] -1,2,4-oxadiazole.

Example 7

Analogously to Example 3, reaction of 3-nitropropionic acid is obtained with 3- [3- (amino (hydroxylmino) methyl) benzenesulfonamido] propionic acid ("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-. By subsequent reaction with 3, 5-dimethylpyrazole-1-form amidinium nitrate (DPFN) gives 5- (2-guanidinoethyl) -3- [3- (carboxy ethylaminosulfonyl) phenyl) -1,2,4-oxadiazole.

Example 8

Analogously to Example 1, the compound is obtained from 4-cyanobenzoyl chloride and 3- [3- (amino (hydroxylmino) methyl) benzenesulfonamido] propionic acid ("D")
5- (4-Cyanophenyl) -3- [3- (carboxyethylaminosulfonyl) phenyl] -1,2,4-oxadiazole.

By subsequent reaction with H₂S, subsequent methylation and reaction with ammonium acetate gives 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 are given equimolar Amounts of methylsulfonyl chloride and cesium carbonate. You stir one Hour, works up as usual and receives (S) -3- [4- (5- (1-BOC-piperidine-4- yl) -1,2,4-oxadiazol-3-yl) -benzamido] -2- (methylsulfonylamino) -propion- acid.

Analogously, "F" and p-toluenesulfonic acid chloride are obtained
(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) benzamido] -2 - (p-tolylsulfonylamino) propionic acid
S) -3- [4- (5- (Piperidin-4-yl) -1,2,4-oxadiazol-3-yl) benzamido] -2- (p-tolylsulfonylamino) propionic acid.

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 Hydrogen phosphate is dissolved in 3 liters of double distilled water with 2N salt acid adjusted to pH 6.5, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Every In jection 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 soy lecithin and 1400 g cocoa butter, pour into molds and leave cool down. Each suppository contains 20 mg of active ingredient.

Example C solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g NaH₂PO₄ · 2 H₂O, 28.48 g Na₂HPO₄ · 12 H₂O and 0.1 g benzalkonium chloride in 940 ml of double distilled water. Adjust to pH 6.8 makes up to 1 l and sterilized by radiation. This solution can be found in Form of eye drops can be used.

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 formula I, 4 kg lactose, 1.2 kg kar Potato starch, 0.2 kg talc and 0.1 kg magnesium stearate are common Formed into tablets in such a way that each tablet contains 10 mg of active ingredient contains.

Example F Dragees

Analogously to Example E, tablets are pressed, which are then made in the usual manner Wise with a coating of sucrose, potato starch, talc, tragacanth and dye are coated.

Example G Capsules

2 kg of active ingredient of formula I are in the usual way in hard gelatin capsules filled so that each capsule contains 20 mg of the active ingredient.

Example H Ampoules

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

Claims (16)

1 compounds of formula I. wherein
R¹ NH₂, -C (= NH) -NH₂, H₂N-C (= NH) -NH-, a phenyl radical substituted simply by -C (= NH) -NH₂, an unsubstituted or simply substituted by NH₂ pyrimidinyl, tetrahydropyrimidinyl, Pyridyl or tetrahydropyridyl radical,
an unsubstituted or simply substituted by pyridyl piperazinyl or piperidinyl, where NH, NH₂, -C (= NH) -NH₂ and H₂N-C (= 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,
R², R ^{2 '} each independently of one another H, A-CO, AO-CO, A-sulfonyl, an unsubstituted or mono-, di- or trisubstituted by Hal, alkyl, alkoxy, alkoxycarbonyl, CONH₂, NH₂ or NO₂ substituted benzoyl, Heteroaroyl or phenylsulfonyl radical,
R³ OH, AO, NH-COOR⁴, 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, His, Ile, Leu, Lys, Met, Phe, Pro, Sar, Ser, Thr, Trp, Taurin, Tyr, Val,
where the amino acids mentioned can also be derivatized and the amino acid residues are linked to the residue W via the amino group,
R⁴ 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 and p are zero, also SO₂,
X, Y are each independently N or O, where X ≠ Y,
Ar unsubstituted or mono-, di- or trisubstituted by Hal, A, AO, AO-CO, CONH₂, NH₂ or NO₂,
Hal 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 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

wherein
R¹, 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, R², R³, n and p have the meanings given in claim 1,
implements, or

• (c) that a compound of formula IV

wherein
n ′ 0, and
R¹, R³, U, V, W, X, Y, m, n and p have the meanings given in claim 1,
means with a compound of the formula V R²-L Vworin L Cl, Br, I, OH or a reactive esterified OH group or easily nucleophilically substitutable leaving group,
implements, or

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

or,

• (e) converting a R³ radical into another R³ 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 a base or acid of the formula I in one of its salts converts.   4. Process for the preparation of pharmaceutical preparations, thereby characterized in that a compound of formula I according to Claim 1 and / or one of their physiologically acceptable Salts together with at least one solid, liquid or semi liquid carrier or auxiliary in a suitable dosage form brings. 5. Pharmaceutical preparation, characterized by a content on at least one compound of the formula I according to claim 1 and / or one of their physiologically acceptable salts. 6. Compounds of formula I according to claim 1 and their physiological harmless salts to combat as GPIIb / IIIa antagonists of thrombosis, heart attack, coronary heart disease and Arteriosclerosis. 7. Compounds of formula I according to claim 1 and their physiologically acceptable salts as α _v integrin inhibitors for combating pathologically angiogenic diseases, tumors, osteoporosis, inflammation and infections. 8. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the preparation of a drug. 9. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts in the Combating thrombosis, heart attack, coronary heart disease atherosclerosis, apoplexy, tumors, osteoporosis, Inflammation and infection.