The present invention relates to new multiheterocyclic compounds as integrin antagonists with a broad spectrum of action having, inter alia, antiosteoporotic, antirestenotic, anticarcinogenic and antiatherosclerotic activity. The present invention moreover relates to the preparation of these compounds and their use for the production of medicaments, and also medicaments comprising them.
Integrins are heterodimeric transmembrane proteins found on the surface of cells, which play an important part in the adhesion of the cells to an extracellular matrix. They recognize extracellular glycoproteins such as fibronectin or vitronectin on the extracellular matrix by means of the RGD sequence occurring in these proteins (RGD is the single letter code for the amino acid sequence arginine-glycine-aspartate).
In general, integrins such as, for example, the vitronectin receptor, which is also called the xcex1vxcex23 receptor, or alternatively the xcex1vxcex25 receptor or the GpIIb/IIIa receptor play an important part in biological processes such as cell migration and cell-matrix adhesion and thus in diseases in which these processes are crucial steps. Cancer, osteoporosis, arteriosclerosis, restenosis (reoccurrence of stenosis after percutaneous transluminal angioplasty) and opthalmia may be.mentioned by way of example.
The xcex1vxcex23 receptor occurs, for example, in large amounts on growing endothelial cells and makes possible their adhesion to an extracellular matrix. Thus the xcex1vxcex23 receptor plays an important part in angiogenesis, i.e. the formation of new blood vessels, which is a crucial prerequisite for tumor growth and metastasis formation in carcinoses. Furthermore, it is also responsible for the interaction between osteoclasts, i.e. cells resorbing mineralized tissue, and the bone structure. The first step in the degradation of bone tissue consists in the adhesion of osteoclasts to the bone. This cell-matrix interaction takes place via the xcex1vxcex23 receptor, which is why the corresponding integrin plays an important part in this process. Osteolytic diseases such as osteoporosis are induced by an inequilibrium between bone formation and bone destruction, i.e. the resorption of bone material caused by accumulation of osteoclasts predominates.
It was possible to show that the blockage of the abovementioned receptors is an important starting point for the treatment of disorders of this type. If the adhesion of growing endothelial cells to an extracellular matrix is suppressed by blocking their appropriate integrin receptors, for example, by a cyclic peptide or a monoclonal antibody, the endothelial cells die. Therefore angiogenesis does not occur, which leads to a cessation or resolution of the tumor growth (cf., for example, Brooks et al., Cell, Volume 79, 1157-1164, 1994).
Moreover, the invasive properties of tumor cells and thus their capability for metastasis formation are markedly decreased if their xcex1vxcex23 receptor is blocked by an antibody (Brooks et al., J. Clin. Invest., Volume 96, 1815, 1995).
The degradation of bone tissue can be suppressed by blockage of the xcex1vxcex23 receptors of the osteoclasts, since these are then unable to accumulate on the bone in order to absorb its substance (WO 98/18461, p. 1, 1.24 to p. 2, 1.13).
By means of the blockage of the xcex1vxcex23 receptor on cells of the smooth aorta vascular musculature with the aid of integrin receptor antagonists, the migration of these cells into the neointima and thus angioplasty leading to arteriosclerosis and restenosis can be suppressed (Brown et al., Cardiovascular Res., Volume 28, 1815, 1994).
In recent years, compounds have therefore been sought which act as antagonists of integrin receptors. For example WO 97/24119 discloses victronectin (xcex1vxcex23) receptor antagonist as antiosteoporosis agents which are structurally related to the compounds described here, but do not have a broad spectrum of action of this type.
It was the object of the present invention to develop compounds which exhibit a high activity as integrin antagonists and in particular against the xcex1vxcex23 and/or the xcex1vxcex25 receptor.
The compounds on which the present invention is based can be described by the following general formula (I): 
where
R1 and R2 together with the formal double bond bridging them form a phenyl ring or a six-membered aromatic heterocycle having 1 or 2 nitrogen atoms, which is optionally substituted by halogen, nitro, cyano, trifluoromethyl, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl, amino, carboxyl, phenoxy, (C6-C10)-aryl, (C1-C6)-alkylamino, (C1-C6)-alkylsulfone or a group of the formula xe2x80x94SO2NRaRb wherein Ra and Rb may independently represent hydrogen or (C1-C6)-alkyl, and
R3=H or (C1-C4)-alkyl, and
A=O, S, (CH2)n where n=1,2,3 or 4 or Nxe2x80x94R7 where R7=H or (C1-C4)-alkyl, or is absent and
X, Y, Z=O, S, N, Nxe2x80x94R8 where R8=H, (C1-C6)-alkyl or (C6-C10)-aryl, or Cxe2x80x94(R9)(R10) where R9, R10=H, (C1-C6)-alkyl or (C1-C10)-aryl, or Cxe2x80x94(R11) if the X, Y or Z in question is participating in a formal double bond, where R11=H, (C1-C6)-alkyl or (C6-C10)-aryl, and
D=O, S, (CH2)n where n=1,2,3 or 4, or Nxe2x80x94R7 where R7=H or (C1-C4)-alkyl, or is absent and
E, G, L=H, halogen, nitro, cyano, trifluoromethyl, hydroxyl, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy or (C1-C6)-alkoxycarbonyl, where E, G and L can be identical or different and
R4=H, (C3-C8)-cycloalkyl, (C1-C6)-alkyl, which is optionally substituted by hydroxyl, (C1-C6)-alkoxy or phenyl, where the latter is optionally in turn substituted on the phenyl ring by halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, trifluoromethoxy or trifluoromethyl, and
R5=H or (C1-C4)-alkyl and
R6=H, (C1-C6)-alkyl or benzyl
and their salts.
Preferred compounds according to the general formula (I) are those where
R1 and R2 together with the formal double bond bridging them form a phenyl ring or a six-membered aromatic heterocycle having 1 or 2 nitrogen atoms, which is optionally substituted by (C1-C6)-alkoxy, nitro or amino, and
R3=H, and
A=O, S, (CH2)n where n=1,2,3 or 4 or Nxe2x80x94H, or is absent and
X, Y, Z=O, S, N, Nxe2x80x94R8 where R8=H, (C1-C6)-alkyl or (C6-C10)-aryl, or Cxe2x80x94(R9)(R10) where R9, R10=H, (C1-C6)-alkyl or (C6-C10)-aryl, or Cxe2x80x94(R11) if the X, Y or Z in question is participating in a formal double bond, where R11=H, (C1-C6)-alkyl or (C6-C10)-aryl, and
D=O, S, (CH2)n where n=1, 2, 3 or 4, or Nxe2x80x94H, or is absent and
E, G, L=H, and
R4=H, benzyl, cyclopropyl, cyclopentyl, cyclohexyl, phenylethyl or (C1-C4)-alkyl, which is optionally substituted by hydroxyl or methoxy, and
R5=H, and
R6=H or methyl.
and their salts.
Particularly preferred compounds according to the general formula (I) are those where
R1 and R2 together with the formal double bond bridging them form a phenyl ring, which is optionally substituted by nitro. and
R3=H and
A=is absent and
X=N, Y=O and Z=N or X=N, Y=N and Z=O, S or X=CH2, Y=O, Z=N and
D=is absent and
E, G, L=H, and
R4=methyl, cyclopropyl or (C1-C4)-alkyl substituted by methoxy and
R5=H, and
R6=H or methyl
and their salts.
The compounds according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
In the context of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Those particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
The present invention also includes ammonium compounds which can be prepared by conversion of the free amines by means of alkylation.
In the context of the present invention, the substituents in general have the following meaning:
(C1-C6)-alkyl in general represents, depending on the abovementioned substituents, a straight-chain or branched hydrocarbon radical having 1 to 6, preferably 1 to 4 carbon atoms. Examples which may be mentioned are methyl, ethyl, propyl isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl.
(C1-C6)-alkoxycarbonyl can be represented, for example, by the formula 
Alkyl here represents a straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms. Lower alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety is preferred. Examples which may be mentioned are the following alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.
(C3-C8)-cycloalkyl in general represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. Examples which may be mentioned are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
(C6-C10)-aryl in general represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
Halogen in the context of the invention represents fluorine, chlorine, bromine and iodine.
(C1-C6)-alkoxy in general represents, depending on the abovementioned substituents, a straight-chain or branched hydrocarbon radical bonded via an oxygen atom and having 1 to 6 carbon atoms. Lower alkoxy having 1 to 4 carbon atoms is preferred. An alkoxy radical having 1 to 3 carbon atoms is particularly preferred. Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy.
(C1-C6)-alkylsulfone can be represented by the formula 
wherein Alkyl represents a straight-chain or branched hydrocarbon radical having 1 to 6, preferably 1 to 4 carbon atoms. Examples which may be mentioned are: methylsulfone, ethylsulfone, propylsulfone, isopropylsulfone.
Six-membered aromatic heterocycles in the context of the invention, depending on the abovementioned substituents, in general represent a 6-membered heterocycle which can contain up to 2 nitrogen atoms and which can optionally also be bonded via a nitrogen atom. Examples which may be mentioned are: pyridyl and pyrimidyl.
In general formula (I) the heterocyclic moiety 
represents an aromatic or partially saturated heterocycle. Preferred examples for this moiety are: 
The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.
The compounds of the general formula (I) according to the invention can be prepared in the following way using process variant (A) or (B):
(A) reaction of a component (a) 
xe2x80x83with a component (b) 
where (b) is first reacted in the presence of sulfonyl chloride, POCl3 or PCl5 to give the acid chloride and is then reacted with (a) in the presence of a base in an inert organic solvent, or a coupling of (a) with (b) is carried out by means of Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP) or carbodiimide reagents, followed by a cyclization reaction which can be effected by means of heat, acids, bases, dehydrating substances and by addition of generally nucleophilic reagents,
where, if appropriate, the COOR6 group is finally hydrolyzed and where Q in one of the two components (a) or (b) is oxygen and in the other components corresponds to Z, or
(B) reaction of a component (axe2x80x2) 
xe2x80x83with a component (b) 
where (b) is first reacted in the presence of sulfonyl chloride, POCl3 or PCl5 to give the acid chloride and then reacted with (axe2x80x2) in the presence of a base in an inert organic solvent, or a coupling of (axe2x80x2) with (b) is carried out by means of BOP or carbodiimide reagents, followed by a cyclization reaction which can be effected by means of heat, acids, bases, dehydrating substances and by addition of generally nucleophilic reagents,
where, if appropriate, the COOR6 group is finally hydrolyzed and where Q in one of the two components (axe2x80x2) or (b) is oxygen and in the other component corresponds to Z.
Preferably, in process variant (A), for component (a), Xxe2x95x90N, Yxe2x95x90O and Qxe2x95x90NH is employed and for component (b), Qxe2x95x90O is employed and in process variant (B), for component (axe2x80x2), Xxe2x95x90NH, Yxe2x95x90NH and Qxe2x95x90O is employed and, for component (bxe2x80x2), Qxe2x95x90O is employed.
Particularly preferably, it applies to both process variants that R1 and R2 together with the formal double bond bridging them form a phenyl radical,
R3, R5, E, G, L=H,
R4, R6 =methyl and
A, D=is absent.
The compounds of the formula (I) according to the invention have a surprisingly wide spectrum of pharmacological action.
The compounds according to the invention exhibit an antagonistic action against integrin inhibitors, in particular the xcex1vxcex23 receptor or the xcex1vxcex25 receptor.
They can be used as active compounds in medicaments for the reduction of changes to vascular walls and are employed for the treatment of arterial hypertension and atherosclerosis. Moreover, they can be employed for the treatment of coronary heart disorders, cardiac insufficiency, disorders of brain function, ischemic brain disorders, (peripheral) circulation disorders, microcirculation disorders and thromboses, functional disorders of the kidney and adrenal gland, bronchospastic and vascular system-related disorders of the airways, sodium retention and edemas as well as osteolytic disorders such as osteoporosis, cancer, carcinoses and ophthalmic diseases.
Furthermore, the proliferation and migration of smooth muscle cells plays a decisive part in the occlusion of vessels. The compounds according to the invention are suitable for inhibiting this proliferation and can therefore also be employed for the treatment of restenosis.
The novel active compounds are distinguished pharmacologically by good kinetic parameters. In particular, they have favorable properties with respect to clearance.
The novel active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceutically suitable excipients or solvents. In this case the therapeutically active compound should in each case be present in a concentration of approximately 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, if water is used as a diluent organic solvents can optionally be used as auxiliary solvents.
Administration is carried out in a customary manner, preferably orally or parenterally, in particular perlingually or intravenously.
In the case of parenteral administration, solutions of the active compound using suitable liquid carrier materials can be employed.
In general, it has proven advantageous in the case of intravenous administration to administer amounts from approximately 0.001 to 1 mg/kg, preferably approximately 0.01 to 0.5 mg/kg, of body weight to achieve effective results, and in the case of oral administration the dose is approximately 0.01 to 100 mg/kg, preferably 0.1 to 50 mg/kg, of body weight.
In spite of this, if appropriate, it may be necessary to depart from the amounts mentioned, namely depending on the body weight or the type of application route, on individual behavior toward the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus in some cases it may be adequate to manage with less than the abovementioned minimum amount, while in other cases the upper limits mentioned must be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into several individual doses over the course of the day.
The present invention is illustrated in greater detail below by working examples.
Starting Compound I 
0.877 g of methyl S-7-carboxy-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate (Tetrahedron Letters 38, 3131-34, 1997) is stirred under reflux for 1 h with thionyl chloride (40 ml), concentrated and the residue is dissolved in 20 ml of chloroform. The solution obtained is added dropwise to a mixture of 0.53 g of benzimidazole-2-carboxamidoxime (J. Chem. Soc. C, 1967, 28) and chloroform (50 ml), pyridine (0.48 g) and triethylamine (0.30 g). It is stirred at room temperature for 2 h, then concentrated and the residue is taken up in ethyl acetate. After this, washing with water, saturated sodium hydrogencarbonate solution and saturated sodium chloride solution and drying over magnesium sulfate takes place, after concentration an amorphous residue being obtained which is stirred with dichloromethane and filtered off with suction. Recrystallization is carried out from ethanol (0.41 g). The mother liquor is concentrated and chromatographically purified (CH2Cl2; CH2 Cl2/CH3OH=30/1). 0.6 g of the title compound is obtained from the mother liquor.