MXPA00006947A - Novel sulfonamide derivatives as inhibitors of bone resorption and as inhibitors of cell adhesion - Google Patents

Abstract

The present invention relates to sulfonamide derivatives of formula (I), in which R1, R2, R4, R5 and R6 have the meanings indicated in the claims, their physiologically tolerable salts and their prodrugs. The compounds of the formula (I) are valuable pharmaceutical active compounds. They are vitronectin receptor antagonists and inhibitors of cell adhesion and inhibit bone resorption by osteoclasts. They are suitable, for example, for the therapy and prophylaxis of diseases which are caused at least partially by an undesired extent of bone resorption, for example of osteoporosis. The invention furthermore relates to processes for the preparation of compounds of the formula (I), their use, in particular as pharmaceutical active ingredients, and pharmaceutical preparations comprising them.

Description

NEW DERIVATIVES OF YOUR PHONAMIDE AS INHIBITORS OF THE RESORTION OF BONES AND AS INHIBITORS OF THE ACCESSION OF CELLS.

Field of Invention The present invention relates to sulfonamide derivatives of the formula I, wherein RRR "1 and * has the meanings indicated below, its physiologically tolerable salts and its pro-medicaments.The compounds of formula I are valuable active pharmaceutical compounds.These are antagonists of the vitronectin receptor and inhibitors of the adhesion of the cell and inhibit bone resorption by osteoclasts, which are appropriate, for example, for therapy and prophylaxis of diseases that are at least partially caused by an undesirable extension of bone resorption, for example of osteoporosis. The invention also relates to a process for the preparation of compounds of the formula I, their use, in particular as pharmaceutical active ingredients. and pharmaceutical preparations comprising them.

Antecedents of the Invention.

Human bones are subject to a process of constant dynamic renewal involving bone resorption and bone formation. These processes are controlled by specialized cell types for these purposes. Bone resorption is based on the destruction of the bone matrix by osteoclast os. Most bone disorders are based on a disturbance in the balance between bone formation and bone resorption. Osteoporosis is a disease characterized by a low bone mass and an increase in bone fragility at an increased risk of bone fracture. This results from a deficiency in a new formation of bone against bone resorption during the ongoing remodeling process. Treatment of conventional osteoporosis includes, for example, the administration of bisphosphonates, estrogens, estrogens / progesterone (a hormone replacement therapy or HRT), estrogen agonists / antagonists (selective estrogen receptor modulators or SERMs), calcitonin, analogs of vitamin D, parathyroid hormone, growth hormone secretagogues, or sodium fluoride (Jardme et al., Annual Reports in Medicinal Chemistry 1996, 31, 211).

Activated osteoclasts are polynuclear cells that have a diameter of more than 400 μm, which remove the bone matrix. Activated osteoclasts bind to the surface of the bone matrix and secrete proteolytic and acidic enzymes in the so-called "sealing zone", the region between their cell membrane and the bone matrix. The acidic environment and the proteases cause bone destruction. The compounds of formula I inhibit bone resorption by osteoclasts.

Studies have shown that the binding of osteoclasts to bones is controlled by integrin receptors on the surface of the osteoclast cell. Integrins are a super family of receptors that include, among others, the fibpnogen receptor ap p3 in blood platelets and the avr3 vitronectin receptor. The avß3 vitronectm receptor is a coprotein gil membrane that is expressed on the cell surface of a number of cells such as endothelial cells, vascular smooth muscle cells, osteoclasts and tumor cells. The vitronectin avß3 receptor, which is expressed in the membrane of the cough teos, controls the process of bone binding and bone resorption and thus contributes to osteoporosis. The vß ^ in this case binds to the bone matrix proteins such as osophotene, bone sialoprotein, and thrombospontine, which contain the arp-Gly-Asp (or RGD) tppeptidic portion.

Horton et al. Describe RGD peptides and an anti-vitronectm receptor antibody (23C6) that inhibits tooth destruction by osteoclasts and osteoclast migration (Horton et al., Exp. Cell, Res. 1991, 195, 368). In J. Cell Biol. 1990, 111, 1713, Sato et al., Discloses equistatma, a RGD peptide of snake venom, as a potent inhibitor of bone resorption in a cultured tissue and as an inhibitor of osteoclast adhesion to bones. Fischer et al. (Endocr mologí 1993, 132, 1411) were able to show in the rat that echistatin also inhibits bone resorption in vivo.

It was further shown that the vitronectm avßj in human cells of the smooth vascular musculature of the aorta stimulates the migration of these cells in the neointima, which finally initiates atherosclerosis and restenosis after angioplasty (Bro et al., Cardio ascular Res. 1994, 28, 1815).

Brooks et al., (Cell 1994, 79, 11157) shows that antibodies against avß or aβj antagonists can cause a decrease in tumors induced by apoptosis of blood vessel cells during angiogenesis. The receptor vitronectmo avß3 is also involved in the progression of a variety of other types of cancer, and is over-expressed in malignant melanoma cells (Engleman et al., Annual Reports in Medicinal Chemistry 1996, 31, 191). The invasion of melanoma correlated with this over-expression (Stracke et al., Encylopedia of Cancer, volume III, 1855, Academic Press, 1997, Hillis et al., Clinical Science 1996, 91, 639). Carrón et al., (Cancer Res. 1998, 58, 1930) describes the inhibition of tumor growth and the inhibition of hypercalcemia of malignancy using an avß3 antagonist.

Cheresh et al., (Science 1995, 270, 1500) discloses anti-ctvβ antibodies or avβ antagonists that inhibit the processes of angiogenesis induced by bFGF in rat eye, a property that can be used therapeutically in the treatment of retinopathies. The influence of the vitronectin receptor or the interactions in which it is involved in this way offers the possibility of influencing different disease states for whose therapies and prophylaxis, there are a continuing need for appropriate pharmaceutical active ingredients.

WO-A-94/12181 discloses substituted aromatic or nonaromatic ring systems, and W0-A-94/08577 describes substituted heterocycles as fibrinogen receptor antagonists and platelet aggregation inhibitors. EP-A-528586 and EP-A-528587 describe phenylalanine derivatives substituted by ammoalkyl or substituted by heterocyclyl, and WO-A-95/32710 discloses aryl derivatives as inhibitors of bone resorption by osteoclasts. WO-A-96/00574 discloses benzodiazepines, and WO-A-96/00730 describes antagonist patterns of the fibpnogen receptor, in particular benzodiazepines that bind to the 5-membered ring in the presence of nitrogen, as antagonists of the viral receptor. tronect ina. WO-A-98/00395 (DE-A-19654483) discloses vitronectome receptor antagonists derived from a tyrosine band. EP-A-820991 (German patent application 19629816.4) describes cycloalkyl derivatives and European patent application 97122520.6 describes derivatives of carbamic ester which are antagonists of the vi tronect ina receptor. Further investigations have shown that the sulfonamide derivatives of the formula I are particularly strong inhibitors of the vitronectome receptor and bone resorption by osteoclasts.

Description of the invention.

The present invention relates to compounds of the formula I wherein R1 and R2 independently from each other, are hydrogen or (C? -C6) alkyl which is substituted or unsubstituted by R3, or in which the radicals R1- and R2- together are a saturated or unsaturated divalent (C2-C9) alkylene radical, for example the group - (CH2) P-, in which p is 2, 3, 4, 5 , 6, 7, 8 or 9, which is unsubstituted or is substituted by one or more groups from the group consisting of halogen, alkyl (C -Ce), alkoxy (Ci-Ce), aryl (C6-C? ), ar lio (C6-Cn) -alkyl (C? -C6), heteroaryl (C5-C14), teroar lio (C5-Cn) -alkyl (Ci-Cß), cycloalkyl (C.-C?) , (C3-C12) -cycloalkyl-alkyl (Ci-Cb) and oxo, where a saturated or unsaturated ring of 5 members up to 7 members is unsubstituted or is substituted by R3, in particular by one or two radicals RJ, and which is a carbocyclic ring or a heterocyclic ring containing one or two nitrogen atoms in the ring, can be fused to a carbon-carbon bond in the racial alkylene (C2-Cs); R is (C1-C10) alkyl, monocycloalkyl (Cj-C20), b? C? Cloalkyl (C5-C0), tr? C? Cloalkyl (C5-C20), alkoxy (Ci-Cs), aryl (Ci, -CN), aryl (Cb-Cu | (C1-C4), heteroaplo (C5-Cn), heteroar 1I0 (C5-CK) (C1-C4), halogen, tr lf luorometilo , cyano, hydroxyl, oxo, nitro, amino, -NH- (C 1 -C 4) alkyl, -N ((C 1 -C 4) alkyl) 2, -NH-CO- (C 1 -C 4) alkyl, -CO-alkyl (C 1 -C 4); R "1 is hydrogen, alkyl (Ci-Cß) -CO-0-alkyl (C? ~ C4) - or alkyl (Ci-Ce) which is unsubstituted or is substituted by a radical of the group consisting of hydroxyl , (C1-C4) alkoxy, (C1-C) alkyl -S (O) 2-, -NR7R7 'and -N + R7R7'R7"Q", where R7, R7' and R7"independently of each other are hydrogen , alkyl (C? -C6), aplo (C3-C) or anlo (C5-C14) -alkyl (Ci-Ce) - and Q ~ is a physiologically tolerable anion, or in which R4 is one of the radicals in which the links, by means of which the radicals are linked, are indicated by the dotted lines; R5 is (C1-C20), monocycloalkyl (C3-C20), chyle bicicloal (C5-C20), chyle tpcicloal (C5-C20) aryl (C6-C.4), heteroaplo (C5-C14), the ap (CrCN) cycloalkyl- (C-C6?) - or heteroap the (C5-C14) cycloalkyl- (Ci-C0) -, where the aryl radical, the heteroaryl radical, the alkyl, monocycloalkyl radical, the bicycloalkyl radical and the radical t ricicloalqui is each unsubstituted or substituted by one, two or three radicals R3 and wherein one or more carbon atoms of the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the tricycloalkyl radical, in particular one , two, three or four carbon atoms, can be replaced by identical or different atoms selected from the series consisting of nitrogen, oxygen and sulfur; R ° is hydrogen, alkyl (Ci-C-O-CO, hydroxyl, alkyl (C? -C6) -O-CO-O- or nitro; in all its forms stereoisomerics and mixtures thereof in all proportions, and their physiologically tolerable salts and their prodrugs.

All the radicals which occur several times in the compounds of the formula I, for example the radicals R3, can each independently of one another, have the indicated meanings, and can in each case be identical or different. Radicals that independently of one another may have an indicated meaning may in each case be identical or different.

The alkyl radicals can be straight chain or branched chain and can be saturated or monounsaturated or polyunsaturated. This also applies if they carry substituents or are present as substituents of other radicals, for example in alkoxy radicals, alkoxycarbonyl radicals or arylalkyl radicals. The same applies for alkylene radicals (= divalent alkyl radicals = saturated or unsaturated alkaline radicals). Examples of radicals suitable alkyl containing from 1 to 20 carbon atoms are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octllo, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl and eicosyl, isomers n of all these radicals, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, isodecllo, 3-methylpentyl, 2, 3, 4-tr ímetilhexilo, sec-butyl, tert-butyl, tert-pentyl. A preferred group of alkyl radicals is formed by the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl radicals. The divalent radicals corresponding to the aforementioned monovalent radicals, for example methylene, 1,1-ethylene (= methylammet), 1,2-ethylene, 1,3-propylene, 1,2-propyl. leno (= 1-methylethylene and 2-met i lethylene), 2, 3-but full (= 1, 2-di et íl- 1, 2-et? leño), 1,4-butylene, 1,6 -hex? leno, are examples of alkylene radicals.

Unsaturated alkyl radicals are, for example, alkenyl radicals such as vinyl, 1-propenyl, aillo, butenyl, 3-methyl-2-butene, or alkynyl radicals such as ethynyl, 1-propynyl or propargyl. The unsaturated alkylene radicals, that is, alkenylene and alkylamine radicals (= alkenodulum and alkamodule radicals), can also be straight chain or branched chain. Examples of alkenylene radicals are vmylene or propenylene, and example propynylene The alkyl radicals can also be unsaturated when these are substituted. An example of an unsaturated, unsaturated radical in the alkyl portion is stipulated (= 2-phenylethyl).

Unless otherwise specified, the cycloalkyl radicals may be monocyclic, bicyclic or tricyclic, that is, they may be monocycloalkyl radicals, bicycloalkyl radicals and tarylickyl radicals, provided they have an appropriate number of carbon atoms. The monocycloalkyl radicals are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclohectadyl or cyclooctadecyl, which can also be substituted by, for example, (C 1 -C 4) alkyl ). Examples of substituted cycloalkyl radicals which may be mentioned are 4-methyl-1-l-cyclohexyl and 2,3-d-methyl-1-chloropentyl.

The bicycloalkyl radicals and tricycloalkyl radicals can be unsubstituted or substituted in any appropriate position to be substituted in any suitable, desirable position, for example by one or more oxo groups and / or one or more identical or different (C1-C) alkyl groups, for example methyl or isopropyl groups, preferably methyl groups. The free bond by means of which the bicyclic or tricyclic radical is linked can be located in any desirable position in the molecule; the radical can thus be linked by means of a linking head atom or an atom in a bridge. The free link can also be located in any desired stereochemical position, for example in an exo position or an endo position. Examples of bicycloalkyl radicals and t-cycloalkyl radicals are, camfanyl, bornyl, adamantyl, such as 1-adamantyl and 2-adaman I0, caranyl, epusobornyl, epiborml, norbornyl and norpmanyl.

Halogen is, for example, fluorine, chlorine, bromine or iodine.

The aryl (CÍ-CI 4) includes aryl (C5-Cu) heterocyclic ICOS radicals (= heteroaryl radicals 1 lo (C-) C? )) in which one or more of the carbon atoms of 5 to 14 rings are replaced by heteroatoms such as nitrogen, oxygen or sulfur, and aryl (C6-Ci) carbocyclic radicals. Examples of carbohydrate C 1 -C 4 -alkyl radicals are phenyl, naphthyl, biphenylyl, anthryl or fluorore where 1-naphthyl, 2-naphthyl and phenyl are preferred. In particular, the phenol radicals can be unsubstituted or substituted by one or more radicals, preferably one, two or three identical or different radicals.In particular, the radicals can be replaced by identical or different radicals from the group consisting of alkyl (C? -C?), in particular (C1-C) alkyl, alkoxy (Ci-Ce), in particular (C1-C4) alkoxy, halogen, such as fluorine, chlorine and bromine, nitro, a mo, tp f luoromet lyo, hydroxyl, methylenedioxy, cyano, hydroxycarbonyl, ammocarbonyl, alkoxycarbonyl (C¿-C4), phenyl, phenoxy, benzyl and benzyloxy Generally, only up to two nitro groups can be present as substituents in the compounds of formula I of according to the invention.

In monosubstituted phenyl radicals, the substituent can be located in position 2, in position 3 or in position 4, position 3 and 4 being preferred. If the phenyl is bisubstituted, the substituents can be in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. Preferably, in the bisubstituted phenyl radicals, the two substituents are placed in position 3,4, relative to the binding site. In the trisubstituted phenyl radicals, the substituents can be in the 2,3,4 position, 2,3,6 position, 2,4,5 position, 2,4,6 position or 3,4,5 position. Similarly, the naphthyl radicals and other aryl radicals can be substituted in any desired position, for example a 1-naphthyl radical in the 2-, 3-, 4-, 5-, 6-, 7- and 8- position, radical 2-naphthol in position 1-, 3-, 4-, 5-, 6-, 7- and 8-.

In addition to carbocyclic systems, aryl groups (C5-C4) can also be monocyclic or polycyclic, for example bicyclic or cyclic, ring systems. aromatic in which 1, 2, 3, 4 or 5 carbon atoms in the ring are replaced by heteroatoms, in particular by heteroatoms identical or different from the group consisting of nitrogen, oxygen and sulfur. Examples of aryl groups (C5-C14) and heteroaplo groups (C -C? 4) are pipdyl of type 2-p? R? D? Lo, 3-p? R? D? Lo and 4-pipdilo, pyrrolilo of type 2-polycarboxylic acid and 3-pyrrolyl, type 2-furyl and 3-pyrrolyl, thienyl of type 2-t? in? lo and 3-t? in?, ididazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolium, tetrazolyl, pyridomethyl, pyrazinyl, pyrimidyl, mdolyl, isomodolyl, mdazolyl, phthalazyl, quinolyl, isocmolyl, qumoxalmyl, quinazole, cinnamyl, b-carbolyl, or benzo-molten derivatives, cyclopenta, fused in cyclohexa or fused in cyclohepta of these radicals. Heterocyclic systems can be substituted in all appropriate positions by the same substituents as the aforementioned carbocyclic aplo systems.

In the series of these groups, monocyclic aromatic ring systems are preferred or bicyclics have 1, 2 or 3 heteroatoms, in particular 1 or 2 heteroatoms, of the group consisting of N, 0 and S, which may be unsubstituted or substituted by 1, 2 or 3 substituents from the group consisting of alkyl (C? -C0), (C? -Cb) alkoxy, fluorine, chlorine, nitro, amino, trifluoromethane, hydroxyl, alkoxycarbonyl (d-Cd, phenyl, phenoxy, benzyloxy and benzyl.) Particularly preferred are of rings of 5 members to 10 monocyclic or aromatic bicyclic members having from 1 to 3 heteroatoms, in particular having 1 or 2 heteroatoms, of the group consisting of N, O and S, which can be substituted by 1 to 2 substituents of the A group consisting of (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, phenyl, phenoxy, benzyl and benzyloxy. 5-membered or 6-membered hetero-pyl groups and 9- or 10-membered heterocyclic bicyclic groups are more particularly preferred. contain 1 or 2, in particular 1, heteroatoms of the group consisting of N, O and S that is not substituted or replaced as described above.

If the two radicals R - and R-- together represent a divalent saturated or unsaturated alkylene radical (C2 - Cg), these two radicals together with the two nitrogen atoms to which they bond and the central carbon atom of the group guanidino to which these two nitrogen atoms are bonded, form a monocyclic 1,3-d-azaheterocyclic ester which is bonded to the nitrogen atom in the (CH2) 2-C0-NH group by means of its 2-position. of radicals of such 1,3-diazaheterocycles which can be substituted as indicated in the alkylene radical (C -C-) and also in the guanidino nitrogen atom, are the 2-ylidazolyl radical, the 4,5-d-h radical Dro-2-? m? dazollo, the radical 1, 4, 5, 6-te trah? dro-2-p? ridiminil or the radical 4, 5, 6, 7-tetrah? dro-lH- l, 3-d? azepm-2-? lo. If a ring of 5 members up to 7 members is fused to a carbon-carbon bond in the alkylene radical (C2-Cq), then the two radicals R1 and R, together with the two nitrogen atoms to which they are bound and the atom The central carbon of the guanidino group to which these two nitrogen atoms are bonded form a bicyclic heterocycle which is bonded to the nitrogen atom in the (CH2) 2-CO-NH group and which can be substituted as indicated. The fused (or condensed) ring of 5 members up to 7 members can be saturated, mono-unsaturated or bi-unsaturated or aromatic. Thus, for example, a cyclopentane ring, cyclohexane ring, cyclohexene ring, cyclohexadiene ring, cycloheptane ring or benzene ring can be condensed. Examples of radicals of such bicyclic heterocycles which can be linked to the nitrogen atom in the group (CH 2) 2 -CO-NH are radical 1, 3a, 4, 5, 6, 6a-hexahydr-1, 3-d? Azapentalen-2-? Lo, the radical 1H-benz? M? Dazol-2-lio, the radical 3a, 4, 5, 6, 7, 7a-hexah? Dro-lH-benz? M? Dazol-2-? Lo, the radical 4,5,6,7-tetrahydro-lH-benz? L? M? Dazol-2-? what, the radical 4, 7-d? h? drohl-benz? m? dazol-2-? it or the lH-imidazo [4, 5-b] pir? dm-2 -lio radical. If a fused ring is replaced and / or if the alkylic radical (C -Cq) is substituted, these are preferably independently of one another, monosubstituted or disubstituted by identical or different R3 radicals. If the alkyl groups represented by R- and / or R1 are substituted, they are preferably independently of one another, monosubsti or di substi tuidos, in particular monosubsti tuidos, by R radicals "identical or different.

The optically active carbon atoms present in the compounds of the formula I can independently of one another have the R configuration or the S configuration. The compounds of the formula I can be present in the form of pure enantiomers or diastereomers or in the form of mixtures of enantiomers, for example in the form of racemates, or mixtures of tereomeric days. The present invention relates to both the pure enantiomers and the mixtures of enantiomers as well as the pure t-eromeric days and the mixtures of diastereomers. The invention comprises mixtures of two or more than two stereoisomers of the formula I and all the ratios of the stereoisomers in the mixtures. The compounds of formula I can optionally be presented as E-isomers or Z-isomers. The invention relates to both the pure isomers E and the pure isomers Z and the E / Z mixtures in all ratios. The invention also encompasses all tautomeric formulas of the compounds of formula I, for example, in addition to the form shown in formula I, also the form in which the acylguanidma unit is presented as a group -C0-N = C (NHR7 -NR2R6, and all other forms differing by different positions of the Molecular hydrogen The tereoisomer days, including the E / Z isomers, can be separated into individual isomers, for example, by chromatography The racemates can be separated into the two enantiomers by common methods, for example, by chiral phase chromatography or by resolution. The stereochemically uniform compounds of the formula I can also be obtained by employing stereochemically uniform starting materials or by using stereo reaction reactions.

The physiologically tolerable salts of the compounds of the formula I are non-toxic salts which are physiologically acceptable, in particular pharmaceutically usable salts. Such salts of compounds of formula I which contain acidic groups, for example carboxyl, are, for example, alkali metal salts or alkaline earth metal salts such as, for example, sodium salts, salts of potassium, magnesium salts and calcium salts, and also salts with physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines, such as, for example, triethylamine, ethanolamine or tris- (2- h? drox? et? l) amine. The compounds of the formula I contain basic groups of the acid addition salts, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic acids and sulfuric acids such as acetic acid, citric acid, benzoic acid. , maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. The compounds of formula I containing a basic group and an acid group, for example the guanidino group and a carboxyl group, can be presented as z ittepones (betaines), which are also included by the present invention.

The physiologically tolerable anion Q ~ which is contained in the compounds of formula I when R 4 is an alkyl radical which is substituted by a positively charged ammonium group, is, in particular, a monovalent anion or an equivalent of a polyvalent anion of a organic or inorganic acid non-toxic, physiologically usable, in particular also pharmaceutically usable, for example the anion or an anion equivalent of one of the aforementioned acids suitable for the formation of acid addition salts Q can thus be, for example, one of the anions (or an equivalent of anion) of the group consisting of chloride, sulfate, phosphate, acetate, citrate, benzoate, maleate, fumarate, tartrate, methanesulfonate and p-toluenesulfonate.

The salts of the compounds of the formula I can be obtained by common methods known to those skilled in the art., for example by combining a compound of formula I with an inorganic or organic acid or base in a solvent or dispersant, or other salts by cation exchange or anion exchange. The present invention also includes all salts of the compounds of the formula which, because of their physiologically low tolerability, are not appropriately engineered for use in pharmaceuticals, but are suitable, for example, as an intermediate for carrying out other chemical modifications of the compounds of formula I or as starting materials for the preparation of physiologically tolerable salts.

The present invention also includes all the solvates of the compounds of the formula I, for example hydrates or adducts with alcohols, and also derivatives of the compounds of the formula I, for example esters, prodrugs and other physiologically tolerable derivatives, as well as active metabolites. of the compounds of the formula I. The invention relates in particular to prodrugs of the compounds of the formula I, which can be converted into compounds of the formula I under physiological conditions. Suitable prodrugs for the compounds of formula I, ie, chemically modified derivatives of the compounds of formula I having properties that are improved in a desired manner, are known to those skilled in the art. More detailed information related to promedications is found, for example, in Fleisher et al., Advance Drug Delivery Reviews 19 (1996) 115-130; Design of Prodrugs, H. Bundgaard, Ed., Elsevier, 1985; H Bundgaards, Drugs of the Future 16 (1991) 443, Saulnier et al., Bioorg.

Med. Chem. Lett. 4 (1994) 1985; Safadi et al., Pharmaceutical Res. 10 (1993) 1350 which are incorporated herein by reference. The appropriate average values for the compounds of the formula I are especially ester prodrugs of carboxylic acid groups, in particular of the group COOH which occurs when R 4 in the group COOR'1 is hydrogen, for example the alkyl esters of this alkyl ester type group (CI-CG.) Or alkyl (C1-C) esters, and also acyl prodrugs and acylatable nitrogen-containing group carbamate prodrugs such as amino groups and in particular the guanidino group. In the acyl prodrugs or carbamate prodrugs, one or more times, for example twice, a hydrogen atom located on a nitrogen atom in these groups is replaced by an acyl group or a carbamate group. The acyl groups and carbamate groups suitable for the acyl prodrugs and carbamate prodrugs are, for example, the groups R10-CO and R110-CO, in which R10 is hydrogen, alkyl (Ci-Ciß), cycloalkyl (C3-C14), cycloalkyl (C3-C1) -alkyl (Ci-Cn,), aplo (C5-C1), in which from 1 to 5 carbon atoms they can be replaced by heteroatoms such as N, 0 or S, or (C5-C14) aryl-alkyl (C? -C8) -, in which from 1 to 5 carbon atoms in the aplo portion can be replaced by heteroatoms such as N , 0 or S, and in which R11 has the meanings indicated for R10 with the exception of hydrogen In the compounds of formula I, the radicals R1 and R2 are preferably hydrogen or together they are a divalent saturated or unsaturated, in particular saturated alkali radical (C2-C5), in particular an alkylene radical (C2-C), especially a alkylene radical (C2-C3), which is unsubstituted or is substituted by one or two identical or different radicals from the group consisting of halogen, alkyl (Ci-Cß), alkox (C? -C6), aplo (C6-) C1), aryl (C6-Ci) -alkyl (C? -C6), hetero (C5-C14), hetero (C5-C1) -alkyl (Ci-C6), cycloalkyl (C3-C12), cycloalkyl (C3-) C12) -alkyl (Ci-Cß) - and oxo, where a saturated or unsaturated 5-membered to 7-membered ring is unsubstituted or substituted by RJ, in particular by one or two radicals R3, and which is a ring carbocyclic or heterocyclic ring that contains one or two nitrogen atoms in the ring, can be fused to a carbon-carbon bond in the alkylene radical. In the compounds of the formula I, the radicals R1 and R2 are particularly preferably hydrogen or the group - (CH2) P-, in which p is the numbers 2, 3, 4 or 5, preferably the numbers 2, 3 or 4 , particularly preferably the numbers 2 or 3, and which is unsubstituted or substituted by one or two identical or different radicals from the group consisting of halogen, alkyl (Ci-Cd), alkoxy (C6), aryl (C6-C4), aryl (C6-C4) -alkyl (Ci-Cd), hetero (C5-Cn), heteroaryl (C5-C14) -alkyl ( Ci-Cß), cycloalkyl (C3-C12), cycloalkyl (C3-C12) -alkyl (Ci-Cß) - and oxo, where a 5-membered ring up to 7 members saturated or unsaturated is unsubstituted or is replaced by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two nitrogen atoms in the ring, can be fused in the group - (CH2) P More particularly preferably, the radicals R1 and R2 together are the group - (CH2) P, in which p is the numbers 2, 3, 4 or 5, preferably numbers 2, 3 or 4, particularly preferably the numbers 2 or 3, which preferably is unsubstituted. Especially, preferably the radicals R- and R'- together are the bivalent radical -CHt-CH_-CH-, that is, R1 and R together with the nitrogen atoms to which they are attached and with the central carbon atom of the Guanidmo group to which these nitrogen atoms are bonded, form a radical 1, 4, 5, 6-tetrah? dro-2-p? r? m? d? n? lo.

P3 preferably is alkyl (Ci-do), monocycloalkyl (C3-C / 0), bicycloalkyl (C5-C0), cycloalkyl (C1-C.0), coxi (Ci-Cß), aplo (C0-C14) , (C5-C14) heteroaryl, aplo (C-C1) -alkyl (Ci-C4), heteroaryl (C5-C14) -alkyl (C1-C4), halogen, trifluoromethyl, cyano, oxo, -N (alkyl (C1 -C)) 2 or -NH-CO-alkyl (C1-C). More preferably, R is (C1-C) alkyl, mono-cloalkyl (Cj-C? O), bicycloalkyl (C5-C1), t-cycloalkyl (C5-C12), (C1-C4) alkoxy, aryl (C) -Ci,), ap lo (C, -Cn) -alkyl (C1-C4), halogen, tr 1 fluoromethylo, cyano, oxo, -N (alkyl (C -C4)) or -NH-CO-alkyi (C -C4). Particularly, preferably RJ is alkyl (Ci-C4), monocycloalkyl (C-C), bicycloalkyl (C5-C? 2), t-cycloalkyl (C = -C?), Alkoxy (C-C,), alk (Ce-Ci4), halogen, trifluoromet lyo, cyano, oxo, -N ((C1-C4) alkyl)) 2 or -NH-CO- (C1-C4) alkyl.

R is preferably substituted or unsubstituted hydrogen or alkyl (C? -C6), particularly, preferably hydrogen or alkyl (Ci-Cß), which is unsubstituted or substituted by a radical of the group consisting of (C1-6) alkoxy C4), alkyl (d-Cí) -? (0) 2- and -NR7R77 where R7 and R7 'independently of one another are hydrogen or (C1-C4) alkyl. R 4 is, more particularly, preferably hydrogen or substituted or unsubstituted (C 1 -C 4) alkyl, further preferably hydrogen or (C 1 -C) alkyl which is substituted or unsubstituted as indicated above.

R is preferably (C1-C20) alkyl »(C3-C20) monocycloalkyl, (C5-C2n) bicycloalkyl, (C5-C2o) t-cycloalkyl, (C6-Ci4) aryl, (C5-C4) heteroaryl, (C6) aryl -C? 4) -alkyl (C? -C6) or heteroaryl (C5-C14) -alkyl (C? -C6), where the aryl radical, the heteroaryl radical, the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the tricycloalkyl radical each one is unsubstituted or is replaced by one, two or three identical or different R3 radicals. More preferably, R5 is (C1-C10) alkyl, (C3-C15) monocycloalkyl, (C5-C15) bicycloalkyl, (C5-C15) r-cycloalkyl, (C6-C4) aryl, (C6-C6) heteroaryl , aryl (C6-C1) -alkyl (C? -C6) - or heteroaryl (C5-C14) -alkyl (C? -C6) -, where the aryl radical, the heteroaryl radical, the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the tricycloalkyl radical are each unsubstituted or substituted by one, two or three identical or different R3 radicals. In addition to these preferences, a preferred group of radicals R5 is formed by the monocycloalkyl (C3-C20), bicycloalkyl (C5-C20) and tri- (C5-C2o) alkylcycloalkyl which can be substituted or otherwise modified as indicated above and that monocycloalkyl (C5-C15), bicycloalkyl (C5-C15), t-cycloalkyl (C5-C15) are also preferred. Another preferred group of radicals R5 is that formed by the radicals alkyl (C1-C20), aplo (C6-C14), heteroaplo (C5-C1), aryl (C6-C14) -alkyl (Ci-Ce) - or heteroaryl (C5-Cn) -alkyl (Ci-Ce), of which aplo (C5-C14) and heteroaryl (C5-C1) are preferred, which can be Replace or otherwise modify as indicated above. Particularly preferred groups of the radicals R5 are formed by the phenyl and naphthyl radicals, that is, phenol, 1-naphthyl and 2-naphthyl, which can be substituted or unsubstituted as indicated above. it is preferably hydrogen or alkyl (Ci-CeJ-O-CO-, particularly, preferably hydrogen or (C1-C4) alkyl -0-CO, in particular hydrogen.

Preferred compounds of formula I are those compounds in which one or more of the radicals have the preferred meanings or have a specific one or some specific of their respective denotations, all combinations of such preferred meanings or specific denotations being an object of the invention. present invention. Particularly preferred compounds of formula I are those compounds in which R1 and R2 are hydrogen or together with a saturated or unsaturated bivalent (C2-C5) alkylene radical, in particular hydrogen or together the - (CH2) P- group, where p is the numbers 2, 3, 4 or 5, wherein the (C2-C5) alkylene radical and the - (CH2) P- group are unsubstituted or substituted by a radical of the group consisting of halogen, (C? -C6) alkyl, (C4-C0) alkoxy ), aryl (C6-Cnl, aryl (C6-Ci4) -alkyl (Ci-Cs), het eroap lo (C5-C ±, hetero-halo (C5-C?) -alkyl (Ci-C »), cycloalkyl ( C, -C? 2), cycloalkyl (Cj-C?) -alkyl (Ci-Cf,) - and oxo, and wherein a saturated or unsaturated 5-membered to 7-membered ring which is unsubstituted or is replaced by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two nitrogen atoms in the ring, can be fused to the carbon-carbon bond in the alkylene radical (C2-C5) and in the group - (CH_) μ-; R is (C1-C10) alkyl, mono-cloalkyl (C3-C0o), bicycloalkyl (C, -Co), tricycloalkyl (Cr-C2o), alkoxy (Ci-Cs), ano (C-C14) ), heteroap lo (C, -C? "), aplo (C6-Ci4) -alkyl (C-C4), heteroaryl (C; -C? 4) -alkyl (C1-C4), halogen, tr lfluoromethyl, cyano, oxo, -N ((C1-C4) alkyl) 2 or -NH-CO-alkylo (C? -C "); R4 is hydrogen or alkyl (C? -Cb) which is unsubstituted or substituted by a radical of the a group consisting of (C1-C) alkoxy, alkyl (C? -C4) -S (0) 2- and NR7R7, where R7 and R7 'independently of one another are hydrogen or (C1-C) alkyl; R5 is (C1-C20) alkyl, (C3-C20) monocycloalkyl, (C5-C20) bicycloalkyl, (C5-C20) tricycloalkyl, (Cs-Cn) aplo, (C5-C14) heteroaryl, aplo 'C6-C? 4) -alkyl (Ci-Cß) - or heteroaryl (C5-C14) -alkyl (Ci-C6) -, where the aryl radical, the heteroaryl radical, the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the radical Each tricycloalkyl is unsubstituted or is substituted by one, two or three radicals R3; R6 is hydrogen or alkyl (C? -C6) -O-CO; in all the forms it is tereosis and mixtures of them in all the relations, and their physiologically tolerable salts and their promedications.

The very particularly preferred compounds of formula I are those compounds in which R1 and R2 are hydrogen or together they are a saturated or unsaturated radical (C2-C4) bivalent alkylene, in particular hydrogen or together the group - (CH2> P-, in which p is the numbers 2, 3 or 4, wherein the alkylene radical (C2-C4) and the group - (CH2)] are unsubstituted or are substituted by a radical of the group consisting of halogen, alkyl (Ci-Cß), alkoxy (Ci-Cß), aplo (C6) -C?), Aryl (C6-C?) -alkyl (C? -C6), heteroaryl (C6-Cn), heteroaryl (C5-C? 4) -alkyl (C? -C6), cycloalkyl (C3-? C12), (C3-C12) -cycloalkyl-C6-C6 alkyl- and oxo, and where a saturated or unsaturated 5-membered to 7-membered ring is unsubstituted or substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or a heterocyclic ring containing one or two nitrogen atoms in the ring, can be fused to the carbon-carbon bond in the alkylene radical (C2-C4) and in the group - (CH2 ) p-; R3 is (C1-C) alkyl, (C3-C10) monocycloalkyl, (C5-C12) bicycloalkyl, (C5-C12) tricycloalkyl, (C1-C) alkoxy, aryl (CD-Ci4>, aplo (C6-) Cn) -alkyl (C1-C), halogen, trifluoromet lyo, cyano, oxo, -N ((C1-C4) alkyl) 2 or -NH-CO- (C1-C4) alkyl; it is hydrogen or alkyl (C? -C6); R5 is (C1-C10) alkyl, (C3-C15) monocycloalkyl, (C5-C5), (C5-C5) bc, c-alkyl (C6-Cu), aryl (C6-Ci4), heteroaryl 1I0 (C5-C14), ar 1I0 (C6-Ci4) -alkyl (Ci-Cis) - or heteroaryl (C5-C14) -alkyl (Ci-C6) -, where the aplo radical, the heteroaryl radical, the radical alkyl, the monocycloalkyl radical, the bicycloalkyl radical and the tri- cycloalkyl radical are each unsubstituted or substituted by one, two or three radicals R3; R is hydrogen or (C1-C) alkyl-O-CO; in all stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.

Especially preferred compounds of formula I are those in which: R1 and R2 are hydrogen or together they are a saturated or unsaturated radical (C2-C3) divalent alkylene, in particular hydrogen or together the group - (CH? Íp-, wherein p is the numbers 2 or 3, wherein the alkylene radical (C2-C3) and the group - (CH2) P- are unsubstituted or are substituted by a radical of the group consisting of halogen, alkyl (Ci-Ce) ), alkoxy (C? -C6), aryl (C6-C?), aryl (C6-C? 4) -alkyl (Cx-C6), heteroaryl (Cs-C14), heteroaryl (C5-C14) -alkyl (Ci-Ce), cycloalkyl (C3-C12), cycloalkyl (C3-C12) -alkyl (Ci-Cß) - and oxo, and where a 5-membered ring up to 7 members saturated or unsaturated which is unsubstituted or is substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or a heterocyclic ring containing one or two nitrogen atoms in the ring, can be fused to the carbon-carbon bond in the alkylene radical (C2-C3) and in the group - (CH2) p-; R is (C1-C4) alkyl, (C3-C10) monocycloalkyl, (C5-C2), (C5-C12) cycloalkyl, (C5-C12) cycloalkyl, (C1-C4) alkoxy, (C6-Ci4) aryl ), halogen, tp f luoromet lyo, cyano, oxo, -N ((C 1 -C) alkyl) 2 or -NH-CO-(C 1 -C 4) alkyl; is hydrogen or alkyl (Ci-Ce) R5 is (C1-C10) alkyl, (C3-C15) monocycloalkyl, (C5-C15) bicycloalkyl, (C -C1) tricycloalkyl, (C6-Ci4) aplo, (C5-C14) heteroaryl, (C6) aryl -Ci4) -alkyl (C? -C6) - or heteroaryl (C5-C1) -alkyl (Ci-Ce) -, wherein the aryl radical, the hetero-radical, the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the tri- cycloalkyl radical each is unsubstituted or is substituted by one, two or three radicals R3; R6 is hydrogen or (C1-C4) alkyl-O-CO; in all forms stereoisomepcas and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.

On the other hand, the preferred compounds of the formula I are those in which R5 is aplo (C5-C1) or heteroary 1I0 (C5-C14), preferably aryl (C6-C14), where the aryl radical and the heteroaryl radical each one is unsubstituted or is replaced by one, two or three identical or different radicals R3 and is preferably unsubstituted or substituted by one or two R radicals identical or different, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs. The still more preferred compounds of formula I are those in which R 5 is a naphthyl radical, such as a 1-naphthyl radical or a 2-naphthyl radical, which is unsubstituted or is substituted by one, two or three radicals R3, and which is preferably unsubstituted, such as an unsubstituted 1-naphthyl radical or unsubstituted 2-naphthyl radical, in all its stereoisomeric forms and mixtures thereof in all ratios, and their salts Physiologically tolerable and their promedications.

Preferred compounds of the formula are additionally those in which the carbon atom to which the two groups R40-CO- and R5-S02-NH- are linked has the S configuration, in all its forms is tereosomeric and mixtures in all the relations, and their physiologically tolerable salts and their promedications.

A specific group of compounds of the formula I is formed by the compounds in which R1 and R2 independently of one another are hydrogen or alkyl (Ci-Ce) which is unsubstituted or substituted by R3, or in which the radicals R1- and R2- together are a saturated or unsaturated radical (C2-Cg) bivalent alkylene, for example the group - (CH2) D-, in which p is the numbers 2, 3, 4 , 5, 6, 7, 8 or 9, which are not substituted or replaced by one or more groups of the group consisting of halogen, alkyl (C? -C6), alkoxy (C? -C6), aryl (C6-C? 4), aryl (C6-C? 4) -alkyl (C? -C6), heteroaryl (C5-C1), hetero (C5-C1) -alkyl (C6-6), cycloalkyl (C3-C12) and cycloalkyl (C3-C12) -alkyl (C6-6) - and oxo, wherein a ring of 5 members to 7 members saturated or unsaturated which is unsubstituted or substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or a heterocyclic ring containing one or two nitrogen atoms in the ring , can be fused to the carbon-carbon bond in the alkylene radical (C2-C9), R3 is alkyl (CI-CB), alkoxy (C? -8), aryl (C5-C14), aryl (C5-Ci4) -alkyl (C1-C4), heteroaryl (C3-Cn), heteroaryl (C5-Ci4) -alkyl (C1-C4), halogen, tpf luoromet lyo, hydroxyl, oxo, nitro, amino, NH- (C1-C4 alkyl), -N (C1-C4 alkyl)) 2 or -NH-CO-alkyl (C? -C?), C0-alkyl (C? -C4); R is hydrogen, alkyl (C6C6) -CO-0-alkyl (Ci-C4), which is unsubstituted or substituted by a radical of the group consisting of hydroxyl, (C1-C4) alkoxy, alkyl (C1-C4) -S (O) 2, NR7R7 'and N + R7R7'R7' 'Q ~, where R7, R7' and R7"independently of one another are hydrogen, alkyl (Ci-Cß), aryl (C5 -C14) or aryl (C5-C14) -alkyl (Ci-Cß) - and Q "is a physiologically tolerable anion, or in which R4 is one of the radicals in which the links, by means of which the radicals are linked, are indicated by the dotted lines, R is (C1-C20) alkyl, (C3-C20) monocycloalkyl, (C5-C20) bicycloalkyl, (C5-C20) cycloalkyl, (C6-Ci4) aryl, heterocyclo (C5-Cn), ar 1I0 (C6-C) ?) -alkyl (Ci-Cß) - or hetero (C5-C14) -alkyl (C? ~ Ce) -, wherein the aryl radical, the heteroaryl radical, the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the radical Each cycloalkyl is unsubstituted or is substituted by one, two or three R3 radicals and wherein one or more carbon atoms of the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the tri-cycloalkyl radical, in particular one, two , three or four carbon atoms, can be replaced by identical or different atoms selected from the series consisting of nitrogen, oxygen and sulfur, R is hydrogen, alkyl (C? -C6) -O-CO, hydroxyl, alkyl (C? -C6) -O-CO-O- or nitro, in all its stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.

The present invention also relates to the processes for the preparation of the compounds of the formula I. The compounds can generally be prepared, for example in the course of a convergent synthesis, by linking two or more fragments that can be derived rosythically from the formula I. In the preparation of the compounds of the formula I, these can generally be advantageous or necessary in the course of the synthesis to introduce functional groups that can start the undesired reactions or side reactions in the respective synthesis step, in form of precursors that are the last to become the desired functional groups, or to temporarily block the functional groups by a strategically appropriate protective group for the synthesis problem. Such strategies are well known to one skilled in the art (see, for example, Greene and Wuts, Protective Group in Organic Synthesis, Wiley, 1991) As examples of precursor groups, nitro groups and cyano groups, it can be mentioned that they are the last ones to be converted by reduction, for example by catalytic hydrogenation, into amino groups and aminomethyl groups, respectively.

The compounds of formula I can be prepared, for example, by linking them in a manner known per se to a carboxylic acid derivative of formula II wherein R and R are defined as indicated for formula I, or in which alternatively functional groups are present in the form of precursors which are the last in converted into the groups present in the compounds of formula I, or in which the functional groups are present in protected form, and wherein X is a nucleophilically appropriate starting group, with guamdma or a guanidine derivative of the formula III wherein R1, R2 and R6 are defined as indicated for formula I, or alternatively functional groups are present in the form of precursors which are the last to be converted into the groups present in the compounds of formula I, or groups are present functional in protected form.

The COX group in formula II is preferably the carboxylic acid group COOH or an activated carboxylic acid derivative. X, for example, is hydroxyl or halogen, in particular chlorine or bromine, alkoxy, preferably methoxy or ethoxy, aryloxy, for example phenoxy or pentaf luorophenoxy, femthio, methylthio, 2-pipdylthio or a radical of a heterocyclic nitrogen bond by means of a nitrogen atom, in particular an azole, such as, for example, 1-ylidazolyl. X may also be, for example, (C 1 -C 4) alkyl-O-CO-O- or tolylsulphonyloxy and the activated acid derivative may thus be an anhydrous mixture.

If X is hydroxyl, that is, if the guanidma of formula III is reacted with a carboxylic acid, then the carboxylic acid is first activated conveniently. The activation can be carried out, for example, with dicyclohexylcarbodumide (DCCI) or with O- ((cyano (ethoxycarbonyl) -methyl) amine) -l, l, 3,3-tetramethyluron tetrafluoroborate. (TOTU, Konig et al., Proc. 21st Europ. Peptide Symp. 1990 (Eds. Giralt, Andreu), Escom, Leiden 1991, page 143) or other conventional activating reagents in peptide chemistry.

In addition to the free guanidmas of the formula III, guanidinium salts can also be used in the reaction with the compounds of the formula II, from which the free guanidines are then prepared in a separate step by means of a base. . The reaction of an activated carboxylic acid derivative of the formula II with the guanidine (derivative) of the formula III is preferably carried out in a manner known per se in an organic solvent, but inert, protic or aprotic. In this case, solvents such as methanol, isopropanol, tert-butanol, dimethyl formamide or tet rahydrofuran at temperatures from 0 ° C to the boiling point of these solvents are suitably tested, for example, in the reaction of methyl esters (X = methoxy) or ethyl esters (X = ethoxy) with guanidmas. The reactions of the compounds of the COX type with guanidines free of salts are advantageously carried out in inert aprotic solvents such as dimethylformamide, tetrahydrofuran, dimethoxyethane or dioxane, if suitable with the addition of a base such as, for example, potassium tert-butoxide or sodium methoxide. However, water can also be used as a solvent in the reaction of compounds of formula II with guanidmas, for example when a base such as sodium hydroxide is used. If X is, for example, chlorine, the reaction is advantageously carried out with the addition of a scavenger, for example an additional base or in the presence of an excess of guamdin (derivative), to bind the resulting halide acid. The reaction mixture is worked and, if desired, the reaction product is then purified by conventional processes familiar to those skilled in the art.

Protective groups can optionally be present in the products obtained from the compounds of formulas II and III, and then removed by standard processes. For example, the tert-butyl ester groups are converted to the carboxylic acid groups by treatment with trichloroetic acid, the benzyl groups are removed by the hydrogenation or the fluorenylmethoxycarbonyl groups are removed. for secondary amines. If desired, additional reactions are then carried out by standard procedures, for example acylation reactions or esterification reactions. In addition, a conversion to a physiologically tolerable salt or prodrug can then be carried out by known methods.

The starting components of the formulas II and III, which are linked to give the compounds of the formula I, are commercially available or can be prepared by or analogously to processes described in the literature. The preparation of the starting components of formula II is illustrated by means of the example in the following Scheme 1, the present invention is not restricted to this synthesis or these starting components. This does not cause any problem for those skilled in the art to carry out modifications of the syntheses shown, which are necessary for the preparation of other compounds according to the invention.

In this way, the caboxybenzaldehyde of the formula IV can react, for example in presence of puridin or piperidine, with the malonic acid ester of the formula V to give the Cinnamic acid derivative of the formula VI which, after hydrogenation, for example in the presence of palladium on carbon, gives the compound of the formula VII. After activation of the carboxylic acid group, the compound of the formula VII can be condensed with the derivative of 2,3-dαamidoprophenyl ester of the formula VIII to give the compound of the formula IX (Scheme 1) . The condensation can be carried out, for example, in the presence of TOTU or other conventional agent to activate the carboxylic acids.

In formula VIII, Y may be the group R5-SO2- which is present in the final compounds of formula I according to the invention and which may then be left in the molecule, or Y may be a group which temporarily protects the ammo group in position 2 and which in the last step is removed to give a free amino group which can then be converted to a group R5-S0 -NH by standard procedures for the preparation of sulphonamides, for example by reaction of the free amine with a chloride sulfonyl of the formula R5-S02-C1. An example of a protecting group represented by Y is the benzyloxycarbonyl group (group Z) which can be removed by catalytic hydrogenation. The sulfonyl chloride of the formula R5-SO.-Cl and other sulfonic acid derivatives suitable for introduction into the group R5-S02 are commercially available or can be prepared in accordance with or analogously to processes described in the literature. Instead of the tert-butyl ester present in the compounds of formula VIII and IX, other esters can be present with either only temporarily protecting the acid group or which can also be present in the final compounds of the formula I according to the invention and can remain in the molecule. Compounds analogous to the compounds of formula VI can also be obtained by other processes for the conversion of a carbonyl group to an alkene, for example by the Wittig reaction.

It burns 1 The compounds of the formula IX are examples of compounds of the formula II in which X is methoxy. These compounds and analogous compounds which are obtained from the synthesis described above and which contain a group which is an activated carboxylic acid derivative, can be reacted directly with the compounds of the formula III. The compounds obtained in the above synthesis, however, can also first be converted under standard conditions by partitioning the methyl ester group or another ester group present in the position relative to the compounds of formula IX, into the corresponding carboxylic acids which are reacted then with the guanidmas of formula III after in situ activation, for example with TOTU or DCCI, or after conversion into an activated carboxylic acid derivative. If, as activated acid derivatives, one tries to prepare, for example, the carboxylic acid chlorides (formula II, X = Cl), this conversion can be carried out, for example, using thionyl chloride. If one tries to prepare, for example, the methyl esters (formula II, X = methoxy) of the carboxylic acids, this can be carried out by treatment with hydrogen chloride gas in methanol. Other acid derivatives activated in a manner known per se can be prepared from carboxylic acid chlorides or directly from the carboxylic acids on which they are based (formula II, X = OH). Examples are the imidazolides (formula II, X = 1-? M? Dazol?) Obtained by treating the acids with carbonyldiimidazole (Staab reference, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)), or mixtures of annidrides which they are obtained, for example, by the reaction with esters of cioroformico acid such as ethyl chloroformate or with tosyl chloride in the presence of amines such as tpetilamina in an inert solvent. A number of methods suitable for the preparation of activated carboxylic acid derivatives are indicated in detail from the source of literature in J. March, Advance Organic Chemistry, Third Edition, John Wiley and Sons, 1985, page 350.

The compounds of formula I are valuable pharmaceutical active ingredients which are suitable, for example, for the therapy and prophylaxis of bone disorders, tumor disorders or cardiovascular disorders. The compounds of the formula I and their physiologically tolerable salts and their prodrugs can be administered to animals, preferably to mammals, and in particular to humans as pharmaceuticals for therapy or prophylaxis. These can be administered by themselves or in mixtures with any other or in the form of pharmaceutical preparations which allow enteral or parenteral administration and which, as an active constituent, contain an effective dose of at least one compounds of the formula I and / or their physiologically tolerable salts and / or their prodrugs in addition to carriers pharmaceutically innocuous and / or additives.

The present invention therefore also relates to the compounds of the formula I and / or their physiologically tolerable salts and / or their prodrugs for use as pharmaceuticals, for the use of the compounds of the formula I and / or their physiologically tolerable salts and / or its prodrugs for the production of pharmaceuticals for the therapy and prophylaxis of the diseases mentioned above or below, for example for the therapy and prophylaxis of bone disorders, and also for the use of the compounds of the formula I and / or its physiologically tolerable salts and / or its prodrugs for the therapy and prophylaxis of these diseases. The present invention also refers to pharmaceutical preparations or pharmaceutical compositions containing an effective dose of at least one compounds of the formula I and / or their physiologically tolerable salts and / or their prodrugs in addition to a conventional pharmaceutically innocuous carrier.

Pharmaceuticals can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard gelatine capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. The administration, however, can be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or dyes, or in other ways, for example in the form of aerosols or nasal sprays.

The pharmaceutical preparations according to the invention are prepared in a manner known per se and familiar to one skilled in the art, pharmaceutically inert organic and inorganic carriers are used in addition to the compound (s) of the formula I and / or its (their) physiologically tolerable salts and / or their prodrugs For the production of pills, tablets, coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. The carriers for soft gelatin carousels and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural oils or hardeners, etc. Suitable carriers for the production of solutions, for example injection solutions, or emulsions or syrups are, for example, water, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. The appropriate carriers for to microcapsules, implants or rods are, for example, copolymers of glycylic acid and lactic acid. The pharmaceutical preparations usually contain about 0 to 5 90% by weight of the compounds of the formula I and / or their physiologically tolerable salts and / or their prodrugs. The amount of the active ingredient of the formula I and / or its physiologically tolerable salts and / or its prodrugs in the pharmaceutical preparations is usually from 0.2 to 500 mg, preferably from 1 to 200 mg.

In addition to the active ingredients and carriers, the pharmaceutical preparations may additionally contain additives, such as, for example, fillers, disintegrators, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavors or flavorings, thickeners, diluents, buffer substances, and also solvents or solubilizers or agents for effecting storage, and also salts for altering the osmotic pressure, coating agents or anti-oxidants. These may also contain two or more compounds of the formula I and / or their physiologically tolerable salts and / or their prodrugs. Additionally, in addition to less a compound of formula I and / or its physiologically tolerable salts and / or its prodrugs, these may also contain one or more therapeutically or prophylactically active ingredients.

The compounds of formula I are antagonists of the vitronectin receptor and inhibitors of cell adhesion. These have, for example, the ability to inhibit the binding of osteoclasts to the bone surface and thereby inhibit bone resorption by osteoclasts. The action of the compounds of formula I can be demonstrated, for example, in an assay in which inhibition of vitronectin binding to cells containing the vitronectin receptor is determined. The details of such an assay are given below. Like the vitronect receptor antagonists, the compounds of the formula I and their physiologically tolerable salts and / or their prodrugs are generally suitable for the therapy and prophylaxis of diseases which are based on the interaction between the vitronectin receptors and their ligands in processes of cell-cell interaction or cell-matrix interaction processes, or it is desired that they can influence by an inhibition of interactions of this type, or by their prevention, alleviate or cure an inhibition of interactions of this type. As explained at the beginning, such interactions, for example, play a part in bone resorption, in angiogenesis or in the proliferation of vascular smooth muscle cells. The compounds of the formula I and their physiologically tolerable salts and / or their prodrugs are therefore suitable, for example, for the relief or cure of diseases that are at least partially caused by a medial extension of bone resorption, angiogenesis or the proliferation of vascular smooth muscle cells.

The bone diseases of treatment and prevention for those compounds of the formula I according to the invention which can be used, are especially teoporosis, hypercalcemia, osteopenia, for example caused by metastasis, dental disorders, hyperparathyroidism, periarticular erosions in rheumatoid arthritis and Paget's disease. In addition, the compounds of formula I can be used for the relief, prevention or therapy of bone disorders that are caused by glucocorticoid, spheroidal or corcyal thermomeral therapy or by a lack of sex hormone (s). All these disorders are characterized by bone loss, which is based on the imbalance between bone formation and bone destruction and which can be favorably influenced by the inhibition of bone resorption by osteocytes. The compounds of the formula I and / or their physiologically tolerable salts and / or their prodrugs can also be used favorably as inhibitors of bone resorption, for example in the therapy or prophylaxis of osteoporosis, in combination with conventional O-teoporosis treatment, for example in combination with beta phosphates, estrogens, estrogen / proges terone, agonists / estrogen ant agonists, calcitonin, vitamin D analogues, parathyroid hormone, growth hormone secretors, or sodium fluoride. The administration of the compounds of the formula and / or their physiologically tolerable salts and / or their prodrugs and other effective active ingredients in the treatment or prophylaxis of osteoporosis such as those listed above may take place simultaneously or sequentially, in any order, and together or separately For use in such treatments or combination prophylaxis the compounds of formula I and / or their physiologically tolerable salts and / or their prodrugs and one or more other active ingredients as those listed above can be presented together in a simple pharmaceutical preparation, for example tablets or granules, or they can be presented in two or more separate pharmaceutical preparations which can be contained in a single package or in two or more separate packages The use of the compounds of the formula and / or their physiologically tolerable salts and / or their compounds in such therapies or prophylaxis of combinations and their use in the production of pharmaceuticals for such therapies or combinations prophylaxis are also The present invention also relates to pharmaceutical preparations comprising efficient amounts of at least one compound of the formula I and their sa is physiologically tolerable and / or their prodrugs together with at least some other active ingredient effective in the treatment or prophylaxis of osteoporosis or in the inhibition of bone resorption as those listed above, together with a conventional pharmaceutically innocuous carrier. The above explanations in the pharmaceutical preparations correspondingly apply for such pharmaceutical combination preparations.

Apart from the use as inhibitors of bone resorption by osteoclasts, the compounds of formula I and their physiologically tolerable salts and / or their prodrugs can be used as inhibitors of tumor growth and tumor metastasis, as anti-inflammatory, for therapy or prophylaxis of cardiovascular disorders such as atherosclerosis or restenosis, or for the therapy or prophylaxis of nephropathies or re-inopathies, such as, for example, diabetic retinopathy. As inhibitors of tumor growth or tumor metastasis, the compounds of formula I and / or their Physiologically tolerable salts and their prodrugs can also be favorably used in combination with conventional cancer therapy. Examples of conventional cancer therapy are given in Bertino (Editor), Encyclopedia of Cancer, Academic Press, 1997, which is incorporated herein by reference. All previous establishments related to the use of the compounds of formula I in combination with conventional osteoporosis therapy, such as, for example, possible modes of administration and pharmaceutical combination preparations, correspondingly apply to the use of the compounds of formula I in combination with conventional cancer When the compounds of formula I are used, the dose may vary within wide limits and, as is conventional, may be appropriated for individual conditions in each individual case. This depends, for example, on the compound used or on the nature and severity of the disease to be treated and whether an acute or chronic condition is treated or whether the prophylaxis is carried out. In the case of oral administration, the daily dose is generally 0.01 to 100 mg / kg, preferably 0.1 to 50 mg / kg, in particular 0.1 to 5 mg / kg, for example 0.3 to 0.5 mg / kg to achieve effective results in an adult weighing about 75 kg (in each case in mg per kg of body weight). Also in the case of intravenous administration, the daily dose is generally approximately 0.01 to 100 mg / kg, preferably 0.05 to 10 mg / kg (in each case in mg per kg of body weight). The daily dose can be divided, in particular in the case of the administration of relatively large amounts, into several, for example 2, 3 or 4, parts of administration. As usual, depending on the individual condition it may be necessary to deviate upwards or downwards from the indicated daily dose.

Apart from the use as active ingredients, the compounds of the formula I can also be used as carriers or carriers of active ingredients in order to transport the active ingredient specifically to the site of action (= target drug, see, for example, Targeted Drug Delivery, RC Juliano, Handbook of Experimental Pharmacoiogy, Vol. 100, Ed. Born, G.V. R. et al., Springer Verlag which is incorporated herein by reference). The active ingredients that are transported are in particular those that can be used for the treatment of the aforementioned diseases.

The compounds of formula I and their salts can be used for diagnostic purposes, for example in in vitro diagnostics, and as auxiliaries in biochemical investigations in which vitronectin receptor blockade or the influence of cell-cell or cell-based interactions the cell-mat riz are desired. These can also be used as synthesis intermediates for the preparation of other compounds, in particular other active pharmaceutical ingredients, which are obtained from the compounds of the formula I, for example by modification or introduction of radicals or functional groups.

Examples The products were identified by means of mass spectrum (MS) and / or NMR spectrum.

Depending on their last step of synthesis and / or working procedures, for example freeze drying, they were carried out, in some cases the compounds were partially or completely obtained in the form of a salt, for example in the form of a acetic acid salt, tri-luoroacetic acid salt or hydrochloric acid salt.

Example 1 Acid (2S) -2- (Naphthalene-l-sulfon? Lammo) -3- (4- (2- (1, 4, 5, 6-tetrah? Drop? Nm? D? N-2-? Lcarbamo? ) -ethyl) -benzoylamine) -propionic acid. a) acid 4 - (-Metox? car on? -v? n? enzoic 18. 74 g (0.12 mol) of potassium salt of monomethyl malonate were suspended in 18 ml of pyridine. 15.01 g (0.1 mol) of 4-carboxybenzaldehyde and 0.85 g (0.01 mol) of piperidma were added at room temperature with stirring. The mixture was refluxed until the CO 2 evolution was complete (about 2 hours), and then an additional 60 ml of pyridine was added and the mixture was stirred at reflux for an additional 1 hour. The reaction mixture was treated with stirring with 500 ml of ice and 110 ml of concentrated hydrochloric acid. After the addition was complete, the mixture was stirred for an additional 20 minutes, and the product was thoroughly filtered with suction, washed with water and recrystallized from isopropanol. Yield 12.85 g. 1 H-NMR (200 MHz, d 6 -DMSO): d = 3.75 (s, 3 H, 0 CH 3); 6.76 (D, J = 15 Hz, 1H, CHCOOCH3); 7.73 (d, J = 15Hz, 1H, Ar-CH); 7.84 (d, J = 9 Hz, 2H, Ar-H); 7.98 (d, J = 9 Hz, 2H, Ar-H); 13.11 (s, br, 1H, COOH). MS (CI +): m / e = 207.2 (M + H +).

HPLC: RP18, Nucleosil 300-5-C18, 250x4 mm; of buffer solution A: H20, 0.1% trifluoroacetic acid trifluoroacetic acid (TFA), buffer solution B. acetonitrile (80% v / v) / H2O (20% v / v), 0.1% TFA; gradient: first 5 minutes 90% buffer B, and then for 20 minutes at 90% buffer B, and then 5 minutes 90% buffer B, flow range lml / rnin; Rj = 18.05 minutes. b) 4- (2-Methoxycarbon? l-et? l) benzoic acid 8 g (38.8 mmol) of 4- (2-methoxycarbonyl-viml) benzoic acid in 250 ml of dioxane were suspended and hydrogenated for 7 hours at room temperature over Pd / C (10% strength) at 1 bar of hydrogen. The mixture was filtered and the solvent removed in vacuo. Yield 8.05 g. 1 H-NMR (200 MHz, do-DMS0): d = 2.67 (t, J = 8 Hz, 2H, CH 2 -C00CH 3); 2.93 (t, J = 8Hz, 2H, Ar-CH2); 3.59 (s, 3H, 0CH3); 7.35 (d, 2H, Ar-H); 7.86 (d, J = 9Hz, 2H, Ar-H); 12.80 (s, br, 1H, COOH). MS (Cl7: m / e = 209.2 (M + H +).

HPLC: RP18, Nucleosil 30 -5-C, x mm; e buffer solution A: H20, 0.1% TFA; of buffer B: acetonitrile (80% v / v) / H2O (20% v / v), 0.1% TFA; gradient: first 5 minutes 90% buffer A, 10% buffer B, and then for 20 minutes at 90% buffer B, and then 5 minutes 90% buffer B, flow range lml / rnin; Ri = 17.03 minutes. c) (2S) -2-benz? lox? carbon? lammo-3- (4- (2-methoxycarbonyl-ethyl) -ben zoi lamino J-propionate ter-butyl 354 mg (1.7 mmol) of 4- (2-meth oxycarbonyl-ethyl-1-benzoic acid) and 500 mg (1.7 mmol) of (2S) -3-ammo-2-benzyl-carbon? Lam? Noprop? Tert-butyl onate were dissolved in 3 ml of dimethyl formamide and treated with 557 mg (1.7 mmol) of O- ((cyano- (ethoxycarbonyl) -methylidene) amino tetraborate) -1, 3, 3 -tetramet? luron (TOTU) and 204 mg (1.7 mmol) of dusopropylethylamine, and the mixture was stirred at room temperature for 7 hours at a pH of 7-8. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate and the The solution was washed three times with KHS04 solution and NaHCO3 solution that was neutral. The organic phase was completely separated and dried and the solvent was removed by vacuum distillation. Yield 770 mg. MS (ES7: m / e = 485.2 (M + H) +. d) tert-butyl ester of (2S) -2-Am? no- 3- (4- (2-methox? carbon? l-et? l) -benzole lamino) -propionic acid 6. 88 g (14.2 mmol) of (2S) -2-benzyloxycarbonilamino-3- (4- (2-methoxycarbonyl) benzole) tert-butyl propionate was dissolved in 200 ml of methanol and 852 mg was added (14.2 g. mmol) of acetic acid. The mixture was hydrogenated for 7 hours at room temperature over Pd / C (5% strength) at 1 bar of hydrogen. The mixture was filtered and the solvent removed m vacuo. The residue was washed with n-heptane and dried in vacuo. Yield 6.9 g. MS (ES +): m / e = 351.2 (M + H) +. e) tert-butyl ester of (2S) -3- (4 - (2-methoxycarbonyl-ethyl) -benzoylamine) -2- (naphthalene-1-sulphonylamine) -propionic acid 0. 123 g (0.35 mmol) of tert-butyl ester of the acid (2S) -2-amino-3- (4 - (2-methox? Carbon? L-ethyl) -benzoylamino) -propionic was dissolved in 2 ml of dimethyl formamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.159 g (0.7 mmol) of 1-naphthalenesul fonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed by vacuum, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase is dried, sodium sulfate, filtered and the solvent removed in vacuo. The residue is chromatographed on silica gel eluting with n-heptane / ethyl acetate (1/1). Yield 47 mg. MS (ES +): m / e = 541.3 (M + H) +. f) acid tert-butyl ester (2S) -2- (naphthalene-1-eulphon? lammo) -3- (4- (2- (1, 4, 5, 6-tetrah? drop? r? m? dm-2-? lcarbamo? l) -ethyl) -benzoilammo) -propionic 47 mg (0.087 mmol) of tert-butyl ester of the acid (2S) -3- (4- (2-methyl toxic rbonyl-ethyl) -benzoylamino) -2- (na ft-1-sulfo onylumino) -propionic was dissolved in 2 ml of dimet and 1 formamide and 86 mg (0.87 mmol) of 2-ammo-1,4,6,6-tetrahydropinmidine was added. The reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with dichloromethane / methanol (1/1), followed by dichloromethane / methanol / acetic acid / water (85/15 / 1.5 / 1.5). yield 46 mg. MS (ES7: m / e = 608 3 (M + H) +. g) (2S) -2 - (naphthalene-1-sulfonylamino) -3- (4 - (2- (1, 4, 5, 6-tetrah? drop? r? m? d? n-2-? lcarbamo? l) -ethyl) -benzol lamino) -propionic 45 mg (0.074 mmol) of tert-butyl ester of (2S) -2- (naphthalene-1-sulfonamino) -3- (4- (2- (1, 4.5.6) was dissolved. -tetrah? drop? r? m? d? n-2-? carbamo? l) -ethyl) -benzol lamino) -propionic in 2 ml of dichloromethane and 2 ml of lupoacetic tpf acid The solution was stirred at room temperature by 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile / water (1/1) and lyophilized. Yield 50 mg. MS (ES +): m / e = 552 (M + H) +.

Example 2 acid (2S) -2- (Qumol? no-8-sulfon? lam? no) -3- (4- (2- (1, 4, 5, 6-tetrah? drop? r? m? d? n- 2-? Lcarbamo? L) -ethyl) -benzoylamino) -propionic a) tert-butyl ester of (2S) -3- (4 - (2-methoxycarbonyl-ethyl) -benzolamine) -2-qu? nol-non-8-sulfonylamino) -propionic acid ester 0.123 g (0.35 mmol) of tert-butyl ester of (2S) -2 -ammo-3- (4- (2-methoxycarbonyl-ethyl) -benzole-lamino) -propionic acid was dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of tetylamine and 0.159 g (0.7 mmol) of 8-qu? nolmosulfonyl chloride. The solution was stirred for 4 hours at room temperature. He The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent removed in vacuo. The residue is chromatographed on silica gel eluting with n-heptane / ethyl acetate (1/1). Yield 67 mg. MS (ES +): m / e = 542.2 (M + H) +. b) tert-butyl ester of the acid (2S) -2- (Qumol? no-8-sulfon? lam) -3- (4- (2- (1, 4,5,6-tetrahydropyr? m? d-n-2-alkylcarbomethyl) -ethyl) -benzoylamino) -propionic acid 65 mg (0.12 mmol) of tert-butyl ester of the acid (2?) -3- (4 - (2-methox? Carbon? L-ethyl) -benzole lamino) -2-qu? Nol? No- was dissolved. 8-sulfonamino) -propionic acid in 1 ml of dimethylformamide and 59 mg (0.6 mmol) of 2-amino-l, 4, 5, 6-tet rahidropir imidine was added. The reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with dichloromethane / methanol (1/1), followed by dichloromethane / methanol / acid acetic / water (85/15 / 1.5 / 1.5). Yield 72 mg. MS (E? +): M / e = 609.3 (M + H) +. c) acid (2S) -2- (Qumolmo-8-sulfonyl mo) -3- (4- (2- (1, 4, 5, 6-tetrah? drop? r? m? d? n-2-? lcarbamo? l) -etl) -benzol lamino) -propionic 72 mg (0.11 mmol) of tert-butyl ester was dissolved from the acid (2S) -2- (qu? Nolmo-8-sulphonylamino) -3- (4- (2- (1, 4,5,6 -tetrah? drop? r? m? dm-2-? lcarboma? l) -ethyl) -benzoilammo) -propionic acid in 2 ml of dichloromethane and 2 ml of rhipfluoroacetic acid were added. The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetom tplo / water (1/1) and lyophilized. Yield 54 mg. MS (EST): m / e = 553 (M + H) +.

Example 3 acid (2S) -2- (4-Acetylamino-benzenesulfoni lamino) -3- (4- (2-d, 4,5,6-tetrahydro-drop? r? m? dm-2-carbamoyl) -ethyl) -benzol lamino) propionic a) tert-butyl ester of (2S) -2- (4-Acetylamino-benzene-sulfonyl-lamino) -3- (4- (2-methoxycarbonyl-ethyl) -benzoylamino) -propionic acid ester 0.123 g (0.35 mmol) of tert-butyl ester of the acid (2 S) -2 -am? No-3- (4 - (2-methoxycarbonyl-et i 1) -benzole lamino) -propionic in 2 ml was dissolved. of dimethylformamide and treated with 0.196 ml (1.4 mmol) of tetylamine and 0.164 g (0.7 mmol) of 4-acetylamino-benzenesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase dried with sodium sulfate, filtered and the solvent removed in vacuo. The residue is chromatographed on silica gel eluting with n-heptane / ethyl acetate (1/2). Yield 90 mg. MS (ES +): m / e = 548 (M + H) +. b) tert-butyl ester of the acid (2S) -2- (4-acetylamino-benzenesulfoni lamino) -3- (4- (2 - (1, 4, 5, 6-tetrah? drop? r? m? d ? n-2-? lcarbamo? l) -ethyl) -benzoylamino) -propionic 87 mg (0.16 mmol) of tert-butyl ester was dissolved from the acid. { 2S) -2- (4-acetylamino-benzenesulfon-lamino) -3- (4- (2-methox-carboml-et-II) -benzoylamino) -propiomco in 1 ml of dimethylformamide and 79 mg (0.8 mmol) was added. of 2 -am? no-1, 4, 5, 6-tetrah? drop? r? m? d? na. The reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with dichloromethane / methanol (1/1), followed by di chloromethane / methanol / acetic acid / water. (85/15/1 5/1 5). Yield 57 mg. MS (ES +): m / e = 615.3 (M + H) +. c) (2S) -2- (4-Acetylamino-benzenesulfonylamino) -3- (4- (2- (1, 4, 5, 6-tetrah? drop? pm? d? n-2-? lcarbamo? l) -ethyl) -benzoylamine) -propionic 57 mg (0.09 mmol) of tert-butyl ester was dissolved from the acid (2S) -2- (4 -acetiammo-benzenesulfonylamino) -3- (4- (2- (1, 4, 5, 6-tetrah? drop? r? m? dm-2-? carbamo? l) -ethyl) -benzoylamine) -propionic acid in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid were added. The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonite / water (1/1) and lyophilized. Yield 42 mg. MS (ES +): m / e = 559.2 (M + H) +.

E j us 4 acid (2S) -2- (2- (1, 4,5,6-Tetrah? drop? nm? d? n-2-licarbamoyl) -ben zenosulfoni lamino) -3- (4- (2- (1, 4, 5, 6-tetrah? Rop? R? M? D? N-2-? Carbamo? L) -ethyl) -benzol lamino) -propionic a) methyl ester of acid 2- ((SS) -1-tert-Butox? carbon? l-2- (4- (2-methox? carbon? l-et? l) -benzoylamino) -ethylsulfamoyl) - benzoic 0.123 g (0.35 mmol) of tert-butyl ester of (2S) -2-amino-3- (4 - (2-methoxycarbonyl-ethyl) -benzoylamino) -propionic acid was dissolved in 2 ml of dimethylformamide and it was treated with 0.196 ml (1.4 mmol) of triethylamine and 0.164 g (0.7 mmol) of 2- (methoxycarbonyl) -benzenesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent removed in vacuo. The residue is chromatographed on silica gel eluting with n-heptane / ethyl acetate. ethyl (1/1). Yield 75 mg. MS (E? +): M / e = 549 (M + H) +. b) tert-butyl ester of the acid (2S) -2- (2- (1,, 5, 6-Tetrah? drop? r? m? d? n-2-licarbamoyl J-benzenesulfoni lamino) -3- (4- (2- (1, 4, 5, 6-tetrah? Drop? Pm? D? N-2-? Lcarbamo? L) -ethyl) -benzoylamm) -propionic 75 mg (0.13 mmol) of methyl ester was dissolved from 2- ((SS) -1- tert-butoxycarboni 1-2- (4- (2-methoxycarbonyl-1-yl) -benzole lamino acid) -etilsul famoyl) -benzoic acid in 1 ml of dimethylformate and 68 mg (0.69 mmol) of 2-ammo-1, 4, 5, 6-tetrahydrofididine were added. The reaction was stirred at room temperature for 20 hours. The solvent was removed m vacuo and the residue was chromatographed on silica gel eluting with dichloromethane / methanol (1/1), followed by dichloromethane / methanol / acetic acid / water (85/15 / 1.5 / 1.5). Yield 54 mg. MS (ES +): m / e = 683.3 (M + H) +. c) acid (2S) -2- (2- (1, 4, 5, 6-Tetr ahydropyridimin-2? -carbamoyl) -becenosul phonilammo) -3- (4- (2- (1, 4, 5, 6-tetrah? Drop? Pm? D? N-2-? Lcarbamo? L) -ethyl) -benzoyl Ipropionic lamino 54 mg (0.08 mmol) of tert-butyl ether of the acid (2S) -2- (2- (1, 4, 5, 6-tetrah? Drop? R? M? Dm-2-? Lcarbamo? ) -benzenesulfonylamino) -3- (4- (2- (1, 4, 5, 6-tetrah? drop? nm? d? n-2-? lcarbamoyl) -ethyl) -benzoyl mo) -propionic acid in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid were added. The solution is stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetom trilo / water (1/1) and lyophilized. Yield 34 mg. M (ES +): m / e = 627 (M + H) ".

General procedure 1 (synthesis of the compueetoe of the examples 5 to 24) Paeo a: Reaction with sulfonyl chloride. 0.2 g of tert-butyl ester of (2S) -2-ammo-3- (4- (2-methox? Carbon? L-et? L) -benzoylamino) -propionic acid ester was dissolved in 2 ml of dimethylformamide and treated with 4 molar eivalents of tpetilamma and 2 molar equivalents of the appropriate sulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed by vacuum, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent removed in vacuo. The residue is chromatographed on silica gel eluting with n-heptane / ethyl acetate (1/1).

Step b: Formation of the acyl guanidma.

The product of the reaction was dissolved in 1 ml of formamide dicmide and 5 molar equivalents of 2-ammo-1, 4, 5, 6-tetrahydropyrimid were added. The reaction mixture was stirred at room temperature for 20 h. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with dichloromethane / methanol (1/1), followed by dichloromethane / methanol / acetic acid / water (85/15 / 1.5 / 1.5).

Step c: Partition of the tert-butyl ester.

The product of step b was dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid was added. The solution was stirred at room temperature for 3 hours. The solvent was removed n vacuo, and toluene was added to the residue and then stirred in vacuo. The residue was dissolved in acetonitr / water (1/1) and lyophilized.

Example 5 Acid (2?) -2- (4-tert-but? L-benzene-sulfon? Lam?) -3- (4- (2- (l, 4,5,6-tetrah? Drop? Pm? Dm-2 -carbamoyl) ethyl) benzoylamino) -propionic The title compound was synthesized in accordance with general procedure 1, using 4-tert-butyl-benzenesulfonyl chloride in step a.

Yield MS (ES +): m / e Product of passage to 83mg 547.2 (M + H) + Product of step b 85mg 614.3 (M + H) + Product of step c 75mg 558.3 (M + H) + (title compound) Example 6 Acid (2?) -2- (propane-1-sul phonylamino) -3- (4- (2- (1, 4, 5, 6-tetrah? Drop? Pm? D? N-2-? Carbamo? ) -ethyl) -benzol lamino) -propionic The title compound was synthesized according to general procedure 1, using propane-1-sulfonyl chloride in step a.

Performance MS (ES +): m / e Product of the passage to 54mg 457.3 (M + H) + Product of step b 55mg 524.3 (M + H) + Product of step c 45mg 468.3 (M + H) + (title compound) Example 7 (2S) -2- (2-Penyl-Ethenesulfonylamino) -3- (4- (2- (1, 4, 5, 6-tetrahydropyrimidin-2-ylcarbamoyl) -ethyl) -benzoylamino) -propionic acid The title compound was synthesized in accordance with general procedure 1, using trans-beta-styrenesul fonyl chloride in step Performance MS (ES +): m / e Product of passage to 49mg 517.1 (M + H) + Product of step b 45mg 584.3 (M + H) * Product of step c 37mg 528.3 (M + H) t (Title compound Example 8 acid (2S) -2- (4-Prop? 1-benzenosul phonilam) -3- (4- (2- (1, 4, 5, 6-tetrah? drop? pm? d? n-2-? carbamo (l) -ethyl) -benzoylamine) -propionic The title compound was synthesized according to general procedure 1, using 4- (n-propyl) -benzenesulfonyl chloride in step a.

Performance MS (ES +): m / e Product of passage to 78mg 533.2 (M + H) + Product of step b 73mg 600.4 (M + H) + Product of step c 55mg 544.3 (M + H) + (title compound) Example 9 acid (2S) -2- (2-Met? l-propane-l-sulfon? lammo) -3- (4- (2- (1, 4, 5, 6-tetrah? drop? r? m? dm- 2-? Lcarbamo? L) -ethyl) -benzoilammo) -propionic The title compound was synthesized in accordance with general procedure 1, using 2-methyl-1-propane-1-sulphonyl chloride in step a.

MS performance (ES7: m / e Product of the step to 21mg 471.3 (M + H) + Product of step b lOmg 538.4 (M + H) + Product of step c 13mg 482.3 (M + H) + (title compound) Example 10 acid (2S) -2- (4-Butox? -benzenesulfon? lam? no) -3- (4- (2- (1, 4, 5, 6-tetrah? drop? r? m? dm-2-? lcarbamo? l) -et íl) -benzoilammo) -propionic The title compound was synthesized according to general procedure 1, using 4 - (n-butoxy) -benzenesulfonyl chloride in step a. Yield MS (ES +): m / e Product of passage to 83mg 563.2 (M + H) + Product of step b 83mg 630.4 (M + H) + Product of step c 63mg 574.3 (M + H) + (title compound) E jmplo 11 acid (2S) -2- (2-C? ano-benzenesulfon? lam? no) -3- (4 - (2- (1, 4, 5, 6-tetrah? drop? pm? d? n-2- lcarbamo? l) -et íl) -benzoilammo) pr opionico The title compound is synthesized according to general procedure 1, using 2-c-ano-benzenesulfonyl chloride in step a.

Performance MS (ES +): m / e Step product at 91mg 516.2 (M + H) + Product of step b 71mg 583.3 (M + H) + Product of step c 73mg 527.3 (M + H) + (title compound) Example 12 acid (2S) -2- (7,7-D? met? l-2-oxo-bicyclo [2.2.1] hept-l? -methanesulfon? lammo) -3- (4 - (2- (1, 4 , 5, 6-tetrah? Drop? R? M? Dm-2-? Lcarbamo? L) -etl) -benzol lamino) -propionic The title compound was synthesized according to general procedure 1, using 20-fluoro or sulphonyl chloride in step a.

Performance MS (ES +): m / e Product of passage to 85mg 565.3 (M + H) + Product of step b 88mg 632.4 (M + H) + Product of step c 71mg 576.4 (M + H) (Title compound) Example 13 acid (2S) -2- (4-Chloro-benzenesulfonylamino) -3- (4- (2- (1, 4, 5, 6-tetrah? drop? nm? d? n-2-? lcarbamo? l) - ethyl) -benzol lamino) -propionic The title compound was synthesized according to general procedure 1, using 4-chloro-benzenesulfonyl chloride in step a.

Performance M? (ES +): m / e Product of passage to 91mg 525.1 (M + H) + Product of step b 82mg 592.3 (M + H) 'Product of step c 64mg 536.3 (M + H)' (Title compound) Example 14 acid (2S) -2- (3-Chloro-benzenesulfonylamino) -3- (4- (2- (1, 4, 5, 6-tetrah? drop? r? m? d? n-2-? carbamo? ) -ethyl) -benzol lamino) -propionic The title compound was synthesized according to general procedure 1, using 3-chloro-benzenesulfonyl chloride in step a.

Performance MS (ES): m / e Product of the step at 65mg 525.2 (M + H) + Product of step b 58mg 592.3 (M + H) + Product of step c 52mg 536.3 (M + H) + (title compound) Example 15 acid (2S) -3- (4- (2- (1, 4, 5, 6-tet rah? drop? r? m? dm-2-licarbamoyl) -ethyl) -benzoylamine) -2- (3-trifluoromethyl) -benzenoeulfoni lamino) -propionic The title compound was synthesized according to general procedure 1, using 3-tr? F luoromet-1-benzenesulfonyl chloride in step a.

Performance M? (ES): m e Product of the step to 86mg 559.2 (M + H) + Product of step b 94mg 626.3. { M + H) + Product of step c 84mg 570.3 (M + H) + (title compound) E xemployment 16 acid (2S) -2- (4-methoxy-benzenesulfonylamino) -3- (4 - (2- (1, 4, 5, 6-tetrah? drop? pm? d? n-2-? lcarbamo? l) - ethyl) -benzol lamino) -propionic The title compound was synthesized according to general procedure 1, using 4-methoxy-benzenesulfonyl chloride in step a.

Performance MS (ES): m / e Step product at 66mg 521.1 (M + H) + Step product b 71mg 588.3 (M + H) + Step product c 49mg 532.3 (M + H) + (title compound) Example 17 (2S) -2-Benzenesulfon? lammo-3- (4- (2- (1, 4, 5, 6-tetrah? dsrop? pm? d? n-2? lcarbamoyl) -ethyl) -benzole lamino) -propionic The title compound was synthesized according to general procedure 1, using benzenesulfonyl chloride in step a.

Yield MS (ES): m e Product of passage to 76mg 491.2 (M + H) + Product of step b 77mg 558.3 (M + H) + Product of step c 64mg 502.3 (M + H) + (title compound) Example 18 acid (2S) -3- (4- (2- (1, 4, 5, 6-Tetrah? drop? r? m? d? n-2-licarbamoyl) -ethyl) -benzole lamino) -2- (t "ofeno-2-eulfoni lamino" -propiomco The title compound was synthesized in accordance with general procedure 1, using 2-t-lofenesulphonyl chloride in step a.

Performance MS (ES +): m / e Passage product at 87mg 497.1 (M + H) + Product from step b 74mg 564.2 (M + H) + Product from step c 64mg 508.2 (M + H) + (title compound) Example 19 acid (2S) -2- (Biphenyl-eulphilamino) -3- (4- (2- (1, 4, 5, 6-tetrah? drop? pm? d? n-2-? lcarbamo? l) - ethyl) -benzoylamino) -propionic The title compound was synthesized according to general procedure 1, using 4-phenylsulfonyl chloride in step a.

Performance MS (ES +): m / e Product of passage to 39mg 567.1 (M + H) + Product of step b 40mg 634.4 (M + H) + Product of step c 33mg 578.3 (M + H) + (Title compote) Example 20 acid (2S) -2- (Naphthalene-2-sulfonyl-lane) -3- (4- (2- (1, 4, 5, 6-terah? drop? r? m? dm-2-? lcarbamo (l) -ethyl) -benzoyl lamino) -prop ionic The title compound was synthesized in accordance with general procedure 1, using 2-naphthalenesulfonyl chloride in step a.

Performance MS (ES +): m / e Product of passage to 76mg 541.2 (M + H) + Product of step b 74mg 608.3 (M + H) + Product of step c 62mg 552.3 (M + H) + (title compound) Example 21 acid (2S) -3- (4- (2- (1, 4,5,6-Tetrah? drop? pm? d? n-2-licarbamoyl) -ethyl) -benzoylamino) -2- (2, 4, 6-t rimetil -ben zenosulfoni lamino) -prop ionic The title compound was synthesized according to general procedure 1, using 2, 4, 6-t-methylbenzenesulfonyl chloride in step a.

Performance MS (ES +): m / e Product of passage to 68mg 533.2 (M + H) + Product of step b 7 lmg 600.4 (M + H) + Product of step c 54mg 544.3 (M + H) + (title compound) Example 22 acid (2S) -3- (4- (2- (1, 4, 5, 6-Tetrah? drop? r? m? d? n-2-licarbamoyl) -ethyl) -benzoylamine) -2- (4 - tp fluoromethyl-benzenesulfon lamino) -prop? omco The title compound was synthesized according to general procedure 1, using 4-trifluoromethyl-benzenesulfonyl chloride in step a.

Performance M? (ES +): m / e Passage product at 105mg 559.3 (M + H) + Product from step b 93mg 626.4 (M + H) + Product from step c 70mg 570.3 (M + H) + (Title compound Example 23 acid (2S) -2- (Butane-1-sulfonylamino) -3- (4- (2- (1, 4, 5, 6-tetrah? drop? r? m? dm-2-? lcarbamo? l) - ethyl) benzol lamino) -propionic The title compound was synthesized in accordance with general procedure 1, using butane-1-sulphonic chloride in step a.

Performance MS (ES +): m / e Step product to 87mg 471.4 (M + H) + Product of step b 60mg 538. (M + H) + Step product c 57mg 482.3 (M + H) + (Title compound) E xemployment 24 (2S) -2-Methanesulfonyl-lammo-3- (4- (2- (1, 4,5,6-tetrah? drop? r? m? d? n-2-? lcarbamoyl) -ethyl) -benzoilam ) -propionic The title compound was synthesized in accordance with general procedure 1, using methanesulfonyl chloride in step a.

Performance MS (ES +): m / e Step product at 87 8mg 429.3 (M + H) + Step product b 98mg 496.4 (M + H) + Step product c 74mg 440.3 (M + H) + (title compound) General procedure 2 (synthesis of the compounds of examples 25 to 27) Reaction with sulfonyl chloride 0-1 ge tert-butyl ester hydrochloride of (2S) -2 -am? No-3- (4 - (2-carboxy-yl) -benzoylamino) -propionic acid ester was dissolved in 3 ml of dimethyl formamide and treatment with 3 molar equivalents of dusopropyl let amine and 2 molar equivalents of the appropriate sulfonyl chloride at 0 ° C. the solution was stirred for 3 hours at 0 ° C. the reaction mixture was diluted by the addition of ethyl acetate and the solution was washed twice with a aqueous potassium hydrogensulfonate solution and once with a saturated aqueous sodium chloride solution. The organic phase was dried with magnesium sulfate, filtered and the solvent removed in vacuo. The residue is chromatographed on silica gel eluting with dichloromethane / methanol / acetic acid / water (97.5 / 2.5 / 0.25 / 0.25).

Step b. Formation of acyl guanidine.

The product from step a was dissolved in 2 ml of tet rahydrofuran and 1.2 molar equivalents of 2-amino-1, 4, 5, 6-tetr ahydropyridine, 4 molar equivalents of dusopropylethylamine, and 1.1 molar equivalents of O- (7-azabenzotrol azol-1-? l) -1, 1, 3, 3-tetramethyluron hexafluorophosphate. The reaction was stirred at room temperature for 20 hours. The solvent was removed m vacuo and the residue was dissolved in ethyl acetate and the solution was washed twice with a saturated aqueous sodium bicarbonate solution and once with a saturated aqueous sodium chloride solution. The organic phase was dried with magnesium sulfate, filtered and the solvent removed in vacuo. He The residue was chromatographed on silica gel eluting with dichloromethane / methanol / acetic acid / water (85/15 / 1.5 / 1.5) followed by dichloromethane / methanol / acetic acid / water (9/1 / 0.1 / 0.1).

Step c: Partition of the tert-butyl ester.

The product of step b ee dissolved in 1.5 ml of tp fluoroacetic acid / water (95/5). The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonite / water (1/1) and lyophilized.

Example 25 acid (2S) -2- (Propane-2-sulfonyl lane) -3- (4- (2- (1, 4, 5, 6-tetrah? drop? r? m? d? n-2- (lcarbamo? l) -ethyl) -benzol lamino) -propionic The title compound was synthesized according to general procedure 1, using propane-2-sulphonyl chloride in step a.

Performance MS (ES +): m / e Step product at 17mg 443.2 (M + H) + (FAB +) Paeo product b 7mg 524.2 (M + H) + (ES +) Product from step c 7.2mg 468.2 (M + H) + (ES +) (Title of the compound ) Example 26 Acid { 2S) -2-Chloromethanesulfon? Lammo-3- (4 - (2- (1, 4, 5, 6-tetrah? Drop? R? M? Dm-2-? Carbamo? L) -ethyl) -bezoylamino) - propionic The title compound was synthesized in accordance with general procedure 1, using chloromethanesulfonyl chloride in step a.

MS performance (ES7: m / e Passage product at 94mg 449.1 (M + H) + (FAB +) Paeo product b 28mg 530.2 (M) + (ES +) Product from step c 34mg 474.2 (M + H) (ES7 (Component title Example 27 acid (2S) -3- (4- (2- (1, 4, 5, 6-Tetrah? drop? pm? dm-2-licarbamoyl) -ethyl) -benzoylamine) -2- (2, 2, 2- trifluoro-etanoeul foni lamino) -propiomco The title compound was synthesized according to general procedure 1, using 2, 2, 2-trifluoroethanesulfonyl chloride in step a.

Performance MS (ES +): m / e Product of paeo at 43mg 483.2 (M + H) + (FAB +) Product of step b 24mg 564.2 (M + H) + (ES +) Product of step c 22mg 508.2 (M + H) + (ES +) (Title of compound) Example 28 (2 S) -2- (4-tert-butyl-benzenesulfonylamino) -3- (4- (2- (1, 4, 5, 6) ethyl ester etrah? drop? pm? d? n-2-? l carbamoyl) -ethyl) benzoylamino) -propionic 700 mg of acid (2 S) -2 - (4-tert-butyl-1-benzenesulfonylamino) -3- (4- (2- (1, 4, 5, 6-tetrahydropyrimidin-2-yl carbamoyl) -ethyl) ) -benzol lamino) -propionic was dissolved in 100 ml of ethanol and 15 drops of concentrated sulfuric acid were added. The reaction solution was boiled for 3.5 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted once with dichloromethane and the combined organic phase was washed twice with a solution of aqueous sodium chloride. The organic phase is dried They are sodium sulfate, filtered and the solvent removed by vacuum. The residue was dissolved in 2N aqueous hydrochloric acid. The hydrochloric acid was removed in vacuo, the residue was dissolved in acetomtril and water was added. This mixture is lyophilized. Yield 480 mg. MS (ES +): m / e = 586.4 (M + H) +.

Example 29 Ethopropyl ester of (2S) -2- (4-tert-butyl-benzene-sulfonylamino) -3- (4- (2- (1, 4, 5, 6-tetrahydropy-1-din-2-carbamoyl) -ethyl ester) ) -benzol lamino) -propionic 700 mg of the acid (2S) -2 - (4-tert-butyl-1-benzenesulfonyl-ammonium) -3- (4- (2- (1, 4, 5, 6-tetrah? Drop? R? M? D? N- 2- (carbamoyl) -ethyl) -benzoylamine) -propionic acid was dissolved in 100 ml of ethanol and 15 drops of concentrated sulfuric acid were added. The reaction solution was boiled for 2.5 days. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with a saturated aqueous sodium bicarbonate solution. This aqueous phase was extracted once with dichloromethane and the combined organic phase was washed with a saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent removed in vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The hydrochloric acid was removed in vacuo, the residue was dissolved in acetonitrile and added to water. This mixture was lyophilized yield 444 mg. MS (ES +): m / e = 600.4 (M + H) +.

Example 30 Ethyl ester of the acid (2S) -2- (Naphthalene-1-sulphonylamino) -3- (4- (2- (1, 4,5,6- tetrahydrochloride (tetrahydrofoam) (2-carbamoyl) -ethyl) -benzolamine) -propionic 590 mg of the acid (2S) -2- (naphthene-1-sulfoni lame) -3- (4- (2- (1, 4,5,6-tetrah? Drop? R? M? D? N-2 -? lcarbamo? l) -ethyl) -benzoylamino) -propionic was dissolved in 80 ml of ethanol and 12 drops of concentrated sulfuric acid were added. The reaction solution was boiled for 3 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted once with dichloromethane and the combined organic phase was washed twice with a saturated aqueous sodium chloride solution. The organic phase is dried, sodium sulfate, filtered and the solvent removed in vacuo. The residue is dissolved in 2N aqueous hydrochloric acid. The hydrochloric acid was removed m vacuo, the residue was dissolved in acetomtplo and added to water. Eeta mixture is lyophilized. Yield 381 mg. MS (ES +): m / e = 580.3 (M + H) +.

Example 31 Isopropyl ester of (2S) -2- (Naphthalene-1-eulomom lamino) -3- (4- (2- (1, 4,5,6-tetr ahydropyr? M? Dm-2-carcarbamoyl) -ethyl ester) ) -benzol lamino) -propionic 1. 5 g of the acid (2S) -2- (naphine-1-sul-fom-lamino) -3- (4- (2- (1, 4,5,6-tetrah? Drop? Pm? Dm-2-? Lcarbamo ?) -ethyl) -benzoylamine) -propionic was dissolved in 250 ml of isopropanol and 1 ml of concentrated sulfuric acid was added. The reaction solution was boiled for 3 days. The solvent was removed by vacuum, the residue was dissolved in dichloromethane and washed three times with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted once with dichloromethane and the combined organic phase was washed twice with a saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent removed in vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The hydrochloric acid was removed in vacuo, the residue was dissolved in acetonitoplo and added to water. This mixture was lyophilized Yield 950 mg. MS (ES +): m / e = 594 4 (M + H) + Example 32 Isobutyl ester of the acid (2S) -2- (naphthalene-1-sulfon? Lam? No-3- (4- (2- (1,, 5,6-tetrah? Drop? Pm? D? N-2- (lcarbamo? l) -ethyl) -benzol lamino) -propionic 600 mg of the acid (2S) -2- (naf, taleno-1-sulfon? Lam? No-3- (4- (2- (1, 4,5,6-tetrah? Drop? Pm? D? N-2 -? lcarbamo?) -ethyl) -benzoylamino) -propionic acid was dissolved in 12 ml of isobutanol and 0.1 ml of concentrated sulfuric acid was added, the reaction solution was boiled for 24 hours, the solvent was removed in vacuo, and the The residue was chromatographed on silica gel eluting with dichloromethane / methanol / acetic acid / water (9/1 / 0.1 / 0.1) The product was dissolved in acetic acid / water and lyophilized Yield 250 mg MS (ES +): m / e = 608.5 (M + H) +.

Pharmacological Test.

The inhibition of bone resorption by the compounds according to the invention it can be determined, for example, with the aid of the osteoclast resorption test ("PIT ASSAY"), for example analogously to WO-A-95/32710 which is incorporated herein by reference.

The inhibitory action of the compounds according to the invention aga the vitronectin receptor vß3 can be determined, for example, as described below.

Test for the measurement of the inhibition of the binding of 293 cells to human vitronectin (test cell Vn / 293). 1. Purification of human vitronectin.

Human vitronectin was isolated from human plasma and purified by affinity chromatography according to the method of Yatohyo et al., Cell Structure and Function, 1988, 23, 281-292. 2. Cell Test Cells 293, a line of human embryonic kidney cells, which were co-transfected with eecuenciae of DNA of the subunits a? and ß of the avr3 vitronectin receptor are selected for a wide range of expression (> 500,000 ccβ3 / cell receptors) according to the FACS method. The selected cells were cultured and sorted again by means of FACS in order to obtain a stable cell line (15 D) with expression ranges of > 1, 000, 000 copies of avß3 per cell.

A tissue culture plate of Linbro type 96 wells with a flat bottom was coated overnight at 4 ° C with human vitronectin (0.01 mg / ml, 0.05 ml / well) in buffered phosphate buffered saline (PBS) and then it was blocked with BSA at 0.5 ° strength (bovine serum albumin). The solutions of the test substances from 10 ~ 10 mol / 1 to 2 × 10 ~ 3 mol / 1 in a DMEM medium containing glucose were prepared and 0.05 ml / well of the solution was added to the plate in each case. Cells that expressed high levels of vß3 (for example 15 D) were suspended in a DMEM medium containing glucose and the suspension was adjusted to a content of 25,000 cells / 0.05 ml of medium. 0.05 ml of eeta cell suspension to each of the complete plates incubated at 37 ° C for 90 minutes. The plate was washed three times with warm PBS in order to remove the unbound cells. Lae bound cells Were used in citrate buffer (25 mM, pH 5.0) containing 0.25? of Triton X-100. The p-nitrophenyl-N-acetyl-β-D-glucosamide from the hexoseamidase substrate was then added and the plate incubated at 37 ° C for 90 minutes. The reaction was stopped with a buffer solution of glycine (50 mM) / EDTA (5 mM) (pH 10.4), and the absorption of each well was measured at 405-650 nm. The data were analyzed in accordance with the standard processes.

The following test results were obtained (inhibitory concentrations IC50) - Example Number Test of Vn / 293 cells IC50 1 6nM 2 52 pM 3 27 nM 5 18 nM 6 32 nM 7 28 nM 8 20 nM 8 69 nM 10 29 nM 11 24 nM 12 27 nM 13 27 nM 14 10 nM 15 6nM 16 26 nM 17 9nM 18 14 nM 19 38 nM 20 5nM 21 21 nM 22 10 nM 23 30 pM 24 100nM

Claims (18)

Claims.

1 . A compue s to l a f a rmul a I characterized because R "and R independently of one another, are hydrogen or alkyl (Ci-Cß) which is substituted or not substituted by RJ, or in which the radicals R1- and R1- together are an alkylene radical (C _ -Cl) saturated or unsaturated divalent, for example the group - (CH2) μ-, in which p is 2, 3, 4, 5, 6, 7, 8 or 9, which is unsubstituted or is replaced by one or more groups of the group consisting of halogen, (C_-C6) alkyl, (C? -C6) alkoxy, (C6-C? 4) aryl, (Cb-Cn) aryl- (C? -Cb) alkyl, hetero- [Cs-] Cn), heteroaryl (C5-C14) -alkyl (C? -C6), cycloalkyl (C3-C12), cycloalkyl (C3-C?) -alkyl (C ± -C6) and oxo, where a saturated or unsaturated ring of 5 members up to 7 members is unsubstituted or is substituted by R3, in particular by one or two radicals R and which is a carbocyclic ring or a heterocyclic ring containing one or two nitrogen atoms in the ring, can be fused to a carbon-carbon bond in the racial alkylene (C_-C9); R is alkyl (Ci-Cio), monocycloalkyl (C? -C.0), bicycloalkyl (C5-C20), tricycloalkyl (C-C20), alkoxy (C1-C9), aryl (C6-Ci4), aryl (Cfc-C]) -alkyl (C 1 -C 4), heteroaryl (C 5 -C 1), heteroaryl (C 5 -C 4) -alkyl (C 1 -C 4), halogen, tr 1 fluoromethol, cyano, hydroxyl , oxo, nitro, amino, -NH- (C1-C4) alkyl, - (alkyl (d- C,)) ¿, -NH-CO-alkylofCi-Cí), -CO-alkyl (d-C4); R is hydrogen, alkyl (C? -C6) -CO-0-alkyl (Ci-C4) - or alkyl (C? -Cb) which is unsubstituted or is substituted by a radical of the group consisting of hydroxyl, (C 1 -C 4) alkoxy, (C 1 -C 4) alkyl -S (0) 2-, -NR 7 R 7 'and -N "R 7 R 7' R 7" Q ", where R 7, R 7 'and R 7" independently of each other are hydrogen , alkyl (C? -C6), aryl (C5-C14) or aryl (C5-Cl) -alkyl (C? -C6) - and Q "is a physiologically anion tolerable, or in which R4 is one of the radicals in which the links, by means of which the radicals are linked, are indicated by the dotted lines; RJ is alkyl (C? -Co) f monocycloalkyl (C3-C_0), bicycloalkyl (C5-C20), tr 1 cycloalkyl (C5-C20), aryl (C6-Ci4), heteroaryl (C5-C? 4) ), ap lo (Cb-C?) -alkyl (C? -C6) - or heteroaryl 1I0 (C5-C14) -alkyl (Ci-Cb) -, where the aplo radical, the heteroaryl radical, the alkyl radical, the The monocycloalkyl radical, the cycloalkyl bike radical and the t-cycloalkyl radical are each unsubstituted or substituted by one, two or three radicals R3 and wherein one or more carbon atoms The carbon of the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the tricalcycloalkyl radical, in particular one, two, three or four carbon atoms, can be replaced by identical or different atoms selected from the series consisting of nitrogen, oxygen and sulfur; R6 is hydrogen, alkyl (C? -Cb) -O-CO, hydroxyl, alkyl (C? -C6) -0-CO-O- or nitro; in all its forms, tereoieomerics and mixtures thereof in all proportions, and their physiologically tolerable salts and their prodrugs.

2. The compound of formula I as claimed in claim 1, characterized in that R1 and R2 are hydrogen or together with a saturated or unsaturated bivalent (C2-C5) alkylene radical, wherein the alkylen radical (C -Cs) is unsubstituted or is substituted by a radical of the group consisting of halogen, alkyl (C -CJ, alkox? (C? -C6), aplo (Cb-C? 4), aryl (C "-C? 4) -alkyl (Ca -C6), heterolabe (C5-C14), hetero-halo (C-C14) -alkyl (C-C6), cycloalkyl (C3-C?), cycloalkyl (C3-C12) -alkyl (Ci-Cß) - and oxo, and where a 5-membered up to 7-membered saturated or unsaturated ring that is unsubstituted or substituted by R, and which is a carbocyclic ring or heterocyclic ring containing one or two nitrogen atoms in the ring, can be fused to the carbon-carbon bond in the alkylene radical (C2-C5); R3 is (C1-C10) alkyl, (C3-C20) monocycloalkyl, (C5-C20) bicycloalkyl, (Cc-C20) t-cycloalkyl, (Ci-C3) alkoxy, (C5-C1) aryl, heteroaryl (C5) -C? 4), aryl (C6-C? 4) -alkyl (C? -C4), hetero (C5-Ci4) -alkyl (C1-C), halogen, tri? Luoromet lio, cyano, oxo, -N ((C1-C) alkyl). or -NH-CO-alkyi (C1-C4); R ee hydrogen or alkyl (C? -Cb) which is unsubstituted or substituted by a radical of the group consisting of alkoxy (Ci-C4), alkyl (Ci-C4) -S (0): - and NR7R7, where R7 and R7 'independently of one another are hydrogen or (C1-C) alkyl; R5 is alkyl (C? -C20), monocycloalkyl (C3-C20), b? C? -alkalkyl (C5-C20), tr? C? -alkalkyl (C5-C20), aryl (C6-Ci4), heteroaryl (C5-C? 4), aplo (C?, -C?) -alkyl (C? -C6) - or heteroaryl (C Cid-alkyl (Cr Ce) -, where the aryl radical, the hetero-hetero radical, the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the t-cycloalkyl radical are each unsubstituted or substituted by one, two or three radicals R3; R6 is hydrogen or alkyl (C? -Cb) -O-CO; in all stereo-stereoomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts and their prodrugs.

3. The compound of formula I as claimed in claims 1 and / or 2, characterized in that R and R are hydrogen or together they are a saturated or unsaturated radical (C2-C4) bivalent alkylene, where the alkylene radical (C2-C4) is unsubstituted or is substituted by a radical of the group consisting of halogen, alkylet-Ce), alkoxy (C.-C6), aplo (C,; -C? 4), aryl (C "-Cn) -alkyl (Ci-C?), heteroaryl (Cb-C) ?), I have terry lio (C5-Cj.) -alkyl (Ci-Cß), cycloalkyl (d-Cp), cycloalkyl (C3-C.2) -alkyl (C4-Cb) - and oxo, and where a ring from 5 members to 7 members saturated or uncaused which is not substituted or replaced by R3, and which is a carbocyclic ring or a tertiary cycloalkyl ring containing one or two nitrogen atoms in the ring, can be fused to the carbon- carbon in the alkylene radical (C -C4); R3 is (C1-C4) alkyl, monocycloalkyl (CrCio), bicycloalkyl (CI-CI /), t-cycloalkyl (C5-C1, (C1-C4) alkoxy, aryl (Cb-C4), aplo (C6-C1 ( ) -alkylated C4), halogen, tr 1 f luoromet lyo, cyano, oxo, -N ((C 1 -C 4) alkyl) or -NH-CO-alkyl (C 1 -C 4); R 4 is hydrogen or alkyl (C, -Cb); R is alkyl (Ci-Cio), monocycloalkyl (CrCJ5), b? C? -Calkalkyl (C3-C15), t-cycloalkyl (C? -Cn), aryl (Cb-Ci), heteroaryl (C = -C? 4 ), ap lo (Cb-C? 4) -alkyl (d-CJ- or hetero (C5-C14) -alkyl (C? ~ C6) -, wherein the aplo radical, the heterolalk radical, the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the t-cycloalkyl radical are each unsubstituted or substituted by one, two or three radicals R3; R6 is hydrogen or alkyl (C? -C <) -O-CO; in all stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts and their prodrugs.

4. The compound of formula I as claimed in one or more of claims 1 to 3, characterized in that R1 and R ~ are hydrogen or together are a saturated or unsaturated alkylene radical (C¿-C? | Bivalent, where the alkylene radical (C-C3) is unsubstituted or substituted by a radical of the group consisting of halogen, alkyloyl -Cb), alkoxy (Ci-Ce), aryl (Cb-C? 4), ar i lo (Cb-C?,) -alkyl (C? -C6), heteroaryl (CG-CH), heteroarylo (C5-C1) -alkyl (Ci-Co), cycloalkyl (C3-C? 2), cycloalkyl (C ^ -C? 2) -alkyl (C? -C6) - and oxo, and where a 5-membered to 7-membered saturated or unsaturated ring is unsubstituted or substituted by R3, and which is a A carbocyclic ring or a heterocyclic ring containing one or two nitrogen atoms in the ring can be fused to the carbon-carbon bond in the alkyl radical (C; -C3); R is (C 1 -C 4) alkyl, u-cycloalkyl (C 3 -C 0), bicycloalkyl (Cb-C 1), tricycloalkyl (C, -C?), Alkoxy (C -C 4), aplo (C) -C1), halogen, trifluoromethyl, cyano, oxo, -N ((C1-C) alkyl) 2 or -NH-CO- (C1-C4) alkyl; R 4 is hydrogen or alkyl (Ci -C,); R is (C1-C10) alkyl, (C3-C5) monocycloalkyl, (C5-C15) b- (c5-C15) alkyl, (C6-C5) alkyl, (C6-) C? 4), heterolalk (C> -Cu), aplo (C6-Cn) -alkyl (Ci-Ce) - or het eroaryl (C, -C44) -alkyl (Cx-Ce) -, where the radical aplo , the heteroaryl radical, the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the t-ricicloalkyl radical each are not replaced or replaced by one, two or three R3 radicals; R6 is hydrogen or (C1-C) -0-C0 alkyl; in all stereo-eomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts and their prodrugs.

5. The composition of formula I as claimed in one or more of the claims 1 and 4, characterized in that R 'is aryl (Cb-C 4) or heteroap lo (C 5 -C 14), where the aryl radical and the radical heteroaryl each is unsubstituted or is replaced by one, two or three identical or different RJ radicals, in all their forms, tereoisomepcas and mixtures thereof in all their proportions, and their physiologically tolerable salts and their prodrugs.

6. The compound of formula I as claimed in one or more of the compounds 1 to 5, characterized in that R 5 is a naphthyl radical, in all its forms it is tereoisomeric and mixtures thereof in all its proportions, and his physiologically tolerable eals and his profane.

7. The compound of formula I as claimed in one or more of claims 1 to 4, characterized in that it is an acid 2- (RJ-sulfonylamino) -3- (4- (2- (1, 4,5,6 -tetrahydropipmidine-2-? 1 carbamoyl) -ethyl) -benzoylamine) propioni co wherein the substituent 2- (R5-eul phonylamm) ee selects from the group consisting of benzenesulfomlamino, 4- (n-propyl) benzene sulfonyl lamino , 4-tert-butylbenzene-fonylamino, 2,4,6-trimethylbenzenesulfonylamino, 4-methoxybenzenesulphonylamine, 4- (n-butoxy) benzenesulphonylamino, 3-chlorobenzenesulphonylamine, 4-chlorobenzene-fonilammo, 3-trifluoromethylbenzene eulphonylamino, -trifluoromethylbenzene-sulfonylamino, 4-acetylammobenzenesul-fom-lamino, 2-cyanobenzene-fom-lamino, naphthalene-1-sulphonylamino, naphthalene-2-sulphonylamino, biphenyl-4-phonolamino, t-pheo-2-eulphonylamino, qumolmo- 8-sul fonilammo, methanesul fonilamino, propane-1-sulfonamino, propane-2-sulfonamino, butane-1-sulphonylamino, 2-methopropane-l-eulphonylate, chloromethanesulphonylamino, 2,2,2-tpf luoroethane-sulfonyl-ammonium , 7, 7-d? Met 11-2-oxo-bicyclo [2.2.1] hepyl-l-methanesulfonyl-ene and 2-phenylethenesulphonylamino, in all their stereoisomeric forms and mixtures thereof in all their proportions, and their physiological salts tolerable and their profarmacos.

8. The compound of formula I as claimed in one or more of claims 1 to 7, characterized in that it is acid (2S) -2- (na ft to eno-1-sulfonamino) -3- (4- (2 - (1, 4,5,6-tetrah? drop? r? m? dm-2-? carbamo?) -et ll) benzoylamo) propionic and their physiologically tolerable salts and their prodrugs.

9. The compound of formula I as claimed in one or more of claims 1 to 8, characterized in that the acid (2?) - 2- (naph such eno-1-sulfonyl lamino) -3- (4- (2- (1, 4,5,6-tetrahydropyrimidin-2-? learbamoyl) -ethyl) benzoylamine) propionate or an alkyl ester (C1-C4) thereof, and their physiologically tolerable salts.

10. The compound of formula I as claimed in one or more of the rei indications 1 to 9, characterized in that it is an ethyl ester of (2S) -2- (naphthalene-1-sulphonylamine) -3- (4- ( 2- (1, 4, 5, 6-tetrah? Drop? R? M? D? N-2-lcarbamoyl) -ethyl) benzolamino) propionic, and their physiologically tolerable salts.

11. A process for the preparation of a compound of the formula I as claimed in claims 1 to 10, characterized in that they comprise linking two or more fragments that can be derived r ethetically from the formula I.

12. The process as claimed in claim 11, characterized in that a carboxylic acid or a carboxylic acid derivative of the formula II wherein R4 and R5 are defined as set forth in claims 1 to 10, or in which the alternatively functional groups are present in the form of precursors or are present in protected form, and wherein X is a nucleophic starting group solely appropriate, with guamdine or a guanidine derivative of formula III, N- R1 H2N- // N - R lil R 6 wherein R1, R- and R6 are defined as set forth in claims 1 to 10, or alternatively functional groups are present in the form of precursors or in protected form.

13. The compound of formula I as claimed in one or more of the claims 1 and 10 and / or its physiologically tolerable salts and / or its prodrugs for use as a pharmaceutical.

14. A pharmaceutical preparation, characterized in that it comprises a compound of formula I as claimed in one or more of claims 1 to 10 and / or its physiologically tolerable saltse and / or its prodrugs in addition to a pharmaceutically innocuous carrier.

15. The compound of formula I as claimed in one or more of claims 1 to 10, and / or its physiologically tolerable salts and / or its prodrugs for use as an antagonist of the vitronectin receptor.

16. The composition of formula I as claimed in one or more of claims 1 to 10, and / or its physiologically tolerable eals and / or its prodrugs for use as an inhibitor of bone resorption or for osteoporosis therapy or prophylaxis .

17. The compound of formula I as claimed in one or more of claims 1 to 10, and / or its physiologically tolerable salts and / or its prodrugs for use as an inhibitor of tumor growth or tumor metatasis.

18. The compound of formula I as claimed in one or more of claims 1 to 10, and / or its physiologically tolerable salts and / or its prodrugs for use as a lanthan antnnf or for the therapy or prophylaxis of cardiovascular disorders, restenosis, arteroecleroeis , nephropathy or retinopathies. Summary of the Invention The present invention relates to derivative of formula I, wherein R R 4, 7 and Rb have the meanings indicated in the claims, physiologically tolerable salts and their pro-drugs. The compotets of formula I have valuable active pharmaceutical compounds. These are antagonists of the vitronectome receptor and inhibitors of cell adhesion and inhibit the resorption of the osteoblast. These are suitable, for example, for the therapy and prophylaxis of diseases that are at least partially caused by an undesirable extension of bone resorption, for example of teoporosis. The invention also refers to a process for the preparation of compounds of formula I, their use, in particular as pharmaceutical active ingredients, and pharmaceutical preparations comprising them.