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MXPA97010389A - Antagonists of the vitronectin receptor, its preparation and employment of mi - Google Patents

Antagonists of the vitronectin receptor, its preparation and employment of mi

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Publication number
MXPA97010389A
MXPA97010389A MXPA/A/1997/010389A MX9710389A MXPA97010389A MX PA97010389 A MXPA97010389 A MX PA97010389A MX 9710389 A MX9710389 A MX 9710389A MX PA97010389 A MXPA97010389 A MX PA97010389A
Authority
MX
Mexico
Prior art keywords
alkyl
aryl
cycloalkyl
group
alkoxy
Prior art date
Application number
MXPA/A/1997/010389A
Other languages
Spanish (es)
Other versions
MX9710389A (en
Inventor
Peyman Anuschirwan
Ulrich Stilz Hans
Wehner Volkmar
Carniato Denis
Mcdowell Robert
Ruxer Jeanmarie
Lefrancois Jeanmichel
Scheunemann Karlheinz
Richard Garek Thomas
Original Assignee
Hoechst Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE19653645A external-priority patent/DE19653645A1/en
Application filed by Hoechst Aktiengesellschaft filed Critical Hoechst Aktiengesellschaft
Publication of MX9710389A publication Critical patent/MX9710389A/en
Publication of MXPA97010389A publication Critical patent/MXPA97010389A/en

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Abstract

Vitronectin receptor antagonists, whose preparation and use are the subject of the present invention, are compounds of formula I ABDEFG in which A, B, D, E, FYG have the meanings indicated in the patent claims, their preparation and its use as medicine. The compounds according to the invention are used as antagonists of the vitronectin receptor and as inhibitors of absorption.

Description

ANTAGONISTS OF THE VITRONECTIN RECEPTOR, its PREPARATION AND EMPLOYMENT OF THE SAME.
A - B - D - E - F - G (I) wherein A, B, D, E, F, and G have the meanings set forth below, as well as their physiologically tolerable salts and the pharmaceutical preparations containing such compounds, their preparation and use as antagonists of the receptor of vitronectin for the treatment and prophylaxis of diseases that are based on the interaction between vitronectin receptors and their ligands in the processes of cell-cell or cell-matrix interaction, co o, p. eg, inflammations, cancer, tumor metastasis, cardiovascular diseases such as arteriosclerosis or restenosis, retinopathies, nephropathies and diseases that are based on an undesirable extension of bone absorption, such as p. e. osteoporosis Human bones are subjected to a constant dynamic process of reconstruction, which involves bone absorption and bone assimilation. These processes are controlled by specialized cell types for this. Bone assimilation is based on the deposition of bone matrix by osteoblasts, and bone absorption is based on the degradation of the bone matrix by osteoclasts. Most bone diseases rely on the alteration of the balance between bone formation and bone absorption. Osteoporosis is characterized by a loss of bone matrix. Activated osteoclasts are plurinucleated cells with a diameter of up to 400 μ, which resect the bone matrix. Activated osteoclasts are deposited on the surface of the bone matrix and secrete proteolytic enzymes and acids in the so-called "sealing zone", the zone between its cell membrane and the bone matrix. The acidic environment and pro-teases promote bone degradation. There are studies that indicate that the accumulation of osteo-clasts in the bones is controlled by integrin receptors on the cell surface of osteoclasts. Integrins are a superfamily of receptors to which, among others, belong the aIIbß3 receptor of fibrinogen in platelets and the avß3 receptor of vitronectin. The ovß3 receptor of vitronectin is a glycoprotein that is in the membrane that is expressed on the cell surface of a series of endothelial cells, vascular smooth muscle cells, osteoclasts and tumor cells. The avß3 receptor of vitronectin that is expressed in the membrane of the osteoclasts controls the process of bone accumulation and bone absorption, and therefore contributes to osteoporosis. For this, avß3 binds to bone matrix proteins such as osteopontin, bone sialoprotein and thrombospontine, which contain the tripeptidic Arg-Gly-Asp (or RGD) motif. The compounds of Formula I according to the invention inhibit, as antagonists of the vitronectin receptor, bone absorption by osteoclasts. The bone diseases against which the compounds can be used according to the invention are, in particular, osteoporosis, hypercalcemia, osteopenia, e.g. ex. caused by metastasis, dental conditions, hyperparathyroidism or, 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 diseases caused by a therapy with glucocorticoids, steroirides or corticosteroids, or by the lack of one or several sex hormones. All these diseases are characterized by a bone loss that is based on the imbalance between bone construction and bone degradation. Horton et al. Disclose RGD peptides and an anti-vitronectin receptor antibody (23C6), which inhibit dental degradation by osteoclasts and the migration of osteoclasts (Horton et al., Exp. Cell. Res. 1991, 195, 368). . Sato et al., In J. Cell. Biol. 1990, 111, 1713, describe echistatin, an RDG peptide of snake venom, as a potent inhibitor of bone absorption in a tissue culture and as an inhibitor of osteoclast binding to bones. Fischer et al. (Endocrinology, 1993, 132, 1411) could demonstrate in rats that echistatin also inhibits bone absorption in vivo. The avß3 receptor of vitronectin in human cells of the smooth vascular musculature of the aorta stimulates the migration of these cells to the neointima, which finally leads to arteriosclerosis and restenosis after angioplasty (Brown et al., Cardiovascular Res. 1994, 28, 1815). Broo s et al. (Cell 1994, 79, 1157) point out that antibodies against avß3 or «vß3 antagonists can produce a retraction of tumors, inducing apoptosis of blood vessel cells during angiogenesis. Cheresh et al. (Science 1995, 270, 1500) describe anti-avß3 antibodies or avß3 antagonists, which inhibit rat angiogenesis processes in the eye, induced by bFGF, which could be of therapeutic use in the treatment of retinopathies. Patent applications WO 94/12181 describe substituted aromatic or non-aromatic cyclic systems, and in WO 94/08577 substituted heterocycles, as antagonists of the fibrinogen receptor and inhibitors of platelet aggregation. EP-A-0 528 586 and EP-A-0 528 587 disclose derivatives of amino-substituted or heterocyclyl-substituted phenylalanine, and aryl derivatives are known from WO 95/32710 as bone-absorbing substances. by the osteoclasts. WO 96/00574 and WO 96/26190 describe benzodiazepines as antagonists of the vitronectin and integrin receptor. In WO 96/00730 molds of fibrinogen receptor antagonists, especially benzodiazepines, which are attached to a nitrogen-carrying ring, are described as antagonists of the vitronectin receptor. In the German patent applications P 19629816.4, P 19629817.2 and P 19610919.1, as well as in EP-A-0 796 855, substituted aromatic cyclic systems and heterocycles 5 are described as antagonists of the vitronectin receptor. The subject of the present invention are compounds of Formula I, A-B-D-E-F-G (I) in which the letters have the following meaning: . where ( ] constitutes an aromatic or non-aromatic cyclic system, monocyclic or polycyclic, of 5 to 10 members, which may contain from 1 to 4 heteroatoms of the series consisting of N, O and S, and may optionally be substituted once or several times with R12, R13, R14 and R15; B a direct bond, alkanediyl (-Cg), arylene (C5-C10), cycloalkylene (C3-C8), -C "C-, -NR2-, -NR2-C (0) -, -NR2-C (0 ) -NR2-, -NR2-C (S) -NR2-, -OC (O) -, -NR2-S (0) -, -NR2-S (0) 2-, -O-, -S-, -CR2 = CR3-, each of which may be substituted one or more times with (C: -C8) alkyl, such as, for example, -methyl-phe nyl-ethyl-, -ethyl-NR2-C (O) -, etc., D a direct bond, alkanediyl (C ^ C, arylene (C5-C10), -O-, -NR2-, -CO-NR2-, -NR2-CO-, -NR2-C (O) -NR2-, -NR2-C (S) -NR2-, -OC (O) -, -C (0) 0-, -S (O) -, -S (0) 2-, -S (0) 2-NR2-, -S (0) -NR2-, -NR2-SO-, -NR-S (0)? -, -S-, -CR2 = CR3-, -CSc-, each of which may be substituted one or more times with alkyl (CC, -CR2 = CR3-, aryl (C ^ -C, like, eg, -methyl-phenyl-CH = CH-, ethyl-O-, etc. ., where, when B is a direct bond, D can not be -CO-NR2-, -C (0) 0-, -S (O) -, -S (0)? -, -S (O) -NR2-, -S (0) 2-NR2-; E a) a template from the series of fibrinogen receptor antagonists, which is taken from the following applications and descriptions of pat entities, and bibliographical citations: Adir et Compagnie FR 928004, June 30, 1992, Fauchere, J.L., et al. 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O well b) a mold defined analogously to the molds of the fibrinogen receptor antagonist series, which is taken from the following patent applications: Smithkline Beecham Corp. WO 96/00574, Jan. 11, 1996, Cousins, R.D. et al.
Fujisawa Pharmaceutical Co. WO 95/29907, Nov. 9, 1995, Kawai, Y. et al., Eli Lilly US 5488058, Jan. 30, 1996, Palkowitz, A.D. et al. US 5484798, Jan.16, 1996, Bryant, H.U. et al .; or it also refers to those molds that can be derived structurally from the previous applications and patent descriptions, and bibliographic citations; F is defined as D; R2, R3 independently of each other, are H, alkyl (d-Cm) which is optionally substituted one or more times with fluorine, cycloalkyl (C3-C12), cycloalkyl (C3-C12) -alkyl (Ci-Cg), aryl ( C5-C14), aryl (C5-C14) -alkyl (dC, R80C (0) R9, R3R8NC (0) R9, R8C (0) R9, R4 R5, R6, R7, independently of each other, are H, fluorine, OH, alkyl (d-C8), cycloalkyl (C3-C14), cycloalkyl (C3-C14) -alkyl (C, -Cβ), or R8OR9, R8SR9, R8C02R9, R8OC (0) R9, R8-aryl- (C5) -C14) -R9, R8N (R2) R9, R8R8NR9, R8N (R2) C (O) OR9, R8S (0) nN- (R2) R9, R80C (0) N (R2) R9, R8C (O) N (R2) R9, R8N (R2) C (O) N (R2) R9, R8N (R2) S (0) nN (R2) R9, R8S (0) nR9, R8SC (O) N (R2) R9, R8C (0) R9, R8N (R2) C (0) R9, R8N (R2) S (0) nR9; R8 H, alkyl (Cj-Ce), cycloalkyl (C3-C14), cycloalkyl (C3-C14) -alkyl (d-C8), aryl (C5-C14), aryl (C5-C14) -alkyl (d ~ C8), wherein the alkyl moiety may be substituted one or more times with fluorine; R9 a direct bond or alkanediyl (Ci-Ca); R10 C (0) Ru, C (S) Rn, S (0) nRn, P (O) (Rn) not a saturated or unsaturated heterocycle, of four to eight members, containing 1, 2, 3 or 4 heteroatoms of the series consisting of N, 0 and S, as, p. ex. , tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiadiazolyl; Ru OH, alkoxy (Cj-C, aryl (C5-C14) -alkoxy (dC?), Aryloxy (C5-C14), alkyl (d-C8) carbonyloxy-alkoxy (d-C4), aryl (C5-C14) - (Cx-C8) alkylcarbonyloxy-alkoxy (Ci-Cg), NH2, mono- or di- (alkyl (d-C8)) amino, aryl (C5-C14) -alkyl (d ~ c.) amino, dialkyl (d-C8) aminocarbonyl ethyloxy, aryl (C5-C14) -dialkyl (d-C8) aminocarbonylmethyloxy or aryl (C5-C14) amino, or the residue of an L- or D-amino acid; R12, R13, R14, R15 , independently of each other, H, alkyl (CJ-CJO) which is optionally substituted once or several times with fluorine, (C3-C12) cycloalkyl, (C3-C12) cycloalkyl-alkyl (d ~ C8), aryl (C5-C14) ), aryl (C5-C14) alkyl (d-Cß), H2N, R8ONR9, R8OR9, R8OC (0) R9, R8R8NR9, R8-aryl (C5-C, 4) -R9, HO-alkyl (C1-C8) -N (R2) R9, R8N (R2) C (O) R9, RTC (O) N (R2) R9, R8C (0) R9, RR3N-C (= NR2) -NR2, R2R3N-C (= NR2) , = 0, = S, where two neighboring substituents of R12 to R15 together can mean also -0CH20-, -0CH2CH20-, -OC (CH3) 20-, and NR2, O, S; n 1 or 2; p, q independently between them, 0 or 1; in all its stereoisomeric forms and mixtures thereof in any proportion, and their physiologically tolerable salts, in which the compounds in which E means are excepted: a) a 6-membered aromatic cyclic system which may contain up to 4 N atoms and which may be substituted with 1 to 4 substituents, either the same or different, or b) 4- methyl-3-oxo-2, 3, 4, 5-tetrahydro-lHl, 4-benzodiazepine.
By template of the series of fibrinogen receptor antagonists is meant the middle part of the molecular structure (of a fibrinogen receptor antagonist), to which, in the case of fibrinogen receptor antagonists through a spacer , a basic and an acid group are attached, the basic group and / or the acid being present in a protected form (pro-drug). In fibrinogen receptor antagonists, the basic group is generally a group containing N, such as p. ex. amidine or guanidine, and the acid group is generally a carboxyl function, where the acid and basic group may be present in protected form. A fibrinogen receptor antagonist is a substance that inhibits the binding of fibrinogen to the GPIIblIIa platelet receptor. An antagonist of the fibrinogen receptor is formed by a middle part (template), to which a basic and an acidic group are bound through a spacer, and the acidic group and the basic one can be present in protected form (pro-drug) . The alkyl radicals can be straight-chain or branched. This is also the case when they carry substituents or appear as substituents of other moieties, for example in alkoxy, alkoxycarbonyl or aralkyl moieties. Examples of suitable alkyl radicals (CJ-CJO) are: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, isopropyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, 2,3,5-trimethylhexyl, sec-butyl, tert-pentyl. Preferred alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Also the alkenyl and alkynyl moieties may be straight or branched chain. Examples of alkenyl radicals are vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl, and alkynyl residues ethynyl, 1-propanol or propargi-lo. Cycloalkyl radicals can be monocyclic or polycyclic, e.g. ex. bicycles or tricyclics. Monocyclic cycloalkyl radicals are, for example, cyclopropyl, cyclobuyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, which may also be substituted, for example, with alkyl (dC4). Examples of the substituted cycloalkyl radical include 4-methylcyclohexyl and 2,3-dimethyl-cyclopentyl. Examples of the basic body of cycloalkyl (C 10 -C 14) monocyclic radicals in R 4, R 5, R 6 and R 7 are, for example, cyclodecane and cyclododecane. The bicyclic and tricyclic cycloalkyl radicals can be unsubstituted or substituted in any suitable position, with one or more oxo groups and / or one or more identical or different alkyl groups (d-C4), e.g. ex. methyl or isopropyl groups, preferably methyl groups. The free bond of the bi- or tricyclic moiety can be found in any position of the molecule, and therefore the moiety can be linked by means of a bridgehead atom or an atom in a bridge. The free bond can also be found in any stereochemical position, for example in an exo or endo position. An example of a bicyclic system is decalin (decahi-dronaphthalene), and of a system substituted with an oxo group 2-decanone. Examples of the basic body of the bicyclic system are norbornane (bicyclo [2.2.1] eptane), bicyclo [2.2.2] octane and bicyclo [3.2.1] octane. An example of a system substituted with an oxo group is camphor (1,7,7-trimethyl-2-oxoxycyclo [2.2.1] heptane). Examples of the fundamental body of the tricyclic system are the tuistano (tricycle [4.4.0.03,8] dean, adamantane (trici-clo [3.3.1.13,7] decane), noradamantane (tricyclo [3.3.1.13,7] non-nano), tricycle [2.2.1.02'6] heptane, tricycle [5.3.2.04,9] dode-cano, tricycle [5.4.0. O2'9] undecane or tricyclo [5.5.1.03'11] tri-decane. Examples of the basic body of cycloalkyl- (C10-C14) tricyclic radicals in R4, R5, R6 and R7 are the tuistane (tricyclo [4.4. O.O3'8] decane), adamantane (tricyclo [3.3.1.13'7 ] -nonano), the tricycle [5.3.2.04,9] dodecane, the tricycle [5.4.0. 0.9] undecane or the tricycle [5.5.1. O3'11] tridecane. Halogen means fluorine, chlorine, bromine, iodine. Examples of the aromatic cyclic system of β-members are phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, tetra-zinyl. Aryl is, for example, phenyl, naphthyl, biphenylyl, an-tryl or fluorenyl, with 1-naphthyl, 2-naphthyl and, especially, phenyl being preferred. The aryl radicals, especially the phenyl radical, can be substituted one or more times, preferably one, two or three times, with the same or different radicals of the series consisting of alkyl (d ~ C8), especially alkyl (d-C4), alkoxy (dC?), especially alkoxy (dC4), halogen, such as fluorine, chlorine and bromine, nitro, amino, trifluoromethyl, hydroxy, methylenedioxy, -OCH2CH20-, -0C (CH3) 2-0-, cyano, idroxycarbonyl , aminocarbonyl, (alkoxy (dC4) carbonyl, phenyl, phenyl, benzyl, benzyloxy, (R170) 2P (0), (R170) 2P (0) -0- or tetrazolyl, wherein R17 means H, alkyl (C) C10), aryl (C6-C14) or aryl (C6-C14) -alkyl (d-C8) In the monosubstituted phenyl residues the substituent can be in position 2, 3 or 4, with positions 3 and 4 being preferred. the phenyl is doubly substituted, the substituents may be in the 1,2, 1,3 or 1,4 positions relative to each other In the doubly substituted phenyl residues the two substituents placed in the position 3 and in the 4, referred to the point of union. The aryl groups can also constitute mono- or polycyclic aromatic systems, in which from 1 to 5 C atoms can be replaced by 1 to 5 heteroatoms, such as p. ex. 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinoline, isoquinoline, quinoxalinyl, quinazolinyl, cyanolyl, ß-carbolinyl or a benzo-ringed, cyclopen-ta-, cyclohexa or cyclohepta-ringed derivative of these residues. These heterocycles may be substituted with the same substituents as the aforementioned carbocyclic aryl systems. In the series of these aryl groups aromatic, oncyclic or bicyclic cyclic systems are preferred, with 1 to 3 heteroatoms of the series consisting of N, 0 and S, which may be substituted with 1 to 3 substituents of the alkyl series (d-C6) ), alkoxy (d-C6), F, Cl, N02, NH2, CF3, OH, alkoxy (d-C4) carbonyl, phenyl, phenoxy, benzyloxy or benzyl. Aromatic cyclic systems, from 5 to 10 members, monocyclic or bicyclic, with 1 to 3 heteroatoms of the series consisting of N, O and S, which can be substituted with 1 or 2 substituents of the alkyl series, are particularly preferred ( Cj-C4), alkoxy (d-C4), phenyl, phenoxy, benzyl or benzyloxy. The L- or D-amino acids can be natural or non-natural amino acids. A-amino acids are preferred. By way of example, the following should be mentioned (see Houben-Weyl, Methoden der organischen Chemie, Volume XV / 1 and 2, Georg Thieme Verlag, Stuttgart, 1974): Aad, Abu,? Abu, ABz, 2ABz, eAca, Ach, Acp, Adpd, Ahb, Aib, ßAib, Ala, ßAla,? Ala, Alg, All, Ama, Amt, Ape, Ap, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit , Cys, (Cys) 2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hile, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, lie, Ise, Iva, Kyn, Lant, Len, Leu, Lsg, Lys, ßLys,? Lys, Met, Mi, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pee, Pen, Phe, Phg, Pie, Pro,? Pro, Pse, Pya, Pyr, Pza, Qin, Ros , Sar, Sec, Sem, Ser, Thi, ßThi, Thr, Thy, Thx, Aunt, Tie, Tly, Trp, Trta, Tyr, Val, tert-butylglycine (Tbg), neopentylglycine (Npg), cyclohexylglycine (Chg), cyclohexyllanin (Cha), 2-thienylalanine (Thia), 2, 2-diphenylamidoacetic acid, 2- (p-tolyl) -2-phenylaminoacetic acid, 2- (p-chlorophenyl) aminoacetic acid; and in addition: pyrrolidine-2-carboxylic acid; piperidin-2-carboxylic acid; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; decahydroisoquinoline-3-carboxylic acid; octahydroindol-2-carboxylic acid; decahydroquinoline-2-carboxylic acid; octahydrocyclopenta [b] pyrrole-2-carboxylic acid; 2-azabicyclo [2.2.2] octane-3-carboxylic acid; 2-azabicyclo [2.2.1] hep-tano-3-carboxylic acid; 2-azabicyclo [3.1.0] exano-3-carbo-xylic acid; 2-azaspiro [4.4] nonane-3-carboxylic acid; 2-azaspiro [4.5] decane-3-carboxylic acid; Spiro acid (bicyclo- [2.2.1] heptane) -2,3-pyrrolidine-5-carboxylic acid; Spiro acid (-bicyclo [2.2.2] octane) -2,3-pyrrolidine-5-carboxylic acid; 2-azatricyclo [4.3.0.16,9] decane) -3-carboxylic acid; decahydro-cyclohepta [b] pyrrole-2-carboxylic acid; decahydrocyclook-ta [c] pyrrole-2-carboxylic acid; octahydrocyclopenta [c] pi-rrol-2-carboxylic acid; octahydroisoindole-1-carboxylic acid; 2, 3, 3a, 4, 6a-hexahydrocyclopenta [b] pyrrole-2-carboxylic acid; 2,3,3a, 4,5,7a-hexahydroindole-2-carboxylic acid; Tetrahydrothiazole-4-carboxylic acid; isoxazolidin-3-carboxyl-co acid; pyrazolidin-3-carboxylic acid; hydroxypyrrolidine-2-carboxylic acid, all of which may be optionally substituted (see the formulas below): N 'CO-.
The heterocycles which provide the aforementioned residues are known, for example, from US-A-4,344,949, US-A 4,347,847, US-A 4,350,704, EP-A 29,488, EP-A 31,741, EP-A 46,953, EP-A 49,605, EP-A 49,658, EP-A 50,800, EP-A 51,020, EP-A 52,870, EP-A 79,022, EP-A 84,164, EP-A 89,637, EP-A 90,341, EP-A 90,362, EP-A 105,102, EP-A 109,020, EP-A 111,873, EP-A 271,865 and EP-A 344,682. In addition, amino acids can also be present as ester or amide, e.g. ex. such as methyl ester, ethyl ester, isopropyl ester, isobutyl ester, tert-butyl ester, benzyl ester, unsubstituted amide, ethylamide, semicarbazide or α-amino-alkyl (C2-Cβ) amide. The functional groups of amino acids can be protected. Suitable protection groups are described, such as p. ex. urethane protection groups, carboxyl protection groups and secondary chain protection groups, in Hubbuch, Kontakte (Merck) 1979, No. 3, p. 14 to 23, and in Büllesbach, Kontakte (Merck) 1980, No. 1, p. 23 to 35. We can mention especially: Aloe, Pyos, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z (N02), Z (Haln), Bobz, Iboc, Adpoc, Mboc, Acm, tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Foot, Trt. The physiologically acceptable salts of the compounds of formula I are especially pharmaceutically or non-toxic usable salts. Such salts are formed, for example, by compounds of formula I containing acid groups, e.g. ex. carboxy, with alkaline or alkaline earth metals, such as Na, K, Mg and Ca, as well as with physiologically tolerable organic amines, such as triethylamine, ethanolamine or tris (2-hydroxyethyl) amine. The compounds of formula I containing basic groups, e.g. ex. an amino group, an amidino group or a guanidino group, form salts with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic or sulphonic acids, such as p. ex. acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, lactic acid, methanesulfonic acid or p-toluene sulfonic acid. The compounds of formula I according to the invention can have optically active carbon atoms, which, independently of one another, can have R or S configuration, and can therefore be present in the form of pure enantiomers or pure diastereomers, or in the form of mixtures of enantiomers or mixtures of diastereomers. Both the pure enantiomers and their mixtures in any proportion, as well as the pure diastereomers and their mixtures in any proportion, are all object of the present invention. The compounds of formula I according to the invention can be presented, independently of each other, as a mixture of E / Z isomers. Therefore, both the pure E and Z isomers and the E / Z isomer mixtures are subject of the present invention. The diastereomers, including the E / Z isomers, can be separated into the individual isomers by means of chromatography. The racemates can be separated into the two enantiomers either by chromatography in chiral phases or by splitting the racemate. The compounds of formula I according to the invention can also contain displaceable hydrogen atoms, and therefore present in different tautomeric forms. Also these tautomers are object of the present invention. Preferred are compounds of formula I which are selective antagonists of the vitronectin receptor, especially in relation to the fibrinogen receptor, ie, which are stronger inhibitors of the vitronectin receptor than of the fibrinogen receptor. Especially preferred are compounds of formula I which are selective antagonists of the vitronectin receptor and in which the distance between R10 and the first nitrogen atom in A is 12 or 13 covalent bonds by the shortest path, as indicated by title example for and R10 = COOH: covalent bonds Further preferred are compounds of formula I in which at least one residue of the series R4, R5, R6 and R7 constitutes a lipophilic moiety. Examples of lipophilic moieties in the series R4, R5, R6 and R7 are p. ex. neopentyl, cyclohexyl, adamantyl, cyclohexyl-alkyl (d-C8), adamantyl-alkyl (d-C8), phenyl, naphthyl, fe-nyl-alkylCj-Cß), naphthyl-alkyl (d-C8), cyclohexylmethylcarbonylamino, 1-adamantylmethyloxycarbonylamino or benzyloxycarbonylamino and in general residues in which R8 means p. ex. neopentyl, cyclohexyl, adamathyl, cyclohexyl-alkyl (Cj-Ca), adamantyl-alkyl (d-C8), phenyl, naphthyl, phenyl-alkyl (d-Cß). Also preferred are compounds of formula I in which they mean: the rest wherein O constitutes a cyclic system aromatic or non-aromatic, mono or polycyclic, from 5 to 10 members, which may contain from 1 to 4 heteroatoms of the series consisting of N, O and S, and may possibly be substituted once or several times with R12, R13, R14 and R15; B a direct bond, alkanediyl (d-C6), arylene (C5-C8), cycloalkylene (C3-Cß), -C "C-, -NR2-, -NR2-C (0) -, -NR2- C ( 0) -NR2-, -NR2-S (0) -, -NR2-S (0) 2-, -O-, -CR2 = CR3-, each of which may be substituted one or more times with alkyl ( Cj-C; D a direct bond, alkanediyl (d-C8), arylene (C5-C8), -O-, -NR2-, -CO-NR2-, -NR2-CO-, -NR2-C (0) -NR2-, -OC (O) -, - C (0) 0-, -S (0) 2-, -S (0) 2-NR2-, -NR2-S (0) 2-, -S-, -CR2 = CR3-, -CSc-, each of which may be substituted once or twice with alkyl (Cx-C8), -CR2 = CR3-, aryl (C5-C6), where, when B is a direct bond, D can not be -CO-NR2-, -C (0) 0-, -S02-, -S (0) 2-NR2-; E a template from the series of fibrinogen receptor antagonists taken from the documents: US 5,250,679, October 5, 1993, Blackburn, B.K. et al. US 5,403,836, April 4, 1995, Blackburn, B.K. et al. US 5,565,449, October 15, 1996, Blackburn, B.K. et al. WO 93/08174, October 15, 1991, Blackburn, B.K. et al. WO 95/04057, February 7, 1995, Blackburn, B.K. et al. EP 0 655 439, November 9, 1994, Denney, M.L. et al. WO 94/18981, September 1, 1994, Claremon D.A. et al. WO 94/08962, April 28, 1994, Harmann, G.D. et al. EP 0 668 278, February 14, 1995, Juraszyk, H. et al. WO 94/12478, June 9, 1994, Keenan, E.Mc.C. et al. it is defined as D; R2, R3 independently of each other, H, alkyl (d-C10) which is optionally substituted one or more times with fluorine, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (d-C6), aryl (C5) -C12), aryl (C5-C12) -alkyl (Ci-Cg), R8OC (0) R9, R8R8NC (0) R9, R8C (0) R9; R4, R5, R6, R7, independently of each other, H, fluorine, OH, alkyl (d-C8), cycloalkyl (C5-C14), cycloalkyl (C5-C14) -alkyl (d-C8), or R8OR9, R8SR9 , R8C02R9, R8OC (0) R9, R8- aryl (C5-C14) -R9, R8N (R2) R9, R8R8NR9, R8N (R2) C (O) OR9, R8S (0) nN- (R2) R9, R8OC (0) N (R) R9, R8C (O) N (R2) R9, R8N (R2) C (0) N (R2) R9, R8N (R2) S (0) nN (R2) R9, R8S (0 ) nR9, R8SC (O) N (R2) R9, R8C (0) R9, R8N (R2) C (0) R9, R3N (R2) S (0) nR9; R8 H, alkyl (Ci-Cg), cycloalkyl (C5-C14), cycloalkyl (C5-C14) -alkyl (d-C6), aryl (C5-C12), aryl (C5-C12) -alkyl (d- C6) ), wherein the alkyl moiety may be substituted with fluorine once or several times; R9 a direct bond or alkanediyl (d-C6); R? O C (0) Rp, C (S) RU, S (0) nRu, P (O) (Rn) not a saturated or unsaturated heterocycle, of four to eight members, containing 1, 2, 3 or 4 heteroatoms of the series consisting of N, O and S; > OH, alkoxy (d-C6), aryl (C5-C12) -alkoxy (d-C6), aryloxy (C5-C12), alkyl (d-C6) carbonyloxy-alkoxy (d-C4), aryl (C5-) C12) -alkyl (d-C6) carbonyloxy-alkoxy (d-C6), NH2, mono- or di- (C1-C6 alkyl) amino, aryl (C5-C12) -alkyl (d-C6) amino, dialkyl (d-C8) aminocarbonylmethyloxy; R12, R13, R14, R15, independently of each other, H, alkyl (d-C8) which is optionally substituted one or more times with fluorine, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl-alkyl (d) -C6), aryl (C5-C12), aryl (C5-C12) alkyl (Cj- C6), NH2, R8ONR9, R3OR9, R8OC (0) R9, R8 ~ aryl (C5-C12) -R9, R8R8NR9, HO -alkyl (d-C8) -N (R2) R9, R8N (R2) C (O) R9, R8C (0) N- (R2) R9, R8C (0) R9, R2RN-C (= NR2), R2R3N-C (= NR2) -NR2, = 0, = S; wherein two substituents of R12 to R15 can together denote -0CH20-, -OCH2CH20-, -OC (CH3) 20-; And NR2, O, S; n 1 or 2; p q independently among them 0 or 1; in all its stereoisomeric forms and mixtures thereof in any proportion, and their physiologically tolerable salts.
Especially preferred are compounds of formula I, in which the following meanings are given: To one of the remains R2 B a direct bond, alkanediyl (d-C6), arylene (C5-C6), cycloalkylene (C5-C6), -C = C-, -NR2-, -NR2-C (0) -, -NR2-S ( 0) 2-, -O-, -CR2 = CR3-, each of which may be substituted once or twice with alkyl (C, -C; D a direct bond, alkanediyl (Cj-Cg), arylene (C5 -C6), -O-, -NR2-, -NR2-C (0) -, -C (0) NR2-, -NR2-C (O) -NR2-, -OC (O) -, -S ( 0) 2-NR2-, -NR-S (0) 2-, -CR2 = CR3-, each of which may be substituted once or twice with alkyl (d-Cg), where, when B is a direct link, D can not be -C- (O) NR2-, -S (0) 2-NR2-; E a) a mold of documents WO 93/08174, US 5,250,679, US 5,403,836, US 5,565,449, namely: wherein Rla, R2a, R: 20a R 21a R22a are defined as R1, R2, R20, 521 R22 in US 5,403,836, column 249, line 9-22; column 252, line 66 to column 253, line 68, and therefore signify: Rla, R2a, independently of each other, from one to three groups of the series consisting of hydrogen, halogen, cyano, carboxamido, carbamoyloxy, formyloxy, formyl , azido, nitro, ureido, thioureido, hydroxy, mercapto, sulfonamido or a residue, optionally substituted, of the series formed by alkyl (d-C12), alkenyl (C2-C12), alkynyl (C3-C12), cycloalkyl (C3-C12), aryl (C6-C14), aryl (C6-C10) -alkyl (C? -C?), Alkyloxy (d-C12), aryloxy (C6-C14) and acylamino (d? C12), in wherein the substituents mean a residue of the series consisting of halogen, cyano, azido, nitro, hydroxy, mercapto, sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy, formyl, alkoxy (d-C4), phenyl, and phenoxy; R20a hydrogen, halogen (fluorine, chlorine, bromine, iodine), alkoxy (d-C4), alkyl (d-C4), phenyl, benzyl or halogeno-alkyl (d-C4); R21a, R22a, independently of each other, means 1. hydrogen, 2. (d-C12) alkyl, 3. (C6-C14) aryl, 4. (C3-C14) cycloalkyl, 5. (C1-C12) alkylaryl (C6-C14), 6. alkyl (d-C12) -cycloalkyl (C3-C14), wherein the residues defined in sections 2 to 6 can be substituted with one or more residues of the series formed by halogen (fluorine, chlorine, bromine, iodine), nitro, hydroxyl, carboxyl, tetrazole, hydroxamate, sulfonamide, trifluorimide, phosphonate, alkyl (d-C6), aryl (C6-C? 4), benzyl, cycloalkyl (C3-C14), COR24a, CONR25R26; wherein R24a is a residue from the series consisting of alkoxy (d ~ C8), alkenoxy (C3-C12), aryloxy (C6-C12), di-alkyl (d-Cß) to ino-alcoxy (d-C8) ), acylamino-alkoxy (d-C8) such as, for example, acetylaminoethoxy, nicotinylaminoethoxy, succinamidoethoxy or pivalethylethoxy; aryl (C6-C12) -alkoxy (dC?), wherein the aryl group may optionally be substituted with one to three residues from the series consisting of nitro, halogen, (d-C4) alkoxy, amino, hydroxyl, hydroxy-alkoxy (C2-C8), dihydroxy-alkoxy (C3-C8); R25 and R26, independently of each other, mean hydrogen, alkyl (d-dc), alkenyl (C3-C10), aryl (C6-C14), alkyl (dC6) -aryl (C6-C10), or R25 and R26 together form a trimethylene, tetramethylene, pentamethylene or 3-oxopen tamemethylene moiety; 7. means Q2-L3, wherein Q2 is hydrogen or Q1; and L3 means a chemical bond, L1 or L2; Q1 is a nitrogen-containing moiety, substituted or unsubstituted, positively charged, L1 is a divalent moiety containing from 3 to 9 methylene groups, in which one or all of the methylene groups may be substituted with one or more alkene groups, alkyne groups, aryl groups or functional groups containing heteroatoms of the series consisting of N, O or S, and L2 is a divalent radical, optionally substituted; wherein the preferred moieties for Q1, L1 and L2 are the moieties as described in US 5,403,836 in column 249, line 27 to column 251, line 6 (Q1), column 251, line 7 to column 252, line 18 (L1) and column 252, line 19-45 (L2); and R22b is defined as R22 in US 5,565,449, column 296, line 38 to column 297, line 38, and means: 1. hydrogen, 2. (d-C12) alkyl, 3. (C6-C14) aryl, 4. (C3-C14) cycloalkyl, 5. alkyl ( Cx-C12) -aryl (C6-C14), 6. alkyl (d-C12) -cycloalkyl (C3-C14), where the residues defined in sections 2 to 6 can be substituted with one or more residues of the series formed by halogen (fluorine, chlorine, bromine, iodine), nitro, hydroxyl, carboxyl, tetrazole, hydroxamate, sulfonamide, trifluoride, phosphonate, alkyl (C, -C), aryl (C6-C14), benzyl, cycloalkyl (C3-) C14), COR2 a, CONR25R26; wherein R24a is a residue from the series consisting of (d-C8) alkoxy, (C3-C12) alkenoxy, (C6-C12) aryloxy, di (C1-C8) alkyl-amino-alkoxy (d-C8), acylamino -alkoxy (d-C8) such as, for example, acetylaminoethoxy, nicotinoylamino-20-toxi, succinamidoethoxy or pivaloylethoxy; aryl (C6-C12) -alkoxy (d ~ C8), wherein the aryl group may be optionally substituted with one to three residues from the series consisting of nitro, halogen, also-25 xi (d-C4), amino, hydroxyl , hydroxy (C2-C8) alkoxy, dihydroxy (C3-C8) alkoxy; R25 and R26, independently from each other, mean hydrogen, alkyl (d-C10), alkenyl (C3-C10), aryl (CÉ-C14), alkyl (d ~ 30C6) -aryl (C6-C10), or R25 and R26 together form a trimethylene, tetramethylene, pentamethylene or 3-oxopen tamemethylene moiety; 7. means Q2-L3, wherein 35 Q2 is hydrogen or Q1; and L3 means a chemical bond, L1 or L2; Q1 is a nitrogen-containing, substituted or unsubstituted, positively charged moiety, L1 is a divalent moiety containing from 3 to 9 methylene groups, in which one or all of the methylene groups can be substituted with one or more alkene moieties, alkyne moieties, aryl moieties or functional groups containing heteroatoms of the series consisting of N, O or S, and L2 is a divalent moiety, optionally substituted; wherein the preferred residues for Q1, L1 and L2 are residues as described in US 5,403,836 in column 289, line 9 to column 293, line 17 (Q1), column 293, line 18 to column 295, line 28 (L1) and column 295, line 29 to column 296, line 11 (L2); or b) a mold of WO 95/04057, namely; wherein R1 and R2b are defined as R1 and R2 in US 5,403,836, column 249, line 9-22, and they mean: R1b, R2b independently of each other, from one to three groups of the series consisting of hydrogen, halogen , cyano, carboxamido, carbamoyloxy, formyloxy, formyl, azido, nitro, ureido, thioureido, hydroxy, mercapto, sulfonamido or a residue, optionally substituted, of the series consisting of alkyl (d-C12), alkenyl (C2-C12), alkynyl (C3-C12), cycloalkyl (C3-C12), aryl (C6-C14), aryl (C6-C10) -alkyl (d-C8), alkyloxy (d-C12), aryloxy (C6-C14) and acylamino (Ct-C12), wherein the substituents constitute a residue of the series consisting of halogen, cyano, azido, nitro, hydroxy, mercapto, sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy, formyl, alkoxy (d-C4) , phenyl and phenoxy; and R25b and R26b ge d f nen as R25 and R26 in the US document . 565,449, and they mean: R25_ and R26b independently of one another, meaning hydrogen, alkyl (d-C10), alkenyl (C3-C10), aryl (C6-C14), alkyl (Cj-Cg) -aryl (C6-C10) ), or R25 and R26b together form a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene moiety; or c) means a mold of EP-A 0 655 439, namely wherein (R2) D are attached to one or more carbon atoms of the 6-membered ring, and independently of each other they mean a residue of the series consisting of H, alkyl, alkyl substituted with halogen, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl, hydroxy, alkoxy, aralkoxy, carbamyl, amino, substituted amino, acyl, cyano, halogen, nitro and sulfo; R means alkyl (d-C4), P is an integer from 1 to 3, or d) means a mold of WO 94/12478, namely wherein R3 'is hydrogen, alkyl (d-C6), aryl-alkyl (C: -C6), or e) a template of WO 94/18981, namely where V is CR a or N, and Da means CH2, CH2-CH2, CH2C (R7a) 2CH2 wherein X is CR3a or N, wherein R3a means CN, C (0) N (R7a) R8a, R 8a wherein V means CR7a or N, and Da means CH2, CH2-CH2, CH2C (R7a) 2CH2 or wherein X means CR3a or N, wherein R3a means CN, C (0) N (R7a) R8a, wherein Y3 is O or H2, and R7a means hydrogen, (Cx-C4) alkyl optionally substituted with OH or (Cx-C4) alkoxy, alkenyl (d-Cg) optionally substituted with (C, -C4) alkoxy, or HO -alkyl (Cx-C4) aryl, aryl optionally substituted with residues, identical or different, from the series consisting of halogen, (Cx-C4) alkoxy, hydroxy or alkyl (Cx-C4), R8a means hydrogen or alkyl (Cx-C4) n is an integer from 0 to 7, and n1 is an integer from 0 to 3; f) means a mold of EP-A 0531 883, namely wherein the following meanings are given: X 'an oxygen, sulfur or nitrogen atom, or a group -NR2-, wherein J2b is a hydrogen atom, a straight or branched chain alkyl group with 1 to 15 carbon atoms, a chain alkenyl or alkynyl group. linear or branched with 3 to 10 carbon atoms in each case, in which the double or triple bond can not be bound immediately to the nitrogen atom, a cycloalkyl or cycloalkylalkyl group with 3 to 7 carbon atoms in the cycloalkyl, an aryl group, an alkyl group with 2 to 6 carbon atoms which, from the position β to the nitrogen atom of the group -NR2- is substituted with a group R3O-, (R3b) 2N-, R4bCO- NR3b-, alkylsulfonyl-NR3-, arylsulphonyl-NR3b-, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl or R5b, or an alkyl group with 1 to 6 carbon atoms which is substituted with one or two aryl groups, R6bOCO-, (R3b) 2NCO-, R5b-CO-, R3O- CO-alkylene-NR3-CO-, (R3b) 2N-CO-alkylene-NR3- CO- or R5bCO-alkylene-NR3-CO-, in which R3b and R5b are defined as above and R6b constitutes a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 5 to 7 carbon atoms carbon or an aralkyl group, Y 'a group NO, a nitrogen atom or a methine group optionally substituted with an alkyl group, Zx, Z2, Z3 and Z4, which may be the same or different, means methino groups, carbon atoms, imino groups or nitrogen atoms, wherein at least one of the radicals Zx to Z4 has to contain a carbon atom and one or two methino groups neighboring a nitrogen atom can each be substituted with carbonyl groups, Z5 and Z6, each of them, a carbon atom or, also, one of the residues Z5 or Z6 means a nitrogen atom and the other residue Z5 or Z6 means a n Carbon atom, > 3b a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an aryl, aralkyl, carboxyalkyl or alkoxycarbonylalkyl group, R 4b a hydrogen atom, an alkyl or alkoxy group with 1 to 6 carbon atoms in each case, an aryl or aralkyl group with 1 to 6 carbon atoms in the alkyl part and R 5b an azetidino, pyrrolidino, hexamethyleneimino or heptamethyleneimino group, or a piperidino group, in which the methylene group in position 4 can be replaced by an oxygen atom , a sulfenyl, sulfinyl or sulfonyl group, or an imino group substituted with a group R3-, R4CO-, alkylsulfonyl or arylsulfonyl, wherein R3 and R4 are defined as mentioned above; F a direct bond, alkanediyl (d-Cg), -O-, -CO-NR2-, - NR2-CO-, -NR2-C (0) -NR2, -OC (O) -, -C (0) 0-, -CO-, -S (0) 2-, -S (0) 2-NR2-, -NR2-S (0) 2-, -CR2 = CR3-, -CSC-, each of which it may be substituted once or twice with alkyl (d-Cg); R2, R3 independently of each other, H, (Cx-C6) alkyl which is optionally substituted one or more times with fluorine, (C5-C6) cycloalkyl, (C5-C6) cycloalkyl (Cx-C4), aryl (C5) -C10), aryl (C5-C10) -alkyl (Cx-C4), R8OC (0) R9, R8R8NC (0) R9, R8C (0) R9; R4, R5, Rd, R7, independently of each other, H, fluorine, OH, alkyl (Cx-Cg), cycloalkyl (C5-C14), cycloalkyl (C5-C14) -alkyl (d-Cg), or R8OR9, R8C02R9 , R8OC (0) R9, R8-aryl (C5-C10) -R9, R8NHR9, R8R8NR9, R? NHC (0) 0R9, R8S (0) nNHR9, R8OC (0) NHR9, R8C (0) NHR9, R8C (0) R9, R8NHC (O) NHR9, R8NHS (O) nNHR9, R8NHC (0) -R9, R8NHS (0) nR9, wherein at least one residue of the series consisting of R4, R5, R6 and R7 means a lipophilic moiety, such as. ex. , benzyloxycarbonylamino, cyclohexylmethylcarbonylamino, etc .; R8 H, (Cx-C6) alkyl, (C5-CX4) cycloalkyl, (C5-CX4) cycloalkyl (Cx-C4) alkyl, (C5-CX0) aryl, (C5-C10) aryl (CX-C4) alkyl ), wherein the alkyl moiety can be substituted with 1 to 6 fluorine atoms; R9 a direct bond or alkanediyl (Cx-C6); R? O C (0) Rn; R11 OH, (C6-C6) alkoxy, (C5-C10) aryl (CX-C6) alkoxy, (C5-C10) aryloxy, (CX-Cg) alkylcarbonyloxy-alkoxy (CX-C4), aryl (C5-) C10) -alkyl (Cx-C4) carbonyloxy-alkoxy (Cx-C4), NH2, mono- or di- (CX-C6 alkyl) amino; R 12 H, alkyl (C x -C 6) which is optionally substituted 0 several times with fluorine, cycloalkyl (C3-C6), cycloalkyl (C3-C6) -alkyl (Cx-C4), aryl (C5-C10), aryl (C5-C10) alkyl (Cx-C4), NH2, R8OR9 , R8OC (0) R9, R8-aryl (C5-C10) -R9, R8R8NR9, R8NHC (0) R9, R8C (0) NHR9, H2N-C (= NH) -, H2N-C (= NH) - NH -, = 0, wherein two substituents R12 together can also mean -OCH20-, -OCH2CH20-; And NR2, O, S; n 1 or 2; and P q independently among them, 0 or 1; in all its stereoisomeric forms and mixtures thereof in any proportion, and their physiologically tolerable salts.
Especially preferred are compounds of formula I in which the following meanings are given: To one of the residues B a direct bond, alkanediyl (Cx-C4), phenylene, pyridinyl, thiophenediyl, furanodiyl, cyclohexylene, cyclopentyl, -C = C-, -CR2 = CR3-, each of which may be substituted twice with alkyl (Cx-C4); D a direct bond, alkanediyl (Cx-C4) or phenylene, -O-, -NR2-, -NR2-C (0) -, -C (0) -NR2-, -NR2-S (0) 2-, NR2-C (O) -NR2-, -CR2 = CR3-, each of which can be substituted once or twice with alkyl (Cx-C4), where, when B is a direct bond, D can not be -C (0) NR2-; E a) a mold taken from WO 93/08174, US 5,250,679, US 5,403,836, US 5,565,449, namely: where R1 R2 R: 21a R 22a and R22b mean here: Rla independently, from one to three groups of the series consisting of hydrogen and halogen (fluorine, chlorine, bromine, iodine); R20a hydrogen; R21a, R22a, independently of each other, means 1. hydrogen, 2. alkyl (Ci-Cg), 3. aryl (C6-C12), 4. cycloalkyl (C6-C12), 5. alkyl (Cx-C6) -aryl (C5-Cx2), 6. (C1-C3) alkyl-cycloalkyl (C6-CX2), wherein the residues defined in sections 2 to 6 may be substituted with one or more residues from the series consisting of fluorine, chlorine, hydroxyl, hydroxamate, sulfonamide, alkyl (d-Cg), aryl (C6-CX2), benzyl, cycloalkyl (C6-CX2); R22b 1. hydrogen, 2. alkyl (d-CX2), 3. aryl (C6-C14), 4. cycloalkyl (C3-C14), 5. alkyl (d-C12) -aryl (C6-C14), 6. alkyl (d-C12) -cycloalkyl (C3-C14), where the residues defined in sections 2 to 6 may be substituted with one or more residues of the series consisting of halogen (fluorine, chlorine, bromine, iodine), nitro , hydroxyl, carboxyl, tetrazole, hydroxamate, sulfonamide, trifluorimide, phosphonate, alkyl (Cx-C6), aryl (C6-C14), benzyl, cycloalkyl (C3-C14), COR24a, CONR25R26; wherein R2 to a residue of the series consisting of alkoxy (Ci-Ca), alkenoxy (C3-C? 2), aryloxy (C6-CX2), di-alkyl (C1-C8) amino-alkoxy (Cx-C8) , acylamino-alkoxy (Cx-C8) such as, for example, acetyl-enoethoxy, nicotinoylamino-toxy, succinamidoethoxy or pivaloylethoxy; aryl (C6-C12) -alkoxy (Cx-C8), wherein the aryl group may optionally be substituted with one to three residues of the 5-series consisting of nitro, halogen, (Cx-C4) alkoxy, amino, hydroxyl, hydroxy - (C2-C8) alkoxy, dihydroxy (C3-C8) alkoxy; R25 and R26, independently of each other, mean hydrogen, alkyl (d-do), alkenyl (C3-C10), aryl (C6-C14), alkyl (CX-C6) -aryl (C6-d0), or R25 and R26 together form a trimethylene, tetramethylene, pentamethylene or 3-oxopen tamemethylene moiety; 15 7. means Q2-L3, wherein Q2 is hydrogen or Q1; and L3 means a chemical bond or L1; Q1 means an amino, amidino, aminoalkyleneimino, iminoalkylene-amino or guanidino group, preferably an amidino group; L1 means aryl (C6-C14) -alkynylene. { C2-CA), aryl (C6-C14) -alkylene (Cx-C3), aryl (C6-C14) -alkyloxy- ene (C! -C3) or -R1 c-CO-NR6cR15c-, wherein R6c means hydrogen, (Cx-C4) alkoxy, (Cx-C4) alkyl or halo-alkyla (d-C4); R14c means a chemical bond, alkylene (d-C8), cycloalkylene (C3-C7), alkenylene (C2-C5), alkynylene (C3-C5), arylene (C6-C10), alkyl (Cx-C3) arallylene (C6-C12), alkyl (Cx-C2) -aryl- (C6-Cxo) -alkylene (Cx-C2), aryl (C6-35 C10) -alkylene (Cx-C2) or aryloxy (C6- C10) -alkylene (Cx-C2), and R15c means a chemical bond, alkylene (Cx-C4), alkenylene (C2-C4), alkynylene (C2-C4), arylene (C6-C10), or alkyl (Cx- C3) arylene (C6-C12); a mold of WO 95/04057, namely: wherein R1, R2, R25b and R26b mean here: R1, Rb independently from each other, from one to three groups of the series consisting of hydrogen and halogen (fluorine, chlorine, bromine, iodine); and > 25b and R: 26b independently from each other, denote hydrogen, alkyl (d-C10), alkenyl (C3-C10), aryl (C6-C14), alkyl (Cx-C6) -aryl (C6-CX0), or R25b and R26b together form a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene moiety; means a mold of EP-A 0 655 439, namely d) means a mold of WO 94/12478, namely e) a mold of WO 94/18981, namely where Y3, V and Da are defined as described above; or f) means a mold of EP-A 0 531 883, namely wherein the following meanings are given: X 'an oxygen, sulfur or nitrogen atom, or a group -NR2b-, wherein R2b is a hydrogen atom, a straight or branched chain alkyl group, with 1 to 15 carbon atoms, a straight or branched chain alkenyl or alkynyl group, with 3 to 10 carbon atoms in each case, in which the double or triple bond can not be immediately bound to the nitrogen atom, a cycloalkyl group or cycloalkylalkyl each with 3 to 7 carbon atoms in the cycloalkyl part, an aryl group, an alkyl group with 2 to 6 carbon atoms which, starting from the β position with respect to the nitrogen atom of the -NRb group -, is substituted with a group R3b0-, (R3b) 2N-, R4bCO-NR3b-, alkylsulfonyl- NRb-, arylsulfonyl-NR3b-, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl or R5b, or an alkyl group with 1 to 6 atoms of carbon that is substituted with one or two aryl groups, R6bOCO-, (R3) 2NCO-, R5b- C0-, R3bO-CO-alkylene-NR3-CO-, (R3b) 2N-CO-alkylene-NR3-CO- or R5bCO-alkylene-NR3b-CO-, wherein R3 and R5b are as defined below and R6b constitutes a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 5 a 7 carbon atoms or an aralkyl group, Y 'a group NO, a nitrogen atom or a methine group optionally substituted with an alkyl group, Zx, Z2, Z3 and Z4, which may be the same or different, mean methine groups, atoms of carbon, imino groups or nitrogen atoms, wherein at least one of the radicals Zx to Z4 is to contain a carbon atom and one or two methino groups neighboring a nitrogen atom can each be substituted with carbonyl groups, Z5 and Z6, each of them, a carbon atom, or also one of the residues Z5 or Z6 means a nitrogen atom and another of the residues Z5 or Z6 means a carbon atom, R3b a hydrogen atom, a group alkyl having 1 to 6 carbon atoms, an aryl, aralkyl, carboxyalkyl or alkoxycarbonyl group, Rb a hydrogen atom, an alkyl or alkoxy group with 1 to 6 carbon atoms in each case, an aryl or aralkyl group with 1 to 6 carbon atoms in the alkyl part and R5b a group azetidino, pyrrolidino, hexamethyleneimino or heptamethyleneimino, or a piperidino group, in which the methylene group in position 4 can be replaced by an oxygen atom, a sulfenyl, sulfinyl or sulphonyl group, or by an imino group substituted with a group R3b , R4bCO-, alkylsulfonyl or arylsulfonyl, wherein R3b and Rb are defined as mentioned above; is a direct bond, alkanediyl (Cx-C6), -0-, -CO-NR2-, -NR2-C0-, -NR2-C (0) -NR2, -S (0) 2-NR2-, -NR2 -S (0) 2-, -CR2 = CR3-, -C = C-, each of which may be substituted once or twice with alkyl (Cx-C4); R2, R3 independently of each other, H, (Cx-C4) alkyl, trifluoromethyl, pentafluoroethyl, (C5-C6) cycloalkyl, (C5-C6) cycloalkyl (Cx-C4) alkyl, phenyl, benzyl; R4 cycloalkyl (C10-CX4), cycloalkyl (Cxo-C14) -alkyl (Cx-C4), OR R16OR9, Ri6NHR9, R16NHC (0) OR9, R16S (O) -NHR9, R160C (0) NHR9, R16C (0) NHR9, R16C (0) R9, R16NHC (0) R9, R16NHS (0) nR9 R5 H, alkyl (Cx-C6), cycloalkyl (C5-C6), cycloalkyl (C5-C6) -alkyl (Cx-C4), trifluoromethyl, pentafluoroethyl, phenyl, benzyl; R8 H, (Cx-C4) alkyl, (C5-C6) cycloalkyl, (C5-C6) cycloalkyl (Cx-C2) alkyl, phenyl, benzyl, trifluoromethyl, pentafluoroethyl; R9 a direct bond or alkanediyl (Cx-C4); R? O C (0) Ru; Ru OH, (CX ~ C6) alkoxy, phenoxy, benzyloxy, (Cx-C4) alkyloxycarbonyloxy (Cx-C4) alkoxy, NH2, mono- or di- (CX-C6 alkyl) amino; R 12 H, (C x C 4) alkyl, trifluoromethyl, pentafluoroethyl, cycloalkyl. { C5-C6), (C5-C6) cycloalkyl-alkyl (Cx-C2), aryl (C5-Cg), aryl (C5-C6) alkyl (Cx-C2), NH2, R8R8NR9, R8NHC (0) R9, H2N -C (= NH), H2N-C (= NH) -NH-; wherein two substituents R12 may further mean -0CH20-, -OCH2CH20-; R16 cycloalkyl (C10-C14), cycloalkyl (C10-C14) -alkyl (Cx-C4), which may optionally be substituted 1 or 2 times with alkyl (Cx-C "), trifluoromethyl, phenyl, benzyl, alkoxy (Cx-) C4), phenoxy, benzyloxy, = 0 or mono- or di- (alkyl (Cx-C4)) -amino, wherein the cycloalkylene moieties are preferably 1-adamantyl or 2-adamantyl, which, as described above, they can be replaced; n 1 or 2; and q 0 or 1; in all its stereoisomeric forms and mixtures thereof in any proportion, and their physiologically tolerable salts. Also preferred are compounds of formula I wherein A, B, D, F and G are defined as above for the compounds of formula I very especially preferred, and E is a mold taken from WO 95/04057, EP 0 655 439, WO 94/18981, WO 94/08962, EP 0 668 278, WO 94/12478 or EP 0 531 883, wherein the latter is preferably defined as above for the especially preferred compounds of formula I, and especially preferably it is defined as was done above for the compounds of formula I very especially preferred. Another object of the present invention is that a known fibrinogen receptor antagonist can be converted to a selective vitronectin receptor antagonist by replacing the basic (with spacer) group of a fibrinogen receptor antagonist with the ABD moiety which is defined as in the formula I, being the distance between R10 and the first atom of N in A, of 12 or 13 covalent bonds by the shortest path between these atoms. The compounds of formula I can be obtained in a general manner, for example by means of a convergent synthesis, by joining two or more retrospective derivative fragments of the formula I. In the preparation of the compounds of formula I, in the course of The synthesis may be necessary in a general way to temporarily block functional groups that in the corresponding stage of the synthesis could give rise to unwanted reactions or secondary reactions, by means of a protection group strategy adapted to the synthesis problem, which is known to those skilled in the art. The method of binding the fragments is not limited to the following examples, but can be used in general for the synthesis of the compounds of formula I. By way of example, compounds of formula I of the type can be obtained A-B-D-E-C (0) NR2-G, with F = C (0) NR2, by co-compression of a compound of formula II A-B-D-E-M II, wherein M represents hydroxycarbonyl, (d-C6) alkoxycarbonyl, activated derivatives of carboxylic acids such as acid chloride, active ester or mixed anhydride, with HNR2-G. For the condensation of two fragments with formation of an amide bond, the known coupling methods of peptide chemistry are advantageously employed (see, eg, Houben-Weyl, Methoden der Organischen Chemie, volume 15/1 and 2/15, Georg Thieme Verlag, Stuttgart, 1974). For this purpose, it is generally necessary to protect the non-reactive amino groups present during condensation by means of reversible protection groups. The same is the case for the carboxyl groups not involved in the reaction, which are preferably used as alkyl (d-C6) -benzyl or tert-buyl-ester. The protection of the amino groups is of more importance when the amino groups to be generated are still present as nitro or cyano groups, and they only form after coupling by hydrogenation. After coupling, the protection groups present are removed in an appropriate manner. For example, the groups N02 (guanidi-no protection), the benzyloxycarbonyl and benzyl ester groups can be separated by hydrogenation. The t-butyl tert-butyl protecting groups are separated in acidic medium, while the 9-fluorenylmethyloxycarbonyl moiety is removed by a secondary amine. By way of example, compounds of formula I are obtained with R10 = S02Ru by oxidizing compounds of formula I with R10 = SH according to procedures known from the literature (cf., p. eg, Houben-Weyl, Methoden der Organischen Chemie, volume E12 / 2, Georg Thieme Verlag, Stuttgart, 1985, p. 1058 et seq.), To give compounds of formula I with R10 = S03H, from which the compounds of formula are then obtained directly or through the corresponding sulfonic acid halide by esterification or formation of an amide bond. I with R10 = S02Rn (R11? OH). Groups of the molecule that are sensitive to oxidation, such as p. e. the amino, amidino or guanidino groups are protected if necessary, carrying out the oxidation by means of suitable protection groups. For example, compounds of formula I are obtained with R10 = S (0) Rn by converting compounds of formula I with R10 = SH into the corresponding sulfide (R10 = S?) And then oxidizing with meta-chloroperbenzoic acid to give the acid sulfinic (R10 = S02H) (see Houben-Weyl, Methoden der Organischen Chemie, volume Ell / 1, Georg Thieme Verlag, Stuttgart, 1985, page 618 et seq.), from which, and by methods known from the literature , the corresponding ester or the corresponding sulfinic acid amide can be obtained with R10 = S (0) Rn (R11? OH). Generally, other methods known in the literature can also be used for the preparation of compounds of formula I with R10 = S (0) nRn (n = 1, 2) (see Houben-Weyl, Methoden der Organischen Chemie, volume Ell / 1, Georg Thieme Verlag, Stuttgart, 1985, pp. 618 et seq., Or Volume Ell / 2, Stuttgart 1985, pp. 1055 et seq.).
Compounds of formula I are prepared with R10 = P (O) (R11). (n = 1, 2) by procedures known from the literature (see Houben-Weyl, Methoden der Organischen Chemie, volume El and E2, Georg Thieme Verlag, Stuttgart, 1982) from appropriate previous steps, having to adapt the method of chosen synthesis to the target molecule. Compounds of formula I can be prepared with R 10 = C (S) RU according to a procedure of the literature (see Houben-Weyl, Methoden der Organischen Chemie, volume E5 / 1 and E5 / 2, Georg Thieme Verlag, Stuttgart 1985). Naturally, compounds of formula I with R10 = S (0) nRu (n = 1, 2), P (0) (Rn) p (n = 1, 2) or C (S) Rn, can also be obtained by bonding of fragments, as described above, which is advisable, for example, when in FG of formula I are contained an aminosulphonic acid, an aminosulfinic acid, an aminophosphonic acid or an aminophosphinic acid (commercial), or derivatives thereof as ester or amide. The compounds of formula I, wherein A-B- means a residue of formula they are obtained according to processes known in the literature by reacting compounds of formula with sulfinic or sulfonic acid derivatives of formula IV Q-S (0) n-D-E-F-G IV in which Q, p. eg, means Cl or NH ?, analogously to S. Birtwell et al., J. Chem. Soc. (1946) 491, or Houben-Weyl, Methoden der Organischen Chemie, volume E4, Georg Thieme Verlag, Stuttgart 1983; p. 620 and ss. Compounds of formula I in which B is -NR2-C (0) -NR2-, -NR2-C (0) 0-NR2-C (0) S-, and A has the indicated meaning, p. ex. treating a compound of formula V Q-D-E-F-G V wherein Q means HNR2-, HO- or HS-, with a suitable carbonic acid derivative, preferably phosgene, diphosgene (trichloromethyl ester of chloroformic acid), triphosgene (bis-trichloromethyl-carbonic acid ester), ethyl ester of acid Chloroform, Chloroformic acid i-butyl ester, bis- (1-hydroxy-1H-benzotriazolyl) carbonate or N, N'-carbonyldiimidazole, in a solvent inert to the reactants used, preferably dimethylformamide (DMF), tetrahydrofuran (THF) ) or toluene, at a temperature between -20 ° C and the boiling point of the solvent, preferably between 0 ° C and 60 ° C, to first give a substituted carbonic acid derivative of formula VI wherein R means -NR2-, -O- or -S-, and Q 'means, according to the carbonic acid derivative employed, chloro, methoxy, etho-xi, isobutoxy, benzotriazole-1-oxy or 1-imidazolyl. The treatment of these derivatives with type VII systems that contain a monocycle or a polycycle Vile it takes place in a polar organic solvent, protic or aprotic, but inert. For this, in the treatment of the methyl ester (Q = OMe) with the corresponding compounds of formula VII, methanol, isopropanol or THF are suitable at temperatures of 20 ° C to the boiling point of these solvents. In the majority of the treatments of compounds of formula VI with compounds free of salts of formula VII, advantageously work in inert aprotic solvents, such as THF, dimethoxyethane or dioxane. But water is also employed using a base (such as, for example, NaOH) as a solvent in the treatment of compounds of formula IV with the compounds of formula VII. When Q means Cl, it is advantageously worked up by adding a base as an acid scavenger, for the separation of the halogen hydrazide. Compounds of formula I wherein F is -R2N-C (O) -NR2- or -R2N-C (S) -NR2-, are obtained for example by treating a compound of formula VIII A - B - D - E - NHR2 VIII with an OCN-G isocyanate or SCN-G isothiocyanate according to methods known in the literature. Compounds of formula I in which F is -C (0) -NR2-, -S02NR2- or -C (0) 0-, can be prepared p. ex. by treating A- B - D - E - C (0) Q OR A - B - D - E - S02Q (Q is a labile group that is easy to replace nucleophilically, such as eg OH, Cl, OMe , etc.) with HR2N-G or HO-G according to literature procedures. Compounds of formula I in which A means a mono- or polycycle of the type they can be prepared, for example a) by treating a compound of formula IX HR2N-D-E-F-G IX with a mono- or polycycle of the type wherein X is a nucleophilically substitutable leaving group, such as. p. ex. halogen or SH, -SCH3, SOCH3 S02CH or HN-N02, by procedures known from the literature (see, eg, AF Mc Ay et al., J. Med. Chem. 6 (1963) 587, MN Buchman et al. ., J. Am. Chem. Soc. 71 (1949), 766, F. Jung et al., J. Med. Chem. 34 (1991) 1110 or G. Sorba et al., Eur. J. Med. Chem. 21 (1986), 391), or b) by treating a 1,2-diamino compound of formula XVII with an isothiocyanate of formula XIII SCN - B - D - E - F - G XIII to give a thiourea derivative of formula XVIII XVIII p. ex. according to F. Janssens et al., J. Med. Chem. 28 (1985) 1925, and then treating, as described above or p. ex. according to A. Mohsen et al., Synthesis (1977) 864 or V. Ojka et al., Indian J. Chem. Sec. B 32 (3) (1993) 394, to give the compounds of formula I with or c) treating an l-nitro-2-amino compound of formula XIX with an isothiocyanate of formula XIII to give a thiourea derivative of formula XX that, after reduction of the nitro group with Pd / C (see eg F. Janssens et al., J. Med. Chem. 28 (1985) 1925), is treated as described above to give compounds of formula I with Compounds of formula I in which A constitutes a mono-or polycycle of the type they are obtained according to methods known from the literature, p. ex. from compounds of formula by reaction with compounds of formula R2-NH-B-D-E-F-G according to M. Yamato et al., Chem. Pharm. Bull 32 (8) (1984) 3053, or, p. ex. , from 1, 2-aminoalcohols of formula XII which are first treated by the reaction with isothiocyanates of formula XIII SCN-B-D-E-F-G XIII to give thioureas of formula XIV which are then treated according to H.S. Chang et al., Chem. Lett. 8 (1986) 1291 or E.A. Ibrahim et al., J. Hete-rocycl. Chem. 19 (4) (1982) to give the compounds of formula I with Compounds of formula I in which A constitutes a mono-or polycycle of the type are obtained by methods known from the literature, p. ex. from 1,2-aminothiols of formula XV which are first treated by reaction with isothiocyanates of formula XIII to give the thioureas of formula XVI that later, p. ex. according to J. Garvin et al., J. Heterocycl. Chem. 28 (1991) 359, are treated to give the compounds of formula I with Compounds of formula I in which D is -CSC- can be obtained, for example, by treating a compound of formula X X-E-F-G X wherein X = I or Br, with a compound of the type A-B-CsCH, in a palladium catalyzed reaction, as described, p. eg, A. Arcadi et al., Tetrahedron Lett. 1993, 34, 2813 or E.C. Taylor et al., J. Org. Chem. 1990, 55, 3222. In the same way, compounds of formula I in which F is -C * C- can be obtained, for example by binding compounds of formula XI A-B-D-E-X XI wherein X means I or Br, with a compound of the HCOG type in a palladium catalyzed reaction. The synthesis of the E-templates of fibrinogen receptor antagonists takes place as described in the corresponding patents, patent applications or publications, incorporating them in the template or joining them to the template during the synthesis of the template or subsequently, preferably during the synthesis. of the mold, functional groups that allow the later splicing of ABD and FG by joining the fragments, as described below for a mold of WO 94/18981 by way of example: there the synthesis, Functional groups for splicing A-B-D and F-G Example for the splicing of A-B-D and F-G: halogen) Known methods of obtaining are described in the bibligraphy, p. eg, in J. March, Advanced Organic Chemistry, 3rd Ed. (John Wiley and Sons, 1985). The compounds of formula I and their physiologically tolerable salts can be administered as medicaments to animals, preferably to mammals and especially to humans, either alone, forming a mixture, or in the form of pharmaceutical preparations which allow enteral or parenteral use and which, as an active component, contain an effective dose of at least one compound of formula I or a salt thereof, together with the usual pharmaceutically acceptable vehicles and excipients. The preparations normally contain about 0.5 to 90% by weight of the therapeutically active compound. Medications can be administered orally, p. ex. in the form of pills, tablets, lacquered tablets, dragees, granules, hard or soft gelatine capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. But administration can also be done rectally, e.g. ex. in the form of suppositories, or parenteral, p. ex. in the form of solutions for injection or infusion, microcapsules or rods, percutaneous, p. ex. in the form of ointments or tinctures, or nasal, p. ex. in the form of nasal sprays. The preparation of the pharmaceutical preparations takes place in a known manner, using pharmacologically inert organic or inorganic vehicles. For the preparation of pills, tablets, dragees and hard gelatine capsules, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used. Vehicles for soft gelatin capsules and suppositories are, p. ex. , fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. As carriers for the preparation of solutions and syrups are suitable, e.g. e. , water, sugar, invert sugar, glucose, polyols, etc. Water, alcohols, glycerin, polyols, vegetable oils, etc. are suitable as vehicles for the preparation of solutions for injection. As carriers for microcapsules, implants or rods, mixed polymeric materials of glycolic acid and lactic acid are suitable. In addition to the active substances and vehicles, the pharmaceutical pre-pads may also contain excipients such as p. ex. fillers, diluents, binders, glidants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings or flavorings, thickeners, diluents, substances for the preparation of powder, in addition to dissolving solvents or agents, or agents to obtain a deposit effect, as well as salts to modify the osmotic pressure, covering substances or antioxidants. They may also contain two or more compounds of formula I or their physiologically tolerable salts; also, in addition to containing at least one compound of formula I, they can carry one or more therapeutically active substances of another type. The dose can vary within wide limits, and in each isolated case it has to be adapted to the particularities of the individual. In oral administration, the daily dose may be from 0.01 to 100 mg / kg, preferably from 0.1 to 5 mg / kg, especially from 0.3 to 0.5 mg / kg of body weight, to obtain -effective results. Also in the case of intravenous application the daily dose is generally from about 0.01 to 100 mg / kg, preferably from 0.05 to 10 mg / kg of body weight. Especially when large amounts are applied, the daily dose can be divided into several partial administrations, eg. ex. in 2, 3 or 4. Eventually it may be necessary, according to the individual behavior, to deviate upwards or downwards from the indicated daily dose. Apart from the active drug substance, the compounds of formula I can be used in diagnostic methods, for example in vitro diagnosis, or as adjuvants in biochemical investigations, in which an inhibition of the vitronectin receptor is sought. The inhibition of bone absorption by the compounds according to the invention can be determined, for example, by means of an osteoclast ("PIT ASSAY") absorption assay, e.g. ex. analogously to WO 95/32710. The test methods by which the antagonist action of the compounds according to the invention can be determined on the avr 3 vitronectin receptor are described below.
Test method 1: Inhibition of the binding of human vitronectin (Vn) to the human vitronectin receptor (VnR) ovß3: ELISA assay. 1. Purification of human vitronectin. Human vitronectin is 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. Purification of the human vitronectin receptor (avß3). Human vitronectin receptor is obtained from human placenta by the method of Pytela et al., Methods Enzymol. 1987, 144, 475. The avr3 human vitronectin receptor can be obtained from some cell lines (eg from 293 cells, a human embryonic kidney cell line), which are co-transfected with DNA sequences. for the two av and ß3 subunits of the vitronectin receptor. The subunits are extracted with octylglycoside and then chromatographed on concanavalin A, heparin-sepharose and S-300. 3. Monoclonal antibodies. Specific murine monoclonal antibodies are prepared for the β3 subunit of the vitronectin receptor, by the method of Newman et al., Blood, 1985, 227-232, or by a similar procedure. The rabbit anti-mouse Fab 2 conjugate in horseradish peroxidase (anti-mouse HRP) was coated by Pei Freeze (catalog no. 715 305-1). 4. ELISA assay. Ninety-well Nunc Maxisorp microtiter plates are covered with a solution of human vitronectin (0.002 mg / ml, 0.05 mL / well) in PBS (phosphate buffered saline) overnight, at 4 ° C. The plates are washed twice with PBS / 0.05% Tween 20, and blocked by incubation (60 min) with bovine serum albumin (BSA, 0.5%, quality for RIA or better) in Tris-HCl ( 50 mM), NaCl (100 mM), MgCl2 (1 M), CaCl2 (1 mM), MnCl2 (1 mM), pH 7). Solutions of known inhibitors and test substances are prepared in concentrations of 2 × 10"12 to 2 × 10 6 mol / L in assay buffer [BSA (0.5%, RIA quality or better) in Tris-HCl (50 mM ), NaCl (100 mM), MgCl2 (1 mM), CaCl2 (1 mM), MnCl2 (1 mM), pH 7]. The blocked plates are emptied and 0.025 mL of this solution, containing a defined concentration (2x10"12 to 2x106) of a known inhibitor or a test substance, is added to each well of each one of them. in each well of the plate 0.025 mL of a solution of the vitronectin receptor in assay buffer (0.03 mg / mL) and incubate the plate in shaker for 60-180 min at room temperature. 6 mL / plate) of a murine monoclonal antibody specific for the β3 subunit of the vitronectin receptor, in assay buffer (0.0015 mg / mL) To this solution is added a second rabbit antibody (0.001 L of original solution / 6 mL of the anti-ß3 murine monoclonal antibody solution) which constitutes a Fe-anti-ra-tON-HRP-antibody conjugate, and this mixture of murine anti-ß3 antibody and conjugated Fe anti-mouse rabbit-HRP-anti- body is left incubating during the incubation time of the receptor-inhibitor. The assay plates are washed 4 times with PBS solution containing 0.05% Tween-20, and 0.05 mL / well of the antibody mixture is pipetted into each well of the plate, and incubated for 60- 180 min. The plate is washed 4 times with PBS / 0.05% Tween-20, and then developed with 0.05 mL / well of a PBS solution containing 0.67 mg / mL of o-phenylenediamine and 0.012% of H202 Alternatively, o-phenylenediamine can be used in a buffer (pH 5) containing Na3P04 (50 mM) and citric acid. Color development is paralyzed with H2SO4 IN (0.05 mL / well). The abosrtion of each well is measured at 492-405 nm and the data is evaluated by standard methods.
Test method 2: Inhibition of quistrine binding to the human vitronectin (VnR) avß3 receptor: ELISA assay. 1. Purification of quistrin. The quistrin is purified by the methods of Dennis et al., As described in Proc. Nati Acad. Sci. USA 1989, 87, 2471-2475 and PROTEINS: Structure, Function and Genetics 1993, 15, 312-321. 2. Purification of the human vitronectin receptor (avß3) • See Test Method 1. 3. Monoclonal Antibodies. See Test Method 1. 4. ELISA assay. The ability of some substances to inhibit the binding of quistrine to the vitronectin receptor can be determined with an ELISA assay. For this purpose 96-well Nunc microtiter plates are covered with a quistrine solution (0.002 mg / mL) by the method of Dennis et al., As described in PROTEINS: Structure, Function and Genetics 1993, 15, 312-321 . The remainder of the experimental run of the ELISA assay takes place as described in Test Method 1, item 4.
Test method 3. Inhibition of the binding of 293 cells transfected with avß3 to human vitronectin. Cell test.
Cells 293, a line of human embryonic kidney cells, which are co-transfected with DNA sequences for the v and β3 subunits of the vitronectin receptor ovß3, are selected according to the FACS method from the point of view of a high expression rate (>500,000 avß3 / cell-receptors). The chosen cells are cultured and sorted again by FAC, to achieve a stable cell line (15 D) with expression rates > 1000000 copies in AV3 per cell. A 96 well tissue culture plate with a flat bottom is covered with human vitronectin (0.01 mg / ml, 0.05 mL / well) in phosphate buffered saline (PBS), overnight and at 4 ° C , and then blocked with 0.5% BSA. Solutions of the test substances are prepared from 10"10 to 2xl0'3 mol / L in glucosed DMEM medium, and 0.05 mL of the solution / well are added to the plate.The cells that express high levels of avß3 (p. (eg 15 D) are suspended in glucose DMEM medium and the suspension is adjusted to a content of 25000 cells / 0.05 mL of medium, 0.05 mL of this cell suspension is added to each well and the plate is incubated. at 37 ° C for 90 min The plate is washed 3 times with hot PBS to remove the unbound cells.The bound cells are lysed in citrate buffer (25 mM, pH 5.0) containing 0.25% Triton X-100 The substrate hexosamidase p-nitrophenyl-n-acetyl-β-D-glucosaminide is then added and the plate is incubated for 90 min at 37 ° C. The reaction is paralyzed with a glycine buffer (50 mM). ) / EDTA (5 mM) (pH .4), and the absorption of each well at 405-650 nm is measured.
The antagonist action of the compounds according to the invention on the fibrinogen receptor IIIb.sub.3, especially for the determination of the selectivity, can be carried out as described in US Pat. No. 5,403,836, p. 237

Claims (2)

  1. CLAIMS Ia. Compounds of formula I, A - B - D - E - F - G (I) where they mean: TO constitutes an aromatic or non-aromatic cyclic system, monocyclic or polycyclic, of 5 to 10 members, which may contain from 1 to 4 heteroatoms of the series consisting of N, O and S, and may optionally be substituted once or several times with R12, R13, R14 and R15; B a direct bond, alkanediyl (Cx-C8), arylene (C5-C10), cycloalkylene (C3-C8), -CSC-, -NR2-, -NR2-C (0) -, -NR2-C (0) -NR2-, -NR2-C (S) -NR2-, -OC (O) -, -NR2-S (0) -, -NR2-S (0) 2-, -O-, -S-, - CR2 = CR3-, each of which may be substituted one or more times with alkyl (Cx-C8); D uri direct bond, alkanediyl (Cx-C8), arylene (C5-C10), -O-, -NR2-, -CO-NR2-, -NR2-CO-, -NR2-C (O) -NR2-, -NR2-C (S) -NR2-, -OC (O) -, -C (0) 0-, -S (O) -, -S (0) 2-, -S (0) 2-NR2- , -S (0) -NR2-, -NR2-S (0) -, -NR2-S (0) 2-, -S-, -CR2 = CR3-, -CSC-, each of which may be substituted once or twice with alkyl (dC?), -CR2 = CR3-, aryl (C5-C6), where, when B is a direct bond, D can not be -CO-NR2-, -C (0) 0-, -S (O) -, -S (0) 2-, -S (0) -NR2-, -S (0) 2-NR2-; a template from the series of fibrinogen receptor antagonists; it is defined as D; R2, R3 independently of each other, are H, (Cx-C10) alkyl which is optionally substituted one or more times with fluorine, (C3-C12) cycloalkyl, (C3-C12) cycloalkyl (d-C8) alkyl, aryl ( C5-C14), aryl (C5-C14) -alkyl (Cx-C8), R8OC (0) R9, R8R8NC (0) R9, R8C (0) R9; R4, R5, R6, R7, independently of each other, are H, fluorine, OH, alkyl (Cx-C8), cycloalkyl (C3-C14), cycloalkyl (C3-CX4) -alkyl (Cx-C8), or R8OR9, R8SR9, R8C02R9, R8OC (0) R9, R8-aryl (C5-CX4) -R9, R8N (R2) R9, R8R8NR9, R8N (R2) C (O) OR9, R8S (0) nN- (R2) R9, R8OC (0) N (R2) R9, R8C (O) N (R2) R9, R8N (R2) C (O) N (R2) R9, R8N (R2) S (0) "N (R2) R9, R8S (0) nR9, R8SC (O) N (R2) R9, R8C (0) R9, R8N (R2) C (0) R9, R8N (R2) S (0) nR9; R8 H, (Cx-C8) alkyl, (C3-CX4) cycloalkyl, (C3-C14) cycloalkyl-alkyl (Ci-Ca), aryl (C5-C14), aryl (C5-C14) -alkyl (Cx- C8) ), wherein the alkyl moiety may be substituted once or several times with fluorine; R9 a direct bond or alkanediyl (Cx-C8); R10 C (0) Rn, C (S) RU, S (0) nRu, P (O) (Rn) not a saturated or unsaturated heterocycle, of four to eight members, containing 1, 2, 3 or 4 heteroatoms of the series consisting of N, O and S, as, p. eg, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiadiazolyl; Ru OH, (C? -C8) alkoxy, (C5-C14) aryl-alkoxy (C? ~ C8), aryloxy (C5-CX4), alkyl (Cx-C8) carbonyloxy-alkoxy (Cx-C4), aryl ( C5-C14) -alkyl (C? -C8) carbonyloxy-alkoxy (Ci-Cg), NH2, mono- or di- ((C? -8) alkyl) amino, aryl (C5-CX4) -alkyl (Cx-) C8) amino, di (Cx-C8) alkyl aminocarbonylmethyloxy, aryl (C5-C14) -dialkyl (Cx-C8) aminocarbonylmethyloxy or aryl (C5-C14) amino, or the residue of an L- or D-amino acid; R12, R13, R14, R15, independently of each other, H, alkyl (Cx-C10) which is optionally substituted one or more times with fluorine, cycloalkyl (C3-C12), cycloalkyl (C3-C12) -alkyl (Cx) -C8), aryl (C5-C14), aryl (C5-C14) alkyl (Cx-C "), H2N, R8ONR9, R8OR9, R3OC (0) R9, R8R8NR9, R8-aryl (C5-C14) -R9, HO-alkyl (d-C8) -N (R2) R9, R8N (R2) C (0) R9, R8C (0) N (R2) R9, R8C (0) R9, R2R3N-C (= NR2) -NR2 , R2R3N-C (= NR2), = 0, = S; wherein two substituents of R12 to R15 together can also mean -0CH20-, -OCH2CH20-; And NR2, 0, S; n 1 62; p, q independently among them, 0 or 1; in all its stereoisomeric forms and mixtures thereof in any proportion, and their physiologically tolerable salts, in which the compounds in which E means are excepted: a) a 6-membered aromatic cyclic system which may contain up to 4 nitrogen atoms and which may be substituted with 1 to 4 substituents, either the same or different, or b) 4- methyl-3-oxo-2, 3, 4, 5-tetrahydro-lHl, 4-benzodiazepine. 2a. Compounds of formula I according to claim Ia, in which they mean: • where) constitutes an aromatic or non-aromatic cyclic system, mono- or polycyclic, of 5 to 10 members, which may contain from 1 to 4 heteroatoms of the series consisting of N, O and S, and optionally one or several times with R12, R13, R14 and R15; B a direct bond, alkanediyl (d-C6), arylene (C5-C8), cycloalkylene (C3-C8), -C "C-, -NR2-, -NR-C (0) -, -NR2- C ( 0) -NR2-, -NR2-S (0) -, -NR2-S (0) 2-, -O-, -CR2 = CR3-, each of which may be substituted one or more times with alkyl ( Cx-C6); D a direct bond, alkanediyl (Cx-C8), arylene (C5-C8), -O-, -NR2-, -CO-NR2-, -NR2-CO-, -NR2-C (O) -NR2-, -OC (O) -, -C (0) 0-, -S (0) 2-, -S (0) 2-NR2-, -NR2-S (0) 2 -, - S-, -CR2 = CR3-, -C * C-, each of which may be substituted once or twice with alkyl (Cx-C "), -CR-CR3-, aryl (C5-C6 1 where, when B is a direct bond, D can not be -CO-NR2-, -C (0) 0-, -S02-, -S (0) 2-NR2-, is defined as D; R2 R3 independently of each other, H, (Cx-C10) alkyl which is optionally substituted one or more times with fluorine, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C5-) aryl C12), aryl (C5-C12) -alkyl (d-C3), R8OC (0) R9, R8R8NC (0) R9, R8C (0) R9; R4, R5, R6, R7, independently of each other, H, fluorine, OH, alkyl (Cx-C8), cycloalkyl (C5-C14), cycloalkyl (C5-C14) -alkyl (Cx-C8), or R8OR9, R8SR9 , R8C02R9, R8OC (0) R9, R8- aryl (C5-CX4) -R9, R8N (R2) R9, R8R8NR9, R8N (R2) C (O) OR9, R8S (0) nN- (R2) R9, R8OC (0) N (R2) R9, R8C (O) N (R2) R9, R8N (R2) C (O) N (R2) R9, R8N (R2) S (0) nN (R2) R9, R8S (0 ) "R9, R8SC (O) N (R2) R9, R8C (0) R9, R8N (R2) C (0) R9, ReN (R2) S (0) .R9; R? H, alkyl (Cj-Cg), cycloalkyl (C, -C14), cycloalkyl (- C14) -alkyl (Cx-C6), aryl (C5-C12), aryl (C5-C12) -alkyl (Cx- C6) , wherein the alkyl moiety can be substituted with fluorine once or several times; R9 a direct bond or alkanediyl (Cx-C6); R10 C (0) Ru, C (S) Rn, S (0) nRu, P (O) (Rn) not a saturated or unsaturated heterocycle, of four to eight members, containing 1, 2, 3 or 4 heteroatoms of the series consisting of N, O and S; R11 OH, (Cx-C6) alkoxy, (C5-C12) aryl (CX-C6) alkoxy, (C5-CX2) aryloxy, (CX-C6) alkylcarbonyloxy-alkoxy (CX-C4), aryl (C5-) Cx2) -alkyl (Cx-C6) carbonyloxy-alkoxy (Cx-C6), NH2, mono- or di- (CX-C6 alkyl) amino, aryl (C5-C12) -alkyl (Cx-C6) amino, dialkyl (Cx-C8) aminocarbonylmethyloxy; R12, R13, R14, R15, independently of each other, H, (Cx-C8) alkyl which is optionally substituted once or several times with fluorine, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl-alkyl (Cx-C6) ), aryl (C5-C12), aryl (C5-C12) alkyl (Cx- C6), H2N, R8ONR9, R8OR9, R8OC (0) R9, R8-aryl (C5-C12) -R9, R8R8NR9, HO-alkyl (Cx-C8) -N (R2) R9, R8N (R2) C (O) R9, R8C (0) N- (R2) R9, R8C (0) R9, R2R3N-C (= NR2), R2R3N-C (= NR2) -NR2, = 0, = S; wherein two substituents of R12 to R15 can together signify -OCH20-, -OCH2CH20-, -OC (CH3) 20-; And NR2, O, S; n 1 6 2; p, q independently among them, 0 or 1; and E is defined as in claim Ia; in all its stereoisomeric forms and mixtures thereof in any proportion, and their physiologically tolerable salts. 3a. Compound of formula I according to one or more of claims Ia and 2a, in which they mean: To one of the remains B a direct bond, alkanediyl (Cx-C6), arylene (C5-C6), cycloalkylene (C5-C6), -CC-, -NR2-, -NR2-C (0) -, -NR2-S (0) 2-, -O-, -CR2 = CR3-, each of which may be substituted once or twice with alkyl (Cx-C6); D a direct bond, alkanediyl (Cx-C6), arylene (C5-C6), -O-, -NR2 -NR2-C (0) -, -C (0) NR2-, -NR2-C (0) -NR2- -OC (O) -, -S (0) 2-NR2-, -NR2-S (0) 2-, -CR2 = CR3-, each of which may be substituted once or twice with alkyl (Cx-C6), where, when B is a direct bond, D can not be -C- (O) NR2-, -S (0) 2-NR2-; E a) means wherein R.sub.
  2. 2, R.sub.2a, R.sub.20a, R.sub.21a, R.sub.22a, and R.sub.2a mean, independently of each other, from one to three groups in the series consisting of hydrogen, halogen, cyano, carboxamido, carbamoyloxy, formyloxy, formyl, azido, nitro, ureido, thioureido, hydroxy, mercapto, sulfonamido or a residue, optionally substituted, of the series formed by alkyl (Cx-C12), alkenyl (C2-Cx2), alkynyl (C3-CX2), cycloalkyl (C3-C12), aryl (C5-C14), aryl (C6-C10) -alkyl (Cx-C8), alkyloxy (Cx-Cx2), aryloxy (C6-C14) and acyl (Cx-C12) amino, wherein the substituents mean a residue of the series consisting of halogen, cyano, azido, nitro, hydroxy, mercapto, sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy, formyl, (Cx-C4) alkoxy, phenyl, and phenoxy; > 20a hydrogen, halogen (fluorine, chlorine, bromine, iodine), alkoxy (Cx-C4), alkyl (Cx-C4), phenyl, benzyl or halogeno-alkyl (Cx-C4); R21a, R22a, independently of each other, means 1. hydrogen, 2. alkyl (CX-CX2), 3. aryl (C6-CX4), 4. cycloalkyl (C3-CX4), 5. alkyl (Cx-Cx2) -aryl (C6-C14), 6. (Cx-C12) alkyl-cycloalkyl (C3-CX4), wherein the residues defined in sections 2 to 6 may be substituted with one or more residues of the series consisting of halogen (fluorine, chlorine, bromine, iodine), nitro, hydroxyl, carboxyl, tetrazole, hydroxamate, sulfonamide, trifluorimide, phosphonate, alkyl (Cx-C6), aryl (C6-CX4), benzyl, cycloalkyl (C3-CX4), COR4a, CONR25R26; wherein R24a is a residue of the series consisting of (Cx-C8) alkoxy, (C3-C12) alkenoxy, aryloxy- (C6-CX2), di (Cx-C8) alkylamino-alkoxy (Cx-C8), acylamino-alkoxy (d-C8), acetylamidoethoxy, nicotinoylaminoethoxy, succinamidoethoxy, pivaloylethoxy; aryl (C6-CX2) - (Cx-C8) alkoxy, wherein the aryl group may optionally be substituted with one to three residues from the series consisting of nitro, halogen, (Cx-C4) alkoxy, amino, hydroxyl, hydroxy (C 2 -C 8) alkoxy, dihydroxy (C 3 -C 8) alkoxy; R25 and R26, independently of each other, denote hydrogen, (Cx-C10) alkyl, (C3-C10) alkenyl, (Cg-C14) aryl, (CX-C6) alkylaryl (C6-Cxo), or R25 and R 26 together form a trimethylene, tetramethylene, pentamethylene or 3-oxopene ethylene moiety; 7. means Q2-L3, wherein Q2 is hydrogen or Q1; and L3 means a chemical bond, L1 or L2; Q1 is a nitrogen-containing moiety, substituted or unsubstituted, positively charged, L1 is a divalent moiety containing from 3 to 9 methylene groups, in which from one to all methylene groups can be replaced with one or more alkene groups, alkyne groups, aryl groups or functional groups containing heteroatoms of the series consisting of N, O or S, and L2 is a divalent radical, optionally substituted; and R22b is: 1. hydrogen, 2. alkyl (d-dü), 3. aryl (C6-C14), 4. cycloalkyl (C3-CX4), 5. alkyl (CX-CX2) -aryl (C6-CX4) 6. alkyl (CX-CX2) -cycloalkyl (C3-C14), in which the radicals defined in sections 2 to 6 may be substituted with one or more radicals from the series consisting of halogen (fluorine, chlorine, bromine, iodine) ), nitro, hydroxyl, carboxyl, tetrazole, hydroxamate, sulfonamide, trifluorimide, phosphonate, alkyl (d- C6), aryl (C6-CX4), benzyl, cycloalkyl (C3-CX4), COR24a, CONR25R26; wherein R2 a is a residue of the series consisting of (Cx-C8) alkoxy, (C3-C12) alkenoxy, aryloxy- (C6-CX2), di (Cx-C8) alkylamino-alkoxy (Cx- 5 C8) ), acylamino-alkoxy (C x -C 8), acetylaminoethoxy, nicotinoylaminoethoxy, succinamidoethoxy, pivaloylethoxy; aryl (C6-CX2) - (Cx-C8) alkoxy, wherein the aryl group may optionally be substituted with one to three residues from the series consisting of nitro, halogen, (Cx-C4) alkoxy, amino, hydroxyl, hydroxy -alkoxy (C2-C8), dihydroxy-alkoxy (C3-C8); R25 and R26, independently of each other, sig-15, hydrogen, alkyl (Cx-C10), alkenyl (C3-C10), aryl (C5-C14), alkyl (CX-C6) -aryl (C6-C10), or R25 and R26 together form a trimethylene, tetramethylene, pentamethylene or 3-oxopen-tamethylene moiety; 7. means Q2-L3, wherein Q2 is hydrogen or Q1; and L3 means a chemical bond, L1 or L2; Q1 is a nitrogen-containing, substituted or unsubstituted, positively charged moiety, L1 is a divalent moiety containing from 3 to 9 methylene groups, in which from one to all methylene groups They can be replaced by one or more alkene radicals, alkyne radicals, aryl radicals or heteroatom-containing functional groups of the series consisting of N, O or S, and L2 is a divalent radical, optionally substituted; wherein R 1b and R 2b mean: R 1b, Rb independently from each other, from one to three groups of the series consisting of hydrogen, halogen, cyano, carboxamido, carbamoyloxy, formyloxy, formyl, azido, nitro, ureido, thioureido, hydroxy, mercapto, sulfonamido or a residue, optionally substituted, of the series consisting of alkyl (CX-CX2), alkenyl (C2-CX2), alkynyl (C3-C12), cycloalkyl (C3-C12), aryl (C6-C14), aryl ( C6-CX0) -alkyl (Cx-C8), alkyloxy (CX-CX2), aryloxy (C6-C14) and acyl (Cx-C12) amino, wherein the substituents constitute a residue of the series consisting of halogen, cyano, azido, nitro, hydroxy, mercapto, sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy, formyl, (Cx-C4) alkoxy, phenyl and phenoxy; Y R2.b and R26b independently from each other, meaning hydrogen, alkyl (Cx-C10), alkenyl (C3-C10), aryl (C6-C14), alkyl (Ci-Cg) -aryl (C6-C10), or R25b and R26b together form a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene moiety; c) means wherein (R2) P are attached to one or more carbon atoms of the 6-membered ring, and independently of each other they mean a residue of the series consisting of H, alkyl, alkyl substituted with halogen, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl, hydroxy, alkoxy, aralkoxy, carbamyl, amino, substituted amino, acyl, cyano, halogen, nitro and sulfo; R means alkyl (Cx-C4), P is an integer from 1 to 3, or d) means wherein R3 'is hydrogen, alkyl (Cx-C6), aryl-alkyl (Cx-C6), or e) means 1. wherein V- is CR7a or N, and Da means CH2, CH2-CH2, CH2C (R7a) 2CH2 or (CH2) n. (CH2) n wherein X is CR3a or N, wherein R3a means CN, C (0) N (R7a) R8a, wherein V means CR7a or N, and Da means CH2, CH2-CH2, CH2C (R7a) 2CH2 or (CH2) n. (CH2) n wherein X means CR3a or N, wherein R3a means CN, C (0) N (R7a) R8a, " wherein Y3 is O or H2, and R7a means hydrogen, (Cx-C4) alkyl optionally substituted with OH or (Cx-C4) alkoxy, (C2-C6) alkenyl optionally substituted with (Cx-C4) alkoxy, or OH- (CX-C4) alkyl aryl, aryl optionally substituted with the same or different moieties, of the series consisting of halogen, (Cx-C4) alkoxy, hydroxy or (Cx-C4) alkyl, R8a means hydrogen or alkyl (Cx-C4) ) n is an integer from 0 to 7, and n 'is an integer from 0 to 3; or f) means wherein the following meanings are given: X 'an oxygen, sulfur or nitrogen atom, or a group -NR2b-, wherein R2b is a hydrogen atom, a straight or branched chain alkyl group with 1 to 15 carbon atoms, a straight or branched chain alkenyl or alkynyl group with 3 to 10 carbon atoms in each case, in which the double or triple bond can not be immediately bound to the nitrogen atom, a cycloalkyl or cycloalkylalkyl group with 3 to 7 carbon atoms in the cycloalkyl part, an aryl group, an alkyl group with 2 to 6 carbon atoms which, starting from the β position with respect to the nitrogen atom of the group -NR2b-, is substituted with a group R3bO-, (R3b) 2N-, R4bCO-NR3b-, alkylsulfonyl-NR3b-, arylsulphonyl-NR3-, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl or R5b, or an alkyl group having 1 to 6 carbon atoms which is substituted with one or two aryl groups, R6bOCO-, (R3) 2NCO-, R5b-CO-, R3bO- CO-alkylene-NR3- CO-, (R3b) 2N-CO-alkylene-NR3-CO- or R5bCO-alkylene-NR3b-CO-, in which R3b and R5b are defined as above and R6b constitutes a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 5 to 7 carbon atoms or an aralkyl group, Y 'a NO group, a nitrogen atom or a methine group optionally substituted with an alkyl group, Zx, Z2, Z3 and Z4, which may be the same or different, mean methino groups, carbon atoms, imino groups or nitrogen atoms, wherein at least one of the radicals Zx to Z4 has to contain a carbon atom and one or two methino groups neighboring a nitrogen atom can each be substituted with carbonyl groups, Z5 and Z6, each of them, a carbon atom or, also, one of the residues Z5 or Z6 means a carbon atom. nitrogen and the other residue Z5 or Z6 means a carbon atom, R3b a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an aryl, aralkyl, carboxyalkyl or alkoxycarbonylalkyl group, R a hydrogen atom, an alkyl group or alkoxy with 1 to 6 carbon atoms in each case, an aryl or aralkyl group with 1 to 6 carbon atoms in the alkene part and R5b an azetidino, pyrrolidino, hexamethyleneimino or heptamethyleneimino group, or a piperidino group, in which the methylene group in position 4 can reee by an oxygen atom, a sulfenyl, sulfinyl or sulfonyl group, or by an imino group substituted with a group R3-, R4CO-, alkylsulfonyl or arylsulfonyl, wherein R3 and R4 are defined as mentioned above; F is a direct bond, alkanediyl (Cx-C6), -O-, -CO-NR2-, -NR2-CO-, -NR2-C (0) -NR2, -OC (0) -, -C (0 ) 0-, -CO-, -S (0) 2-, -S (0) 2-NR2-, -NR2-S (0) 2-, -CR2 = CR3-, -C ^ c-, each one of which it may be substituted once or twice with alkyl (Cx-C6); R2, R3 independently of each other, is H, (Cx-C6) alkyl which is optionally substituted one or more times with fluorine, cycloalkyl (C5-C6), cycloalkyl (C5-C6) -alkyl (Cx-C "), aryl (C5-Cx0), aryl (C5-C10) -alkyl (Cx-C4), R8OC (0) R9, R8R8NC (0) R9, R8C (0) R9; R5, R6, R7, independently of each other, H, fluorine, OH, alkyl (Cx-C6), cycloalkyl (C5-C14), cycloalkyl (C5-CX4) -alkyl (Cx-C6), or R8OR9, R8COaR9, R8OC (0) R9, R8-aryl (C5-C10) -R9, R8NHR9, R8R8NR9, R8NHC (0) OR9, R8S (0) nNHR9, R? OC (0) NHR9, R8C (0) NHR9, R8C (0) R9, R8NHC (O) NHR9, R8NHS (O) nNHR9, R8NHC (0) -R9, R? NHS (0) nR9, wherein at least one residue of the series consisting of R4, R5, R6 and R7 means a residue lipophilic; R8 H, (Cx-C6) alkyl, (C5-C14) cycloalkyl, (C5-Cx4) cycloalkyl (Cx-C4) alkyl, (C5-Cxo) aryl, (C5-CX0) aryl (CX-C4) alkyl ), wherein the alkyl moiety can be substituted with 1 to 6 fluorine atoms; R9 a direct bond or alkanediyl (Cx-C6); R? O C (0) Rn; Ru OH, (Cx-C6) alkoxy, aryl (C5-Cxo) -alkoxy (Cx-C6), aryloxy (C5-C10), alkyl (Cx-C6) carbonyloxy-alkoxy (Cx-C4), aryl (C5-) Cx0) - (Cx-C4) alkyl carbonyloxy-alkoxy (Cx-C4), NH2, mono- or di- (CX-C6 alkyl) amino; R 12 H, (Cx-Cg) alkyl which is optionally substituted once or several times with fluorine, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl (CX-C4) alkyl, (C5-C10) aryl, aryl (C5-C10) (Cx-C4) alkyl, NH2, R8OR9, R8OC (0) R9, R8-aryl (C5-C10) -R9, R8R8NR9, R8NHC (0) R9, R8C (0) NHR9, H2N-C (= NH) -, H2N-C (= NH) -NH-, = 0, wherein two neighboring substituents R12 together can also mean -OCH20-, -OCH2CH20-; And NR2, O, S; n 1 or 2; and p, q independently among them, 0 or 1; in all its stereoisomeric forms and mixtures thereof in any proportion, and their physiologically tolerable salts. 4a. Compounds of formula I according to one or several of claims Ia to 3a, in which the following meanings are given: To one of the remains B a direct bond, alkanediyl (Cx-C4), phenylene, pyridinyl, thiophenediyl, furanodiyl, cyclohexylene, cyclopentyl, -C ^ C-, -CR2 = CR3-, each of which may be substituted twice with alkyl (Cx-C4); D a direct bond, alkanediyl (Cx-C4) or phenylene, -O-, -NR2-, -NR2-C (0) -, -C (0) -NR2-, -NR2-S (0) 2-, NR2-C (0) -NR2-, -CR2 = CR3-, each of which can be substituted once or twice with alkyl (Cx-C4), where, when B is a direct bond, D can not be -C (0) NR2-; E a) wherein Rla, R 2 R 21a R 22a and R 22b mean here: R independently, from one to three groups in the series consisting of hydrogen and halogen (fluorine, chlorine, bromine, iodine); * R20a hydrogen; R21a, > 22a independently between them, they mean 1. hydrogen, 2. (Cx-C6) alkyl, 3. (C6-CX2) aryl, 4. (C6-Cx2) cycloalkyl, (C6-C6) alkylaryl (C6-) C12), 6. (Cx-C6) alkyl-cycloalkyl (C6-C12), in which the radicals defined in sections 2 to 6 can be substituted with one or more radicals from the series consisting of fluorine, chlorine, hydroxyl, hydroxamate , sulfonamide, alkyl (Cx-C6), aryl (C6-C12), benzyl, cycloalkyl (C6-C12); R22b signifies 1. hydrogen, 2. (d-C12) alkyl, 3. (C6-C14) aryl, 4. (C3-C14) cycloalkyl, (CX-C12) alkyl (C6-C14) alkyl, alkyl (Cx-C12) -cycloalkyl (C3-C14), in which the radicals defined in sections 2 to 6 can be substituted with one or more radicals from the series consisting of halogen (fluorine, chlorine, bromine, iodine), nitro, hydroxyl, carboxyl, tetrazole, hydroxamate, sulfonamide, trifluorimide, phosphonate, alkyl (Cx-C6), aryl (C6-C14), benzyl, cycloalkyl (C3-CX4), COR24a, CONR25R26; wherein R24a is a residue from the series consisting of (CX-C8) alkoxy, (C3-C12) alkenoxy, (C6-CX2) aryloxy, di (Cx-C8) alkylamino-alkoxy (Cx-) C8), acylamino-alkoxy (Cx-C8), acetylaminoethoxy, nicotinoylaminoethoxy, succinamidoethoxy or pivaloylethoxy; aryl (C6-CX2) -alkoxy (Cx-C8), wherein the aryl group may optionally be substituted with one to three residues from the series formed by nitro, halogen, (Cx-C4) alkoxy, amino, hydroxyl, hydroxy-alkoxy (C2-C?), dihydroxy-alkoxy (C3-C8); R25 and R25, independently of each other, mean hydrogen, alkyl (Cx-C10), alkenyl (C3-C10), aryl (C6-C14), alkyl (d-) C6) -aryl (C6-CX0), or R25 and R26 together form a trimethylene, tetramethylene, penta ethylene or 3-oxopen tamemethylene moiety; 7. means Q2-L3, wherein Q2 is hydrogen or Q1; and L3 means a chemical bond or L1; Q1 means an amino, amidino, aminoalkyleneimino, iminoalkyleneamino or guanidino group, preferably an amidino group; L1 means aryl (C6-CX4) -alkynylene (C2-C4), aryl (C6-C14) -alkylene (Cx- C3), aryl (C6-CX4) -alkyloxy- ene (Cx-C3) or -R14c-CO -NR6cR15c-, wherein R6c means hydrogen, (Cx-C4) alkoxy, (Cx-C4) alkyl or halogen-alkyl (Cx-C4); R14c means a chemical bond, alkylene (Cx-C8), cycloalkylene (C3-C7), alkenylene (C2-C5), alkynylene (C3-C5), arylene (C6-C10), alkyl (Cx-C3) a- rilene (C6-CX2), alkyl (Cx-C2) -aryl- (C6-CX0) -alkylene (Cx-C2), aryl (C6-Cxo) -alkylene (Cx-C2) or aryloxy (C6-20 Cx0) -alkylene (Cx-C2), and R15c means a chemical bond, alkylene (C-C4), alkenylene (C2-C4), alkynylene (C2-C4), arylene (C6-CXQ), or alkyl (Cx-C3) ) arylene (C6-C12); 25 or b) means wherein R 1b, R 2b, R 25b and R 26b mean here: R 1b, R 2b independently from each other, from one to three groups of the series consisting of hydrogen and halogen (fluorine, chlorine, bromine, iodine); and R "and R .26b independently of each other, mean hydrogen, (Cx-C10) alkyl, (C3-C10) alkenyl, (C6-Cx4) aryl, (CX-C6) alkyl (C6-CX0) alkyl, or R 25b and R 26 together form a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene moiety; d) and) where Y3, V and Da are defined as described above; or f) wherein the following meanings are given: X 'an oxygen, sulfur or nitrogen atom, or a group -NR2b-, wherein R2b is a hydrogen atom, a straight or branched chain alkyl group, with 1 to 15 carbon atoms, a straight or branched chain alkenyl or alkynyl group, with 3 to 10 carbon atoms in each case, in which the double or triple bond can not be bound immediately to the nitrogen atom, a group cycloalkyl or cycloalkyl-alkyl each with 3 to 7 carbon atoms in the cycloalkyl part, an aryl group, an alkyl group with 2 to 6 carbon atoms which, from the β-position with respect to the nitrogen atom of the group -NR2-, is substituted with a group R3bO-, (R3b) 2N-, R4bCO-NR3-, alkylsulfonyl- NR3b-, arylsulfonyl-NR3b-, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl or R5b, or an alkyl group with 1 to 6 carbon atoms which is substituted with one or two aryl groups, R6bOCO-, (R3b) 2NCO-, R5b- CO- , R3bO-CO-alkylene-NR3-CO-, (R3b) 2N-CO-alkylene- NR3b-CO- or R5CO-alkylene-NR3b-CO-, in which R3b and R5 are as defined below and R6b constitutes a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 5 to 7 carbon atoms or an aralkyl group, Y 'a NO group, a nitrogen atom or a methine group optionally substituted with an alkyl group, Zx, Z2, Z3 and Z4, which may be the same or different, mean methino groups , carbon atoms, imino groups or nitrogen atoms, where at least one of the remains Zx to Z4 has to contain a carbon atom, and one or two methine groups neighboring a nitrogen atom can be replaced in each case by carbonyl groups, Z5 and Z6, each of them, a carbon atom, or also one of carbon atoms. the radicals Z5 or Z6 means a nitrogen atom and the other of the radicals Z5 or Z6 means a carbon atom,) 3b a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an aryl group, aralkyl , carboxyalkyl or alkoxycarbonyl, R4 a hydrogen atom, an alkyl or alkoxy group with 1 to 6 carbon atoms in each case, an aryl or aralkyl group with 1 to 6 carbon atoms in the alkyl part and R5b an azetidino group, pyrrolidino , hexamethyleneimino or heptamethyleneimino, or a piperidino group, in which the methylene group in position 4 can be replaced by an oxygen atom, a sulfenyl, sulfinyl or sulfonyl group, or by an imino group substituted with a group R3b, R4CO- , alkylsulfonyl or arylsulfonyl, wherein R3b and R4b are defined as mentioned above; F is a direct bond, alkanediyl (Cx-C6), -O-, -CO-NR2-, -NR2-CO-, -NR2-C (O) -NR2, -S (O) 2-NR2-, -NR2-S (O) 2-, -CR2 = CR3-, -CSc-, each of which may be substituted once or twice with alkyl (Cx-C4); R5 R2, R3 independently of each other, H, (Cx-C4) alkyl, trifluoromethyl, pentafluoroethyl, (C5-C6) cycloalkyl, (C5-C6) cycloalkyl (Cx-C4) alkyl, phenyl, benzyl; R4 cycloalkyl (CX0-C14), cycloalkyl (Cx0-C14) -alkyl (Cx-C4), or R16OR9, R16NHR9, R16NHC (0) OR9, R16S (O) nNHR9, R16OC (O) NHR9, R16C (0) NHR9 , R16C (0) R9, R16NHC (0) R9, R16NHS (O) nR9; R5 H, (Cx-C6) alkyl, (C5-C6) cycloalkyl, (C5-C6) cycloalkyl (Cx-C4) alkyl, trifluoromethyl, pentafluoroethyl, phenyl, benzyl; R8 H, (Cx-C4) alkyl, (C5-C6) cycloalkyl, (C5-C6) cycloalkyl (Cx-C2) alkyl, phenyl, benzyl, trifluoromethyl, pentafluoroethyl; R9 a direct bond or alkanediyl (d-C4); R10 C (0) Ru; R11 OH, (Cx-C6) alkoxy, phenoxy, benzyloxy, (Cx-C4) alkyl carbonyloxy-(Cx-C4) alkoxy, NH2, mono- or di- (CX-C6 alkyl) amino; R12 H, (Cx-C4) alkyl, trifluoromethyl, pentafluoroethyl, (C5-C6) cycloalkyl, (C5-C6) cycloalkyl (Cx-C2) alkyl, (C5-C6) aryl, (C5-C6) aryl, alkyl ( Cx-C2), NH2, R8R8NR9, R8NHC (0) R9, H2N-C (= NH), H2N-C (= NH) -NH-; wherein two R12 neighboring substituents may further denote -OCH20-, -OCH2CH20-; R16 cycloalkyl (C10-C14), cycloalkyl (Cx0-C14) -alkyl (Cx-C4), which may optionally be substituted 1 or 2 times with alkyl (Cx-C4), trifluoromethyl, phenyl, benzyl, alkoxy (Cx-C4) ), phenoxy, benzyloxy, = 0 or mono- or di- (CX-C4) alkyl-amino, wherein the cycloalkylene moieties are preferably 1-adamantyl or 2-adamantyl, which, as described above, may be substituted; n 1 or 2; and q 0 6 1; in all its stereoisomeric forms and mixtures thereof in any proportion, and their physiologically tolerable salts. 5a. Compound of formula I according to one or more of claims Ia to 4a, in which the distance between R10 and the first atom of N in A, by the shortest path between these atoms, is 12 to 13 covalent bonds, in all their stereoisomeric forms and their mixtures in any proportion, and their physiologically tolerable salts. 6a. A process for preparing a compound of formula I according to one or more of claims Ia to 5a, characterized in that, by condensation of fragments, two or more fragments that can be derived from formula I are retrosynthesized. 7a. Compound of formula I according to one or more of claims Ia to 5a, and / or its physiologically tolerable salts, for use as a medicament. 8a. Compound of formula I according to one or several of claims Ia to 5a, and / or its physiologically tolerable salts, to be used as an inhibitor of bone absorption by osteoclasts, as an inhibitor of tumor growth or of tumor matastasis, as inhibitor of inflammation, for the treatment or prophylaxis of cardiovascular diseases, for the treatment or prophylaxis of nephropathies or retinopathies, or as an antagonist of the vitronectin receptor for the treatment or prophylaxis of diseases that are based on the action between vitronectin receptors and their ligands by cell-cell or cell-matrix interaction processes. 9a. Pharmaceutical preparations containing at least one compound of formula I according to one or more of claims Ia to 5a, and / or its physiologically tolerable salts, together with pharmaceutically acceptable vehicles and / or excipients.
MXPA/A/1997/010389A 1996-12-20 1997-12-18 Antagonists of the vitronectin receptor, its preparation and employment of mi MXPA97010389A (en)

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