EA003102B1 - Sulfonamide derivatives as inhibitors of bone resorption and inhibitors of cell adhesion, process for preparation thereof, use and pharmaceutical composition - Google Patents

Abstract

1. A compound of the formula I in which R<1> and R<2> together are a bivalent (C2-C3)-alkylene radical; R<4> is hydrogen or (C1-C6)-alkyl; R<5> is (C1-C10) alkyl, (C6-C14) aryl, (C5-C14)heteroaryl or (C6-C14)aryl (C1-C10) alkyl group, where the aryl radical, the heteroaryl radical, the alkyl radical are optionally substituted by R<3>, or 2-oxo-bicyclo [2.2.1]hepto-1-yl-methyl group; R<3> is (C1-C4)alkyl, (C1-C4)alkoxy, halogen, trifluoromethyl, cyano, oxo, NHCO-(C1-C4)alkyl or -C(O)NH-(C5-C14) heteroaryl radical or phenyl; R<6> is H; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs. 2. Compounds of the formula I as claimed in claim 1, in which R<5> is (C6-C14)aryl, (C5-C14)heteroaryl, where aryl or heteroaryl is optionally substituted by R<3>; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs. 3. Compounds of the formula I as claimed in claim 1, in which R<5>is a naphthyl in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs. 4. Compounds of the formula I as claimed in one or more of claims 1 to 3, which is a 2-(R<5>-sulfonylamino)-3-(4-(2-( 1,4,5, 6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)-benzoylamino) propionic acid wherein the 2-(R<5>-sulfonylamino) substituent is selected from the group consisting of benzenesulfonylamino, 4-(n-propyl)benzenesulfonylamino, 4-tert-butylbenzenesulfonylamino, 2,4,6trimethylbenzenesulfonylamino, 4-methoxybenzenesulfonylamino, 4-(n-butoxy)benzenesulfonylamino, 3-chlorobenzenesulfonylamino, 4-chlorobenzenesulfonylamino, 3-trifluoromethylbenzenesulfonylamino, 4-trifluoromethylbenzenesulfonylamino, 4-acetylaminobenzenesulfonylamino, 2-cyanobenzenesulfonylamino, naphthalene-1-sulfonylamino, naphthalene-2-sulfonylamino, biphenyl-4-sulfonylamino, thiophene-2-sulfonylamino, quinoline 8-sulfonylamino, methanesulfonylamino, propane-1-sulfonylamino, propane-2-sulfonylamino, butane-1-sulfonylamino, 2-methylpropane-1-sulfonylamino, chloromethanesulfonylamino, 2,2,2-trifluoroethanesulfonylamino, 7,7-dimethyl-2-oxo-bicyclo(2.2. 1 ]hept-1-ylmethanesulfonylamino and 2-phenylethenesulfonylamino in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts and its prodrugs. 5. A compound of the formula I as claimed in one or more of claims 1 to 4, which is (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2- ylcarbamoyl)-ethyl)benzoylamino)propionic acid and its physiologically tolerable salts and its prodrugs. 6. A compound of the formula I as claimed in one or more of claims 1 to 5, which is (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4, 5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)benzoylamino)propionic acid or a (C1-C4)-alkyl ester thereof, and its physiologically tolerable salts. 7. A compound of the formula I as claimed in one or more of claims 1 to 6, which is (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6- tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)benzoylamino)propionic acid ethyl ester, and its physiologically tolerable salts. 8. A process for the preparation of a compound of the formula I as claimed in claims 1 to 7, which comprises linking two or more fragments which can be derived retrosynthetically from the formula I, wherein a carboxylic acid or a carboxylic acid derivative of the formula II: in which R<4> and R5 are defined as indicated in claims 1 to 7, or alternatively functional groups are present in the form of precursors or in protected form, and X is a nucleophilically substitutable leaving group, is reacted with a guanidine or guanidine derivative of the formula Ill: in which R<1>, R<2> and R<6> are defined as indicated in claims 1 to 7, or alternatively functional groups are present in the form of precursors or in protected form. 9. A compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts and/or its prodrugs as an active ingredient for use as a pharmaceutical. 10. A pharmaceutical preparation, comprising at least one compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts and/or its prodrugs in addition to a pharmaceutically innocuous carrier. 11. A compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts and/or its prodrugs for use as a vitronectin receptor antagonist. 12. A compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts and/or its prodrugs for use as an inhibitor of bone resorption or for the therapy or prophylaxis of osteoporosis. 13. A compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts and/or its prodrugs for use as an inhibitor of tumor growth or tumor metastasis. 14. A compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts and/or its prodrugs for use as anti inflammatory or for the therapy or prophylaxis of cardiovascular disorders, restenosis, arteriosclerosis or retinopathies.

Description

The present invention relates to a sulfonamide derivative of the formula I

in which K ¹ , K ² , K ⁴ , K ⁵ and K ⁶ have the following meanings, their physiologically tolerated salts and their predecessors. The compounds of formula I are valuable pharmaceutically active compounds. They are vitronectin receptor antagonists and cell adhesion inhibitors, and also inhibit bone resorption by osteoclasts. In particular, they are suitable for the treatment and prevention of diseases, at least partially due to an undesirable degree of resorption of bone tissue, for example, osteoporosis. The invention also relates to methods for producing compounds of formula (I), their use, in particular as pharmaceutically active ingredients, and to pharmaceutical preparations containing them.

Human bones are subject to a process of constant dynamic renewal, including bone resorption and bone formation. These processes are regulated by specialized cell types. Bone resorption is based on the destruction of the bone matrix by osteoclasts. Most bone diseases are a consequence of the imbalance between the formation and resorption of bone tissue. Osteoporosis is a disease characterized by low bone mass and increased bone fragility, which increases the risk of fractures. The reason for this is the lack of formation of new bone tissue in relation to the resorption of bone tissue with a constantly ongoing reconstructive process. Common treatments for osteoporosis include, but are not limited to, the use of bisphosphonates, estrogens, estrogen / progesterone (hormone replacement therapy), estrogen agonists / antagonists (selective modulators of estrogen receptors), calcitonin, vitamin аналогов analogues, parathyroid hormone, and secretion enhancers or sodium fluoride (1atbsche e! a1., Appia1 Keroyk ίη Mebusha1 Sötyuu 1996, 31, 211).

Activated osteoclasts are multinucleated cells with a diameter of up to 400 μm, which remove the bone matrix. Activated osteoclasts, attached to the surface of the bone matrix, secrete proteolytic enzymes and acids into the so-called sealing zone - the area between the membranes of their cells and the bone matrix. Acidic environment and proteases cause bone destruction. The compounds of formula I prevent bone resorption by osteoclasts.

Studies have shown that the attachment of osteoclasts to bones is carried out using integrin receptors on the surface of osteoclast cells. Integrins are a superfamily of receptors that includes 1i (eg, ay, fibrinogen a _11b in ₃ on platelets and vitronectin receptor α _ν β _3. The latter is a membrane glycoprotein that is expressed on the surface of cells, such as endothelial cells, smooth muscle cells blood vessels, osteoclast cells and cancer cells Vitronectin receptor α _ν β ₃ expressed on the membrane of osteoclasts regulates the process of bone attachment and resorption of bone tissue, thus being one of the factors causing osteoporosis In this case, α _ν β ₃ forms a bond with bone matrix proteins such as osteopontin, bone sialoprotein and thrombospontin, which includes the tripeptide link ArgO1y-Akr (or (CFU).

Noyoi et al. Describe COEpeptides and an antibody to the vitronectin receptor (23 C6), which inhibits the destruction of dental osteoclasts and prevents the migration of osteoclasts (Noyoi e! A1., Exp. Ce11. Kek. 1991, 195, 368). B 1. Ce11 Bu1. 1990, 111, 1713, 8io e! a1. describe echistatin (EsYabi), a snake venom COE peptide that is a powerful inhibitor of bone resorption in tissue culture and an inhibitor of osteoclast attachment to bones. B1ksyet e! a1. (Eibostoshodu, 1993, 132, 1411) were able to show in rats that echistatin also inhibits bone resorption ίη νί \ Ό.

It was further shown that vitronectin α _ν β ₃ on the smooth muscle cells of the vessels of the human aortic vessels stimulates the migration of these cells into neointima, which ultimately leads to arteriosclerosis and recurrent stenosis after angioplasty (Wto and e! A1., Satbuyuaksiat Kek. 1994, 28, 1815).

Go to her a1. (Ce11, 1994, 79, 1157), it was also shown that antibodies to α _ν β ₃ or antagonists of α _ν β ₃ can cause cancer tumors to decrease as a result of inducing apoptosis of blood vessel cells during angiogenesis. The vitronectin receptor α _ν β ₃ is also related to the development of many other types of cancer and is expressed in increased amounts in the cells of malignant melanoma (Ед1етай е! А1., Aiia1 Keroyk and Mebssa1 S'NetMgu 1996, 31, 191). The invasiveness of melanoma was correlated with such overexpression (8task e! A1., Jesus loboris Saiseg, woite III, 1855, Asabetk Rgekk, 1997; H1Shk her a1., S11shsa1 8s1eise, 1996, 91, 639). Saggoi to her a1. (Saiseg Kek. 1998, 58, 1930) describe the inhibition of tumor growth and hypercalcemia associated with its malignancy using the α _ν β ₃ antagonist.

CH.sub.2H.sub.1 a1. (8c1eise, 1995, 270, 1500) describe antibodies to α _ν β ₃ or antagonists of α _ν β ₃ inhibiting the processes of LECE-induced angiogenesis in the rat eye. This effect could be used therapeutically in the treatment of retinopathies. The influence of the vitronectin receptor or the processes in which it is involved, thus provides the opportunity to act on various disease states, for the treatment and prevention of which there remains a need for suitable pharmaceutically active ingredients.

EDO-A-94/12181 describes substituted aromatic or non-aromatic ring systems, and EDO-A-94/08577 describes substituted heterocycles as fibrinogen receptors and platelet aggregation inhibitors. EP-A-528586 and EP-A-528587 disclose aminoalkyl and heterocyclyl substituted phenylalanine derivatives, and EDO-A-95/32710 disclose aryl derivatives having an inhibitory effect on bone resorption by osteoclasts. EDO-A-96/00574 describes benzodiazepines, and EDO-A-96/00730 describes antagonistic fibrinogen receptor patterns, in particular benzodiazepines associated with a nitrogen-containing five-membered ring, which are antagonists of the vitronectin receptor. EDO-A-98/00395 (EE-A-19654483) describes vitronectin receptor antagonists based on the tyrosine structure. EPA-820991 (German patent application 19629816.4) describes cycloalkyl derivatives, and European patent application 97122520.6 describes carbamic ester derivatives which are antagonists of the vitronectin receptor. Subsequent studies have shown that sulfonamide derivatives of formula I are particularly potent inhibitors of the vitronectin receptor and bone resorption by osteoclasts.

The present invention relates to compounds of formula I

wherein

K ¹ and K ² , independently of one another, are hydrogen or (C1- _C6 ) alkyl, unsubstituted or substituted by the radical K ³ , or

K ¹ and K ² together represent a saturated or unsaturated divalent (C ₂ C ₉ ) alkylene radical, for example, a group - (CH ₂ ) _p - in which p is 2, 3, 4, 5, 6, 7, 8 or

9, which may be unsubstituted or substituted with one or more groups selected from halogen, _(C1-C6) alkyl, _(C1-C6) alkoxy, (C1 _{C6 4)} aryl, (C ₆ -C 1 ₄₎ aryl, - _(C1-C6) alkyl-, (C ₅ C] ₄₎ heteroaryl, (C ₅ -C] ₄₎ heteroaryl _(C1-C6) alkyl-, (C ₃ -C 1 ₂₎ cycloalkyl, (C ₃ -C1 ₂₎ cycloalkyl- _(C1-C6) alkyl- and oxo, where 5-7chlennoe saturated or unsaturated ring which may be unsubstituted or substituted by radicals to ^3, in particular one or two radicals K ^3, and which is carbocyclic or heterocyclic ring containing one or two atoms nitrogen in the ring may be fused to the carbon-carbon bond of a (C ₂ -C ₉ ) alkylene radical;

K ³ is (C1-Ci) alkyl, (C ₃ -C ₂₀ ) monocycloalkyl, (C ₅ -C ₂₀ ) bicycloalkyl, (C ₅ -C ₂₀ ) tricycloalkyl, (C] -C ₈ ) alkoxy, (C ₆ - C1 ₄₎ aryl, (C ₆ -C 1 ₄₎ aryl- _(C1-C4) -alkyl-, (C ₅ -C] ₄₎ heteroaryl, (C5-C 1 -C ₄₎ heteroaryl- _(C1-C4) alkyl, halogen, trifluoromethyl, cyano, hydroxyl, oxo, nitro, amino, -1 \ 1H- _(C1-C4) alkyl, u _((C1-C4) alkyl) _2, -ΝΗSO- _(C1-C4) alkyl , -CO- (C] -C ₄ ) alkyl;

I ⁴ is hydrogen, (C1-C6) alkyl-COO- (C1-C4) alkyl or (C1-C6) alkyl, which may be unsubstituted or substituted by a radical from the group consisting of hydroxyl, (C] -C4) alkoxy , - (C1-C4) alkyl-8 (O) 2-, -ΝΕΕ and -Ν ⁺ Κ ⁷ Κ ⁷ 'Κ ⁷ ρ ·, where I ⁷ , I ⁷ ' and I ⁷ independently represent hydrogen, ( C1-C6) alkyl, (C ₅ C1 ₄ ) aryl or (C ₅ -C _{4 4} ) aryl (C1-Cb) alkyl, and ζ) 'is a physiologically tolerated anion, or R ⁴ is one of the following radicals:

he sn, sn, '' he

in which the bonds through which the radicals are attached are indicated by dashed lines;

I ⁵ denotes _(C1-C20) alkyl, (C ₃ -C ₂₀₎ monocycloalkyl, (C ₅ -C ₂₀₎ bicycloalkyl, (C ₅ C ₂₀₎ tricycloalkyl, _(C6 -C1 ₄₎ aryl, (C ₅ - C] ₄ ) heteroaryl, (C ₆ -C _{4 4} ) aryl- (C1-C ₆ ) alkyl- or (C ₅ Cl ₄ ) heteroaryl- (C1-Cb) alkyl-, where the radicals are aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl each may be unsubstituted or substituted by one, two or three radicals I ³ and where in the radicals alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl one or more carbon atoms, in particular one, two, three or four carbon atoms, can be replaced by the same or times ary atoms selected from the group consisting of nitrogen, oxygen and sulfur;

I ⁶ is hydrogen, _(C1-C6) alkyl-OCO-, hydroxy, _(C1-C6) -alkyl-O-CO-O- or nitro;

in all stereoisomeric forms and their mixtures in any proportions, as well as physiologically tolerated salts of these compounds and their precursors.

All radicals that occur several times in compounds of formula I, for example, B ³ radicals, each, independently of one another, have the above meanings and in each case can be the same or different. Radicals, which may independently have the indicated values, can be the same or different in each case.

Alkyl radicals can be simple or branched, saturated, monounsaturated or polyunsaturated. This also applies when they have substituents or are themselves substituents of other radicals, for example, alkoxy, alkoxycarbonyl or arylalkyl radicals. The same applies to alkylene radicals (i.e., divalent alkyl radicals or, equivalently, saturated or unsaturated alkanediyl radicals). Examples of suitable alkyl radicals containing from 1 to 20 carbon atoms are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl and eicosyl, n-isomers of all of these radicals, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, isodecyl, 3methylpentyl, 2,3,4-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl. Preferred alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl radicals. Examples of alkylene radicals are divalent radicals corresponding to the aforementioned monovalent radicals, for example, methylene, 1,1-ethylene (methylmethylene), 1,2-ethylene, 1,3propylene, 1,2-propylene (1-methylene and 2methylene), 2 , 3-butylene (1,2-dimethyl-1,2ethylene), 1,4-butylene and 1,6-hexylene.

Unsaturated alkyl radicals are, for example, alkenyl radicals such as vinyl, 1-propenyl, allyl, butenyl, 3methyl-2-butenyl or alkynyl radicals such as ethynyl, 1-propynyl or propargyl. Unsaturated alkylene radicals, i.e. alkenylene and alkynylene radicals (alkendiyl and alkindiyl radicals) can likewise be simple or branched. Examples of alkenylene radicals are vinylene or propenylene, and examples of alkynylene radicals are ethynylene or propynylene. Alkyl radicals may also be unsaturated when they are substituted. An example of an unsaturated alkyl moiety of an arylalkyl radical is styryl (2-phenylethenyl).

Unless otherwise specified, cycloalkyl radicals can be monocyclic, bicyclic or tricyclic, i.e., they can be monocycloalkyl, bicycloalkyl and tricycloalkyl radicals, provided that they have a suitable number of carbon atoms. Monocycloalkyl radicals are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotetradecyl or cyclooctadecyl, which may also be substituted, for example, (C ₁ -C ₄ ) Examples of substituted cycloalkyl radicals that should be mentioned are 4-methylcyclohexyl and 2,3dimethylcyclopentyl.

Bicycloalkyl radicals and tricycloalkyl radicals can be unsubstituted or optionally substituted at any suitable position, for example, one or more oxo groups and / or one or more identical or different (C1-C4) alkyl groups, for example, methyl or isopropyl groups, preferably methyl groups . The free bond through which a bicyclic or tricyclic radical is attached can be at any desired position in the molecule. Thus, a radical can be attached via a bridging atom or some atom in a bridge. The free bond can also be in any desired stereochemical position, for example, in the exo position or endo position. Examples of bicycloalkyl radicals and tricycloalkyl radicals are camphanyl, bornyl, adamantyl, such as 1-adamantyl and 2-adamantyl, caranyl, episisobornyl, epibornyl, norbornyl and norpinanil.

Halogen is, for example, fluorine, chlorine, bromine or iodine. (C ₅ -C _{4 4} ) Aryl includes heterocyclic (C ₅ -C _{4 4} ) aryl radicals ((C ₅ C 14) heteroaryl radicals) in which one or more carbon atoms of a 5-14 membered ring are replaced by heteroatoms such as nitrogen, oxygen or sulfur, and carbocyclic (C6C14) aryl radicals. Examples of carbocyclic (C6-C14) aryl radicals are phenyl, naphthyl, biphenylyl, antryl and fluorenyl, of which 1-naphthyl, 2-naphthyl and phenyl are preferred. Unless otherwise specified, aryl radicals, especially phenyl radicals, can be unsubstituted or substituted by one or more radicals, preferably one, two or three identical or different radicals. Aryl radicals, in particular, can be substituted by identical or different radical from the group consisting of _(C1-C8) -alkyl, in particular _(C1-C4) alkyl, _(C1-C8) -alkoxy, in particular (C1-C4) alkoxy, halogen such as fluorine, chlorine and bromine, nitro, amino, trifluoromethyl, hydroxyl, methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, _(C1-C4) alkoxycarbonyl, phenyl, phenoxy, benzyl or benzyloxy. Typically, no more than two nitro groups can be substituted in the compounds of formula I of the present invention.

The substituent in the monosubstituted phenyl radicals may be in positions 2, 3 or 4, of which positions 3 and 4 are preferred. If phenyl is bisubstituted, the substituents may be in the positions 2,3, 2,4, 2,5, 2,6, 3,4 or 3,5. It is preferred that the two substituents in the di-substituted phenyl radicals are in position 3.4 with respect to the phenyl moiety. Substituents in trisubstituted phenyl radicals may be in the 2,3,4, 2,3,5, 2,3,6, 2,4,5, 2,4,6 and 3,4,5 positions. Naphthyl and other aryl radicals can be likewise substituted at any desired position, for example, a 1-naphthyl radical at positions 2, 3, 4, 5, 6, 7 and 8, and a 2-naphthyl radical at positions 1, 3, 4, 5, 6, 7 and 8.

Along with the fact that (C ₅ -C ₁₄ ) aryl groups can be carbocyclic systems, they can also be monocyclic or polycyclic, for example, bi- or tricyclic, aromatic ring systems in which 1, 2, 3, 4 or 5 atoms carbon rings are replaced by heteroatoms, in particular the same or different heteroatoms from the group consisting of nitrogen, oxygen and sulfur. Examples of heterocyclic (C ₅ -C ₁₄ ) aryl groups and (C ₅ -C ₁₄ ) heteroaryl groups are pyridyl, in particular 2-pyridyl, 3pyridyl and 4-pyridyl, pyrrolyl, in particular 2pyrrolyl and 3-pyrrolyl, furyl, in particular 2 furyl and 3-furyl, thienyl, in particular 2-thienyl and 3-thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indolyl, indolazinyl, indazolyl, indazolyl, indazolyl quinoxalinyl, quinazolinyl, cinnolinyl, β-carbolinyl or fused benzo, cyclopenta, cyclohe or self-cyclopenta derivatives of these radicals. Heterocyclic systems can be substituted in all suitable positions with the same substituents as the carbocyclic aryl systems mentioned above.

Among these heteroaryl groups, monocyclic or bicyclic aromatic ring systems having 1, 2 or 3 heteroatoms, in particular 1 or 2 heteroatoms (Ν, O and 8), and which may be unsubstituted or substituted by 1, 2 or 3 substituents from a group comprising (C1-C6) alkyl, (C1-C6) alkoxy, fluoro, chloro, nitro, amino, trifluoromethyl, hydroxyl, (C1-C4) alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl. Particularly preferred in this case are monocyclic or bicyclic aromatic 5-10 membered ring systems having 1-3 heteroatoms, in particular 1-2 heteroatoms (Ν, O and 8), which can be substituted by 1-2 substituents from the group including ( C ₁ -C ₄ ) alkyl, (C1-C4) alkoxy, phenyl, phenoxy, benzyl and benzyloxy. Even more preferred are five- or six-membered monocyclic heteroaryl groups and nine- or ten-membered bicyclic heteroaryl groups containing 1 or 2, in particular 1, heteroatoms (Ν, O and 8), which are unsubstituted or substituted as described above.

If two radicals B ¹ and B ² together represent a divalent saturated or unsaturated (C2-C9) alkylene radical, these two radicals together with the two nitrogen atoms to which they are attached and the central carbon atom of the guanidine group to which these two atoms are attached nitrogen, form a monocyclic 1,3-diazaheterocycle, which is connected to the nitrogen atom in the group (SNL-CO-ΝΗ in position 2. Examples of radicals of such 1,3-diazheterocycles, which can be substituted as indicated for (C2-C9) alkylene radical as well as guanidine at the nitrogen atom, the radicals 2imidazolyl, 4,5-dihydro-2-imidazolyl, 1,4,5,6tetrahydro-2-pyrimidinyl or 4,5,6,7-tetrahydro-1H-1,3-diazepin-2- If a 5-7 membered ring is fused via a carbon-carbon bond in a (C2-C9) alkylene radical, the two radicals B ¹ and B ² together with the two nitrogen atoms to which they are attached and the central carbon atom of the guanidine group, to which these two nitrogen atoms are attached form a bicyclic heterocycle which is connected to the nitrogen atom in the group (CH ^ -CO-ΝΗ and which can be substituted as indicated above. The fused 5-7 membered ring may be saturated, monounsaturated, di-unsaturated or aromatic. Thus, for example, a cyclopentane ring, a cyclohexane ring, a cyclohexene ring, a cyclohexadiene ring, a cycloheptane ring or a benzene ring may be condensed. Examples of radicals of such bicyclic heterocycles that can be bonded to the nitrogen atom in the (CH2) ₂ CO-группе group are 1,3a, 4,5,6,6hexahydro-1,3-diazapentalen-2-yl, 1H-benzimidazole radicals -2-yl, 3a, 4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl, 4,5,6,7-tetrahydro-1H-benzimidazol-2-yl, 4,7-dihydro -1H-benzimidazol-2yl or 1H-imidazo [4,5-b] pyridin-2-yl. If the fused ring is substituted and / or if a (C ₂ -C ₉ ) alkylene radical is substituted, they are preferably independently substituted by one or two identical or different B ³ radicals. If the alkyl groups representing B ¹ and / or B ² are substituted, they are preferably substituted independently by one or two, preferably one, the same or different K ³ radicals.

The optically active carbon atoms contained in the compounds of the formula I can independently be K or 8. The compounds of the formula I can exist as pure enantiomers or pure diastereomers, or as mixtures of enantiomers, for example, as racemates or mixtures of enantiomers. The present invention relates to both pure enantiomers and mixtures of enantiomers, as well as pure diastereomers and mixtures of diastereomers. The invention encompasses mixtures of two or more stereoisomers of formula I at any ratios of stereoisomers in the mixtures. Compounds of formula I may exist as E or Ζ isomers. The invention also encompasses both pure Isomers and pure Ζ-isomers, and mixtures of E / Ζ in any proportions. The invention also relates to tautomeric forms of the compounds of formula I, for example, along with the form shown in formula I, as well as to the form in which the acylguanidine block is represented as a group -ΟΘ-Ν = Ο (ΝΗΚ ¹ ) -ΝΚ ² Κ ⁶ , and to all other forms that differ in different positions of mobile hydrogen atoms. Diastereomers, including the Ε / Ζ isomers, can be separated into individual isomers, for example, by chromatography. Racemates can be resolved into two enantiomers by conventional methods, for example, chromatography on chiral phases or by resolution. Stereochemically homogeneous compounds of formula I can also be obtained using stereochemically homogeneous starting materials or using stereoselective reactions.

Physiologically tolerated salts of the compounds of formula I are non-toxic, that is, physiologically acceptable, in particular pharmaceutically acceptable salts. Such salts of compounds of formula I containing acidic groups, for example carboxyl groups, are, for example, alkali and alkaline earth metal salts, such as, for example, sodium salts, potassium salts, magnesium salts and calcium salts, as well as salts with physiologically tolerated quaternary ammonium ions and salt adducts with ammonia and physiologically tolerated organic amines, such as, for example, triethylamine, ethanolamine or tris (2-hydroxyethyl) amine. The compounds of formula I containing basic groups form salt adducts with acids, for example, with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic and sulfonic acids, such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. Compounds of formula I containing one basic group and one acid group, for example, a guanidine group and a carboxyl group, can exist as zwitterions (betaines), which are also included in the present invention.

The physiologically tolerated O ^- anion contained in the compounds of formula I, in which the K ⁴ radical is an alkyl radical substituted with a positively charged ammonium group, is, in particular, a monovalent anion or one equivalent of a multivalent anion, non-toxic, physiologically suitable and, at the same time, a pharmaceutically acceptable inorganic or an organic acid, for example, an anion or an anionic equivalent of one of the above acids capable of forming acid-salt adducts. Thus, O ^- may be, for example, one of the anions (or anion equivalents) from the group consisting of chloride, sulfate, phosphate, acetate, citrate, benzoate, maleate, fumarate, tartrate, methanesulfonate and p-toluenesulfonate.

Salts of compounds of formula I can be prepared by conventional methods known to those skilled in the art, for example by reacting a compound of formula I with an inorganic or organic acid or base in a solvent or dispersant, or from other salts by cationic or anionic exchange. The present invention also includes all salts of compounds of formula I which, due to poor physiological tolerance, are not suitable for direct pharmaceutical use, but are useful, for example, as intermediates for other types of chemical modification of compounds of formula I or as starting materials for physiologically tolerated salts.

The present invention also includes all solvates of compounds of formula I, for example, hydrates or adducts with alcohols, as well as derivatives of compounds of formula I, for example, esters, precursors and other physiologically tolerated derivatives, as well as active metabolites of compounds of formula I. The invention also relates to precursors of compounds of formula I, which can be converted to compounds of formula I under physiological conditions. Suitable precursors of compounds of formula I, i.e. chemically modified derivatives of compounds of formula I having properties that can be improved by the desired method are known to those skilled in the art. More detailed information regarding medicinal precursors can be found, for example, in P1cY1cg c1 a1., Ayuapsey Aegid IeNuetu Keu1e ^ 8 19 (1996) 115-130; EMDP οί

Rgobgidk, N. Vipbdaagb, Εά., Е15СУ1СГ. 1985; Η. Vipbdaagb, Egidk oG! Ke Riige 16 (1991) 443; 8a1sheg e! A1., Vuogd. Mek. Sket. Le1E 4 (1994) 1985; 8aTab1 e! A1., Rkagtasei11sa1 Kek. 10 (1993) 1350, all of which are included in the invention as reference material. Particularly suitable precursors of compounds of the formula I are ester precursors of carboxylic acid groups, in particular with the COOH group, which is present when K ⁴ in the COOC ⁴ group is hydrogen, for example, alkyl esters from this group, such as (C1- C6) alkyl esters or (C1-C4) alkyl esters, as well as acyl precursors and acylated carbamate precursors with nitrogen-containing groups such as amino groups, and especially guanidine groups. In acyl or carbamate precursors, one or more, for example, two hydrogen atoms located at the nitrogen atom of the above nitrogen-containing groups, are replaced by an acyl or carbamate group. Acyl and carbamate groups suitable for acyl and carbamate precursors are, for example, K ¹⁰ —CO and K ^P O — CO groups in which K ¹⁰ is hydrogen, (C1-C18) alkyl, (C3-C14) cycloalkyl, (C3- C1 ₄₎ cycloalkyl- _(C1-C8) -alkyl-, _{(C5) 4)} aryl, wherein 1-5 carbon atoms may be replaced by heteroatoms such as Ν, O, or 8, or (C ₅ -C 1 ₄₎ aryl- _(C1-C8) alkyl, wherein 1-5 carbon atoms in the aryl part can be replaced by heteroatoms (Ν, O, or 8), and in which the ¹¹ K have the same meanings as K ^10, with the exception of hydrogen.

The radicals K ¹ and K ² in the compounds of formula I are preferably hydrogen or together form a saturated or unsaturated, in particular a saturated divalent (C2C5) alkylene radical, in particular a (C2-C4) alkylene radical, in particular a (C2-C3) alkylene radical, which is unsubstituted or substituted by one or two identical or different radicals from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C6-C! 4) aryl, (C6-C14) aryl- (C1 -C6) alkyl-, (C5-C14) heteroaryl, (C5-C14) heteroaryl (C1-C6) alkyl-, (C3-C12) cycloalkyl, (C3-C12) cycloalkyl- (C1-C6) al kyl and oxo groups, where a 5-7 membered saturated or unsaturated ring which may be unsubstituted or substituted by a K ³ radical, in particular one or two K ³ radicals, and which is a carbocyclic or heterocyclic ring containing one or two nitrogen atoms in ring may be fused to the carbon-carbon bond of the alkylene radical. The radicals K ¹ and K ² in the compounds of formula I most preferably represent hydrogen or a group - (CH2) _p , in which p is 2, 3, 4 or 5, preferably 2, 3 or 4, and especially preferably 2 or 3, and which is unsubstituted or substituted by one or two identical or different radicals from the group consisting of halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₆ -C ₁₄ ) aryl, (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₆ ) alkyl-, (C5-C14) heteroaryl, (C5-C14) heteroaryl (C ₁ -C ₆ ) alkyl-, (C ₃ -C ₁₂ ) cycloalkyl, (C ₃ -C ₁₂ ) cycloalkyl- (C1-C6) alkyl and oxo group, where 5-7 membered saturated or unsaturated the e ring, which may be unsubstituted or substituted by a K ³ radical, in particular one or two K ³ radicals, and which is a carbocyclic or heterocyclic ring containing one or two nitrogen atoms in the ring, can be fused to a carbon-carbon bond in the group - (CH ₂ ) p. Even more preferably, the radicals K ¹ and K ² together form a - (CH2) p group in which p is 2, 3, 4 or 5, preferably 2, 3 or 4, and particularly preferably 2 or 3, and which is preferably unsubstituted. It is especially preferred that the radicals K ¹ and K ² together form the divalent radical —CH ₂ —CH ₂ —CH ₂ -, i.e. when K ¹ and K ² together with the nitrogen atoms to which they are attached and the central carbon atom of the guanidine group to which these two nitrogen atoms are bonded form a 1,4,5,6-tetrahydro-2-pyrimidinyl radical.

K ^{3 is} preferably (C1-C10) alkyl, (C3-C20) monocycloalkyl, (C5-C20) bicycloalkyl, (C5-C20) tricycloalkyl, (C1-C8) alkoxy, (C6-C14) aryl, (C5-C14 ) heteroaryl, (C6-C14) aryl (C1-C4) alkyl-, (C5-C14) heteroaryl- (C1-C4) alkyl-, halogen, trifluoromethyl, cyano, oxo, -Ν ((Οι-Ο4) alkyl) 2 or -NΗ-CO- (C1-C4) alkyl. More preferably, when K ³ is (C 1 -C ₄ ) alkyl, (C ₃ -C ₁₀ ) monocycloalkyl, (C ₅ -C ₁₂ ) bicycloalkyl, (C ₅ -C ₁₂ ) tricycloalkyl, (C ₁ -C ₄ ) alkoxy , (C ₆ -C ₁₄ ) aryl, (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₄ ) alkyl, halogen, trifluoromethyl, cyano, oxo, ^ ((C1-C ₄ ) alkyl) 2 or - NΗ-CO- (C ₁ -C ₄ ) alkyl. Particularly preferred is K ³ , denoting (C ₁ -C ₄ ) alkyl, (C ₃ -C ₁₀ ) monocycloalkyl, (C5-C12) bicycloalkyl, (C5C12) tricycloalkyl, (C1-C4) alkoxy, (C6-C14) aryl, halogen, trifluoromethyl, cyano, oxo, A _(C1-C4) -alkyl) ₂ or -NH-CO- (C ₁ -C ₄₎ alkyl.

K ^{4 is} preferably hydrogen or unsubstituted or substituted (C1-C6) alkyl, particularly preferably hydrogen or (C1-C6) alkyl, which is unsubstituted or substituted by a radical from the group consisting of (C1-C4) alkoxy, (C1-C4) alkyl -8 (O) 2- and -ΝΡΉ ⁷ 'where R ⁷ and R ^7' independently of one another are hydrogen or _(C1-C4) alkyl. Most preferred is K ⁴ denoting hydrogen or unsubstituted or substituted (C 1-4) alkyl, more preferred is K ⁴ denoting hydrogen or (C ₁ -C ₄ ) alkyl, which is unsubstituted or substituted as described above.

⁵ preferably denotes (C1-C20) alkyl, (C3-C20) monocycloalkyl, (C5-C20) bicycloalkyl, (C5-C20) tricycloalkyl, (C6-C14) aryl, (C5-C14) heteroaryl, (C6-C14 ) aryl- (C1-C6) alkyl or (C5-C14) heteroaryl- (C1-C6) alkyl-, where each of the radicals is aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl is unsubstituted or substituted with one, two or three identical or various radicals In ³ . More preferably, B ⁵ is (C1-C ₁₀ ) alkyl, (C ₃ -C ₁₅ ) monocycloalkyl, (C ₅ -C ₁₅ ) bicycloalkyl, (C ₅ -C ₁₅ ) tricycloalkyl, (C ₆ -C ₁₄ ) aryl, ( C ₅ -C ₁₄ ) heteroaryl, (C ₆ -C ₁₄ ) aryl (C ₁ -C ₆ ) alkyl- or (C ₅ -C ₁₄ ) heteroaryl- (C ₁ -C ₆ ) alkyl-, where each of the radicals is aryl , heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl are unsubstituted or substituted with one, two or three identical or different B ³ radicals. Along with these preferences, the preferred group of B ⁵ radicals includes (C3-C20) monocycloalkyl, (C5-C20) bicycloalkyl and (C5C20) tricycloalkyl radicals, which may be substituted or otherwise modified as described above, and of which are more preferred ( C5-C15) monocycloalkyl, (C5-C15) bicycloalkyl and (C5-C15) tricycloalkyl. Another preferred group of B ⁵ radicals are (C 1 -C ₂₀ ) alkyl, (C ₆ -C ₁₄ ) aryl, (C ₅ C ₁₄ ) heteroaryl, (C ₆ -C ₁₄ ) aryl (C ₁ -C ₆ ) alkyl - or (C5-C14) heteroaryl- (C1-C6) alkyl-, of which more preferred are (C ₆ -C ₁₄₎ aryl and (C ₅ -C ₁₄₎ heteroaryl, which may be substituted or otherwise modified, as set forth higher. Particularly preferred B ⁵ radical groups are phenyl and naphthyl radicals, i.e. phenyl, 1-naphthyl and 2-naphthyl, which may be unsubstituted or substituted as described above.

B ^{6 is} preferably hydrogen or (C ₁ -C ₆ ) alkyl-O-CO-, more preferably hydrogen or (C ₁ -C ₄ ) alkyl-O-CO-, in particular hydrogen.

Preferred compounds of formula I are compounds in which one or more radicals have preferred meanings or have one or another feature in the corresponding symbols, all combinations of such preferred values or features in the symbols are the subject of the present invention. Particularly preferred compounds of formula I are those compounds in which B ¹ and B ² are hydrogen or together form a saturated or unsaturated divalent (C2-C5) alkylene radical, in particular hydrogen or a group - (CH ₂ ) _P -, in which p is 2, 3, 4 or 5, where (C ₂ -C ₅ ) alkylene radical and the group - (CH ₂ ) _P - are unsubstituted or substituted by a radical from the group comprising halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₆ -C ₁₄ ) aryl, (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₆ ) alkyl-, (C ₅ -C ₁₄ ) hetero aryl, (C ₅ -C ₁₄ ) heteroaryl- (C ₁ -C ₆ ) alkyl-, (C ₃ -C ₁₂ ) cycloalkyl, A (C ₃ -C ₁₂ ) cycloalkyl- (C ₁ -C ₆ ) alkyl and oxo group, and wherein a 5-7 membered saturated or unsaturated ring which may be unsubstituted or substituted by a radical B ³ , in particular one or two radicals B ³ , and which is a carbocyclic or heterocyclic ring containing one or two nitrogen atoms in the ring, can be fused via a carbon-carbon bond in the (C2-C5) alkylene radical and in the - (CH2) p- group;

B ³ represents (C1-C10) alkyl, (S3S20) monocycloalkyl, (C5-C20) bicycloalkyl, (C5C ₂₀₎ tricycloalkyl, (C ₁ -C ₈₎ alkoxy, (C ₆ -C ₁₄₎ aryl, (C5- C14) heteroaryl, (C6-C14) aryl- (C1-C4) alkyl-, (C5-C14) heteroaryl- (C1-C4) alkyl-, halogen, trifluoromethyl, cyano, oxo, —Y ((C ₁ -C ₄ ) alkyl) ₂ or -IN-CO- (C ₁ -C ₄ ) alkyl;

B ⁴ represents hydrogen or (C1C6) alkyl, which is unsubstituted or substituted by a radical from the group consisting of (C1-C4) alkoxy, (C1-C4) alkyl-8 (O) 2- and -PV ⁷ B ⁷ ′, wherein B ⁷ and B ⁷ ', independently of one another are hydrogen or _(C1-C4) alkyl;

⁵ represents (C ₁ -C ₂₀ ) alkyl, (C ₃ C20) monocycloalkyl, (C5-C20) bicycloalkyl, (C5C ₂₀ ) tricycloalkyl, (C ₆ -C ₁₄ ) aryl, (C ₅ -C ₁₄ ) heteroaryl , (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₆ ) alkyl- or (C ₅ -C ₁₄ ) heteroaryl- (C1-C6) alkyl-, where each of the radicals is aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl is unsubstituted or substituted with one, two or three B ³ radicals;

B ⁶ represents hydrogen or (C1C6) alkyl-O — CO—;

in all stereoisomeric forms and their mixtures in any proportions, as well as physiologically tolerated salts of these compounds and their precursors.

Particularly preferred compounds of formula I are those in which

B ¹ and B ² are hydrogen or together form a saturated or unsaturated divalent (C ₂ -C ₄ ) alkylene radical, in particular hydrogen or a group - (CH2) P-, in which p is 2, 3 or 4, where (C ₂ -C ₄ ) alkylene radical and the group - (CH2) P- are unsubstituted or substituted by a radical from the group consisting of halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₆ -C ₁₄ ) aryl, (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₆ ) alkyl-, (C5-C14) heteroaryl, (C5-C14) heteroaryl (C1-C6) alkyl-, (C3-C12) cycloalkyl, ( C3-C12) cycloalkyl- (C1-C6) alkyl and oxo groups, and wherein the 57 membered saturated or unsaturated ring is the swarm is unsubstituted or substituted by a B ³ radical, in particular one or two B ³ radicals, and which is a carbocyclic or heterocyclic ring containing one or two nitrogen atoms in the ring, can be fused to a carbon-carbon bond in (C ₂ -C ₄ ) alkylene radical and in the group - (CH ₂ ) _p -;

I ³ represents (C ₁ -C ₄ ) alkyl, (C ₃ Ciu) monocycloalkyl, (C ₅ -C ₁₂ ) bicycloalkyl, (C ₅ C] ₂ ) tricycloalkyl, (C] -C ₄ ) alkoxy, (C ₆ -C ₁₄₎ aryl, (C ₆ -C 1 ₄₎ aryl- _(C1-C4) -alkyl-, halogen, trifluoromethyl, cyano, oxo, N ((C ₁ -C ₄₎ alkyl) ₂ or NH-CO- ( C ₁ -C ₄ ) alkyl;

I ⁴ represents hydrogen or (C ₁ C6) alkyl;

I ⁵ represents (C ₁ -C ₁₀ ) alkyl, (C ₃ C15) monocycloalkyl, (C5-C15) bicycloalkyl, (C5C ₁₅ ) tricycloalkyl, (C ₆ -C ₁₄ ) aryl, (C ₅ -C ₁₄ ) heteroaryl , (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₆ ) alkyl- or (C ₅ -C ₁₄ ) heteroaryl- (C ₁ -C ₆ ) alkyl-, where each of the radicals is aryl, heteroaryl, alkyl, monocycloalkyl , bicycloalkyl and tricycloalkyl are unsubstituted or substituted by one, two or three radicals I ³ ;

I ⁶ represents hydrogen or (C1C ₄ ) alkyl-O-CO-;

in all stereoisomeric forms and their mixtures in any proportions, as well as physiologically tolerated salts of these compounds and their precursors.

The most preferred compounds of formula I are compounds in which

Z ¹ and Z ² are hydrogen or together form a saturated or unsaturated divalent (C ₂ -C ₃ ) alkylene radical, in particular hydrogen or a group - (CH2) p-, in which p is 2 or 3, where (C ₂ -C ₃ ) the alkylene radical and the group - (CH2) p- are unsubstituted or substituted by a radical from the group consisting of halogen, (C ₁ -C ₆ ) alkyl, (C ₁ C6) alkoxy, (C6-C14) aryl, (C6-C14 ) aryl- (C1-C6) alkyl-, (C5-C14) heteroaryl, (C5-C14) heteroaryl (C1-C6) alkyl-, (C3-C12) cycloalkyl, (C3-C12) cycloalkyl- (C1-C6 ) an alkyl and oxo group, and wherein the 57 membered saturated or unsaturated ring which is unsubstituted or substituted by an H ³ radical, in particular one or two H ³ radicals, which is a carbocyclic or heterocyclic ring containing one or two nitrogen atoms in the ring, can be fused to a carbon-carbon bond in the (C2-C3) alkylene radical and in the group - (CH2) p-;

I ³ represents (C1-C4) alkyl, (C3C10) monocycloalkyl, (C5-C12) bicycloalkyl, (C5C ₁₂ ) tricycloalkyl, (C ₁ -C ₄ ) alkoxy, (C ₆ -C ₁₄ ) aryl, halogen, trifluoromethyl , cyano, oxo, —Y ((C ₁ -C ₄ ) alkyl) ₂ or —CH — CO— (C ₁ -C ₄ ) alkyl;

I ⁴ represents hydrogen or (C1C6) alkyl;

I ⁵ represents (C ₁ -C ₁₀ ) alkyl, (C ₃ C15) monocycloalkyl, (C5-C15) bicycloalkyl, (C5C ₁₅ ) tricycloalkyl, (C ₆ -C ₁₄ ) aryl, (C ₅ -C ₁₄ ) heteroaryl , (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₆ ) alkyl- or (C ₅ -C ₁₄ ) heteroaryl- (C1-C6) alkyl-, where each of the radicals is aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl is unsubstituted or substituted by one, two or three radicals I ³ ;

I ⁶ represents hydrogen or (C1C4) alkyl-O-CO-;

in all stereoisomeric forms and their mixtures in any proportions, as well as physiologically tolerated salts of these compounds and their precursors.

Along with this, preferred compounds of formula I are compounds in which I ⁵ is (C ₆ -C ₁₄ ) aryl or (C ₅ -C ₁₄ ) heteroaryl, preferably (C6-C14) aryl, where aryl and heteroaryl radicals are unsubstituted or substituted with one, two or three identical or different radicals and I ³ are preferably unsubstituted or substituted by one or two identical or different radicals of ³ I, in all their stereoisomeric forms and mixtures thereof in any proportions, as well as physiologically tolerated salts of these compounds and redshestvenniki. Even more preferred are compounds of formula I in which R ⁵ is a naphthyl radical, such as 1-naphthyl and 2-naphthyl radicals, which is unsubstituted or substituted by one, two or three R ³ radicals and which is preferably unsubstituted, such as unsubstituted radicals 1 naphthyl and 2-naphthyl, in all stereoisomeric forms and their mixtures in any proportions, as well as physiologically tolerated salts of these compounds and their precursors.

Preferred compounds of formula I are also compounds in which the carbon atom to which the two groups H ⁴ O — CO— and Ρ ³ -8Ο are bonded _; -ΝΗ-. has an 8-configuration, in all stereoisomeric forms and their mixtures in any proportions, as well as physiologically tolerated salts of these compounds and their precursors.

A separate group of compounds of formula I are compounds in which I ¹ and I ² , independently of one another, are hydrogen or (C ₁ -C ₆ ) alkyl, which is unsubstituted or substituted by a radical I ³ , or in which the radicals I ¹ and I ² together form a saturated or unsaturated divalent (C ₂ -C ₉ ) alkylene radical, for example, a group - (CH ₂ ) _p - in which p is 2, 3, 4, 5, 6, 7, 8 or 9 and which is unsubstituted or substituted by one or more groups from the group consisting of halogen, (C ₁ -C ₆ ) alkyl, (C ₁ C ₆ ) alkoxy, (C ₆ -C ₁₄ ) aryl, (C ₆ -C ₁₄ ) aryl- (C _1- C ₆ ) al keel, (C ₅ -C ₁₄ ) heteroaryl, (C ₅ -C ₁₄ ) heteroaryl (C1-C6) alkyl, (C3-C12) cycloalkyl, (C3-C12) cycloalkyl- (C1-C6) alkyl and oxo, and where the 57-membered saturated or unsaturated ring, which is unsubstituted or substituted by an R ³ radical, in particular one or two R ³ radicals, and which is a carbocyclic or heterocyclic ring containing one or two nitrogen atoms in the ring, can be fused to carbon-carbon bond (C ₂ -C ₉ ) alkylene radical;

B ³ represents a _(C1-C8) alkyl, (C _g C ₈₎ alkoxy, (C ₅ -C ₁₄₎ aryl, (C ₅ -C ₁₄₎ aryl (C ₁ -C ₄₎ alkyl, (C ₅ -C ₁₄ ) heteroaryl, (C ₅ -C ₁₄ ) heteroaryl (C ₁ -C ₄ ) alkyl, halogen, trifluoromethyl, hydroxyl, oxo, nitro, amino, PI- (C ₁ -C ₄ ) alkyl, K ((C ₁ -C ₄ ) alkyl) ₂ , PI-CO- (C ₁ -C ₄ ) alkyl or CO (C ₁ -C ₄ ) alkyl;

IN⁴ represents hydrogen, (C1-C6) alkyl-CO-O- (C1-C4) alkyl or (C1-C6) alkyl, which is unsubstituted or substituted by a radical from the group consisting of hydroxyl, (C1-C4) alkoxy, (C1 -C4) alkyl-8 (O) 2-, -ΝΒ⁷Β⁷'and Ν⁺Β⁷Β⁷'Β⁷'^^-, where in⁷, IN⁷'and B⁷ independently of one another, hydrogen, (C1-C₆) alkyl, (C₅-FROM₁₄) aryl or (C₅-FROM₁₄) aryl- (C_one-FROM₆) alkyl, and C) denotes a physiologically tolerated anion, or Β⁴ represents one of the radicals

in which free bonds through which radicals are attached are indicated by dashed lines;

B ⁵ is (C ₁ -C ₂₀ ) alkyl, (C ₅ C ₂₀ ) monocycloalkyl, (C ₅ -C ₂₀ ) bicycloalkyl, (C ₅ C ₂₀ ) tricycloalkyl, (C ₆ -C ₁₄ ) aryl, (C ₅ -C ₁₄ ) heteroaryl, (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₆ ) alkyl or (C ₅ -C ₁₄ ) heteroaryl- (C ₁ -C ₆ ) alkyl, where each of the radicals is aryl, heteroaryl , alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl is unsubstituted or substituted by one, two or three B ³ radicals and where in the radicals alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl one or more carbon atoms, in particular one, two, three or four carbon atoms, one can be replaced aco or various atoms selected from the group consisting of nitrogen, oxygen and sulfur;

B ⁶ is hydrogen, (C ₁ -C ₆ ) alkyl-OCO; hydroxyl, (C ₁ -C ₆ ) alkyl-O-CO-O- or nitro;

in all stereoisomeric forms and their mixtures in any proportions, as well as physiologically tolerated salts of these compounds and their precursors.

The present invention also relates to methods for producing compounds of formula I. Compounds can generally be obtained, for example, using convergent synthesis by combining two or more fragments that can be isolated from formula I by the reverse synthesis method. In the preparation of compounds of formula I, it is usually appropriate or necessary to introduce functional groups in the synthesis process that could lead to undesirable or adverse reactions at the corresponding stage of synthesis, in the form of their precursors, which later turn into the desired functional groups, or temporarily block functional groups using the technology of protective groups suitable for the synthesis task. This kind of technique is well known to specialists (see, for example, Ogeepe apy AiK Rgo! Es11te Ogirs ίη Ogdashs 8upShey8, AIUu, 1991). As an example of precursor groups, mention may be made of nitro and cyano groups, which later can be converted, for example, by catalytic hydrogenation, into amino and aminomethyl groups, respectively.

Compounds of formula I can be prepared, for example, by linking carboxylic acids or carboxylic acid derivatives of formula II by known methods.

in which B ⁴ and B ^{5 are} defined as in formula I or in which functional groups are present in the form of their precursors, which later are converted to groups present in the compounds of formula I, or the functional groups are present in protected form and where X is capable of nucleophilic the substitution of the leaving group, with guanidines or guanidine derivatives of the formula III

Ν - K ¹

Η, Ν—

Ν — 1 “k 'in which B ¹ , B ² and B ^{6 are} defined as indicated for formula I or in which functional groups are present in the form of their precursors, which later turn into groups present in the compounds of formula I, or functional groups are present in protected form.

The COX group in formula II is preferably a COOH carboxylic acid group or an active carboxylic acid derivative group. X represents, for example, hydroxyl or halogen, in particular chlorine or bromine, an alkoxy group, preferably methoxy or ethoxy, an aryloxy group, for example, phenoxy or pentafluorophenoxy, phenylthio, methylthio, 2-pyridylthio or a nitrogen-containing heterocycle radical attached via a nitrogen atom, in particular, azole, such as, for example, 1-imidazolyl. In addition, X may be, for example, ((C ₁ -C ₄ ) alkyl) -O-CO-O- or tolylsulfonyloxy, and the active acid derivative may thus be a mixed anhydride.

If X is hydroxyl, i.e. if the guanidine of formula III interacts with a carboxylic acid, it is advisable to activate the carboxylic acid first. Activation can be carried out, for example, using dicyclohexylcarbodiimide (ESS1) or O [(cyano (ethoxycarbonyl) methylene) amino] 1,1,3,3-tetramethyluronium tetrafluoroborate (TOTi, Kbshd s1 a1., Prg. 21 k! Egor. Rerybe 8th of 1990 (Ebk. Spay Apbtei), Exot, Le1bep 1991, p. 143) or other activating reagents commonly used in peptide chemistry.

Along with the free guanidines of formula III, guanidinium salts can also be used to react with the compounds of formula II, which are then converted to the free guanidines ίη qui or in a separate step using bases. The reaction of the active carboxylic acid derivatives of formula II with the guanidine (derivative) of formula III is preferably carried out in a known manner in a protic or aprotic polar but inert organic solvent. In this case, solvents such as methanol, isopropyl alcohol, tert-butanol, dimethylformamide and tetrahydrofuran, were found to be suitable at temperatures from 0 ° C to the boiling points of these solvents, in particular for the reaction of methyl esters (X = methoxy) and ethyl esters esters (X = ethoxy) with guanidines. Reactions of compounds of the COX type with salt-free guanidines are expediently carried out in aprotic inert solvents such as dimethylformamide, tetrahydrofuran, dimethoxyethane or dioxane, if suitable with the addition of alkali, such as, for example, potassium tert-butoxide or sodium methoxide. However, water can also be used as a solvent in the reaction of compounds of formula II with guanidines, for example, using a base such as sodium hydroxide. If, for example, X is chlorine, it is advisable to carry out the reaction with the addition of an acid neutralizer, for example, with an additional base or with an excess of guanidine (derivative), in order to bind the resulting hydrohalic acid. The reaction mixture is treated and the reaction product is optionally purified using known methods.

Protective groups that may still remain in products derived from compounds of formulas II and III are removed by standard methods. For example, ester tert-butyl groups are converted to carboxyl groups by trifluoroacetic acid treatment, benzyl groups are removed by hydrogenation, and fluorophenylmethoxycarbonyl groups are removed using secondary amines. If desired, further reactions are carried out using standard methods, for example, an acylation or esterification reaction. Finally, using known methods can be carried out the conversion of these compounds into physiologically tolerated salts or drug precursors.

The starting components of formulas II and III, which are combined to form compounds of formula I, can be acquired or can be obtained analogously to the methods described in the literature. The preparation of the starting components of formula II is illustrated by the example in Scheme 1 below, the invention being not limited to this synthesis alone or to the starting components. It is not a problem for a person skilled in the art to make the changes shown in the synthesis required to obtain other compounds of the invention.

Thus, for example, a carboxybenzaldehyde of the formula IV can be reacted in the presence of pyridine or piperidine with a malonic acid ester salt of the formula V to form a cinnamic acid derivative of the formula VI, which, after hydrogenation, for example, in the presence of palladium on carbon, gives the compound of the formula VII . After activating the carboxylic acid group, a compound of formula VII can be condensed with a 2,3-diaminopropionic acid derivative of formula VIII to form a compound of formula IX (Scheme 1). Condensation can, for example, be carried out in the presence of LTTE or another agent commonly used to activate carboxylic acids.

Scheme 1

Υ in formula VIII may be a group B ⁵ 8 O ₂ -, which is present in the final compounds of formula I of the present invention and which may remain in the molecule, or Υ may be a group that temporarily protects the amino group at position 2 and which in one of the following the steps are removed to free the amino group, which is then converted to the Β ⁵ -8Θ2-группу group using standard sulfonamide production techniques, for example, by reacting a free amine with a sulfonyl chloride of formula B ⁵ -8O2-C1. An example of a protecting group denoted by является is a benzyloxycarbonyl group (Ζ group) which can be removed by catalytic hydrogenation. Sulfonyl chlorides of the formula B ⁵ -8O2-C1 and other sulfonic acid derivatives suitable for introducing the B ⁵ -8O2- group can be obtained or can be obtained in accordance with or by analogy with the procedures described in the literature. Instead of the tert-butyl ester moiety present in formulas VIII and IX, other ester moieties may be present which either temporarily protect the acid group or may be present in the final compounds of formula 1 of the invention and may remain in the molecule. Compounds similar to the compound of formula VI can also be prepared using other methods for converting a carbonyl group to an alkene, for example, using the Wittig reaction.

Compounds of formula IX are examples of compounds of formula II in which X is a methoxy group. These and similar compounds, which are obtained using the synthesis described above and which contain a group related to the active derivatives of a carboxylic acid, can be directly reacted with compounds of the formula III. However, the compounds obtained in this synthesis can be first converted under standard conditions of cleavage of the ester methyl or other ester group, which is in a suitable position in the compounds of formula IX, with the formation of the corresponding carboxylic acids, which are then reacted with guanidines of the formula III, being pre-activated ίη hay, for example, using LTTE or ESA !, or converted into an active derivative of a carboxylic acid. If, as active derivatives of a carboxylic acid, it is expected to produce, for example, acid chlorides (formula II, X = C1), such a conversion can be carried out using, for example, thionyl chloride. If it is intended to obtain methyl esters from carboxylic acids, for example (formula II, X = methoxy), this reaction can be carried out by treatment with gaseous hydrogen chloride in methanol. Other active derivatives of carboxylic acids can be obtained by known methods from carboxylic acid chlorides or directly from the carboxylic acids themselves (formula

II, X = OH). An example is imidazolides (formula II, X = 1-imidazolyl), which are obtained by treating the acids with carbonyldiimidazole (81aaB, A1che \\\ Siet. Sh1. Her. Epd1. 1, 351367 (1962)), or mixed anhydrides, which are obtained, for example by reaction with chloroformic acid esters, such as ethyl chloroformate, or with tosyl chloride in the presence of amines, such as triethylamine, in an inert solvent. A number of suitable methods for the preparation of activated carboxylic acid derivatives with detailed references are given in I. Magsy, Ayupeey Ogdashs SjetSchgu, Tyyyy Eyyup, 1oyp \ UPeu & 8opz, 1985, p. 350.

The compounds of formula I are valuable pharmaceutically active ingredients that are suitable, for example, for the treatment and prophylaxis of bone disorders, tumor diseases and cardiovascular disorders. The compounds of formula I and their physiologically tolerated salts and precursors can be administered to animals, preferably mammals, and especially humans as pharmaceuticals for therapy and prevention. They can be administered individually or in mixtures with each other, or in the form of pharmaceutical preparations that can be administered orally or parenterally and which contain as an active ingredient an effective dose of at least one compound of formula I and / or their physiologically tolerated salts and / or their precursors in admixture with conventional pharmaceutically harmless carriers and / or additives.

The present invention thus also relates to compounds of formula I and / or their physiologically tolerated salts and / or their precursors for use as pharmaceuticals, to the use of compounds of formula I and / or their physiologically tolerated salts, and / or their precursors for the manufacture of pharmaceuticals for the treatment and prophylaxis of the diseases mentioned above and further, for example, for the treatment and prophylaxis of bone disorders, as well as the use of compounds of formula I, and / or their physiological tolerable salts, and / or their precursors for the treatment and prevention of these diseases. The present invention further relates to pharmaceutical preparations or pharmaceutical compositions which contain an effective dose of at least one compound of formula I and / or their physiologically tolerated salts and / or their precursors in admixture with a conventional pharmaceutically harmless carrier.

Pharmaceutical agents can be administered orally, for example, in the form of pills, tablets, glazed tablets, coated tablets, granules, hard and soft gelatine capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. However, the introduction can also be carried out rectally, for example, in the form of suppositories, or parenterally, for example, intravenously, intramuscularly or subcutaneously in the form of solutions for injection or infusion solutions, microcapsules, implants or rods, or transdermally, or topically, for example, in the form of ointments , solutions or tinctures, or by other methods, for example, in the form of aerosols or nasal sprays.

The pharmaceutical preparations of the present invention are prepared using methods known to those skilled in the art using inert inorganic or organic carriers in combination with a compound or compounds of the formula I and / or its physiologically tolerable salts and / or its (their) precursors. For the manufacture of pills, tablets, coated tablets and hard gelatine capsules, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like can be used. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or solidified oils, and the like. Suitable carriers in the manufacture of solutions, for example injection solutions, emulsions or syrups, are, for example, water, alcohols, glycerin, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitable carriers for microcapsules, implants or sticks are for example, copolymers of glycolic and lactic acids. Pharmaceutical preparations typically contain from about 0.5 to about 90% by weight of compounds of formula I and / or their physiologically tolerated salts and / or their precursors. The amount of the active ingredient of formula I and / or its physiologically tolerated salts and / or its precursors in a pharmaceutical preparation is usually from 0.2 to 500 mg, preferably from 1 to 200 mg.

Along with the active ingredients and carriers, pharmaceutical preparations may also contain additives, such as, for example, fillers, disintegrating agents, binders, lubricants, moisturizing agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavoring or aromatic additives, thickeners, diluents, buffers, as well as solvents or solubilizers, or agents providing storage of products, salts for changing the osmotic pressure, coating agents and antioxidants. The preparations may also contain two or more compounds of the formula I, and / or their physiologically tolerated salts, and / or their precursors. In addition, in addition to at least one compound of formula I and / or its physiologically tolerated salts and / or its precursors, the preparations may also contain one or more therapeutically or prophylactically active ingredients.

The compounds of formula I are vitronectin receptor antagonists and cell adhesion inhibitors. They have, for example, the ability to prevent the attachment of osteoclasts to the bone surface and, thus, inhibit the resorption of bone tissue by osteoclasts. The action of the compounds of formula I can, for example, be demonstrated in a test in which the inhibition of vitronectin binding to cells containing a vitronectin receptor is determined. Details of this test are given below. As antagonists of the vitronectin receptor, the compounds of formula I and their physiologically tolerated salts or their precursors are generally suitable for the treatment and prevention of diseases associated with the interaction between vitronectin receptors and their ligands in the processes of intercellular interaction or in the processes of cell-matrix interaction, or which may be affected by the inhibition of interactions of this kind. Thus, in order to prevent, alleviate or treat such diseases, inhibition of the interactions of the above types is desirable. As explained at the outset, such interactions, in particular, play a role in bone resorption, in angiogenesis and proliferation of vascular smooth muscle cells. The compounds of formula I and their physiologically tolerable salts and their precursors are thus suitable, for example, for alleviating or treating diseases, at least partially due to an undesirable degree of bone resorption, angiogenesis and proliferation of vascular smooth muscle cells.

Bone diseases, for the treatment and prevention of which the compounds of the formula I corresponding to the invention can be used, are primarily osteoporosis, hypercalcemia, osteopenia caused, for example, by metastases, dental diseases, hyperparathyroidism, periarticular erosion in rheumatoid arthritis and Paget's disease. In addition, the compounds of formula I can be used to alleviate, prevent or treat bone diseases resulting from glucocorticoid, steroid or corticosteroid therapy or due to lack of sex hormone (s). All these diseases are characterized by loss of bone mass due to imbalance between bone formation and destruction, and they can be beneficially affected by inhibition of bone resorption by osteoclasts. The compounds of formula I and / or their physiologically tolerable salts and / or their precursors can also be used successfully as an inhibitor of bone resorption, for example, in the treatment or prevention of osteoporosis, in combination with conventional methods of treating osteoporosis, for example, in combination with bisphosphonates, estrogens, estrogen / progesterone, estrogen agonists and antagonists, calcitonin, vitamin B analogs, parathyroid hormone, growth hormone secretion enhancing agents or sodium fluoride. The administration of the compounds of formula I and / or their physiologically tolerated salts and / or their precursors and other active ingredients that are effective for the treatment and prevention of osteoporosis, such as those listed above, can be carried out simultaneously or sequentially, in several doses, and together or separately . For use in such a combination treatment or prophylaxis, the compounds of formula I, and / or their physiologically tolerable salts, and / or their precursors and one or more other active ingredients, such as those listed above, may be contained together in a single pharmaceutical preparation, for example, tablets or granules , or separately in two or more pharmaceutical preparations, which may be in the same package or in two or more separate packages. The use of the compounds of formula I and / or their physiologically tolerated salts and / or their precursors in such combination therapy or prophylaxis, or their use in the manufacture of pharmaceuticals for such combination therapy or prophylaxis are also objects of the present invention. The invention further relates to pharmaceutical preparations containing effective amounts of at least one compound of formula I and / or its physiologically tolerated salts and / or its precursors together with at least one other active ingredient effective in with respect to the treatment or prevention of osteoporosis, or with respect to inhibiting bone resorption similar to those listed above, together with a conventional pharmaceutically harmless carrier. The above explanations regarding pharmaceuticals apply accordingly to such combined pharmaceuticals.

Along with their use as osteoclast resorption inhibitors of the bone tissue, the compounds of formula I and their physiologically tolerable salts or precursors can be used as inhibitors of tumor growth and tumor metastasis, anti-inflammatory drugs, for the treatment and prevention of cardiovascular disorders such as arteriosclerosis or recurrent stenosis, or for the treatment and prevention of nephropathy or retinopathy, such as, for example, diabetic retinopathy. As inhibitors of tumor growth or tumor metastases, the compounds of formula I and / or their physiologically tolerated salts and / or their precursors can also be successfully used in combination with conventional anti-cancer therapy. Examples of conventional anticancer therapy are provided by VGNpo (ed.) In Jesus Soreb, Sapseg, Lsabeiis Rgekk, 1997, which is incorporated herein by reference. All of the above statements regarding the use of compounds of formula I in combination with conventional therapy for osteoporosis, concerning, for example, methods of use and combined pharmaceutical preparations, also apply to the use of compounds of formula I in combination with traditional anti-cancer therapy.

When using compounds of formula I, the dose can vary widely and, as is customary, depends on individual conditions in each individual case. It depends, for example, on the compound used or on the nature and severity of the disease, as well as on whether treatment of an acute or chronic disease is carried out or whether its prevention is carried out. When administered orally, the daily dose is usually from 0.01 to 100 mg / kg, preferably from 0.1 to 50 mg / kg, hour, from 0.1 to 5 mg / kg, for example 0.3-0.5 mg / kg to obtain effective results in the treatment of an adult weighing approximately 75 kg (in all cases we are talking about mg per 1 kg of body weight). In the case of intravenous administration, the daily dose is usually from about 0.01 to 100 mg / kg, preferably from 0.05 to 10 mg / kg (in each case, per 1 kg of body weight). The daily dose can be divided, in particular, with the introduction of relatively large quantities, into several, for example, 2, 3 or 4 single doses. As a rule, depending on the individual reaction, it may be necessary to increase or decrease the indicated daily dose.

Along with their use as active ingredients, the compounds of formula I can also be used as solvents or carriers of active ingredients for the selective transport of active ingredients to their site of action (drug positioning; see, for example, Tagdeb Bid BePuegu. V. C. 1 and 11aio, Naibooc ίί Exreptepaa1 Pactusodus, Uo1. 100, Eb. Here, C.W.W. e1 a1., 8rgdeg Ug1ad, which is incorporated into this invention by reference). The active ingredients to be transported are primarily ingredients that can be used to treat the diseases mentioned above.

The compounds of formula I and their salts can also be used for diagnostic purposes, for example, for diagnosing ίη νίΐτο, and as auxiliary substances in biochemical studies that require blocking of the vitronectin receptor or effect on intercellular or cellular matrix interactions. They can also be used as intermediates for the synthesis of other compounds, in particular other pharmaceutically active ingredients, which can be obtained from compounds of formula I, for example, by modifying them or introducing radicals or functional groups.

Examples

Products were identified by mass spectra (MS) and / or NMR spectra. Depending on how the last stage of the synthesis and / or processing procedure was carried out, for example, cryogenic drying, in some cases, the compounds were obtained partially or completely in the form of a salt, for example, in the form of an acetic acid salt, trifluoroacetic acid salt or hydrochloric acid salt.

Example 1 (28) -2- (Naphthalene-1-sulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2ylcarbamoyl) ethyl) benzoylamino) propionic

but). 4- (2-Methoxycarbonylvinyl) benzoic acid.

18.74 g (0.12 mol) of potassium monomethyl malonate are suspended in 18 ml of pyridine and 15.01 g (0.1 mol) of 4-carboxybenzaldehyde and 0.85 g (0.01 mol) of piperidine are added at room temperature with stirring. The mixture was heated under reflux until the evolution of CO ₂ ceased (approximately 2 hours), an additional 60 ml of pyridine was added, and the mixture was stirred at reflux for another 1 hour. After this, 500 ml of ice and 110 ml of concentrated hydrochloric acid were added to the reaction mixture with stirring. . After complete addition, the mixture is stirred for another 20 minutes, the product is filtered off under reduced pressure, washed with water and recrystallized from isopropyl alcohol. Yield 12.85 g.

Ή-NMR (200 MHz, b _6- DMSO): δ = 3.75 (s, 3H, OCH ₃ ); 6.76 (d, E = 15 Hz, 1H, CHSSOOCH ₃ ); 7.73 (d, 1 = 15 Hz, 1H, Ar-CH); 7.84 (d, 1 = 9 Hz,

2H, Ar-H); 7.98 (d, 1 = 9 Hz, 2H, Ar-H); 13.11 (broad s, 1H, COOH).

MS (SG): w / e = 207.2 (Μ + Ή).

HPLC: KR18, ΝηοΙοοδίΙ 300-5-C18, 250x4 mm; buffer A: H ₂ O, 0.1% trifluoroacetic acid (TFA); buffer B: acetonitrile (80 vol.%), H ₂ O (20 vol.%), 0.1% TFU; gradient: the first 5 minutes 90% of buffer A and 10% of buffer B, then after 20 minutes to 90% of buffer B, then after 5 minutes 90% of buffer B; bulk velocity 1 ml / min; retention time 18.05 minutes

b) 4- (2-Methoxycarbonylethyl) benzoic acid.

g (38.8 mmol) of 4- (2-methoxycarbonylvinyl) benzoic acid is suspended in 250 ml of dioxane and hydrogenated for 7 hours at room temperature over 10% Pc / C at a hydrogen pressure of 1 bar. The mixture was filtered and the solvent was evaporated in vacuo. Yield 8.05 g.

Ή-NMR (200 MHz, b _6- DMSO): δ = 2.67 (t, 1 = 8 Hz, 2H, CH3-COOCCH); 2.93 (t, 1 = 8 Hz, 2H, Ar-CH ₂ ); 3.59 (s, 3H, OCH ₃ ); 7.35 (d, 2H, Ar-H); 7.86 (d, 1 = 9 Hz, 2H, Ar-H); 12.80 (s broad s, 1H, COOH).

MS (SG): w / e = 209.2 (Μ + Ή).

HPLC: KR18, ΝηοΙοοδίΙ 300-5-C18, 250x4 mm; buffer A: H ₂ O, 0.1% TFA; buffer B: acetonitrile (80 vol.%), H ₂ O (20 vol.%), 0.1% TFU; gradient: the first 5 minutes 90% of buffer A and 10% of buffer B, then after 20 minutes to 90% of buffer B, then after 5 minutes 90% of buffer B; bulk velocity 1 ml / min; retention time 17.03 min.

c) tert-Butyl (28) -2-benzyloxycarbonylamino-3- (4- (2-methoxycarbonylethyl) benzoylamino) propionate.

354 mg (1.7 mmol) of 4- (2-methoxycarbonylethyl) benzoic acid and 500 mg (1.7 mmol) of tert-butyl (2§) -3-amino-2-benzyloxycarbonylaminopropionate are dissolved in 3 ml of dimethylformamide and treated with 557 mg (1.7 mmol) O - ((cyano (ethoxycarbonyl) methylidene) amino -1,1,3,3-tetramethyluronium tetrafluoroborate (TOTI) and 204 mg (1.7 mmol) of diisopropylethylamine, after which the mixture was stirred at room temperature in for 7 hours at pH 78. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate and the solution was washed three times with solutions KN8O №1NS0 ₄ and ₃ (each time) until neutral reaction. The organic phase was separated, dried and the solvent removed in vacuo. Yield 770 mg.

MS (E8 ⁺ ): w / e = 485.2 (M + H ⁺ ).

ά). (28) -2-amino-3 (4- (2-methoxycarbonylethyl) benzoylamino) propionic acid tert-butyl ester.

6.88 g (14.2 mmol) of tert-butyl (28) -2-benzyloxycarbonylamino-3- (4- (2-methoxycarbonylethyl) benzylamino) propionate was dissolved in 200 ml of methanol and 852 mg (14.2 mmol) of acetic acid was added. The mixture is hydrogenated for 7 hours at room temperature over 5%

RB / C at a hydrogen pressure of 1 bar. After that, the mixture was filtered and the solvent was removed in vacuo. The residue was washed with n-heptane and dried in vacuo. Yield 6.9 g.

MS (E8 ⁺ ): t / e = 351.2 (M + H ⁺ ).

e). (28) -3- (4- (2-methoxycarbonylethyl) benzoylamino) -2- (naphthalene-1-sulfonylamino) propionic acid tert-butyl ester.

0.123 g (0.35 mmol) of (28) -2-amino-3- (4- (2-methoxycarbonylethyl) benzoylamino) propionic acid tert-butyl ester is dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.159 g (0.7 mmol) of 1-naphthalenesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane, and the resulting solution was washed three times with water. The organic phase is dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was chromatographed on silica gel, eluting with nheptane / ethyl acetate (1/1). Yield 47 mg.

MS (E8 ⁺ ): t / e = 541.3 (M + H ⁺ ).

ί). (28) -2- (Naphthalene 1-sulfonylamino) -3 - (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid tert-butyl ester.

mg (0.087 mmol) of (28) -3- (4- (2-methoxycarbonylethyl) benzoylamino) -2- (naphthalene-1-sulfonylamino) propionic acid tert-butyl ester was dissolved in 2 ml of dimethylformamide and 86 mg (0.87) was added mmol) 2-amino1,4,5,6-tetrahydropyrimidine. The reaction mixture was stirred for 20 hours at room temperature. The solvent was removed in vacuo and the residue was chromatographed on silica gel, eluting with dichloromethane / methanol (1/1) and then dichloromethane / methanol / acetic acid / water (85/15 / 1.5 / 1.5). Yield 46 mg.

MS (E8 *): t / e = 608.3 (M + H ⁺ ).

e). (28) -2- (Naphthalene-1-sulfonylamino) 3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

mg (0.074 mmol) of (28) -2- (naphthalene-1-sulfonylamino) -3- (4- (2 (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic tert-butyl ester acids are dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid are added. The solution was stirred for 3 hours at room temperature. The solvent was removed in vacuo, toluene was added to the residue, and then removed in vacuo. The residue was dissolved in acetonitrile / water (1/1) and lyophilized. Yield 50 mg.

MS (E8 ⁺ ): t / e = 552 (M + H ⁺ ).

Example 2. (28) -2- (Quinoline-8-sulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2ylcarbamoyl) ethyl) benzoylamino) propionic acid.

a). (28) -3- (4- (2-methoxycarbonylethyl) benzoylamino) -2- (quinoline-8-sulfonylamino) propionic acid tert-butyl ester.

0.123 g (0.35 mmol) of (28) -2-amino-3- (4- (2-methoxycarbonylethyl) benzoylamino) propionic acid tert-butyl ester is dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.159 g (0.7 mmol) of 8-quinoline sulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane, and the resulting solution was washed three times with water. The organic phase is dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was chromatographed on silica gel, eluting with nheptane / ethyl acetate (1/1). Yield 67 mg.

MS (E8 ⁺ ): t / e = 542.2 (M + H ⁺ ).

b) (28) -2- (Quinoline8-sulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid tert-butyl ester.

mg (0.12 mmol) of (28) -3- (4- (2-methoxycarbonylethyl) benzoylamino) -2- (quinoline-8-sulfonylamino) propionic acid tert-butyl ester was dissolved in 1 ml of dimethylformamide and 59 mg (0 6 mmol) of 2-amino1,4,5,6-tetrahydropyrimidine. The reaction mixture was stirred for 20 hours at room temperature. The solvent was removed in vacuo and the residue was chromatographed on silica gel, eluting with dichloromethane / methanol (1/1) and then dichloromethane / methanol / acetic acid / water (85/15 / 1.5 / 1.5). Yield 72 mg.

MS (E8 ⁺ ): t / e = 609.3 (M + H ⁺ ).

c) (28) -2- (Quinolin-8-sulfonylamino) -3 (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

mg (0.11 mmol) of (28) -2- (quinolin-8-sulfonylamino) -3- (4- (2 (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino tert-butyl ester ) propionic acid is dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid are added. The solution was stirred for 3 hours at room temperature. The solvent was removed in vacuo, toluene was added to the residue, and then removed in vacuo. The residue was dissolved in acetonitrile / water (1/1) and lyophilized. Yield 54 mg.

MS (E8 ⁺ ): t / e = 553 (M + H ⁺ ).

Example 3. (28) -2- (4-Acetylaminobenzenesulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

I Ο = δ = Ο

ν ^ΝΗ o

a). (28) -2- (4-Acetylaminobenzenesulfonylamino) -3- (4- (2methoxycarbonylethyl) benzoylamino) propionic acid tert-butyl ester.

0.123 g (0.35 mmol) of (28) -2-amino-3- (4- (2-methoxycarbonylethyl) benzoylamino) propionic acid tert-butyl ester is dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.164 g (0.7 mmol) of 4-acetylaminobenzenesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane, and the solution was washed three times with water. The organic phase is dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was chromatographed on silica gel, eluting with nheptane / ethyl acetate (1/2). Yield 90 mg.

MS (E8 ⁺ ): t / e = 548 (M + H ⁺ ).

b) (28) -2- (4-Acetylaminobenzenesulfonylamino) -3- (4- (2 (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid tert-butyl ester.

mg (0.16 mmol) of (28) -2- (4-acetylaminobenzenesulfonylamino) 3- (4- (2-methoxycarbonylethyl) benzoylamino) propionic acid tert-butyl ester was dissolved in 1 ml of dimethylformamide and 79 mg (0.8 mmol) was added ) 2amino-1,4,5,6-tetrahydropyrimidine. The reaction mixture was stirred for 20 hours at room temperature. The solvent was removed in vacuo and the residue was chromatographed on silica gel, eluting with dichloromethane / methanol (1/1) and then dichloromethane / methanol / acetic acid / water (85/15 / 1.5 / 1.5). Yield 57 mg.

MS (E8 ⁺ ): t / e = 615.3 (M + H ⁺ ).

c) (28) -2- (4-Acetylaminobenzenesulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

mg (0.09 mmol) of (28) -2- (4-acetylaminobenzenesulfonylamino) 3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic tert-butyl ester acids are dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid are added. The solution was stirred for 3 hours at room temperature. The solvent was removed in vacuo, toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile / water (1/1) and lyophilized. Yield 42 mg.

MS (E8 ⁺ ): t / e = 559.2 (M + H ⁺ ).

Example 4. (28) -2- (2- (1,4,5,6-Tetrahydropyrimidin-2-ylcarbamoyl) benzenesulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2ylcarbamoyl ) ethyl) benzoylamino) propionic

butoxycarbonyl-2- (4- (2-methoxycarbonylethyl) benzoylamino) ethylsulfamoyl) benzoic acid.

0.123 g (0.35 mmol) of (28) -2-amino-3- (4- (2-methoxycarbonylethyl) benzoylamino) propionic acid tert-butyl ester is dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.164 g (0.7 mmol) of 2- (methoxycarbonyl) benzenesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane, and the resulting solution was washed three times with water. The organic phase is dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was chromatographed on silica gel, eluting with n-heptane / ethyl acetate (1/1). Yield 75 mg.

MS (E8 ⁺ ): t / e = 549 (M + H ⁺ ).

b) (28) -2- (2- (1,4,5,6tetrahydropyrimidin-2-ylcarbamoyl) benzenesulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-) tert-butyl ether ilcarbamoyl) ethyl) benzoylamino) propionic acid.

mg (0.13 mmol) of 2 ((18) -1-tert-butoxycarbonyl-2- (4- (2-methoxycarbonylethyl) benzoylamino) ethylsulfamoyl) benzoic acid methyl ester is dissolved in 1 ml of dimethylformamide and 68 mg (0.69 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine. The reaction mixture was stirred for 20 hours at room temperature. The solvent was removed in vacuo and the residue was chromatographed on silica gel, eluting with dichloromethane / methanol (1/1) and then dichloromethane / methanol / acetic acid / water (85/15 / 1.5 / 1.5). Yield 54 mg.

MS (E8 ⁺ ): t / e = 683.3 (M + H ⁺ ).

c) (28) -2- (2- (1,4,5,6-Tetrahydropyrimidin-2-ylcarbamoyl) benzenesulfonylamino) -3 (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl ) benzoylamino) propionic acid.

mg (0.08 mmol) of (28) -2- (2- (1,4,5,6-tetrahydropyrimidin-2-carbamoyl) benzenesulfonylamino) -3- (4- (2 (1,4,5, 6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid is dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid are added. The solution was stirred for 3 hours at room temperature. The solvent was removed in vacuo, toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile / water (1/1) and lyophilized. Yield 34 mg.

MS (E8 ⁺ ): t / e = 627 (M + H ⁺ ).

General procedure 1 for the synthesis of compounds in examples 5-24.

Stage a. The reaction with sulfonyl chloride.

0.2 g of (28) -amino-3 (4- (2-methoxycarbonylethyl) benzoylamino) propionic acid tert-butyl ester is dissolved in 2 ml of dimethylformamide and 4 mol. eq. triethylamine and 2 mol. eq. corresponding sulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane, the resulting solution was washed three times with water. The organic phase is dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was chromatographed on silica gel, eluting with n-heptane / ethyl acetate (1/1).

Stage b. The formation of acylguanidine.

The product of step a is dissolved in 1 ml of dimethylformamide and 5 molar equivalents of 2-amino-1,4,5,6-tetrahydropyrimidine are added. The reaction mixture was stirred for 20 hours at room temperature. The solvent was removed in vacuo and the residue was chromatographed on silica gel, eluting with dichloromethane / methanol (1/1) and then dichloromethane / methanol / acetic acid / water (85/15 / 1.5 / 1.5).

Stage c. Decomposition of tert-butyl ether.

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

Example 5. (28) -2- (4-tert-Butylbenzenesulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

I 0 = 3 = 0

Exit MS (E8 ⁺ ): t / e Stage A Product 83 mg 547.2 (M + H) ⁺ The product of stage b 85 mg 614.3 (M + H) ⁺ The product of stage C (the title compound) 75 mg 558.3 (M + H) ⁺

Example 6. (28) -2- (Propane-1-sulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2ylcarbamoyl) ethyl) benzoylamino) propionic

The title compound was synthesized according to general procedure 1 using propane-1 sulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 54 mg 457.3 (M + H) ⁺ The product of stage b 55 mg 524.3 (M + H) ⁺ The product of stage C (specified in the connection header) 45 mg 468.3 (M + H) ⁺

Example 7. (28) -2- (2-Phenylethanesulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2ylcarbamoyl) ethyl) benzoylamino) propionic acid.

I O = 8 = O

The title compound was synthesized according to general procedure 1 using trans-β-styrenesulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 49 mg 517.1 (M + H) ⁺ The product of stage b 45 mg 584.3 (M + H) ⁺ The product of stage C (specified in the connection header) 37 mg 528.3 (M + H) ⁺

Example 8. (28) -2- (4-Propylbenzenesulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

The title compound was synthesized according to general procedure 1 using 4-tert-butylbenzenesulfonyl chloride in step a.

0 = 3 = 0

The title compound was synthesized according to general procedure 1 using 4- (npropyl) benzenesulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 78 mg 533.2 (M + H) ⁺ Product stage b 73 mg 600.4 (M + H) ⁺ The product of stage C (the title compound) 55 mg 544.3 (M + H) ⁺

Example 9. (28) -2- (2-Methylpropane-1sulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

The title compound was synthesized according to General Procedure 1 using 2-methylpropane-1sulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 21 mg 471.3 (M + H) ⁺ Product stage b 10 g 538.4 (M + H) ⁺ The product of stage C (specified in the connection header) 13 mg 482.3 (M + H) ⁺

Example 10. (28) -2- (4-Butoxybenzenesulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

I

0 = 8 = 0

.0

The title compound was synthesized according to general procedure 1 using 4- (nbutoxy) benzenesulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 83 mg 563.2 (M + H) ⁺ Product stage b 83 mg 630.4 (M + H) ⁺ The product of stage C (specified in the connection header) 63 mg 574.3 (M + H) ⁺

Example 11. (28) -2- (2-Cyanobenzenesulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

I

0 = 8 = 0

The title compound was synthesized according to general procedure 1 using 2-cyanobenzenesulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 91 mg 516.2 (M + H) ⁺ Product stage b 71 mg 583.3 (M + H) ⁺ The product of stage C (specified in the connection header) 73 mg 527.3 (M + H) ⁺

Example 12. (2 8) -2- (7,7-Dimethyl-2-oxobicyclo [2.2.1] hept-1-ylmethanesulfonylamino) 3- (4- (2- (1,4,5,6-tetrahydropyrimidine- 2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

The title compound was synthesized according to general procedure 1 using 10-camphorsulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 85 mg 565.3 (M + H) ⁺ Product stage b 88 mg 632.4 (M + H) ⁺ The product of stage C (specified in the connection header) 71 mg 576.4 (M + H) ⁺

Example 13. (28) -2- (4-Chlorobenzenesulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

The title compound was synthesized according to general procedure 1 using 4-chlorobenzenesulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 91 mg 525.1 (M + H) ⁺ Product stage b 82 mg 592.3 (M + H) ⁺ The product of stage C (specified in the connection header) 64 mg 536.3 (M + H) ⁺

Example 14. (28) -2- (3-Chlorobenzenesulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

I 0 = 3 = 0 ό. _ο

The title compound was synthesized according to general procedure 1 using 3-chlorobenzenesulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 65 mg 525.2 (M + H) ⁺ Product stage b 58 mg 592.3 (M + H) ⁺ The product of stage C (specified in the connection header) 52 mg 536.3 (M + H) ⁺

Example 15. (28) -3- (4- (2- (1,4,5,6-Tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) -2- (3-trifluoromethylbenzenesulfonylamino) propionic acid.

I 0 = 8 = 0

E

The title compound was synthesized according to general procedure 1 using 3-trifluoromethylbenzenesulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 86 mg 559.2 (M + H) ⁺ Product stage b 94 mg 626.3 (M + H) ⁺ The product of stage C (specified in the connection header) 84 mg 570.3 (M + H) ⁺

Example 16. (28) -2- (4-Methoxybenzenesulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

The title compound was synthesized according to general procedure 1 using 4-methoxybenzenesulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 66 mg 521.1 (M + H) ⁺ Product stage b 74 mg 588.3 (M + H) ⁺ The product of stage C (specified in the connection header) 49 mg 532.3 (M + H) ⁺

Example 17. (28) -2-Benzenesulfonylamino 3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

I

0 = 8 = 0

The title compound was synthesized according to general procedure 1 using benzenesulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 76 mg 491.2 (M + H) ⁺ Product stage b 77 mg 558.3 (M + H) ⁺ The product of stage C (the title compound) 64 mg 502.3 (M + H) ⁺

Example 18. (28) -3- (4- (2- (1,4,5,6-Tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) -2- (thiophen-2-sulfonylamino) propionic acid.

I

0 = 8 = 0 ί

The title compound was synthesized according to general procedure 1 using 2-thiophenesulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 87 mg 497.1 (M + H) ⁺ Product stage b 74 mg 564.2 (M + H) ⁺ The product of stage C (specified in the connection header) 64 mg 508.2 (M + H) ⁺

Example 19. (28) -2- (Biphenyl-4-sulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2ylcarbamoyl) ethyl) benzoylamino) propionic acid.

0 = 3 = 0

The title compound was synthesized according to General Procedure 1 using 4-biphenylsulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 39 mg 567.1 (M + H) ⁺ Product stage b 40 mg 634.4 (M + H) ⁺ The product of stage C (specified in the connection header) 33 mg 578.3 (M + H) ⁺

Example 20. (28) -2- (Naphthalene-2-sulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propio-

is used according to general procedure 1 using 2-naphthalenesulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 76 mg 541.2 (M + H) ⁺ Product stage b 74 mg 608.3 (M + H) ⁺ The product of stage C (specified in the connection header) 62 mg 552.3 (M + H) ⁺

Example 21. (28) -3- (4- (2- (1,4,5,6-Tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) -2- (2,4,6-trimethylbenzenesulfonylamino)

is carried out in accordance with general procedure 1 using 2,4,6-trimethylbenzenesulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 68 mg 533.2 (M + H) ⁺ Product stage b 71 mg 600.4 (M + H) ⁺ The product of stage C (specified in the connection header) 54 mg 544.3 (M + H) ⁺

Example 22. (28) -3- (4- (2- (1,4,5,6-Tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) -2- (4-trifluoromethylbenzenesulfonylamino) propionic acid.

v 0 = 5 = 0

P-4-P

R

The title compound was synthesized according to general procedure 1 using 4-trifluoromethylbenzenesulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 105 mg 559.3 (M + H) ⁺ Product stage b 93 mg 626.4 (M + H) ⁺ The product of stage C (specified in the connection header) 70 mg 570.3 (M + H) ⁺

Example 23. (28) -2- (Butane-1-sulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2ylcarbamoyl) ethyl) benzoylamino) propionic acid.

0 = 5 = 0

The title compound was synthesized according to general procedure 1 using butane-1-sulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 87 mg 471.4 (M + H) ⁺ Product stage b 60 mg 538.4 (M + H) ⁺ The product of stage C (specified in the connection header) 57 mg 482.3 (M + H) ⁺

Example 24. (28) -2-Methanesulfonylamino 3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

0 = 8 = 0

The title compound was synthesized according to general procedure 1 using methanesulfonyl chloride in step a.

Exit MS (E8 ⁺ ): t / e Stage A Product 87.8 mg 429.3 (M + H) ⁺ The product of stage b 98 mg 496.4 (M + H) ⁺ The product of stage C (specified in the connection header) 74 mg 440.3 (M + H) ⁺

I 0 = 3 = 0 A

General procedure 2 for the synthesis of compounds in examples 25-27.

Stage a. The reaction with sulfonyl chloride.

0.1 g of (28) -2-amino-3- (4- (2-carboxyethyl) benzoylamino) propionic acid tert-butyl ester hydrochloride is dissolved in 3 ml of dimethylformamide and treated with 3 mol. eq. diisopropylethylamine and 2 mol. eq. the corresponding sulfonyl chloride at 0 ° C. The solution was stirred for 3 hours at 0 ° C. The reaction mixture was diluted with ethyl acetate and the solution was washed twice with an aqueous solution of potassium bisulfate and once with a saturated aqueous solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was chromatographed on silica gel, eluting with a mixture of dichloromethane / methanol / acetic acid / water (97.5 / 2.5 / 0.25 / 0.25).

Stage b. The formation of acylguanidine.

The product of stage a is dissolved in 2 ml of tetrahydrofuran and 1.2 mol. eq. 2-amino1,4,5,6-tetrahydropyrimidine, 4 mol. eq. diisopropylethylamine and 1.1 mol. eq. O- (7-azabenzotriazol-1-yl) -1,1,3,3tetramethyluronium hexafluorophosphate. The reaction mixture was stirred for 20 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate, and the resulting solution was washed twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The organic phase is dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue is chromatographed on silica gel, eluting with a mixture of dichloromethane / methanol / acetic acid / water (85/15 / 1.5 / 1.5) and then with a mixture of dichloromethane / methanol / acetic acid / water (9/1 / 0.1 / 0, one).

Stage c. Decomposition of tert-butyl ether.

The product of step b is dissolved in 1.5 ml of a trifluoroacetic acid / water mixture (95/5). The solution was stirred for 1 h at room temperature. The solvent was removed in vacuo, toluene was added and then it was removed in vacuo. The residue was dissolved in acetonitrile / water (1/1) and lyophilized.

Example 25. (28) -2- (Propan-2-sulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2ylcarbamoyl) ethyl) benzoylamino) propionic acid.

The title compound was synthesized according to general procedure 2 using propane-2sulfonyl chloride in step a.

Exit MS: t / e Stage A Product 17 mg 443.2 (M + H) ⁺ (RAB ⁺ ) The product of stage b 7 mg 524.2 (M + H) ⁺ (E8 ⁺ ) The product of stage C (specified in the connection header) 7.2 mg 468.2 (M + H) ⁺ (E8 ⁺ )

Example 26. (28) -2-Chloromethanesulfonylamino-3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2ylcarbamoyl) ethyl) benzoylamino) propionic acid.

0 = 8 = 0

The title compound was synthesized according to general procedure 2 using chloromethanesulfonyl chloride in step a.

Exit MS: t / e Stage A Product 94 mg 449.1 (M + H) ⁺ (RAB ⁺ ) The product of stage b 28 mg 530.2 (M) ⁺ (E8 ⁺ ) The product of stage C (specified in the connection header) 34 mg 474.2 (M + H) ⁺ (E8 ⁺ )

Example 27. (28) -3- (4- (2- (1,4,5,6-Tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) -2- (2,2,2-trifluoroethanesulfonylamino) propionic acid.

The title compound was synthesized according to general procedure 2 using, in step a, 2,2,2-trifluoroethanesulfonyl chloride.

Exit MS: t / e Stage A Product 43 mg 483.2 (M + H) ⁺ (RAB ⁺ ) The product of stage b 24 mg 564.2 (M + H) ⁺ (E8 ⁺ ) The product of stage C (specified in the connection header) 22 mg 508.2 (M + H) ⁺ (E8 ⁺ )

Example 28. Ethyl ester of (28) -2- (4-tert-butylbenzenesulfonylamino) -3- (4- (2- (1,4,5,643 tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

700 mg (28) -2- (4-tert-butylbenzenesulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid is dissolved in 100 ml of ethanol and add 15 drops of concentrated sulfuric acid. The reaction solution is boiled 3.5

h. The solvent is removed in vacuo, the residue is dissolved in dichloromethane and washed three times with saturated aqueous sodium bicarbonate. The aqueous phase is extracted once with dichloromethane and the combined organic phase is washed twice with a saturated aqueous solution of sodium chloride. Next, the organic phase is dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was dissolved in 2N. hydrochloric acid. The acid is removed in vacuo, the residue is dissolved in acetonitrile and poured into water. The resulting mixture was subjected to freeze drying. Yield 480 mg.

MS (E8 +): t / e = 586.4 (M + H) ⁺ .

Example 29. Isopropyl ether (28) -2 (4-tert-butylbenzenesulfonylamino) -3- (4- (2 (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

700 mg (28) -2- (4-tert-butylbenzenesulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid is dissolved in 100 ml of isopropyl alcohol and add 15 drops of concentrated sulfuric acid. The reaction solution is boiled for 2.5 days, the solvent is removed in vacuo, the residue is dissolved in dichloromethane and washed three times with saturated aqueous sodium bicarbonate. The aqueous phase is extracted once with dichloromethane and the combined organic phase is washed twice with a saturated aqueous solution of sodium chloride. Then the organic phase is dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was dissolved in 2N. hydrochloric acid. The acid is removed in vacuo, the residue is dissolved in acetonitrile and poured into water. The resulting mixture was subjected to freeze drying. Yield 444 mg.

MS (E8 ⁺ ): t / e = 600.4 (M + H) ⁺ .

Example 30. Ethyl ether (28) -2 (naphthalene-1-sulfonylamino) -3- (4- (2- (1,4,5,6tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

I 0 = 3 = 0

590 mg (28) -2- (Naphthalene-1-sulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2ylcarbamoyl) ethyl) benzoylamino) propionic acid was dissolved in 80 ml of ethanol and added 12 drops of concentrated sulfuric acid. The reaction solution was boiled for 3 hours, the solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with saturated aqueous sodium bicarbonate. The aqueous phase is extracted once with dichloromethane and the combined organic phase is washed twice with a saturated aqueous solution of sodium chloride. Then the organic phase is dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was dissolved in 2N. hydrochloric acid. The acid is removed in vacuo, the residue is dissolved in acetonitrile and poured into water. The resulting mixture was subjected to freeze drying. Yield 381 mg.

MS (E8 ⁺ ): t / e = 580.3 (M + H) ⁺ .

Example 31. Isopropyl ether (28) -2 (naphthalene-1-sulfonylamino) -3- (4- (2- (1,4,5,6tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

I

0 = 3 = 0

1.5 g of (28) -2- (Naphthalene-1-sulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2ylcarbamoyl) ethyl) benzoylamino) propionic acid was dissolved in 250 ml of isopropyl alcohol and add 1 ml of concentrated sulfuric acid. The reaction solution is boiled for 3 days, the solvent is removed in vacuo, the residue is dissolved in dichloromethane and washed three times with saturated aqueous sodium bicarbonate. The aqueous phase is extracted once with dichloromethane and the combined organic phase is washed twice with a saturated aqueous solution of sodium chloride. Next, the organic phase is dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was dissolved in 2N. hydrochloric acid. The acid is removed in vacuo, the residue is dissolved in acetonitrile and poured into water. The resulting mixture was subjected to freeze drying. Yield 950 mg.

MS (E8 ⁺ ): t / e = 594.4 (M + H) ⁺ .

Example 32. Isobutyl ether (28) -2 (naphthalene-1-sulfonylamino) -3- (4- (2- (1,4,5,6tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid.

600 mg (28) -2- (Naphthalene-1-sulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2ylcarbamoyl) ethyl) benzoylamino) propionic acid is dissolved in 12 ml of isobutyl alcohol and add 0.1 ml of concentrated sulfuric acid. The reaction solution was boiled for 24 hours, the solvent was removed in vacuo and the residue was chromatographed on silica gel, eluting with dichloromethane / methanol / acetic acid / water (9/1 / 0.1 / 0.1). The product is dissolved in acetic acid / water and freeze dried. Yield 250 mg.

MS (E8 ⁺ ): t / e = 608.5 (M + H) ⁺ .

Pharmaceutical testing

Inhibition of bone resorption by compounds of the present invention can be determined, for example, using an osteoclast bone resorption test (RGG Α88ΑΥ), which can be carried out, for example, similarly to that described in UO-A-95/32710, which is included in the present invention in as reference material.

The inhibitory effect of the compounds of the invention with respect to the vitronectin receptor α _ν β ₃ can be determined, for example, as described below.

Test for measuring inhibition of 293 cell binding to human vitronectin (Yi / 293 cell test)

1. Purification of human vitronectin.

Human vitronectin was isolated from human plasma and purified using affinity chromatography according to the method of Υαίοΐινο е! A1., Ce11 81gis1ige apb Gipsbop, 1988, 23, 281-292.

2. Cell test.

Cells of the 293 human embryonic kidney cell line, into which the DNA sequences responsible for α _ν and in the ₃ subunits of the vitronectin receptor α _ν β ₃ were inserted, were selected due to the high expression rate (> 500,000 α _ν β ₃ receptors per cell) according to the method EAC8. The selected cells were also cultivated and sorted according to the EAC8 method in order to obtain a stable cell line (15Ό) with an expression rate of more than 1,000,000 copies of α _ν β ₃ per cell.

A 96-well plate for tissue culture with a flat bottom is coated overnight at 4 ° C. with human vitronectin (0.01 mg / ml, 0.05 ml per well) in phosphate buffered left-hand solution and then blocked with 0.5% SAB (bovine serum albumin). Solutions of the test substances are prepared in concentrations from 10 ^-10 to 2x10 ^-3 mol / L in the IMEM glucose-containing medium and in all cases these solutions are placed on the plate in an amount of 0.05 ml per cell. Cells expressing high levels of α _ν β ₃ (e.g. 15Ό) are suspended in IMEM glucose-containing medium and the cell concentration in suspension is adjusted to 25,000 per 0.05 ml of medium. 0.05 ml of such a cell suspension is introduced into each well and the plate is incubated for 90 min at 37 ° C. The plate is washed three times with phosphate buffered saline to remove unbound cells. Bound cells are lysed in citrate buffer (25 mM, pH 5.0) containing 0.25% Triton X-100. After this, the substrate of hexosamidase p-nitro-phenyl-N-acetyl-β-glucosaminide is added and the plate is incubated for 90 minutes at 37 ° C. The reaction was stopped with glycine (50 mM) / EDTA (5 mM) buffer (pH 10.4) and the optical absorbance in each well was measured at 405-650 nm. The data obtained are analyzed by standard methods.

The following results were obtained (inhibitory concentrations of IC ₅₀ )

Example No. IK ₅₀ in the test vitronectin with cells 293 one 6 nM 2 52 nM 3 27 nM 5 18 nM 6 32 nM 7 28 nM 8 20 nM nine 69 nM 10 29 nM eleven 24 nM 12 27 nM thirteen 27 nM 14 10 nM fifteen 6 nM sixteen 26 nM 17 9 nM eighteen 14 nM nineteen 38 nM twenty 5 nM 21 21 nM 22 10 nM 23 30 nM 24 100 nM

CLAIM

Claims (14)

1. Sulfonamide derivatives of the general formula I wherein B ¹ and B ² together form a divalent (C ₂ -C ₃ ) alkylene radical; B ⁴ is H or (C ₁ -C ₆ ) alkyl; B ⁵ is (C ₁ -C ₁₀ ) alkyl, (C ₆ -C ₁₄ ) aryl, (C ₅ -C ₁₄ ) heteroaryl or (C ₆ -C ₁₄ ) aryl (C ₁ -C ₁₀ ) alkyl group, where aryl , heteroaryl or alkyl is optionally substituted with a B ³ or 2-oxobicyclo [2.2.1] hept-1-methyl group; B ³ is (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkyloxy, halogen, trifluoromethyl, cyano, oxo, NCO- (C ₁ -C ₄ ) alkyl or -C (O) XH- (C ₅ C ₁₄ ) a heteroaryl radical or phenyl; B ⁶ is H; in all stereoisomeric forms and their mixtures in any proportions, as well as physiologically tolerated salts of these compounds and their precursors. 2. The compounds of formula I according to claim 1, in which B ⁵ is (C ₆ -C ₁₄ ) aryl, (C ₅ -C ₁₄ ) heteroaryl, where aryl or heteroaryl is optionally substituted with B ³ ; in all stereoisomeric forms and their mixtures in any proportions, as well as physiologically tolerated salts of these compounds and their precursors. 3. The compounds of formula I according to claim 1, in which ⁵ is naphthyl, in all stereoisomeric forms and their mixtures in any proportions, as well as physiologically tolerated salts of these compounds and their precursors. 4. The compounds of formula I according to one or more of claims 1 to 3, which are 2- (B ⁵ sulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid in which the substituent 2 (B ⁵ -sulfonylamino) is selected from the group consisting of benzenesulfonylamino, 4- (npropyl) benzenesulfonylamino, 4-tert-butylbenzenesulfonylamino, 2,4,6-trimethylbenzenesulfonylamino, 4-methoxybenzo n-butoxy) benzenesulfonylamino, 3chlorobenzenesulfonylamino, 4-chlorobenzenesulfonylamino, 3-trifluoromethylbenzenesulfonylamino, 4-trifluoromethane lbenzenesulfonylamino, 4-acetylaminobenzenesulfonylamino, 2-cyanobenzenesulfonylamino, naphthalene-1-sulfonylamino, naphthalene-2-sulfonylamino, biphenyl4-sulfonylamino, thiophenyl-2-sulfonylamino, quinoline-2-sulfonylamino-2-sulfonylamino-2-sulfonylamino-2-sulfonylamino butane-1-sulfonylamino, 2methylpropane-1-sulfonylamino, chloromethanesulfonylamino, 2,2,2-trifluoroethanesulfonylamino, 7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1ylmethanesulfonylamino and 2-phenylethanesulfonylamino in all of them mixtures in any proportion physiological tolerated salts of these compounds and their precursors. 5. The compound of formula I according to one or more of claims 1 to 4, which is (28) 2- (naphthalene-1-sulfonylamino) -3- (4- (2 (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid and its physiologically tolerated salts and precursors. 6. The compound of formula I according to one or more of claims 1 to 5, which is (28) 2- (naphthalene-1-sulfonylamino) -3- (4- (2 (1,4,5,6-tetrahydropyrimidine-2 -alkarbamoyl) ethyl) benzoylamino) propionic acid or its (C1-C4) alkyl ether and its physiologically tolerated salts. 7. The compound of formula I according to one or more of claims 1 to 6, which is ethyl ester (28) -2- (naphthalene-1-sulfonylamino) -3- (4- (2- (1,4,5,6 Tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid and its physiologically tolerated salts. 8. A method of obtaining compounds of the formula I according to claims 1-7, comprising linking two or more fragments that can be isolated from formula I by the reverse synthesis method, characterized in that the carboxylic acid or carboxylic acid derivative of the formula II in which B ⁴ and B ^{5 are} defined as in claims 1 to 7 or in which functional groups are present in the form of their precursors or in a protected form, and where X is a nucleophilic substitution leaving group, they are reacted with guanidines or guanidine derivatives formula III in which B ¹ , B ² and B ^{6 are} defined as described in claims 1 to 7 or in which functional groups are present in the form of their precursors or in a protected form. 9. The use of compounds of formula I according to one or more of claims 1 to 7, and / or their physiologically tolerated salts, and / or their precursors as an active ingredient in a pharmaceutical preparation. 10. Pharmaceutical preparations containing at least one compound of formula I according to one or more of claims 1 to 7, and / or their physiologically tolerable salts, and / or their precursors in combination with a pharmaceutically harmless carrier. 11. The use of compounds of formula I according to one or more of claims 1 to 7, and / or their physiologically tolerated salts, and / or their precursors as antagonists of the vitronectin receptor. 12. The use of compounds of formula I according to one or more of claims 1 to 7, and / or their physiologically tolerated salts, and / or their precursors as inhibitors of bone resorption or for the treatment or prevention of osteoporosis. 13. The use of compounds of formula I according to one or more of claims 1 to 7, and / or their physiologically tolerated salts, and / or their precursors as inhibitors of tumor growth or tumor metastasis. 14. The use of compounds of formula I according to one or more of claims 1 to 7, and / or their physiologically tolerated salts, and / or their precursors as anti-inflammatory drugs or for the treatment or prevention of cardiovascular disorders, recurrent stenosis, arteriosclerosis or retinopathies.