UA63990C2 - Novel sulfonamide derivatives as bone tissue resoprtion inhibitors and cells adhesion inhibitors - Google Patents

Abstract

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

Description

Description of the invention

This invention relates to sulfonamide derivatives of the formula I:

And in which B", 22, B", BZ and 25 have the indicated lower values than their physiologically tolerated salts and their predecessors. Compounds of the formula | are valuable pharmaceutically active compounds. They are antagonists of the vitronectin receptor and inhibitors of cell adhesion, and also prevent the resorption of 75 bone tissue by osteoclasts. In particular, they are suitable for therapy and prevention of diseases, at least partially caused by an undesirable degree of bone tissue resorption, for example, osteoporosis. In addition, the invention relates to methods of obtaining compounds of formula (I), their use, in particular, as pharmaceutically active ingredients, and pharmaceutical preparations containing them.

Human bones are subject to a process of constant dynamic restoration, which includes resorption of bone tissue and bone formation. These processes are regulated by specialized cell types. Resorption of bone tissue is based on the destruction of the bone matrix by osteoclasts. Most bone diseases are the result of an 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 /--SEM resorption of bone tissue during the constantly ongoing reconstructive process. Conventional treatment for osteoporosis includes, in particular, the use of bis-phosphonates, estrogens, estrogen/progesterone therapy (hormone replacement therapy), estrogen agonist/antagonist therapy (selective estrogen receptor modulators), calcitonin, vitamin O analogs, parathyroid hormone, growth hormone secretagogues or sodium fluoride (dagaipe ei ai. Appia! Kerogiz ip Medisipa! Spetivigu 1996, 31, 211). at

Activated osteoclasts are multinucleated cells with a diameter of up to 400 μm, which remove the bone matrix. Activated osteoclasts, attaching 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. The acidic environment and proteases cause the destruction of bone. Compounds of the formula | tissues by osteoclasts.

Research has shown that attachment of osteoclasts to bones is carried out with the help of integrin receptors on the surface of osteoclast cells. Integrins are a superfamily of receptors, which includes ipeg aa, the fibrinogen receptor (c415 Bz on platelets and the vitronectin ou/B3z receptor. The latter is a membrane glycoprotein expressed on the surface of cells such as endothelial cells, vascular smooth muscle cells , osteoclast cells and cancer cells. Vitronectin receptor 9383, expressed on the membrane of 70 osteoclasts, regulates the process of attachment to bone and resorption of bone tissue, thus being 8 s one of the factors that cause osteoporosis. In this case, o3uBz will form a connection with by proteins of bone "from the matrix, such as osteopontin, bone sialoprotein and thrombospontin, which includes a tripeptide link

Agda-Oiu-Avr (or (KOB)).

Nopop and co-authors describe KOYUO-peptides and vitronectin receptor antibody (2336), which inhibits 75 destruction by osteoclasts of teeth and prevents osteoclast migration (Nopop et al., Ehr. Seyi. Kez. 1991, 195,

F 368). V. I. Se Vioi. 1990, 111, 1713, According to a). describe echistatin (espiviayp), a KOYUO-peptide of snake (95) venom, which is a strong inhibitor of bone tissue resorption in tissue culture and an inhibitor of osteoclast attachment to bone. Rizspeg her aiYi. (Epadoshypoiosdu, 1993, 132, 1411) were able to show in rats that echistatin also inhibits the resorption of bone tissue. (Se) 50 Further, it was shown that vitronectin ou/Vz on smooth muscle cells of human aorta vessels stimulates the migration of these cells into the neointima, which ultimately leads to arteriosclerosis and reversible stenosis after angioplasty (Vgomup et al., Sagaiomazsiag Kev. 1994 , 28, 1815).

Vgookzg ei ai. (SeiYi, 1994, 79, 1157) it was also shown that 9/3 antibodies or o3/Bz antagonists can be the cause of the reduction of cancer tumors as a result of inducing apoptosis of blood vessel cells in the process of angiogenesis. The vitronectin receptor ouVz is also related to the development of many other types of cancer and is expressed in (F) increased amounts in cells of malignant melanoma (Epdietap ei ai., Appia! Kerogov ip Meadisipa! Spetivigu ko 1996, 31, 191). Invasiveness of melanoma was correlated with such superexpression (5igasKe ei aiYi., Epsusioredia oi

Sapseg, moitste II, 1855, Asadetis Rgezv, 1997; in Niyiv ei ai., Siipisai Zsiepse, 1996, 91, 639). Satop ey a). (Sapseg Kevz. 1998, 58, 1930) describe the inhibition of tumor growth and associated with its malignancy, hypercalcemia when using the ou/Vz antagonist.

Spegezn ei ai. (Zsiepse, 1995, 270, 1500) describe o3Bz antibodies or o/Bz antagonists, which inhibit the processes of BSE-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 participates thus provides an opportunity to influence various disease states, for the therapy and prevention of which there is still a need for suitable pharmaceutically active ingredients.

UM/O-A-94/12181 describes substituted aromatic or non-aromatic cyclic systems, and UUO-A-94/08577 describes substituted heterocycles as receptors for fibrinogen and inhibitors of platelet aggregation. EP-A-528586 and

EP-A-528587 discloses aminoalkyl- and heterocyclyl-substituted derivatives of phenylalanine, and UKHO-A-95/32710 discloses aryl derivatives that inhibit the resorption of bone tissue by osteoclasts. UMO-A-96/00574 describes benzodiazepines, and UUO-A-96/00730 describes antagonistic patterns of the fibrinogen receptor, in particular, benzodiazepines linked to a nitrogen-containing five-membered ring that are antagonists of the vitronectin receptor.

MUO-A-98/00395 (OE-A-19654483) describes vitronectin receptor antagonists based on a tyrosine structure. EP-A-820991 (German patent application 19629816.4) describes cycloalkyl derivatives, and European patent application 97122520.6 describes carbamine ester derivatives that are vitronectin receptor antagonists. Subsequent studies have shown that sulfonamide derivative formulas | are particularly strong inhibitors of the vitronectin receptor and the resorption of bone tissue by osteoclasts.

This invention relates to compounds of the formula I: o z i vod mov - Sh-i -0 Mn nn 2 nya viz t 20 I in which

IN! and 2, independently of each other, mean either hydrogen (C4-Cv)-alkyl, which is unsubstituted or substituted by the KZ radical, or

IN! and 2 together, represent a saturated or unsaturated divalent (C 2-Ce)-alkylene radical, with 25, for example, the group -""СНо)р-, in which P is 2, 3, 4, 5, 6, 1, 8 or 9, which may be unsubstituted or substituted d) by one or more groups selected from: halogen, (C 4-C 4 )-alkyl, (C 4-C 4 )-alkyl, (C 4-C 4 )-aryl, (Cv-C4454)-aryl-(C4-Cv)-alkyl-, (Cv5-C414)-heteroaryl, (Cv-C14)-heteroaryl-(C41-Cv)-alkyl-, (C3-C42)-cycloalkyl, (C3-C42)-cycloalkyl-(C1-Cv)-alkyl- and oxo groups, where 5-7- is a saturated or unsaturated ring, which can be unsubstituted or substituted by a KO radical, in particular, one or two KZ radicals, and which a 30 carbocyclic or heterocyclic ring containing one or two nitrogen atoms in the ring can be condensed (Fd) by the carbon-carbon bond of the (Co-Co)-alkylene radical;

BZ stands for (C.i-Ci0)-alkyl, (C.sub.3-CiO)-monocycloalkyl, (Ci-Ci)-bicycloalkyl, /(Ci-Ci)-tricycloalkyl, F (Ci-Ce)-alkyl, (Ci- C14)-aryl, (Св-С4454)-aryl-(С.-С.))-alkyl-, (С5-С14)-heteroaryl, "(9 35 (Св5-С14)-heteroaryl-(С1-С4) -alkyl-, halogen, trifluoromethyl, cyano, hydroxyl, oxo, nitro, amino, "co -MH-(C4-C,y)-alkyl, -M(C4-Cu)-alkyl)", -MH-CO- (C.-C.)-alkyl, -C-(C.-C.sub.1)-alkyl;

B means hydrogen, (C4-Cv)-alkyl-CO-O-(C4-Cv)-alkyl- or (C.-Cv)-alkyl, which may be unsubstituted or substituted by a radical, from the group including hydroxyl, ( C4-C4)-Alkoxy, -(C4-C4)-alkyl-5(O)2, -MA/B" and "-M'B"B"t"su, where B", B" and B" , independently of each other, denote hydrogen, (C4-C14)-alkyl, (C1-C14)-aryl, or (Ce-C14)-aryl-(C1-C14)-alkyl-, and C) denotes an anion which is physiologically transferred, or K 4 means one of the following radicals: 2" / o -4 ev, - no ny it on 45. "0 DAMY tre syu -7 on M / n in which bonds, through which radicals are attached , indicated by dashed lines; i-o BO means (Ci-Cr)-alkyl, (C3-C2O)-monocycloalkyl, (Cr-Cr)-bicycloalkyl, (Cr-C2o)-tricycloalkyl, (se) 50 (C6C., )-aryl, (Cv-C44)-heteroaryl, (Cv-Ci4)-aryl-(C1-Cv)-alkyl- or (Cv5-C44)-heteroaryl-(C1-Cv)-alkyl-, where o are aryl radicals , heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl each can be unsubstituted or substituted by one, two or three KZ radicals and where in the radicals alkyl, monocycloalkyl, bi cycloalkyl tricycloalkyl one or more carbon atoms, in particular, one, two, three or four carbon atoms, may be replaced by the same or different atoms selected from the group consisting of nitrogen, oxygen and sulfur;

EZ means hydrogen, (C1-C8)-alkyl-O-CO-, hydroxyl, (C4-C8)-alkyl-O-CO-O- or nitro group; (F) in all stereoisomeric forms and their mixtures in any proportions, as well as salts of these compounds that are physiologically tolerated and their precursors.

All radicals that occur several times in the compounds of formula I, for example, radicals BK Z, each, independently of each other, have the above values and can be the same or different in each case. Radicals that can independently have the specified values can be the same or different in each case.

Alkyl radicals can be simple or branched, saturated, monounsaturated or polyunsaturated. This also applies to the case when they have substituents or are themselves substituents in other 65 radicals, for example, alkyl, alkyl, or arylalkyl radicals. The same applies to alkylene radicals (ie, 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 ecosyl, n-isomers of all these radicals, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, isodecyl, 3-methylpentyl, 2,3,4-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl. The group of preferred alkyl radicals includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl radicals. Examples of alkylene radicals are divalent radicals corresponding to the monovalent radicals mentioned above, for example, methylene, 1,1-ethylene (methylmethylene), 1,2-ethylene, 1,3-propylene, 1,2-propylene (1-methylethylene and 2 -methylethylene), 2,3-butylene (1,2-dimethyl-1,2-ethylene), 1,4-butylene and 1,6-hexylene. 70 Unsaturated alkyl radicals are, for example, alkenyl radicals such as vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl or alkynyl radicals such as ethynyl, 1-propynyl or propargyl. Unsaturated alkylene radicals, i.e. alkenylene and alkynylene radicals (alkenediyl and alkynedeyl radicals) can similarly be simple or branched. Examples of alkenylene radicals are vinylene or propenylene, and examples of alkynylene radicals are ethynylene or propynylene. Alkyl radicals can also /5 be unsaturated in the case when they are substituted. An example of an arylalkyl radical unsaturated in the alkyl part is styryl (2-phenylethenyl).

Unless otherwise specified, cycloalkyl radicals may be monocyclic, bicyclic or tricyclic, i.e. they may be monocycloalkyl, bicycloalkyl and tricycloalkyl radicals provided 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 can also be substituted, for example, by (C4-C/)-alkyl. Examples of substituted cycloalkyl radicals worth mentioning are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.

Bicycloalkyl radicals and tricycloalkyl radicals can be unsubstituted or, if desired, substituted in any suitable position, for example, by one or more oxo groups and/or one or more identical or different (C,i-C);)-alkyl groups, e.g. , methyl or isopropyl groups, and) mainly methyl groups. The free bond through which the bicyclic or tricyclic radical is attached can be in any desired position in the molecule. Thus, a radical can be attached through a bridging atom or any atom in the bridge. The free bond can also be in any desired stereochemical position, for example, in the exo-position or the endo-position. Examples of bicycloalkyl radicals and tricycloalkyl radicals are campanyl, bornyl, adamantyl, such as 1-adamantyl Me) and 2-dadamantyl, caranyl, epiisobornyl, epibornyl, norbornyl and norpinanyl. Gee!

A halogen is, for example, fluorine, chlorine, bromine or iodine. (Св5-С14)-Aryl includes heterocyclic (Сб-С14)-aryl radicals ((Сб-С14)-heteroaryl radicals) in which one or more carbon atoms of the 5-14-membered ring me) are replaced by heteroatoms, such as nitrogen, oxygen or sulfur, and carbocyclic (Св-С.44)-aryl radicals. Examples of carbocyclic (C1-C14)-aryl radicals are phenyl, naphthyl, biphenylyl, anthryl and fluorenyl, of which 1-naphthyl, 2-naphthyl and phenyl are preferred. Unless otherwise specified, aryl radicals, especially phenyl radicals, may be unsubstituted or substituted by one or more radicals, preferably one, two or three identical or different radicals. Aryl radicals, in particular, can be replaced by the same or "different radicals from the group including (C.-Cv)-alkyl, especially (C.4-Cv)-alkyl, (Ci-Cv)-alkyl, especially pt") c (Ci-C.) -Alkoxy, halogen, such as fluorine, chlorine and bromine, nitro, amino, tri-fluoromethyl, hydroxyl, . methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C4-C/)- alkoxycarbonyl, phenyl, phenoxy, benzyl or a benzyloxy. Of course, as substitutes in compounds of the formula | of this invention can have no more than two nitro groups.

The substituent in monosubstituted phenyl radicals can be in positions 1, 3 or 4, of which positions 3 and 4 are preferred. If the phenyl is disubstituted, the substituents can be in the 2,3 positions,

Ge» 2.4, 2.5, 2.6, 3.4 or 3.5. It is preferable that the two substituents in the disubstituted phenyl radicals are in the 3,4 position relative to the site of attachment of the phenyl. Substituents in trisubstituted phenyl radicals can be in the 2,3,4, 2,3,5, 2,3,6, 24,5, 2,4,6 and 3,4,5 positions. Naphthyl and other aryl radicals can

Ge) be similarly substituted in any desired position, for example, the 1-naphthyl radical in the 5p positions 2, 3, 4, 5, 6, 7 and 8, and the 2-naphthyl radical in the 1, 3, 4, 5 positions ,6, 7 18. ik Along with the fact that (C5-C44)-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 carbon atoms of the ring are replaced by heteroatoms, in particular, the same or different heteroatoms from the group including nitrogen, oxygen and sulfur. Examples of heterocyclic (C5-C44)-aryl groups and two "C1-C4)-heteroaryl groups are opyridyl, in particular, 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrrolyl, in particular 2-pyrrolyl and 3-pyrrolyl , furyl, in particular 2-furyl and 3-furyl, thienyl, in particular 2-thienyl and 3-thienyl, imidazolyl, (F) pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, ka indolyl , isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinolinyl,

B-carbolinyl or condensed benzo-, cyclopenta-, cyclohexa- or cyclopenta- derivatives of the named radicals. for Heterocyclic systems can be substituted in all suitable positions by the same substituents as the above-mentioned carbocyclic aryl systems.

Among the named heteroaryl groups, preferred are monocyclic or bicyclic aromatic ring systems having 1, 2 or C heteroatoms, especially 1 or 2 heteroatoms (M, O and 5), and which may be unsubstituted or substituted with 1, 2 or C substituents with groups including (C--Cv)-alkyl, (C4-Cv)-alkoxy, fluorine, chlorine, nitro, 65 amino, trifluoromethyl, hydroxyl, (C4-C/)-alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl . Especially preferred in this case are monocyclic or bicyclic aromatic 5-10-membered ring systems having

1-3 heteroatoms, especially 1-2 heteroatoms (M, O and 5), which can be replaced by 1-2 substituents from the group including (C.4-C)-alkyl, (C.41-C/)-alkyl, 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, especially 1, heteroatoms (M, O, and 5), which are unsubstituted or substituted as indicated above.

If two radicals B! and K2 together mean a divalent saturated or unsaturated (Co-Co)-alkylene radical, these same 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 nitrogen atoms are attached will form a monocyclic 1 ,3-diazaheterocycle conjugated with a nitrogen atom in the group (СН»)»-СО-МН in position 2. Examples of radicals are 70 such 1,3-diazaheterocycles that can be substituted as indicated for (С 2-С9)-alkylene radical, as well as by the guanidine nitrogen atom, there are radicals 2-imidazolyl, 4,5-dihydro-2-imidazolyl, 1,4,5,6-tetrahydro-2-pyrimidinyl or 4,5,6,7-tetrahydro-1H -1,3-diazepin-2-yl. If the 5-7-membered ring is condensed along the carbon-carbon bond in the (C»o-Co)alkylene radical, the two radicals K' and K2 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 a nitrogen atom in the group (СНо)»-СО-МН and which can be substituted as indicated above. The fused 5-7-membered ring can be saturated, monounsaturated, monounsaturated, or aromatic. Thus, for example, there may be a condensed cyclopentane ring, cyclohexane ring, cyclohexene ring, cyclohexadiene ring, cycloheptane or benzene ring. Examples of radicals of such bicyclic heterocycles that can be bound to a nitrogen atom in the (CH 2)-CO-MH group are the radicals 1, Za, 4, 5, 6, ba-hexahydro-1,3-diazapentalen-2- yl, 1nH-benzimidazol-2-yl, Za, 4, 5, b, 7,

Tta-hexahydro-1H-benzimidazol-2-yl, 4, 5, b, 7-tetrahydro-1H-benzimidazol-2-yl, 4,7-dihydro-AN-benzimidazol-2-yl or 1H-imidazo|4, 5-b|pyridin-2-yl. If the condensed ring is substituted and/or if the (C»2-Co)-alkylene radical is substituted, they are preferably substituted independently of each other by one or/and two identical or different KO radicals. If the alkyl groups representing BC! and/or B? , are o substituted, they are substituted mostly independently of each other by one or two, preferably one, the same or different radicals of KZ.

Optically active carbon atoms contained in the compounds of the formula I can independently have the configuration K or 5. Compounds of the formula | may exist as pure enantiomers or pure o diastereomers, or as mixtures of enantiomers, for example, as racemates or mixtures of enantiomers. Gee!

The present invention relates to both pure enantiomers and mixtures of enantiomers, as well as pure diastereomers and mixtures of diastereomers. The invention covers mixtures of two or more stereoisomers of the formula | at any Me ratios of stereoisomers in mixtures. Compounds of the formula | can exist in the form of E or 2-isomers. with

The invention also covers both pure E-isomers and pure 2-isomers, as well as mixtures of E/7 in any proportions. Invention

Zo also applies to tautomeric forms of compounds of formula I, for example, along with the form shown in formula I, and ise) also to the form in which the acylguanidine block is represented in the form of the group -СО-М-С(МНЕ 73-МВ2Е, and all

Other forms that differ in different positions of mobile hydrogen atoms. Diastereomers, incl

E/27-isomers can be separated into individual isomers, for example, by chromatography. Racemates "can be separated into two enantiomers by a conventional method, for example, chromatography on chiral phases -

Or by splitting. Stereochemically homogeneous compounds of the formula | can also be obtained using stereochemically homogeneous starting materials or materials using stereoselective reactions. c» Salts of compounds of formula I that are physiologically tolerated 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, salts of alkali and alkaline earth metals, such as, for example, sodium salts, cadmium salts, magnesium salts and calcium salts, as well as salts with quaternary ammonium physiologically tolerated ions and salt adducts with ammonia and physiologically tolerated organic amines, such as triethylamine, ethanolamine or tris(2-hydroxyethyl)amine. Compounds of formula I containing basic groups will form salt adducts with acids, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, with organic carboxylic and sulphonic acids such as (Te) 20 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 acidic group, for example, a guanidine group and a carboxyl group, can exist in the form of zwitterions (betaines), which are also included in the present invention.

The physiologically tolerable anion 7 contained in the compounds of formula I, in which the radical BC 7 is an alkyl radical substituted by a positively charged ammonium group, is, in particular, a monovalent anion

HF) or one equivalent of a polyvalent anion of a non-toxic, physiologically suitable and at the same time pharmaceutically acceptable inorganic or organic acid, for example, an anion or an anionic equivalent of one of the above-mentioned acids capable of forming acid-salt adducts. Thus, O7 can be, for example, one of the anions (or anionic equivalents) from the group consisting of chloride, sulfate, phosphate, acetate, citrate, benzoate, maleate, fumarate, tartrate, methanesulfonate, and p-toluenesulfonate.

Salts of compounds of the formula | can be obtained by conventional methods known to specialists, for example, by the interaction of compounds of the formula | with an inorganic or organic acid or base in a solvent or dispersant, or from other salts by cation or anion exchange. The present invention also includes all salts of the compounds of the formula !, which, due to poor physiological tolerance, are not suitable for direct pharmaceutical use, but are applicable, for example, as intermediates for carrying out other types of chemical modification of the compounds of the formula | or as starting substances for obtaining physiologically tolerated salts.

This 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 derivatives that are physiologically tolerated, as well as active metabolites of compounds of formula I. The invention concerns also precursors of compounds of formula I, which can be converted into compounds of formula I! in 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 in a desired manner, are known to those skilled in the art. More detailed information regarding medicinal 70 predecessors can be found, for example, in Rieizpeg ei ai, Admapsei Ogyd Oeiimegu Kemiemuv 19 (1996) 115-130;

Oezvidp oyi Rgodgidvz, N. Vypaddaaga, Eada.,.Eivemieg, 1985; N. Vypadaaga, Ogydvoi (She Eshisge 16 (1991) 443; zatsipieg ek aiY.,, Viogd. Mey. Spet. Gen. 4 (1994) 1985; Zaiadi ei ai., RpagptasetiisaY Kev. 10 (1993) 1350, all of which are included in the invention as reference material. Particularly suitable precursors of the compounds of the formula are ester precursors of carboxylic acid groups, in particular, with the COOH group, which is in the case when B? in the 75 group COOB" is hydrogen, for example, alkyl ethers of this groups such as (C1-C8)-alkyl ethers or (C4-C6)-alkyl ethers, as well as acyl precursors and allylation-capable carbamate precursors with nitrogen-containing groups such as amino groups and especially guanidine groups. carbamate precursors, one or more, for example, two hydrogen atoms located at the nitrogen atom of the above-mentioned nitrogen-containing groups, are replaced by an adyl or carbamate group. Suitable acyl and carbamate precursors are, for example, groups K!9-СО and K10- SO, in which B 79 means is hydrogen, (C4-C40)-alkyl, (C4-Cv)-alkyl. (C3-C145)-cycloalkyl, (C3-C1454)-cycloalkyl- - (C1-C14)-aryl, in which 1-5

Св5-С4,-Си4)-aryl-(С1-Св)-alkyl-. in which 1-5 carbon atoms in the aryl part can be replaced by heteroatoms (M, O or 5), in which VK! has the same values as B 19, except for hydrogen.

Radicals КВ and 22 in the compounds of formula I are mainly hydrogen or together form a saturated or unsaturated, in particular, saturated divalent (Co-Cv)-alkylene radical, in particular, (Co-C/)-alkylene radical, (9 especially (Co- C3)-alkylene radical, which is unsubstituted or substituted by one or two identical or different radicals from the group, which includes halogen-(C.4-C)-alkyl, (C1-C)-alkyl, (C-C14)-aryl , (Св-С44)-aryl- (С1-Св)-alkyl-, (Св-С14)-heteroaryl, (С5-С44)-heteroaryl- (С4-Св)-alkyl-, (С5-С12) -cycloalkyl, (C3-C42)-cycloalkyl-(C1-Cv)-alkyl- and oxo group, where 5-7- is a saturated or unsaturated ring, which can be unsubstituted or substituted by a radical v, in particular, by one or two radicals c, and which is Ge) carbocyclic or heterocyclic ring containing one or two nitrogen atoms in the ring, can be condensed by the carbon-carbon bond of the alkylene radical. Radicals B! and 22 in compounds of the formula | most preferably means hydrogen or the group -"("СНо)р, in which p is 2, C, 4 or 5, preferably 2, C or 4 and, especially preferably, 2 or C and which is unsubstituted or substituted by one or two with the same or different radicals from the group that includes halogen, (Ci-Ci)-alkyl, (C--Ci)-alkoxy, (Ci-Ci4)-aryl, (C.4-Ci)-aryl- (Ci -Cv)-alkyl-, (Cv-C14)-heteroaryl, (C5-C44)-heteroaryl- (C4-Cv)-alkyl-, (C5-C12)-cycloalkyl, (C3-C42)-cycloalkyl- (C4 -Cv)-alkyl- and oxo group, where 5-7- is a saturated or unsaturated ring, which can be unsubstituted or substituted by a BU radical, in particular, by one or two KO radicals, and which is a "carbocyclic or heterocyclic ring containing one or two nitrogen atoms in the ring, can be condensed 7-3) with the carbon-carbon bond in the group "(СН 2)р". Even more preferably, if the radicals B and 2 together form the group "(CH"o)p, in which P is 2, З, 4 or 5, preferably 2, З or 4 and, especially preferably, 2 or З and which » is mostly unreplaced. Especially preferably, when the radicals KE and B? will jointly form a divalent radical -bno-sno-SnH»o-, i.e. when Viv, 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 connected, will form 1,4,5 ,6-tetrahydro-2-pyrimidinyl (o) radical. 2) 3 preferably means (C4-C10)-alkyl, (C3-C20)-monocycloalkyl, (Cv-C20)-bicycloalkyl, (C5-Sod)-tricycloalkyl, (Ci-Cv)-alkyl, (Cv-Ci4) -aryl, (Св-С14)-heteroaryl, (Св-Си4)-aryl- (С.1-С.44)-alkyl-, and (Св-С44)-heteroaryl-(С4-С.у)- alkyl-, halogen, trifluoromethyl, cyano, oxo, -M(C4-Cu)-alkyl)" or (Ce) 20 -MH-CO-(C4-C4)-alkyl. More preferably, when B means (C.i-C.sub.1)-alkyl, (C.sub.83-C.sub.10)-monocycloalkyl, o (C.sub.5-C.sub.2)-bicycloalkyl, (C.sub.1-C.sub.12)-tricycloalkyl, (C.sub.4-C.sub.4)- alkoxy, (C1-C14)-aryl, (C1-C14)-aryl- (C1-C14)-alkyl-, halogen, trifluoromethyl, cyano, oxo, -M(C1-Ca)-alkyl)" or -MH- CO-(C.-Cu)-alkyl. Especially preferred is VU, which means (C1-C10)-alkyl, (C3-C10)-monocycloalkyl, (C1-C42)-bicycloalkyl, (C1-C12)-tricycloalkyl, (C4-C1)-alkyl, two "C1-C14)-aryl, halogen, trifluoromethyl, cyano, oxo, -M(C1-C1)-alkyl)" or -"MH-CO-(C.-C.)-alkyl.

B" preferably means hydrogen or unsubstituted or substituted ((CHe)p-.,)-alkyl, especially preferably hydrogen

Ф, or (C.i-Cv)-alkyl, which is unsubstituted or substituted by a radical from the group, which includes (Ci-Ci)-alkoxy, imo) (C4-Ca)-alkyl-Z(O)5- and - MA"B", where VK" and B", independently of each other, mean hydrogen or (C1-C4)-alkyl.

Most preferred B", which means hydrogen or unsubstituted or substituted (C4-C6)-alkyl, more preferred 60 Kk, which means hydrogen or (C1-C))-alkyl, which is unsubstituted or substituted as indicated above. means (C1-C20)-alkyl, (C3-C20)-monocycloalkyl, (C1-C20)-bicycloalkyl, (C5-C20)-tricycloalkyl, (C1-C44)-aryl, (C1-C44)-heteroaryl (C1-C14)-aryl-(C4-C)-or (C-C44)-heteroaryl-(C1-C1)-alkyl-, where each of the aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl radicals is unsubstituted or substituted by one, two or three identical or different KZ radicals. More preferably, EC means (C4-C10)-alkyl, (C3-C15)-monocycloalkyl, (C1-C5)-bicycloalkyl,

(C5-C5)-tricycloalkyl, (C5-C44)-aryl, (C5-C14)-heteroaryl, (C5-C14)-aryl-(C4-C5)-alkyl- or (C5-C4)-heteroaryl -( -(C1-Cv)-alkyl-, where each of the radicals aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl is unsubstituted or substituted by one, two or three identical or different radicals KO. Along with the mentioned advantages in the predominant group of radicals BC? include the radicals (C 3-C200)-monocycloalkyl, (-C5-C.0)-bicycloalkyl and (C1-C00)-tricycloalkyl, which can be substituted or modified in another way, as indicated above, and of which the most preferred (Co 5-C45)-monocycloalkyl, (C5-C5)-bicycloalkyl and (C5-C5)-tricycloalkyl. Another predominant group of B radicals consists of radicals (C41-C20)-alkyl, (C5-C14)-aryl , (C1-C4)-heteroaryl, (C1-C14)-aryl-(C4-C1)-alkyl- or (C1-C-4)-heteroaryl- (C1-C1)-alkyl-, of which more preferred are (C1-C14)-aryl and (C1-C44)-heteroaryl, which can be substituted or modified in another way as indicated above. Particularly preferred radical groups E? are p phenyl and naphthyl adicals, ie phenyl, 1-naphthyl and 2-naphthyl, which may be unsubstituted or substituted as indicated above. 29 preferably means hydrogen or (C4-C1)-alkyl-0O-CO-, more preferably hydrogen or (C1-C1)-alkyl-0O-CO-, 75 especially hydrogen.

Preferred compounds of formula I are compounds in which one or more radicals have predominant values or have one or another feature in the respective designations, and all combinations of such predominant values or features in the designations constitute the subject of this invention. Particularly preferred compounds of the formula are those compounds in which B and B? is hydrogen or together form a saturated or unsaturated divalent 20 (С,-Сб5)-alkylene radical, especially hydrogen or the group -(СНо)р-, in which P is 2, З, 4 or 5, where (С2-Св)- the alkylene radical and the group "(СНо)р- are unsubstituted or substituted by a radical from the group including halogen, (Ci-Ci)-alkyl, (C--Ci)-alkyl, (Ci-Ci)-aryl, (Ci- C14)-aryl-(C1-C8)-alkyl-, (C8-C44)-heteroaryl, (C8-C14)-heteroaryl-(C1-C8)-alkyl-, (C3-C125)-cycloalkyl, ( C3-C12)-cycloalkyl-(C1-Cv)-alkyl- and oxo group, and where 5-7- is a saturated or unsaturated ring, which can be unsubstituted or substituted by a KU radical, especially CM 25 by one or two KU radicals, and which is a carbocyclic or heterocyclic ring containing one or two nitrogen atoms in the ring, can be condensed along the carbon-carbon bond in the (C 5-Cv)-alkylene radical and in the "CH"e)p- group;

BZ is (C4-C0)-alkyl, (C3-Cr)-monocycloalkyl, (Cr-Cr)-bicycloalkyl, (Cr5-C0)-tricycloalkyl, (Cr-Cr)-alkyl, (Cr-C14) -aryl, (С5-С44)-heteroaryl, (Св-С14)-aryl-(С4-С,)-alkyl-, o 30 (Св-С44)-heteroaryl-(С4-Св)-alkyl- , halogen, trifluoromethyl, cyano, oxo, -M(C.4-C)-alkyl)" or F -MH-CO-(C 1-C.)-alkyl;

B" represents hydrogen or (C1-C8)-alkyl, which is unsubstituted or substituted by a radical from the group that includes F (C.-C4)-alkoxy, (C1-C8)-alkyl-8(O)"- and -MA'B", where K" and KE", independently of each other, mean hydrogen or 0 35 (C, -C 5 )-alkyl; "at

Vo represents (C 4-Sod)-alkyl, (C3-Cor)-monocycloalkyl, (Cv-Sod)-bicycloalkyl, (Cv-Coo)-tricycloalkyl, (CoCi4)-aryl, (Cv-C44)-heteroaryl , (Cv-Ci4)-aryl-(Ci-Cv)-alkyl- or (Cv5-C14)-heteroaryl-(Ci-Cv)-alkyl-, where each of the radicals is aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl is unsubstituted or "substituted by one, two or three radicals of KZ; 40 25 represents hydrogen or (С1-Св)-alkyl-ОО-СО-; no) c in all stereoisomeric forms and their mixtures in any proportions, as well as salts of these compounds that are physiologically tolerated and their precursors.

Particularly preferred compounds of formula I are compounds in which:

B is hydrogen or together form a saturated or unsaturated divalent (С2-Са)-alkylene radical, especially hydrogen or the group "СН»5)р-, in which P is 2, З or 4, where (С2-С/ )-alkylene radical and the group "("СНо)р- are unsubstituted or substituted by a radical from the group including halogen, (С1-Св)-alkyl, (С4-Св)-alkyl, (95) (Сб-С454)- aryl, (Св-Си5)-aryl-(Си-Св)-alkyl-, (Св-С.45)-heteroaryl, (С5-С.445)-heteroaryl- (С.4-Св)-alkyl-, with a (C3-C42)-cycloalkyl, (C3-C42)-cycloalkyl- (C41-C4)-alkyl- and oxo group, and where the 5-7-chain is a saturated or unsaturated group that is unsubstituted or substituted by a BZ radical, especially one or two KU radicals, and which is a) carbocyclic or heterocyclic ring containing one or two nitrogen atoms in the ring, can be condensed by the carbon-carbon bond in the (Co-C/)-alkylene radical and in the group ""СНо)р-;

BZ is (C 1-C4)-alkyl, (C3-C10)-monocycloalkyl, (C1-C12)-bicycloalkyl, (C5-C12)-tricycloalkyl, (C.-C1)-alkyl, (C8-C12) -aryl, /(C1-C44)-aryl-(C4-C6)-alkyl-, halogen, trifluoromethyl, cyano, oxo, 55 M(C1-C4)-alkyl)" or MH-CO-(C.4- C,)-alkyl; o VE is hydrogen or (C1-Cv)-alkyl;

Bo is (Ci 4-Ci0)-alkyl, (Ci-Ci5)-monocycloalkyl, (Ci-Ci)-bicycloalkyl, (Ci5-Ci)-tricycloalkyl, where (Ci-Ci4)-aryl, (Ci-Ci) )-heteroaryl, (Cv-C14)-aryl- (Ci-Cv)-alkyl- or (Cv5-C44)-heteroaryl-(C1-Cv)-alkyl-, where each of the radicals is aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl is unsubstituted or substituted by one, two or three BZ radicals; is hydrogen or (C4-C1)-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. c The most preferred compounds of formula I are compounds in which:

IN! and 2 are hydrogen or together form a saturated or unsaturated divalent (C 2-C3)-alkylene radical, especially hydrogen or a group -"(CH"o)p-, in which P is 2 or 3, where (C2-C3)- the alkylene radical and the group -"(СНо)р- are unsubstituted or substituted by a radical from the group including halogen, (С4-Св)-alkyl, (С4-Св)-alkoxy, (Св-С44)-aryl, (Св- C4454)-aryl-(C4-Cv)-alkyl-, (Cv-C44)-heteroaryl, (Cv-C44)-heteroaryl- (C4-Cv)-alkyl-, (C3-C42)-cycloalkyl, (C3- C42)-cycloalkyl- (C41-Cv)-alkyl- and oxo group, and where the 5-7--one saturated or unsaturated ring, which is unsubstituted or substituted by a radical in, in particular, by one or two radicals in, and which is a carbocyclic whether a heterocyclic ring containing one or two nitrogen atoms in the ring can be condensed along the carbon-carbon bond in the (C2-C3)-alkylene radical and in the "СНо)р- group;

BZ is (Ci 4-Ci)-alkyl, (Ci-Ci0)-monocycloalkyl, (Ci-Ci2)-bicycloalkyl, (Ci-Ci)-tricycloalkyl, 70. (Ci-Ci)-alkyl, (Ci -C.4)-aryl, halogen, trifluoromethyl, cyano, oxo, -M(C4-C6)-alkyl)" or -"MH-SK-(C1-Ca)-alkyl;

VE is hydrogen or (C1-Cv)-alkyl;

BO is (C 4 -C 10 )-alkyl, (C 3 -C 5 )-monocycloalkyl, (C 1 -C 10 )-bicycloalkyl, (C 5 -C 5 )-tricycloalkyl, (C 1 -C 4 )-aryl, (C 1 -C 44 )-heteroaryl , (Св-Си4)-aryl-(С1-Св)-alkyl- or (Св5-С44)-heteroaryl-(С1-Св)-alkyl-, where each of the radicals is aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl is unsubstituted or substituted by one, two or three radicals of KZ; 25 is hydrogen or (C4-C1)-alkyl-O-CO-; in all stereoisomeric forms and their mixtures in any proportions, as well as salts of these compounds that are physiologically tolerated and their precursors.

Along with that. preferred compounds of the formula ! there are compounds in which K 9 is (Св-Си4)-aryl or (Св-С,,)-heteroaryl, preferably (Се-С14)-aryl, where the aryl and heteroaryl radicals are unsubstituted or substituted by one, two or three identical or different KO radicals and preferably unsubstituted or substituted by one or two identical or different KZ radicals, in all stereoisomeric forms and their mixtures in any proportions, as well as physiologically tolerated salts of these compounds and their precursors. Still with 29 more preferred compounds of formula I, in which B? is a naphthyl radical, such as the radicals 1-naphthyl and Ge) 2-naphthyl, which is unsubstituted or substituted by one, two or three radicals in, and which is preferably unsubstituted, such as the unsubstituted radicals 1-naphthyl and 2-naphthyl, in in all stereoisomeric forms and their mixtures in any proportions, as well as physiologically tolerated salts of these compounds and their precursors. o 30 Preferable compounds of formula I are also compounds in which the carbon atom to which two groups of К7О-СО - and 259-505-МН- are bonded has the З-configuration, in all stereoisomeric forms and their mixtures in any proportions, as well as Me salts of these physiologically tolerated compounds and their precursors. Gee!

A separate group of compounds of formula I consists of compounds in which B and 22, independently of each other, are hydrogen or (C1-Cv)-alkyl, which is unsubstituted or substituted by the radical KU, or in which the radicals BK and B, together, about 35 form a saturated or unsaturated divalent (C 2-Ce)-alkylene radical, for example, the group "СНо)р- In which p is 2, З, 4, 5, 6, 7, 8 or 9 and which is unsubstituted or substituted by one or more groups from the group consisting of halogen, (C4-C8)-alkyl, (C41-C8)-alkyl, (C8-C44)-aryl, (C8-C14)-aryl-(C1-C8)-alkyl, ( C1-C414)-heteroaryl, (C1-C4454)-heteroaryl-(C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C42)-cycloalkyl-(C1-C8)-alkyl and oxo, and where " 5-7--len saturated or unsaturated ring, which is unsubstituted or substituted by the KU radical, in particular, by one or two EKZ radicals, and which is a carbocyclic or heterocyclic ring containing one or two C with nitrogen atoms in the ring , can be condensed by the carbon-carbon bond of the (Co-Co)-alkylene radical; c" BZ represents (C1-C8)-alkyl, (C4-C8)-alkyl, (C8-C1)-aryl, (C8-C14)-aryl- (C1-C8)-alkyl, (C5- C1)-heteroaryl, (C1-C14)-heteroaryl-(C1-C1)-alkyl, halogen, trifluoromethyl, oxyhydroxyl, oxo, nitro; amino, MH-(C4-Cu)-alkyl, M(C4-Cu)-alkyl), MH-CO-(C.-C)-alkyl or CO-(C.-C.)-alkyl; b 175 B" represents hydrogen, (C 1-Cv)-alkyl-CO-O- (C.4-C.)-alkyl or (C1-Cv)-alkyl, which is an unsubstituted or substituted radical from the group that includes hydroxyl, (C4-C6)-alkoxy, (C1-C4)-alkyl-5(0)»-, -MA/B'i M'vB'v "in" a, where B,

Mami B" or c", independently of each other, mean hydrogen, (C.4-C)-alkyl, (C.-C.14)-aryl or (C.-C.44)-aryl-(Ce) (C.-C) -alkyl, and C means an anion that is physiologically transferred or B is one of the radicals: so 020 - -u tot on 62 sn, sn, ach tk tron nin My on 55 in which free bonds, through which attached radicals, indicated by dashed lines;

K represents (C 4-Coo)-alkyl, (Cv-Co0)-monocycloalkyl, (Cv-Cord)-bicycloalkyl, (Cv-Coo)-tricycloalkyl,

F, (Cv-C44)-aryl, (Cv-C14)-heteroaryl, (Cv-C44)-aryl-(C4-Cv)- or alkyl (Cv-C45)-heteroaryl-(C.i-Cv) )-alkyl, where each of the aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl, and tricycloalkyl radicals is unsubstituted or substituted by one, two, or three radicals, and where the alkyl, monocycloalkyl, bicycloalkyl, and tricycloalkyl radicals contain one or more carbon atoms, in particular, one, two, three or four carbon atoms may be replaced by the same or different atoms selected from the group consisting of nitrogen, oxygen and sulphur; means hydrogen, (C.4-Cv)-alkyl-O-CO-, hydroxyl, (C.4-Cv)-alkyl-O-CO-O- or nitro group; in all stereoisomeric forms and their mixtures in any proportions, as well as physiologically tolerated salts of these compounds and their precursors. 65 This invention also relates to methods of obtaining compounds of formula I. Compounds, as a rule, can be obtained, for example, using convergent synthesis by combining two or more fragments,

which can be isolated from the formula | by the reverse synthesis method. When obtaining compounds of the formula, it is usually advisable or necessary to introduce functional groups in the process of synthesis, which could lead to undesirable or side reactions at the corresponding stage of synthesis, in the form of their precursors, which are later transformed into desired functional groups, or to temporarily block functional groups using technique suitable for the synthesis of protective groups. This kind of technique is well known to specialists (see, for example, Geepe apa MUtsiv, Rgoiesime Sgotsre ip Oidapis Zupipevziz, MUMPeu, 1991). As an example of precursor groups, we can mention nitro- and cyano groups, which can later be transformed, respectively, into amino- and aminomethyl groups, by reduction, for example, by catalytic hydrogenation. 70 Compounds of the formula | can be obtained, for example, by linking carboxylic acids or carboxylic acid derivatives of formula II by known methods:

Gee)

BUT o M goes ut5. 8-0 внх оо в 2 ня - in which V" and EZ are defined as in formula I or in which functional groups are present in the form of their predecessors, which later turn into groups contained in compounds of formula I, or functional groups are present in a protected form and where X means a leaving group capable of nucleophilic substitution, with guanidines or guanidine derivatives of the PP formula:

M-v Sh nya-y m--k Sh her village

K in which B", 22 and 25 are defined as indicated for the formula I! or in which the functional groups are present in the form of their i) predecessors, which are later transformed into groups that are present in the compounds of the formula I, or the functional groups are present in the protected form .

The COX group in formula I is mainly a COOH carboxylic acid group or an active oxa carboxylic acid derivative group. X represents, for example, hydroxyl or halogen, in particular, chlorine or bromine, an oxy group, preferably methoxy or ethoxy, an aryloxy group, for example, phenoxy or pentafluorophenoxy, a phenylthio, b» methylthio, 2-pyridylthio group or a radical of a nitrogen-containing heterocycle attached through a nitrogen atom , in particular, azole, (such as, for example, 1-imidazolyl. In addition, X can be, for example, (C 4 -C /)-alkyl)-O-CO- or tolylsulfonyloxy, and the active acid derivative can thus to be a mixed anhydride. at

If X represents a hydroxyl, that is, if the guanidine of the formula P interacts with a carboxylic acid, then it is advisable to activate the carboxylic acid first. Activation can be done, for example, with the help of dicyclohexylcarbodiimide (OCSCI) or O-(cyano(ethoxycarbonyl)methylene)amino!|-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTIU, Kopid eii aiYi., Rgos. 21 8vi Etsyhor Reriide Zutr. 1990 (Edv. Sigai Apagets), Ezsot,

Eidep 1991, p. 143) or other activating reagents, usually used in peptide chemistry. "

Along with the free guanidines of the formula III, guanidine salts can also be used for the reaction with the compounds of the formula I, which are then converted into free guanidines separately or in a separate step with the use of bases. Reaction of active derivatives of carboxylic acids of formula II with guanylin (derivative) of formula ;" PI is mainly carried out by a known method in a protic or aprotic polar but inert organic solvent. In this case, solvents such as methanol, isopropyl alcohol, tert-butanol, dmethylformamide and tetrahydrofuran, at a temperature from 0"C to the boiling point of these solvents

He" turned out to be suitable, in particular, for the reaction of complex methyl ethers (X-methoxy) and complex ethyl ethers (X-:ethoxy) with guanidines. Reactions of compounds of the COX type with guanidines that do not contain salt are expediently carried out in aprotic inert solvents such as dimethylformamide, tetrahydrofuran, dimethoxyethane, or dioxane, if appropriate, with the addition of an 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, when 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 hydrohalic acid that is formed. The reaction mixture is processed and the reaction product, if desired, is purified using known methods.

The protective groups that may still remain in the products obtained from the compounds of the formulas II and I are removed by standard methods. For example, ester tert-butyl groups are converted into carboxyl groups

F) treatment with trifluoroacetic acid, benzyl groups are removed by hydrogenation, and fluorophenylmethoxycarbonyl groups are removed with the help of secondary amines. If desired, further reactions are carried out using standard methods, for example, adylation or esterification reactions. Finally, with the use of well-known methods, the transformation of the mentioned compounds into physiologically tolerated salts or drug precursors can be carried out.

Initial components of formulas I! and PS, which combine to form compounds of formula I, can be purchased or can be obtained similarly to the methods described in the literature. The preparation of the starting components of the formula HER is illustrated by an example in Scheme 1 below, and the invention is not limited either to this synthesis or to the 65 starting components. It is not a problem for a specialist to make changes in the shown synthesis necessary to obtain other compounds corresponding to the invention.

Thus, for example, a reaction of carboxybenzaldehyde of the formula IM in the presence of pyridine or piperidine with a salt of the complex ester of malonic acid of the formula M can be carried out with the formation of a derivative of cinnamic acid of the formula MI, which after hydrogenation, for example, in the presence of palladium on carbon, gives a compound of the formula MII

After activation with a carboxylic acid group, compounds of formula MI can be condensed with derivative 2,

Z-diaminopropionic acid of the formula MI! with the formation of a compound of formula IX (Scheme 1). Condensation can, for example, be carried out in the presence of LTPC or another agent commonly used to activate carboxylic acids.

M in formula MI can be the group KZ-505-, which is present in the final compounds of formula I of this 70 invention and which can remain in the molecule, or M can be a group that temporarily protects the amino group in position 2 and which is in one of the following stages is removed with the release of the amino group, which is then converted into the K?805-MN group using standard methods of obtaining sulfonamides, for example, the reaction of a free amine with the sulfonyl chloride of the formula K?8505-SI. An example of a protecting group denoted by M is a benzyloxycarbonyl group (2-group), which can be removed by catalytic hydrogenation. Sulfonyl chlorides 75 of the formula K?50»-CI and other sulfonic acid derivatives suitable for the introduction of group B 505- can be purchased or can be obtained in accordance with or by analogy with the procedures described in the literature. Instead of the complex tert-butyl ether fragment, which is contained in the formulas MI and IX, other complex ether fragments may be present, which

Scheme 1 9 sv i o nu ok o i no" U , m pd, s o-sv, o

M M

Ge) Mn, o ne-- Mn shk U U o: sv M Ga") no in Fu m o-sv, MI (22) 3 O so , (in) 3 o--sn, (Se) nyu-i On their own, they either temporarily protect the acid group, or may be present in the final compounds of formula I, which correspond to the invention, and may remain in the molecule.

Compounds similar to the compound of formula MI can also be obtained using other methods of converting a carbonyl group into an alkene, for example, using the Wittig reaction. » Compounds of formula II are examples of compounds of formula II, in which X represents a methoxy group. These and similar compounds obtained by the synthesis described above and containing a group related to active carboxylic acid derivatives can be directly reacted with compounds of formula I.

However, the compounds obtained in this synthesis can be first converted under standard cleavage conditions with an ester metal or other ester group located in a suitable position in 2) compounds of formula IX to form the corresponding carboxylic acids, which are then reacted with guanidines of the formula III, having been previously activated by using, for example, using TOT or OSCI, or converted into an active derivative of a carboxylic acid. If as active carboxylic acid derivatives

Ge) 20 is expected to obtain, for example, chloride anhydrides (formula II, X-CI), such a transformation can be carried out using, for example, thionyl chloride. If it is intended to obtain from carboxylic acids, for example, complex methyl ethers (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 chloride anhydrides of carboxylic acids or directly from carboxylic acids themselves 29 (its formula, X-OH). An example is imidazolides (formula II, X-1-imidazolyl), obtained by treatment with acids

HF) carbonyldiimidazole (5iaab, Apdemu. Spet. Ipi E4Y. EEpadi. 1(351-367 (1962)) or mixed anhydrides obtained, for example, by reaction with chloroformic acid esters, such as ethyl chloroformate, or with de 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 literature references, are given 60 in U. Magsi, Aduapsed Ogdapis Spetivigu, Triga Edyiop, dopp UMieu Ye Zopv, 1985, p.350.

Compounds of formula I! are valuable pharmaceutical active ingredients suitable, for example, for therapy and prevention of bone disorders, tumor diseases and cardiovascular disorders. Compounds of the formula | and their physiologically tolerated salts and precursors can be administered to animals, mainly mammals, and especially to humans as pharmaceutical agents for therapy and prevention. They can be administered individually or in mixtures with each other, or in the form of pharmaceutical preparations that allow oral or parenteral administration and that contain as an active ingredient an effective dose of at least one compound of the formula! and/or their physiologically tolerated salts and/or their precursors in admixture with conventional pharmaceutically harmless carriers and/or additives.

This invention, thus, also applies to compounds of formula I! and/or physiologically tolerated salts and/or their precursors for use as pharmaceutical agents, use of compounds of formula I and/or physiologically tolerated salts and/or their precursors for the production of pharmaceutical agents for the therapy and prevention of the above-mentioned and further diseases, for example, for the therapy and prevention of bone disorders, as well as the use of compounds of formula I and/or physiologically tolerated salts and/or their precursors for therapy 7/0 | prevention of these diseases. The present invention, in addition, relates to pharmaceutical preparations or pharmaceutical compositions containing 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.

Pharmaceuticals can be administered orally, for example, in the form of pills, tablets, glazed tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, /5 emulsions, or suspensions of aerosol mixtures. However, the administration 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 or injections of infusion solutions, microcapsules, or rod implants, or percutaneously, or locally, for example, in the form of ointments or tincture solutions, or in other ways, for example, in the form of aerosols or nasal sprays.

The pharmaceutical preparations of this invention are prepared using methods known to specialists, using inert inorganic or organic carriers in combination with the compound or compounds of formula I and/or its physiologically tolerated salts and/or its precursors. For the production of pills, tablets, coated tablets and hard gelatin capsules can be used, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils, etc. Suitable carriers for the production of solutions, for example, solutions for injections, or emulsions and) syrups, are, for example, water, alcohols, glycerin, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitable carriers for microcapsules or stick implants are, for example, copolymers of glycolic and lactic acids. Pharmaceutical preparations usually contain from about 0.5 to 9095 wt. compounds of the formula | physiologically tolerated salts and/or their precursors. The amount of the active ingredient of the formula I and/or its physiologically tolerated salts and/or its precursors in the pharmaceutical preparation is usually from 0.2 to 500 mg, preferably from 1 to 200 mg. Gee!

Along with active ingredients and carriers, pharmaceutical preparations may also contain additives such as, for example, fillers, disintegrating agents, binding agents, lubricating agents, wetting agents, stabilizers, emulsifiers, preservatives, sweetening agents, dyes, flavoring or flavoring (au additives, thickeners, thinners, buffer substances, as well as solvents or solubilizers, or agents that ensure the preservation of products, salts for changing osmotic pressure, covering agents and antioxidants.

Preparations may also contain two or more compounds of formula I and/or their physiologically tolerated salts or their precursors. Along with this, in addition to at least one compound of the formula | and/or its physiologically tolerated salts and/or its precursors, preparations may also contain one or more therapeutically or prophylactically active ingredients. . Compounds of the formula | are antagonists of the vitronectin receptor and inhibitors of cell adhesion. They have, and? 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 compounds of the formula! can, for example, be demonstrated in a study that determines the inhibition of vitronectin binding to cells that

Ge" contain a vitronectin receptor. Details of this study are given below. As antagonists of the vitronectin receptor compounds of the formula! and their physiologically tolerated salts or their precursors, as a rule, are suitable for the therapy and prevention of diseases associated with the interaction between vitronectin receptors and their

He) by ligands in the processes of intercellular interaction or in the processes of cell-matrix interaction, or which can be affected by the inhibition of interactions of this kind. Thus, to prevent or facilitate the treatment of such diseases, inhibition of interactions of the above types is desirable. As was explained at the beginning, such interactions, in particular, play a role in the resorption of bone tissue, in angiogenesis and proliferation of vascular smooth muscle cells. Formula compounds ! and their salts, which are physiologically tolerated and their precursors are suitable, for example, for the relief or treatment of diseases, at least in part, due to the undesirable second degree of bone tissue resorption, angiogenesis and proliferation of vascular smooth muscle cells.

Bone diseases, for the treatment and prevention of which can be used according to the invention (F, compounds of formula I, are primarily osteoporosis, hypercalcemia, osteopenia, caused, for example, by metastases, dental diseases, hyperparathyroidism, periarticular erosions in rheumatoid arthritis and Paget's disease.

In addition, compounds of the formula | can be used to alleviate or prevent the therapy of bone diseases arising as a result of glucocorticoid, steroid or corticosteroid therapy or due to the absence of sex hormone(s). All of these diseases are characterized by bone loss caused by an imbalance between cyst formation and destruction, and can be beneficially affected by inhibition of bone resorption by osteoclasts. The compounds of formula I and/or their physiologically tolerated salts or their precursors can also be successfully used as bone resorption inhibitors, e.g. in the therapy or prevention of osteoporosis, in combination with conventional methods of osteoporosis treatment, e.g. in combination with bisphosphonates , estrogens, estrogen/progesterone, estrogen agonists and antagonists, calcitin, analogues of vitamin OO, parathyroid hormone, means of increasing the secretion of growth hormone or sodium fluoride. Introduction of compounds of the formula ! and/or salts that are physiologically tolerated and/or their precursors and other active ingredients that are effective in the treatment and prevention of osteoporosis, similar to those listed above, can be carried out simultaneously or sequentially, in several doses, and jointly or separately. For use in such combined treatment or prophylaxis of compounds of formula I! and/or their physiologically tolerated salts and/or their precursors and one or more other active ingredients similar to those listed above may be contained together in one pharmaceutical preparation, for example, tablets or granules, or separately in two or more pharmaceutical preparations that 7/0 May be in the same package in two or more separate packages. The use of compounds of the formula and the physiologically tolerated salts and/or their precursors in such combined therapy or prophylaxis, or their use in the production of pharmaceuticals for such combined therapy or prophylaxis are also subjects of this invention. The invention also relates to pharmaceutical preparations containing effective amounts of at least one compound of formula I and/or their physiologically tolerated salts and/or their precursors together with at least one other active ingredient effective in treatment or prevention osteoporosis, or in terms of inhibiting bone resorption, similar to those listed above, together with a conventional pharmaceutically innocuous carrier. The above explanations relating to pharmaceutical preparations apply accordingly to such combined pharmaceutical preparations.

Along with their use as inhibitors of bone tissue resorption by osteoclasts, compounds of the formula of their physiologically tolerated salts or precursors can be used as inhibitors of tumor growth and tumor metastasis, anti-inflammatory agents, for therapy and prevention of cardiovascular disorders, such as arteriosclerosis or reversible stenosis , or for therapy and prevention of nephropathies or retinopathy, such as, for example, diabetic retinopathy. As inhibitors of tumor growth or tumor metastases compounds of the formula

They or their physiologically tolerated salts and/or their precursors can also be successfully used in combination with traditional anticancer therapy. Examples of traditional anticancer therapy are given in Vegipo (editor) in Epsusioredia oi Sapseg, Asadetis Rgezz, 1997, which is incorporated herein by reference i) material. All of the above statements regarding the use of compounds of the formula | in combination with the traditional therapy of osteoporosis, which concerns, for example, methods of application and combined pharmaceutical preparations, extend accordingly to the use of compounds of the formula | in combination with traditional anticancer therapy.

When using compounds of formula I, the dose can vary widely and, as is customary, depends on the individual conditions in the individual case. It depends, for example, on the used compound or on the nature and degree of the disease, as well as on whether the treatment of an acute or chronic disease is carried out, or whether it is being prevented. When administered orally, the daily dose is usually from 0.01 to 100 mg/ kg, preferably from 0.1 to b5BOmg/kg, hour, from 0.1 to b5Bmg/kg, for example "about 0.3-0О0.5mg/kg to obtain effective results in the treatment of an adult weighing approximately 75kg (in all cases we are talking about mg per kg of body weight.) In the case of intravenous administration, the daily dose is usually from about 0.01 to 10 Ω/kg, preferably from 0.05 to 1 Ω/kg (in each case per kg of body weight).

The daily dose can be divided, in particular, when relatively large amounts are administered, 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, compounds of the formula | can also be used as ;" solvents or carriers of active ingredients for the purpose of selective transport of active ingredients to the site of their action (positional drugs; see, for example. M.K. ei ai.. Zrhipdeg Mepad, which is included in the present invention as a reference

Ge" material). The active ingredients intended for transport are mainly ingredients that can be used for the treatment of the above-mentioned diseases. o Compounds of formula I! and their salts can, in addition, be used for diagnostic purposes, for example, for

Ge) diagnosis of ip migo, and as auxiliary substances in biochemical studies, in which blocking of the 5o receptor of vitronectin or influence on intercellular or cell-matrix interactions is required. They can also be used as synthesis intermediates to obtain other compounds, in particular, other pharmaceutically active ingredients that can be obtained from compounds of formula I, for example, by modifying them or introducing radicals or functional groups.

Examples

The products were identified by mass spectra (MS) and/or NMR spectra. Depending on how the final stage of the synthesis or processing procedures, such as cryogenic drying, was performed, in some cases the compounds

F) obtained partially or completely in the form of a salt, for example, in the form of an acetic acid salt, a trifluoroacetic acid salt or a hydrochloric acid salt.

Example 1 in (25)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid b5

M li (c)

H

(a) 4--2-Methoxycarbonylvinyl)benzoic acid 18.74 g (0.12 mol) of potassium monomethylmalonate is suspended in 1838 mol of pyridine and added at room temperature and stirring 15.01 g (0.1 mol) of 4-carboxybenzaldehyde and 0.85 g (0.01 mol) of piperidine. The mixture is boiled under reflux until the release of CO" stops (about 2 hours), an additional bomol of pyridine is added and the mixture is stirred under reflux for another 1 hour. After that, 50 mol of ice and 110 mol of concentrated hydrochloric acid are added to the reaction mixture with stirring. After the addition is complete, the mixture is stirred for another 20 minutes, the product is filtered under reduced pressure, washed with water and recrystallized from isopropyl alcohol. Output 12.85 g. "H-YAMER" (200 MHz, a5-DMSO): 5- 3.75 (s, ZN, OSN"); 6.76 (d, U-15Hz, IN, SNSOOSN"); 7.73 (d, U -15Hz, 1N,

Ag-CH); 7.84 (d, U-9Hz, 2H, AgH-H); 7.98 (d, U-9Hz, 2H, Ag-H); 13.11 (c extended, 1H, COOH).

MS (SI) gt/e-207.2 (MAN).

TOP: KR'I18, Mysieovii 300-5-Si8, 250x4mm; buffer A: HNO, 0.195 trifluoroacetic acid (TFA); buffer B: 20 acetonitrile (80 vol. 95), HO (2006. 90), 0.190 TFU; gradient: the first 5 min. 90905 buffer A and 1095 buffer B, then after 20 min. to 9095 buffer B, then after 5 min. 9095 buffer B; volumetric rate Tml/min; holding time 18.05 min. c) 4--2-Methoxycaronylethyl)benzoic acid 8 g (38.8 mmol) of 4-(2-methoxycarbonylvinyl)'benzoic acid is suspended in 250 mol of dioxane and hydrogenated for 7 hours at room temperature above 1095 Pa/C at a hydrogen pressure of 1 bar. The mixture is filtered and the solvent is evaporated under vacuum. Output 8.05 g. 7H-NMR (200MHz, as-DMSO): 5-2.67 (t, U-8Hz, 2H, СНо-СООСН»); 2.93 (t, 9-8Hz, 2H, Ag-СНо); 3.59 (c, ZN, o

OSNU"); 7.35 (d, 2H, AG-H); 7.86 (d, U-9Hz, 2H, AG-H); 12.80 (c extended, 1H, COOH).

MS (SI): t/e-209.2 (MAN).

TOP: KR18, Mysieovii 300-5-318, 250x4mm; buffer A: HO, 0.195 TFU; buffer B: acetonitrile (8006.905), No o (2006.90), 0.195 TFU; gradient: first bhv. 9095 buffer A and 1095 buffer B, then after 20 min. to 9095 buffer B, and then after 5 min. 9095 buffer B; volume rate ml/min; retention time 17.03 min. c) tert-butyl(25)-2-benzyloxycarbonylamino-3-(4-(2-methoxycarbonylethyl)benzoylamino)propionate b"

354 mg (1.7 mmol) of 4-(2-methoxycarbonylethyl)benzoic acid and 500 mg (1.7 mmol) of tert-butyl(25)-C-amino-2-benzyloxycarbonylaminopropionate are dissolved in 3 mol of dimethylformamide and treated with 557 mg (1.7 mmol) O-((cyano(ethoxycarbonyl)methylidene)amino-1,1,3,3-tetramethyluronium |se) tetrafluoroborate (TOTU) and 204 mg (1.7 mmol) of diisopropylethylamine, after which the mixture was stirred at room temperature for 7 hours at pH 7-8. The solvent is removed under vacuum, the residue is dissolved in ethyl acetate, and the solution is washed three times with KNZO solutions); and MansCO3 (each time) to a neutral reaction. The organic phase is separated, dried and the solvent is removed under vacuum.

Output 77Omg. MS (EB"): m/e-485.2 (MAN). With c a) tert-butyl ether (25)-2-amino-3-(4-(-2-methoxycarbonylethyl)benzoylamino)propionic acid "from 6b.88m (14.2mmol)" of tert-Butyl(25)-2-benzyloxycarbonylamino-3-(4--2-methoxycarbonylethyl)benzylamino)propionate is dissolved in 200 mol of methanol and 852mg (14.2mmol) of acetic acid is added. The mixture is hydrogenated for 7 hours at room temperature above 595 Pa/C at a hydrogen pressure of 1 bar.After that, the mixture is filtered and the solvent is removed under vacuum.

Ф The residue is washed with n-heptane and dried in a vacuum. Exit 6b, 9g. MS (EB"): m/e-351.2 (MAN). o f) tert-Butyl ether (25)-3-(4-(2-methoxycaronyl-ethyl)benzoylamino)-2-("Naphthalene-1 -sulfonylamino)propionic acid and 0.123m (0.35mmol) of tert-butyl ether (Ce) 20 (25)-2-amino-3-(4-(2-methoxycarbonylethyl)benzoylamino)propionic acid are dissolved in 2mmol of dimethylformamide and 0.196 bmol (14 mmol) of triethylamine and 0.159 m (0.7 mmol) of 1-naphthalene sulfonyl chloride are treated. The solution is stirred for 4 hours at room temperature. The solvent is removed in vacuo, the residue is dissolved in dichloromethane and the resulting solution is washed three times with water. The organic phase is dried over sodium sulfate, filtered and the solvent is removed in vacuo. The residue is chromatographed on 59 silica gel, eluting with a mixture of n-heptane/ethyl acetate (1/1). Yield 47 mg. MS (EB"): t/e-541.3 (MAN).

GF) In tert-Butyl ether

GF (25)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propio new acid in 47 mg (0.087 mmol ) tert-butyl ether (25)-3-(4-(-2-methoxycarbonylethyl)benzoylamino)-2-(naphthalene-1-sulfonylamino)propionic acid is dissolved in 2 mol of dimethylformamide and 8 mg (0.87 mmol) of 2-amino- 1,4,5,6-tetrahydropyrimidine. The reaction mixture was stirred for 20 hours at room temperature.

The solvent is removed in vacuo and the residue is chromatographed on silica gel, eluting with a mixture of dichloromethane/methanol (1/1) and then dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5). Output 4bmg. MS (E5U: t/e-608.3 (MAN U.

(25)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propio nova acid 45mMg (0.074mmol) tert- The butyl ether (25)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propio new acid is dissolved in 2 mol of dichloromethane and add 2 mol of trifluoroacetic acid. The solution is stirred for an hour at room temperature. The solvent is removed in vacuo, toluene is added to the residue and then removed in vacuo. The residue is dissolved in a mixture of acetonitrile/water (1/1) and subjected to freeze drying. 70 Exit BOmg. MS (EB"): t/e-552 (MAN).

Example 2 (25)-2-(Quinoline-8-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)pro pionic acid

M

Oh-Oh Ah,

N Mn. О-5th so - a) tert-Butyl ether (25)-3-(4-(2-methoxycarbonylethyl)benzoylamino)-2-(quinoline-8-sulfonylamino)propionic acid 0.123m (0.35 mmol) of tert-Butyl ether (25)-2-amino-3-(4-(-2-methoxycarbonylethyl)benzoylamino)propionic acid is dissolved in 2 mol of dimethylformamide and treated with 0.19 bmol (14 mmol) of triethylamine and 0.159 m (0.7 mmol) of 8-quinolinesulfonyl chloride. The solution is stirred for 4 hours at room temperature. The solvent is removed in vacuo, the residue is dissolved in dichloromethane and the resulting solution is washed three times with water. The organic phase is dried over sodium sulfate, filtered and the solvent is removed under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of n-heptane/ethyl acetate (1/1). Output b7mg. MS (EB"): t/e-542.2 (MAN).

B) tert-Butyl ether o zo (25)-2-(quinoline-8-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propion 5 mg (0.12 mmol) of tert-butyl ether Fu (25)-3-(4-(-2-methoxycarbonylethyl)benzoylamino)-2-(quinoline-8-sulfonylamino)-propionic acid is dissolved in a mole of dimethylformamide and add 5O9mg (0.bmmol) of 2-amino-1,4,5,6-tetrahydro-pyrimidine. The reaction mixture is stirred for 20 hours at room temperature. The solvent is removed in vacuo and the residue is chromatographed (9 silica gel, eluting with a mixture of dichloromethane/methanol (1/1) and then dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5). Yield 72 mg. MS ( EB"): m/e-609.3 (MAN). c) "(25)-2-(Quinoline-8-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidine) -2-ylcarbamoyl)ethyl)benzoylamino)propionic acid - with 72 mg (0.11 mmol) of tert-Butyl ether c (25)-2-(quinoline-8-sulfonylamino)-3-(4-(2-(1, 4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propion"" acid is dissolved in 2 mol of dichloromethane and 2 mol of trifluoroacetic acid is added. The solution is stirred

From an hour at room temperature. The solvent is removed in vacuo, toluene is added to the residue and then removed in vacuo. The residue is dissolved in a mixture of acetonitrile/water (1/1) and subjected to freeze drying. Output (o) Ba4mg. MS (EB5"): t/e-553 (MAN). c Example C (25)-2-(4-acetylaminobenzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidine-2 -ylcarbamoyl-) (Ce) ethyl) benzoylamino)-propionic acid

M o o SA o tn n nn y 0:x5:0 55 . with

МН от име) a) tert-Butyl ether (25)-2--4-Acetylaminobenzenesulfonylamino)-3-(4-(2-methoxycarbonylethyl)benzoylamino)propionic acid 60 0.123m (0.35 mmol) tert-Butyl ether ( 25)-2-amino-3-(4-(2-methoxycarbonylethyl)benzoylamino)propionic acid is dissolved in 2mmol of dimethylformamide and treated with 0.19bmol (14mmol) of triethylamine and 0.164m (0.7mmol) of 4-acetylaminobenzenesulfonyl chloride. The solution is stirred for 4 hours at room temperature. The solvent is removed in vacuo, the residue is dissolved in dichloromethane and the solution is washed three times with water. The organic phase 65 is dried over sodium sulfate, filtered and the solvent is removed in vacuo. The residue is chromatographed on silica gel, eluting with a mixture of n-heptane/ethyl acetate (1/2). Output 9Omg MS. (EC): t/e-548 (MAN).

B) tert-butyl ether (25)-2-(4-acetylaminobenzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamine o)propionic acid 87 mg ( 0.1 mmol) of tert-Butyl ether (25)-2-(4-acetyl-aminobenzenesulfonylamino)-3-(4-(2-methoxycarbonylethyl)benzoylamino)propionic acid is dissolved in 1 mmol of dimethylformamide and 7O9 mg (0.8 mmol) of 2- amino4,4,5,6-tetrahydropyrimidine.

The reaction mixture was stirred for 20 hours at room temperature. The solvent is removed in vacuo and the residue is chromatographed on silica gel, eluting with dichloromethane/methanol (1/1) and then 7/0 dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5). Output 57 mg. MS (EV"): m/e-615.3 (MAN). c) (25)-2-(4-acetylaminobenzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidine- 2-ylcarbamoyl)ethyl)benzoylamine o)-propionic acid 57mg (O.09mmol) tert-butyl ether 75. (25)-2-(4-acetylaminobenzenesulfonylamino)-3-(4-(2-(1,4,5 ,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamine o)propionic acid is dissolved in 2 mol of dichloromethane and 2 mol of trifluoroacetic acid is added. The solution is stirred for 3 hours at room temperature. The solvent is removed in vacuo, toluene is added to the residue and then removed in vacuo. The residue dissolved in a mixture of acetonitrile/water (1/1) and subjected to freeze-drying.

Output 42 mg. MS (EB"): m/e"-559.2 (MAN U. 20 Example 4 (25)-2-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)benzenesulfonylamino)-3- (4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid "still r zv Со"он с nn. Mn Ge)

Fi at 05:55:00 a) Methyl ether at 30 2-(15)-1-tert-butoxycarbonyl-2-(4-(2-methoxycarbonylethyl)benzoylamino)dethylsulfamoyl)benzoic acid b 0.123m (0.35mmol) tert -Butyl ether of (25)-2-amino-3-(4-(2-methoxycarbonylethyl)benzoylamino)propionic acid is dissolved in 2mmol me) dimethylformamide and treated with 0.19bmol (14mmol) triethylamine and 0.164m (0.7mmol) s 2 -(methoxycarbonyl)benzenesulfonyl chloride. The solution is stirred for 4 hours at room temperature.

Z The solvent is removed in vacuo, the residue is dissolved in dichloromethane and the resulting solution is washed three times with water. The organic phase is dried over sodium sulfate, filtered and the solvent is removed under vacuum. The residue is chromatographed on silica gel eluting with a mixture of n-heptane/ethyl acetate (1/1). Output 75 mg. MS (EB"): t/e-549 (Men, « 20 B) tert-Butyl ether with (25)-2-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)benzenesulfonylamino)- 3-(4-(2-(1,4,5,6-tetrahydropyrimides with n-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid; with 75 mg (0.133 mmol) of methyl ether 2-(15)-1- tert-butoxycarbonyl-2-(4-(-2-methoxycarbonylethyl)benzoylamino)ethylsulfamoyl)benzoic acid is dissolved in a mole of dimethylformamide and 8Zmg (0.69 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine is added.

Fu The reaction mixture is stirred for 20 hours at room temperature. The solvent is removed in vacuo and the residue is chromatographed on silica gel, eluting with dichloromethane/methanol (1/1) and then with dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5). Output 54 mg. MS (EB"): m/e-683.3 (MAN). c) that 20 (25)-2-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-benzenesulfonylamino)-3 -(4-(2-(1,4,5,6-tetrahydrotrimidiso n-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid o 5 mg (0.08 mmol) tert-Butyl ether (25)-2-(2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)-benzoylamino)propionic acid is dissolved in 2 mol of dichloromethane and 2 mmol of trifluorooptic acid is added. The solution is stirred for 1 hour at room temperature. The solvent is removed in vacuo, toluene is added to the residue and then removed in vacuo. The residue is dissolved in a mixture of acetonitrile/water

F) (1/1) and subjected to lyophilic drying. Output ZA4mg. MS (EVB"): t/e-627 (MAN). ko General procedure 1 for the synthesis of compounds in examples 5-24

Stage a: Reaction with sulfonyl chloride in 0.2m of tert-Butyl ether (25-amino-3-(4--2-methoxy-carbonylethyl)benzoylamino)propionic acid is dissolved in 2 mol of dimethylformamide and 4 molar equivalents of triethylamine and 2 molar equivalents of the corresponding sulfonyl chloride. The solution is stirred for 4 hours at room temperature. The solvent is removed under vacuum, the residue is dissolved in dichloromethane, the resulting solution is washed three times with water. The organic phase is dried over sodium sulfate, filtered and the solvent is removed under vacuum. The residue is chromatographed on 65 silica gel, eluting with a mixture of n-heptane/ethyl acetate (1/1).

Stage p: Formation of acylguanidine

The product of stage a is dissolved in one mole 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 is removed in vacuo and the residue is chromatographed on silica gel, eluting with a mixture of 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 stage B is dissolved in 2 mol of dichloromethane and 2 mol of trifluoroacetic acid is added. The solution is stirred for an hour at room temperature, the solvent is removed under vacuum, toluene is added to the residue and then removed under vacuum. The residue is dissolved in a mixture of acetonitrile/water (1/1) and subjected to freeze drying. 70 Example 5 (25)-2-(4-tert-Butyl-benzenesulfonylamino)-3-(4-(2-(1D5,6b-tetrahydrochrymidin-2-ylcarbamoyl)ethyl)benzoylamino)-propionic acid

M o -0 and; ) -g4 s Y a; -x i15 1 Plural

Ooh5550

The title compound is synthesized according to general procedure 1 using 4-tert-Butylbenzenesulfonyl chloride at stage a.

Output of MS (EVU); that

The product of stage a 8Zmg 547.2 (m-n)x s

Product of stage 5 8Bmg 614.3 (m-n)x o

Product of stage c (The title compound) 75mg 558.3 (MEN)

Example 6 (25)-2-"Propane-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcaroamoyl)ethyl)benzoylamino)propionic acid

Ge) ' (o)

M o x ), -th U4

СН «о (2)

N

H Mn o-850 (ze)

In |se)

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

Exit MC (EV); that

Product of stage a Baimg 457.3 (Men)X - s Product of stage 5 BBmg 524.3 (m-n)x m » Product of stage c (Specified compound in the title) 45mg 468.3 (MEN) p

Example 7 (25)-2-(2-phenyl-ethenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)n

Phosphoric acid (95) M her

S |e and M on (Se) ti n Mn s 50 o-8x0 (42) zh

The title compound was synthesized according to general procedure 1 using transbeta-styrenesulfonyl chloride at stage a. i) Output of MS (EVU); te co Product of stage a dOmg 5171 (m-n)x

The product of stage 5 ABmg 584.3 (m-n)x 60 The product of stage c (The compound mentioned in the title) C7mg 528.3 (MEN)

Example 8 (25)-2-(4-propylbenzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid b5

M o h

S Y o 4 AH,

N : n mn 02550 5 .

The title compound was synthesized according to general procedure 1 using 4-(n-propyl)benzenesulfonyl chloride at step a 70.

Output of MS (EVU); that

The product of stage a t7vmg 533.2 (MAN)7

Product of stage 5 7Zmg 6004 (MA-N)7

Product of stage c (The title compound) 55mg 544.3 (MEN)

Example 9 (25)-2-(2-methylpropane-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid.

Gee).

M g (o! u-m

With me

N n Mn 05:50 a.m. 6)

The title compound was synthesized according to general procedure 1 using 2-methylpropane-1-sulfonyl chloride at stage a.

Output of MS (EVU); that aw!

Product of stage a 21mg 471.3 (MANn)" b"

Stage 5 product 1Omg 5384 (MeN)7

The product of stage c (The compound specified in the title) 1Zmg 482.3 (MEN) Ge) (ze)

Example 10 (25)-2-(4-butoxybenzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamine (Ce) o)propionic acid

M U. | y o x - I

S Kon «

N : n Plc. p. O:5:0 with . t k whale

The title compound was synthesized according to general procedure 1 using 4-(n-butoxy)benzenesulfonyl chloride at stage a. (at)

Exit MC (EV); that

Product of stage a 8Zmg 563.2 (m-n)x se) Product of stage 5 8Zmg 630.4 (m-n)x (se) 20 Product of stage c (Compound indicated in the title) bZmg 574.3 (MEN) "2 Example 11 (25)-2-(2-cyanobenzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid

N . N KN ko o-5:0 h 60

The title compound was synthesized according to the general procedure | using 2-cyanobenzenesulfonyl chloride at stage a.

Output of MS (EVU); te 6BE Product of stage a 9Img 516.2 (m-n)x

The product of stage 5 7img 583.3 (m-n)x

The product of stage c (The compound specified in the title) 7Z3mg 527.3 (MEN)

Example 12 (25)-2-(7,7-dimethyl-2-oxo-bicyclo|2.2.1|hept-1-ylmethanesulfonylamino)-3-(4-(2-(1.. 4,5,6- tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid

With o sne-Oi

M M on yin hwo o

The title compound was synthesized according to general procedure 1 using 10-camphorsulfonyl chloride at stage a. 000000 let's raise nine

Example 13 (25)-2-(4-chlorobenzenesulfonylamino)-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)pro pionic acid that

S u tu 1 M on

Y n Mn (o) bh58o ; | "c) si

The title compound is synthesized according to general procedure 1 using 4-chlorobenzenesulfonyl chloride at stage a. F

Output of MS (EVU); that co

Product of stage a 9Img 5251 (Manu and ( ) co

Stage 5 product 82mg 592.3 (MEN)

Product of stage c (The title compound) b4mg 536.3 (MEN)

Example 14 "-2-(3-Chlorobenzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)n 20 25)-2-(3-Chlor 3-(4-(2-(1,4,5,6 2 b b -o opionic acid).

Pho;

M o

b; "» S U - I-i A i M i n ! Mn o:5:0 sho s (o) si s The compound specified in the title was synthesized according to general procedure 1 using stage a

Z-chlorobenzenesulfonyl chloride. se) s 50 Exit MS (EV): t/e

Product of stage a bBmg 525.2 (m-n)x s Product of stage 5 BvVmg 592.3 (m-n)x

The product of stage c (The title compound) 52 mg 536.3 (MN) 99 Example 15

HF) (25)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)-2-(3-trifluoromethylbenzene-sulfonylamino)propionic acid ime) 9 .

Siy -/ mon

N

60 N nn o-8:0

IS

IS

E c The compound indicated in the title is synthesized according to the general procedure 1 using stage a

C-trifluoromethylbenzenesulfonyl chloride.

MS exit (EVU); that

Product of stage a 8bmg 559.2 (ME.N)"

Product of stage 5 Zamg 626.3 (M.N)

Product of stage c (Title compound) 84mg 570.3 (MEN)

Example 16 (28)-2-(4-methoxybenzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamine 70 o)propionic acid

M Z 9

SA,

In YN kn o-v-o a o

The title compound is synthesized according to general procedure 1 using 4-methoxybenzenesulfonyl chloride at stage a.

Exit MC (EV); that

Product of stage a bbmg 5211 (M-N)U

Product of stage 5 Tt74mg 588.3 (m-n)x

Product of stage c (Compound indicated in the title) 49 mg 532.3 (MEN) c o

Example 17 (25)-2-benzenesulfonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid

N and nn

OO b o c

The title compound was synthesized according to general procedure 1, using benzenesulfonyl chloride at step a and c.

MS exit (EVU); that

Product of stage a 7bmg 491.2 (m-n)x "

The product of stage 5 77mg 558.3 (m-n)x with c The product of stage c (The compound specified in the title) b4mg 502.3 (MEN) :z» Example 18 (25)-3-(4-(2-(1) ,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)-2-(thiophene-2-sulfonylamino)propionic acid t CA

MN M on (95) N nn nn srya

St

Fo Sho dk and -

The title compound is synthesized according to general procedure 1 using 2-thiophenesulfonyl chloride at stage a 2.

Exit MC (EV); that

Product of stage a 87mg 4971 (m-n)x o Product of stage 5 Tt4mg 564.2 (m-n)x

Product of stage c (Specified compound in the title) b4mg 508.2 (MEN) name)

Example 19 60 (28)-2-"B-fens-4-sulfonshamcho)-3-(4-(2-(1,4,5,6-tetrahydrotrimschin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid b5

M u | o x y

S N o on

Н Нн Кн still 0-85о 70 The compound indicated in the title was synthesized according to general procedure 1 using 4-biphenylsulfonyl chloride at stage a.

Exit MC (EV); that

The product of stage a ZOmg 567.1 (m-n)x

The product of stage 5 dOmg 634.4 (m-n)x

Product of stage c (Specified compound in the title) ЗЗмг 578.3 (MEN)

Example 20 (25)-2-(Naphthalene-2-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid o

M ha i

Ms. N., etc

N shi Mn! Oh8x0 with 25. Oh oh

The title compound is synthesized according to general procedure 1 using 30 2-Naphthalenesulfonyl chloride at stage a. (at)

Output of MS (EVU); that Ge"!

The product of stage a 7bmg 541.2 (m-n)x

The product of stage 5 7t74mg 608.3 (m-n)x o 35 The product of stage c (The compound indicated in the title) b2mg 552.3 (MAN)" (Ce)

Example 21 (25)-3-(4-(2-(1,4,5. "b-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)-2-(2,4,6-trimethylbenzenesulfonylamino)propionic acid - s M Z o o x "» S N Ou mon " n N Mn

O:8:50 45 (o) d) The title compound was synthesized according to general procedure 1 using 2,4,6-trimethylbenzenesulfonyl chloride at stage a. se) at 50 Exit MS (EV): te

Product of stage a b8mg 533.2 (m-n)x mk Product of stage 5 71mg 6004 (m-n)»

The product of stage c (The compound indicated in the title) 54 mg 544.3 (MAN)"

Example 22

HF) (25)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)-2-(4-trifluoromethylbenzene-sulfonylamino)propionic acid rime) o so 4 iya Um Y Y n M on bo | N N cn

O25:0 - ate)

E bo The compound specified in the title is synthesized according to the general procedure 1 using stage a

4-trifluoromethylbenzenesulfonyl chloride.

MS output (ECU); that

The product of stage a is 105 Mg 559.3 (MaN)7

The product of stage 5 9Zmg 626.4 (mol

Product of stage c (The title compound) 7Omg 570.3 (MEN)

Example 23 (25)-2-(Butane-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid m u o

One o2550 ate AI

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

Output of MS (EVU); that

Product of stage a 87mg 4714 (m-n)h

Product of stage 5 bomg 538.4 (Men)

The product of stage c (The title compound) 57 mg 482.3 (MEN) rya Example 24 ch (25)-2-methanesulfonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) )ethyl)benzochamino)propionic (o) acid

M 9 o s-m AH y. and And and about ogvho b"

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

Exit MC (EV); t/e (Se)

Product of stage a 87.mg 429.3 (MEN)"

Stage 5 product 98mg 4964 (m-n)x

The product of stage c (The compound specified in the title) 74mg 440.3 (M.H)" « 70 General procedure 2 for the synthesis of compounds in examples 25-27 n-s Stage a: Reaction with sulfonyl chloride with 0.1m tert-butyl ether hydrochloride (25)-2-amino-3-(4-(2-carboxyethyl)benzoylamino)propionic acid is dissolved in Zmol of dimethylformamide and treated with molar equivalents of diisopropylethylamine and 2 molar equivalents of the corresponding sulfonyl chloride at 0"С. The solution 75 is stirred for 3 hours at 0"C. The reaction mixture is diluted by adding ethyl acetate and the solution twice

F is washed with an aqueous solution of potassium bisulfate and once with a saturated aqueous solution of sodium chloride. (95) The organic phase is dried over magnesium sulfate, filtered and the solvent is removed in vacuo. The residue is chromatographed on silica gel, eluting with a mixture of dichloromethane/methanol/acetic acid/water (97.5/2.5/0.25/0.25). (Se) 50 Stage r: Formation of acylguanidine

The product of stage a is dissolved in a mole of tetrahydrofuran and 1.2 molar equivalents of 2-amino-1,4,5,6-tetrahydropyrimidine, 4 molar equivalents of diisopropylethylamine, and 1.1 molar equivalents of O-(7-azabenzotriazol-1-yl)-hexafluorophosphate are added. 1,1,3,3-tetramethyluronium. The reaction mixture was stirred for 20 hours at room temperature. The solvent is removed in vacuo, the residue is dissolved in ethyl acetate, and the resulting solution is washed twice with saturated aqueous sodium bicarbonate solution and once with saturated

HF) with an aqueous solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and the solvent is removed under vacuum. 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 (9/1/0.1/0.1) .

Stage c: Decomposition of tert-Butyl ether 60 The product of stage B is dissolved in 1.5 mol of a mixture of trifluoroacetic acid/water (95/5). The solution is stirred for 1 hour at room temperature. The solvent is removed in vacuo, toluene is added and then removed in vacuo. The residue is dissolved in a mixture of acetonitrile/water (1/1) and subjected to freeze drying.

Example 25 (21)-2-"Propan-2-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)prop 65 (ionic acid o

M u chi-OYA

Soch N ro

N vn o-8350

J

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

Output of MS (EVU); that

Product of stage a 97mg 4432 (m-n)

Product of stage 5 7 mg 5242 (m-n)

Product of stage c (Title compound) 7.2 mg 468.2 (MAN)"

Example 26 (25)-2-chloromethanesulfonylamino-3-(4-(2-(1,4,5,6-tetrahydrogarimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid. m o

b; (S N Z ro n N Kn

Oh520

M. a

The title compound was synthesized according to general procedure 2 using chloromethanesulfonyl chloride at stage a. with

Exit MC (EV); that about

Product of stage a Zamg 4491 (Main)

Product of stage 5 28mg 530.2 (m-n)x

The product of stage c (The compound indicated in the title) C4mg 474.2 (MAN)" o

Example 27 (o) (25)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)2-(2,2,2-trifluoroethanesulfonylamino)propion acid

U-m: M on zv -M i Yang (Se) and . 0-820

That's it. . in "

The title compound was synthesized according to general procedure 2 using 2,2,2-trifluoroethanesulfonyl chloride at stage a. - s a Exit MS (EV); t/e t i Product of stage a 4Zmg 483.2 (MeN)7

Stage 5 product 24mg 564.2 (m-n)x

The product of stage c (The title compound) 22 mg 508.2 (MEN) (o) so Example 28

Ethyl ether se) (25)-2-(4-tert-Butylbenzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino 20 )propionic acid se) at

M o o F u -GU ud Y M 2-7

N shi kn

Ox550 - F o Tom (25)-2-(4-tertbutylbenzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino) 60 -propionic acid is dissolved in 100 mol of ethanol and add 15 drops of concentrated sulfuric acid.

The reaction solution is boiled for 3.5 hours. The solvent is removed in vacuo, the residue is dissolved in dichloromethane and washed three times with a saturated aqueous solution of 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 diluent is removed under vacuum. The residue is dissolved in 2N. hydrochloric acid. The acid is removed under vacuum, the residue is dissolved in acetonitrile and poured into water. The resulting mixture is subjected to lyophilic drying. Output 480 mg. MS (EB"): t/e-586.4 (MAN).

Example 29

Isopropyl ether (25)-2-(A-tert-Butylbenzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid in

Si vish 70 o 7O0mg 75. (25)-2-(4-tert-Butylbenzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)-propionic acid is dissolved in 100 mol of isopropyl alcohol and 15 drops of concentrated sulfuric acid are added. 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 a saturated aqueous solution of 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 is removed under vacuum.

The residue is dissolved in 2N. hydrochloric acid. The acid is removed under vacuum, the residue is dissolved in acetonitrile and poured into water. The resulting mixture is subjected to lyophilic drying. Yield 44.4 mg. MS (E5B"): t/e-600.4 (Mn).

Example 30 p

Ethyl ether o (25)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propio new acid

Sochi "about | "in)

M. I

0:5:0 Ge)

F

Dissolve 590 mg of (25)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)-propio" with new acid in 80 mol of ethanol and add 12 drops of concentrated sulfuric acid. The reaction solution is boiled for an hour, the solvent is removed in vacuo, the residue is dissolved in dichloromethane and washed three times with a saturated aqueous solution of 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 is removed under vacuum. The remainder of the solution is dissolved in 2 n. hydrochloric acid. The acid is removed under vacuum, the residue is dissolved in acetonitrile and poured. into the water The resulting mixture is subjected to lyophilic drying. Exit Zv'mg. MS (EB"): t/e-580.3 (MAN). and? Example 31

Isopropyl ether (25)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propio b of new acid

M U. and her o S kt o- (Te) nn tn o 50 o-8:50 o Sh 1.5m (21)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-( 1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)proton 55 of this acid is dissolved in 250 mol of isopropyl alcohol and Tmol of concentrated sulfuric acid is added.

The reaction solution is boiled for 3 days, the solvent is removed in vacuo, the residue is dissolved in

HF) dichloromethane and washed three times with a saturated aqueous solution of 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 is removed under vacuum.

The residue is dissolved in 2N. hydrochloric acid. The acid is removed under vacuum, the residue is dissolved in acetonitrile and poured into water. The resulting mixture is subjected to lyophilic drying. Output 95 Ohms. MS (EB"): t/e-594.4 (M.N) and

Example 32

Isobutyl ether 65 (25)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propio new acid

And 5 »

OO n nn 02-5:0 ; bOOmg of (25)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)-prolyonic acid is dissolved in 12 mol of isobutyl alcohol and add. 0.1 mol of concentrated sulfuric acid.

The reaction solution is boiled for 24 hours, the solvent is removed in vacuo and the residue is chromatographed on silica gel eluting with a mixture of dichloromethane/methanol/acetic acid/water (9/1/0.1/0.1). The product is dissolved in an acetic acid/water mixture and subjected to freeze drying. Output 25O0mg. MS (E5"): t/e-608.5 (MAN)7.

Pharmaceutical testing

Inhibition of bone tissue resorption by the compounds of this invention can be determined, for example, using the test for bone tissue resorption by osteoclasts ("RIT AZBAK"), which can be carried out, for example, similarly to that described in UMO-A-95/32710, included in this invention as reference.

The inhibitory effect of the compounds of the invention on the vitronectin A uBz receptor can be determined, for example, as described below.

Test to measure inhibition of binding of 293 cells to human vitronectin (Mp/293 cell test) 20 1. Purification of human vitronectin

Human vitronectin was isolated from human plasma and purified by affinity chromatography according to the method of Uaiopuo ei ai, Seiyi Zigisitsge apa Rypsiyop, 1988, 23, 281-292. 2. Cell test

Cells 293-line of human embryonic kidney cells, into which the DNA sequences of ch 25 responsible for au and Bz-subunits of the vitronectin a/Bz receptor were introduced, were selected due to the high rate of expression ("500,000 AuBz receptors per cell) by the RASZ5 method. Selected cells were cultivated and sorted also according to (o) the RAS5 method in order to obtain a stable cell line (1503) with an expression rate of more than 1,000,000 copies of AmBz per cell. A 9b-well plate for tissue culture with a flat bottom is covered overnight at 4"C with human vitronectin (0.01 mg/ml, 0.05 mol per cell) in a phosphate-buffered saline solution and then block

O.596 SAB (bull's serum albumin). Prepare solutions of tested substances in concentrations from 10719 Me to 2x10Zmol/l in OMEM medium, which contains glucose, and in all cases place these solutions on a plate in He! amount of O0.O05mol per cell. Cells expressing high levels of AkBz (for example, 150) are suspended in OMEM medium, which contains glucose, and the concentration of cells in the suspension is brought up to 25,000 per 0.005mol me) of medium. About 0.05 ml of such a cell suspension is injected into each cell and the plate is incubated for 10 h. "o 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, pH5.0) containing 0.2595 Triton X-100. After that, add the hexosamidase substrate p-nitrophenyl-M-acetyl-pD-O-glucosaminid and the plate is incubated for 9 hours at 37"C. The reaction is stopped with glycine (Homm)"EDTA buffer (5 mm) (pH 10.4) and the optical absorbance of "40 V in each cell at 405-650 nm is measured. The data obtained are analyzed by standard methods. Example of Mo Zh5BO in the vitronectin test with cells 293 1 bnM 45 2 Ba2nM

Gee! 3 2inM 18nM o 6 З2nM

Ge) 7 28nM 50 8 2onM ish 9 bonmM o 10 g29nM 11 da4nM 12 27nM 55 13 27nM 14 1onM o 15 bnM ime) 16 2bnM 17 ZNM 60 18 14nM 19 ZvnM

BM

21 2inm 22 1onM bo 23 zonM

24 100nM

Claims (1)

The formula of the invention 1. Sulfonamide derivatives of formulas I: (8) ЧО) 70 o vi o M »- i i-i Mn M-v: vo: re in which V! and 2, independently of each other, mean hydrogen or (C4-C8)-alkyl, unsubstituted or substituted by the RU radical, or in which the radicals BK 7 and K2 together represent a saturated or unsaturated divalent (C,-Co)-alkylene a radical that is unsubstituted or substituted by one or more groups from among the following: halogen, (Ci-Ci)-alkyl, (C--Ci)-alkyl, (Ci-Ci)-aryl, (Ci-Ci)-aryl- (C1-C)-alkyl-, (C-C.44)-heteroaryl, (C-C445)-heteroaryl-(C1-C)-alkyl-, (C3-C.42)-cycloalkyl, (C3-C .42)-cycloalkyl-(C4-Cv)-alkyl- or oxo group, where the 5-7--len is a saturated or unsaturated ring, which can be unsubstituted or substituted by the BZ radical and which is a carbocyclic or heterocyclic ring containing one or two nitrogen atoms in the ring, it can be condensed to the carbon-carbon bond of the (Co-Co)-alkylene radical; BZ means (Ci-CiO)-alkyl, (Ci-CiO)-monocycloalkyl, (Ci-CiO)-bicycloalkyl, /(Ci-CiO)-tricycloalkyl, (C.-Ce)-Alkoxy, (Cv-C14)-aryl, (Cv-C4454)-aryl-(C.-C.))-alkyl-, (Cv5-C14)-heteroaryl, (Cv-C445) -heteroaryl-(C.4-C)-alkyl-, halogen, trifluoromethyl, cyano, hydroxyl, oxo, nitro, amino, o -MNA(C1-C)-alkyl-, M(C4-C)-alkyl )", -"MH-CO-(C1-Cu)-alkyl-, -CO-(C1-Cu)-alkyl; Fo B means hydrogen, (C1-Cv)-alkyl-CO-O-(C4-Cv)-alkyl- or (C4-Cv)-alkyl, which is an unsubstituted or substituted radical from the group including: hydroxyl, (C --Cu)-Alkoxy, (C4-C)-alkyl-9(0)5-, -MV/B/ and -M'B/B'VHO, where F B", v' and v", independently from each other, mean hydrogen, (Ci-Ci)-alkyl, (Ci-Ci4)-aryl or (Ci-Ci)-aryl-(Ci-Ci)-alkyl-i, and C) means an anion that is physiologically transferred, or K 4 means one of the following radicals: -- MSN, ", - 7. » " o , i ni ton s , o Н, СН, (95) - oyu Z - On o shkat so 70 ve a C (42) o bolton on o in which bonds, through which conjugated radicals, indicated by dashed lines lines; BO means (C1-C0)-alkyl, (C3-C0)-monocycloalkyl, /(C5-C00)-bicycloalkyl, /(C5-C00)-tricycloalkyl, o (CoC, d)naryl, (Cv -С44)-heteroaryl, (Св-Си4)-aryl-(Си-Св)-alkyl- or (Св5-С14)-heteroaryl-(С1-Св)-alkyl-, where the radicals are aryl, heteroaryl, alkyl, monocycloalkyl , bicycloalkyl and tricycloalkyl are unsubstituted or substituted by one, two or three K»z radicals and where in the alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl radicals one or more carbon atoms may be replaced by the same or different atoms selected from the group consisting of nitrogen, oxygen and sulfur; 25 means hydrogen, (C.4-Cv)-alkyl-O-CO-, hydroxyl, (C4-Cv)-alkyl-O-CO-O- or nitro group; in all stereoisomeric forms and their mixtures in in any proportions, as well as salts of these compounds, because their predecessors are also physiologically tolerated. 2. Compounds of formula I according to claim 1, in which B! her CC? means hydrogen eyes together form a saturated eyes unsaturated divalent (С,-Сб5)-alkylene radical, where (С2-Св)-alkylene radical, which is an unsubstituted or substituted radical from the group that includes halogen, (С.--Св)- alkyl, (C--Cv)-alkoxy, (Cv-Ci4)-aryl, (Cv-C4454)-aryl-(C.4-Cv)-alkyl-, (Cv5-C14)-heteroaryl, (C5-C14 )-heteroaryl-(C1-C8)-alkyl-, (C3-C12)-cycloalkyl, (C3-C42)-cycloalkyl-(C1-C8)-alkyl- and oxo group, where the 5-7- chain is saturated or the unsaturated ring, which can be unsubstituted or substituted by the BZ radical and which is a carbocyclic or heterocyclic ring containing one or two nitrogen atoms in the ring, can be condensed by the carbon-carbon bond of the (Co-Cv)-alkylene 70 radical; BZ means (Ci-CiO)-alkyl, (Ci-CiO)-monocycloalkyl, (Ci-CiO)-bicycloalkyl, /(Ci-CiO)-tricycloalkyl, (C.-C.)-Alkoxy, (C.-C.14)-aryl, (C.5-C.44)-heteroaryl, (C.-C.14)-aryl-(C.4-C.)-alkyl-, (C.-C.44)-heteroaryl -(C 4-C.y)-alkyl-, halogen, trifluoromethyl, cyano, oxo, -M(C 4-C.u)-alkyl)" or -MH-CO-(C 1-C.)-alkyl; t B" means hydrogen or (C1-C8)-alkyl, which is an unsubstituted or substituted radical from the group including (C,-C,)-Alkoxy, (C1-C4)-Alkyl-B(O)2- and -MA"B", where B and KE", independently of each other, mean hydrogen or (C.-Sul)-alkyl; IN? means (C1-C0)-alkyl, (C3-C00)-monocycloalkyl, /(C1-C0)-bicycloalkyl, (C5-C00)-tricycloalkyl, (C1-C0)-aryl, (C1-C4)- heteroaryl, (C1-C14)-aryl-(C1-C1)-alkyl- or (C5-C44)-heteroaryl-(C1-C1)-alkyl-, where each of the radicals is aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl is unsubstituted or substituted by one, two or three KU radicals; B is hydrogen or (C.1-Cv)-alkyl-O-CO-; in all stereoisomeric forms and their mixtures in any proportions, as well as salts of these compounds, which are physiologically tolerated, and their precursors. Gee) 3. Compounds of the formula | according to claim 1 and/or 2, in which B and B? is hydrogen or together form a saturated or unsaturated divalent (С»о-Су)-alkylene radical, where (Со-С/)-alkylene radical is an unsubstituted or substituted radical from the group including halogen, о зо (С1-Св)- alkyl, (C1-Cv)-alkoxy, (Ce-Std)-aryl, (Ce-Cia)-aryl(C1-Cv)-alkyl-, | (Cv-C4)-heteroaryl, (Cv-C445)-heteroaryl-(C1-Cv)-alkyl-, (C3-C12)-cycloalkyl, (C3-C42)-cycloalkyl-(Ci-Cv)-alkyl- and oxo group, and where o) a 5-7-membered saturated or unsaturated ring, which is an unsubstituted or substituted KZ radical and which is a Fo carbocyclic or heterocyclic ring containing one or two nitrogen atoms in the ring, can be condensed for carbon- the carbon bond of the (C2-C.)-alkylene radical; so 35 BZ means (C.sub.-Sul)-alkyl, (C.sub.3-C.sub.10)-monocycloalkyl, /(C.sub.1-C.sub.12)-bicycloalkyl, /(C.sub.1-C.sub.12)-tricycloalkyl, "o (C.-C,)-Alkoxy, (Seb-Ci4)-aryl, /(Ci-Ci4)-aryl-(C1-C/)-alkyl-, halogen, trifluoromethyl, cyano, oxo, -M(C1- C)-alkyl)" or -MH-CO-(C.-C.)-alkyl; "B" means hydrogen or (C.4-Ci)-alkyl; "BO" means (Ci-Ci0)-alkyl, (Ci-Ci5)-monocycloalkyl, (Ci-Ci5)-bicycloalkyl, (Ci-Ci5)-tricycloalkyl, 40 (C,.-C,,)-aryl, (Cv-C44)-heteroaryl, (Cv-Ci4)-aryl-(Ci-Cv)-alkyl- or (Cv5-C14)-heteroaryl-(C1-Cv) )-alkyl-, where each of the aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl radicals is unsubstituted or "» substituted by one, two or three KZ radicals; " 2? means hydrogen or (C.4-C)-alkyl-O-CO-; in all stereoisomeric forms and their mixtures in any proportions, as well as salts of these compounds, which are physiologically tolerated, and their precursors. 4. Compounds of formula I according to any of claims 1-3, in which about B and B? is hydrogen or together form a saturated or unsaturated divalent (Co-C3)-alkylene o radical, where the (Co-C3)-alkylene radical is an unsubstituted or substituted radical from the group that includes halogen, 50 (C1-C8)-alkyl, (C1-C)-Alkoxy, (Cv-C44)-aryl, (Cv-C445)-aryl-(C1-Cv)-alkyl-, (Cv5-C14)-heteroaryl, is), (Cv-C445)- heteroaryl-(C1-C8)-alkyl-, (C3-C12)-cycloalkyl, (C3-C42)-cycloalkyl-(C.4-C8)-alkyl- and oxo group, and where o 5-7--lenen saturated whether the unsaturated ring, which is an unsubstituted or substituted EZ radical and which is a carbocyclic or heterocyclic ring containing one or two nitrogen atoms in the ring, can be condensed on the carbon-carbon bond of the (Co-C3)-alkylene radical; 55 BZ means (C-Sul)-alkyl, (C3-C10)-monocycloalkyl, /(Cv-C12)-bicycloalkyl, /(Cv-C12)-tricycloalkyl, (C.-C.)-Alkoxy, (C.-C.4)-aryl, halogen, trifluoromethyl, cyano, oxo, -M(C4-C4)-alkyl)" or -MH-CO-(C1-Su) -alkyl; o VE means hydrogen or (C4-Cv)-alkyl; o BO means (Ci-Ci0)-alkyl, (Ci-Ci5)-monocycloalkyl, (Ci-Ci5)-bicycloalkyl, (Ci-Ci5)-tricycloalkyl, (Ci-Ci)-aryl, (Ci-Ci4) -heteroaryl, (Cev6-C14)-aryl-(C1-Cv)-alkyl- or (C5-C14)-heteroaryl-(C1-Cv)-alkyl-, where 60 each of the radicals is aryl, heteroaryl, alkyl, monocycloalkyl , bicycloalkyl and tricycloalkyl is unsubstituted or substituted by one, two or three KU radicals; is hydrogen or (C4-C1)-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. 5. Compounds of formula I according to any of claims 1-4, in which B? means (Св-С14)-aryl or (Св5-С44)-heteroaryl, where each of the aryl and heteroaryl radicals is unsubstituted or substituted by one, two or three identical or different RU radicals, in all stereoisomeric forms and their mixtures in any proportions, as well as salts of these physiologically tolerated compounds and their precursors. 6. Compounds of formula I according to any of claims 1-5, in which B? means the naphthyl radical, in all stereoisomeric forms and mixtures thereof in any proportion, as well as physiologically tolerated salts of these compounds and their precursors. 7. Compounds of formula I according to any of claims 1-4, which are 2-(22-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl) )benzoylamino)-propionic acid, in which the 2-(B?-sulfonylamino) substituent is selected from the group consisting of benzenesulfonylamino, 4-(n-propyl)benzenesulfonylamino, 4-tert-butylbenzenesulfonylamino, 2,4,6-trimethylbenzenesulfonylamino, 4-methoxybenzenesulfonylamino, 4-(n-butoxy)benzenesulfonylamino, 3-chlorobenzenesulfonylamino, 4-chlorobenzenesulfonylamino, 3-trifluoromethylbenzenesulfonylamino, 4-trifluoromethylbenzenesulfonylamino, 4-acetylaminobenzenesulfonylamino, 2-cyanobenzenesulfonylamino, naphthalene-1-sulfonylamino, 72 naphthalene-2-one biphenyl-4-sulfonylamino, thiophene-2-sulfonylamino, quinoline-3-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-ylmethane sulfonylamino and 2-phenylethenesulfonylamino, in all stereoisomeric forms and their mixtures in any proportions, as well as physiologically tolerated salts of these compounds and their precursors. 8. The compound of formula I according to any of claims 1-7, which is (25)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidine) -2-ylcarbamoyl)ethyl)benzoylamino)propio new acid and its physiologically tolerated salts and their precursors. 9. The compound of formula I according to any of claims 1-8, which is (28)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6- tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propio d) a new acid or its (C4-Cu)-alkyl ether and its physiologically tolerated salts. 10. The compound of the formula |! according to any of claims 1-9, which is ethyl ether (25)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidine-2- ylcarbamoyl)ethyl)benzoylamino)propio new acid and its physiologically tolerated salts. at 11. Compounds of the formula | according to any of claims 1-10 and/or their physiologically tolerated salts and/or their Ge! precursors for use as pharmaceuticals. 12. Compounds of the formula | according to any of claims 1-10 and/or their physiologically tolerated salts and/or their me) precursors for use as antagonists of the vitronectin receptor. co 13. Compounds of the formula | according to any one of claims 1-10 and/or their physiologically tolerated salts and/or their Zo precursors for use as bone resorption inhibitors or for the therapy or prevention of osteoporosis. 14. Compounds of the formula | according to any of claims 1-10 and/or their physiologically tolerated salts and/or their precursors for use as inhibitors of tumor growth or tumor metastasis. " 15. Compounds of the formula | according to any of claims 1-10 and/or their physiologically tolerated salts and/or their precursors for use as anti-inflammatory agents for the therapy or prevention of cardiovascular disorders, reversible stenosis, or arteriosclerotic retinopathies. "» 16. The method of obtaining compounds of the formula | according to any of claims 1-10, which differs in that it is subjected to " the interaction of a carboxylic acid or a derivative of a carboxylic acid of the formula II: o (B (0 7 oo and g) Uch n X so 62 in which B 7 and 2 are defined in claims 1-10 or in which the functional groups are present in the form of their predecessors or in a protected form, and where X means a leaving group capable of nucleophilic substitution, with guanidines or guanidine derivatives of the PP formula: Ш-вИ. (1) OO nm eat) VI 6o ve in which EK", В? and KZ are defined in claims 1-10 or in which functional groups are present in the form of their predecessors or in a protected form 17. A pharmaceutical preparation containing at least one compound of formula I according to any of claims 1-10 and/or in its physiologically tolerated salts and/or its precursors in combination with a pharmaceutically harmless carrier. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2004, M 2, 15.02.2004. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. c o «c) Fo (22) so (Se) shi c z (22) (95) se) at 50 (42) F) name) 60 b5