CN1177832C - Novel sulfonamide derivatives as bone resorption inhibitors and as cell adhesion inhibitors - Google Patents

Abstract

The invention relates to the compounds in which R¹、R²、R⁴、R⁵And R⁶Sulfonamide derivatives of the formula , having the meaning indicated in the claims, their physiologically tolerated salts and their prodrugs. The compounds of formula are valuable pharmaceutical active compounds. They are vitronectin receptor antagonists and inhibitors of cell adhesion and inhibit bone resorption by osteoclasts. For example, they are suitable for the treatment and prevention of diseases which are caused at least in part by an undesirable degree of bone resorption, for example of osteoclasts. The invention further relates to processes for the preparation of the compounds of formula , in particular their use as pharmaceutically active ingredients and pharmaceutical preparations containing them.

Description

Novel sulfonamide derivatives as bone resorption inhibitors and as cell adhesion inhibitors

The present invention relates to formula I sulfonamide derivatives, their physiologically tolerable salts and their prodrugs,

wherein R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ have the meanings indicated below. The compounds of formula I are valuable pharmaceutically active compounds. They are vitronectin receptor antagonists and inhibitors of cell adhesion and inhibit bone resorption by osteoclasts. For example, they are suitable for the treatment and prevention of diseases caused at least in part by an undesirable degree of bone resorption, eg osteoporosis. The invention also relates to processes for the preparation of said compounds of formula I, in particular their use as pharmaceutically active ingredients and pharmaceutical preparations containing them.

Human bone undergoes a constant dynamic process of restoration, including bone resorption and bone formation. These processes are controlled by various types of cells that are specialized for these purposes. Bone resorption is based on the destruction of the bone matrix by osteoclasts. Most bone disorders are based on a disturbance in the balance between bone formation and bone resorption. Osteoporosis is a disease characterized by decreased bone mass and increased bone fragility leading to increased fracture risk. This is due to a deficit in new bone formation for bone resorption during the ongoing remodeling process. Conventional osteoporosis treatment includes, for example, administration of bisphosphonates, estrogens, estrogen/progestogens (hormone replacement therapy or HRT), estrogen agonists/antagonists (selective estrogen receptor modulators or SERMs), Calcitonin, vitamin D analogues, parathyroid hormone, growth hormone secretagogue, or sodium fluoride (Jardine et al., Annual Reports in Medicinal Chemistry 1996, 31, 211).

Activated osteoclasts are bone matrix depleted multinucleated cells with diameters up to 400 μm. Activated osteoclasts attach to the bone matrix surface and secrete proteolytic enzymes and acids into the so-called "seal zone", which is the area between their cell membrane and the bone matrix. An acidic environment and proteases cause bone destruction. Compounds of formula I inhibit bone resorption by osteoclasts.

Various studies have shown that attachment of osteoclasts to the bone is controlled by integrin receptors on the surface of the osteoclasts. Integrins are a superfamily of receptors which include notably the fibrinogen receptor α _lib β ₃ and the vitronectin receptor α _v β ₃ on platelets. The vitronectin receptor _αvβ3 is a membrane glycoprotein expressed on the cell surface of various cells such _as endothelial cells, vascular smooth muscle cells, osteoclasts and tumor cells. The vitronectin receptor _αvβ3 expressed on the osteoclast membrane controls the _process of attachment to bone and bone resorption and thus contributes to osteoporosis. In this case, _αvβ3 binds to bone matrix proteins such _as osteopontin, bone sialoprotein and thrombospontin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).

Horton and co-workers describe RGD peptide and anti-vitronectin receptor antibody (23C6) that inhibit tooth destruction by osteoclasts and osteoclast migration (Horton et al., Exp. Cell. Res. 1991, 195, 368) . In J. Cell Biol. 1990, 111, 1713, Sato et al. describe echistatin (an RGD peptide from snake venom) as a potent inhibitor of bone resorption in tissue Inhibitor of osteocyte adhesion to bone. Fisher et al. (Endocrinology 1993, 132, 1411) were able to show in rats that serastatin also inhibits bone resorption.

This further shows that vitronectin α _v β ₃ on human aortic vascular smooth muscle cells stimulates the migration of these cells into neovascular intima, eventually leading to atherosclerosis and restenosis after angioplasty (Brown et al., Cardiovascular Res.1994, 28, 1815).

Brooks et al. (Cell 1994, 79, ₁₁₅₇ ) showed that antibodies against _αvβ3 or _αvβ3 antagonists can cause tumor _shrinkage by mediating apoptosis of vascular cells during angioplasty. The vitronectin receptor _αvβ3 is also involved in the development of various other types of cancer and is overexpressed in _malignant melanoma cells (Engleman et al., Annual Reports in Medicinal Chemistry 1996, 31, 191). The melanoma cell invasion is associated with this overexpression (Sracke et al., Encylopedia of Cancer, Vol. III, 1855, Academic Press, 1997; Hillis et al., Clinical Science 1996, 91, 639). Carron et al. (Cancer Res. 1998, 58, ₁₉₃₀ ) describe the use of _αvβ3 antagonists to inhibit the growth of such tumors and to inhibit hypercalcemia of malignancies.

Cherest et al. (Science 1995, 270, 1500) describe an anti _{- αvβ3} antibody or an _αvβ3 antagonist that inhibits the bFGF-induced angioplasty process in the rat eye, which can be used therapeutically in _the treatment of Nature of retinopathy. The influence of the vitronectin receptor or of the interactions in which it is involved thus offers the possibility of influencing different disease states, the treatment and prevention of which continue to require suitable pharmaceutical active ingredients.

WO-A-94/12181 describes substituted aromatic or non-aromatic ring systems and WO-A-94/08577 describes substituted heterocycles as fibrinogen receptor antagonists and platelet aggregation inhibitors. EP-A-528586 and EP-A-528587 disclose aminoalkyl-substituted or heterocyclyl-substituted phenylalanine derivatives, and WO-A-95/32710 discloses bone Aryl Derivatives of Reuptake Inhibitors. WO-A-96/00574 describes benzodiazepines and WO-A-96/00730 describes fibrinogen receptor antagonist templates, especially those attached to nitrogen-containing 5-membered rings as glass The benzodiazepine class of zonulin receptor antagonists. WO-A-98/00395 (DE-A-19654483) describes vitronectin receptor antagonists derived from a tyrosine backbone. EP-A-820991 (German patent application 19629816.4) describes cycloalkyl derivatives and European patent application 97122520.6 describes carbamate derivatives which are vitronectin receptor antagonists. Further studies have shown that the sulfonamide derivatives of formula I are particularly potent vitronectin receptors and inhibitors of bone resorption by osteoclasts.

The present invention relates to compounds of formula I, all stereoisomeric forms thereof and mixtures thereof in any proportion and their physiologically tolerable salts and their prodrugs,

in

R ¹ and R ² are independently of each other hydrogen or unsubstituted or substituted by R ³ (C ₁ -C ₆ )-alkyl, or wherein the radicals R ¹ - and R ² - together are saturated or unsaturated Divalent (C ₂ -C ₉ )-alkylene groups, such as the group -(CH ₂ ) _p - in which p is 2, 3, 4, 5, 6, 7, 8 or 9. It is unsubstituted or consists of one or more selected from halogen, (C ₁ -C ₆ )-alkyl, (C ₁ -C ₆ )-alkoxy, (C ₆ -C ₁₄ )-aryl, ( C ₆ -C ₁₄ )-aryl-(C ₁ -C ₆ )-alkyl-, (C ₅ -C ₁₄ )-heteroaryl, (C ₅ -C ₁₄ )-heteroaryl-(C ₁ - C ₆ )-alkyl-, (C ₃ -C ₁₂ )-cycloalkyl, (C ₃ -C ₁₂ )-cycloalkyl-(C ₁ -C ₆ )-alkyl- and oxo group substitution , wherein 5-membered to 7-membered saturated or unsaturated ring is unsubstituted or substituted by R ³ especially by one or two groups R ³ and is carbocyclic or contains one or two ring nitrogens A heterocyclic ring of atoms can be fused to a carbon-carbon bond in (C ₂ -C ₉ )-alkylene; R ³ is (C ₁ -C ₁₀ )-alkyl, (C ₃ -C ₂₀ )-mono Cycloalkyl, (C ₅ -C ₂₀ )-bicycloalkyl, (C ₅ -C ₂₀ )-tricycloalkyl, (C ₁ -C ₈ )-alkoxy, (C ₆ -C ₁₄ )-aryl Base, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₄ )-alkyl-, (C ₅ -C ₁₄ )-heteroaryl, (C ₅ -C ₁₄ )-heteroaryl-( C ₁ -C ₄ )-alkyl-, halogen, trifluoromethyl, cyano, hydroxyl, oxo, nitro, amino, -NH-(C ₁ -C ₄ )-alkyl, -N((C ₁ -C ₄ )-alkyl) ₂ , -NH-CO-(C ₁ -C ₄ )-alkyl, -CO-(C ₁ -C ₄ )-alkyl; R ⁴ is hydrogen, (C ₁ - C ₆ )-Alkyl-CO-O-(C ₁ -C ₄ )-Alkyl- is either unsubstituted or composed of hydroxyl, (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ )-Alkyl (C ₁ -C ₆ )-alkyl groups substituted by groups of -S(O) ₂ -, -NR ⁷ R ^7' and -N ⁺ R ⁷ R ^7' R ^{7” Q-} , wherein R ⁷ , R ^7' and R ^7" are independently hydrogen, (C ₁ -C ₆ )-alkyl, (C ₅ -C ₁₄ )-aryl or (C ₅ -C ₁₄ )-aryl-(C ₁ -C ₆ )-alkyl- and Q ^- is a physiologically tolerable anion, or wherein R ⁴ is one of the following groups

wherein the bond by which the groups are attached is indicated by a dashed line;

R ⁵ is (C ₁ -C ₂₀ )-alkyl, (C ₃ -C ₂₀ )-monocycloalkyl, (C ₅ -C ₂₀ )-bicycloalkyl, (C ₅ -C ₂₀ )-tricycloalkane radical, (C ₆ -C ₁₄ )-aryl, (C ₅ -C ₁₄ )-heteroaryl, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₆ )-alkyl- or (C ₅ -C ₁₄ )-heteroaryl-(C ₁ -C ₆ )-alkyl-, wherein each of aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl is unsubstituted or substituted by one, two or three groups R ³ , and wherein among said alkyl, said monocycloalkyl, said bicycloalkyl and said tricycloalkyl, one or Multiple carbon atoms, in particular one, two, three or four carbon atoms, may be replaced by identical or different atoms selected from nitrogen, oxygen and sulfur;

R ⁶ is hydrogen, (C ₁ -C ₆ )-alkyl-O-CO-, hydroxy, (C ₁ -C ₆ )-alkyl-O-CO-O- or nitro.

All radicals which can occur several times in the compounds of the formula I, such as the radical R ³ , can independently of one another have the indicated meanings and can be identical or different in each case. The radicals which independently of one another have the indicated meanings may be identical or different in each case.

Preferably, the compound of formula I of the present invention is (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylaminomethyl) Acyl)-ethyl)-benzoylamino)propionic acid or its (C ₁ -C ₄ )-alkyl esters and its physiologically tolerable salts.

Alkyl groups may be straight-chain or branched and may be saturated or mono- or polyunsaturated. This also applies, for example, to alkoxy, alkoxycarbonyl or arylalkyl if they have substituents or occur as substituents of other groups. The same applies to alkylene groups (=divalent alkyl groups=saturated or unsaturated alkanediyl groups). Examples of suitable alkyl groups having 1 to 20 carbon atoms are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, deca Dialkyl, tetradecyl, hexadecyl, octadecyl and eicosyl, all normal isomers of these groups, isopropyl, isobutyl, isopentyl, neopentyl, Isohexyl, isodecyl, 3-methylpentyl, 2,3,4-trimethylhexyl, sec-butyl, tert-butyl, tert-amyl. One preferred group of alkyl groups is formed by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Divalent groups corresponding to the above-mentioned monovalent groups such as 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, 1,6-hexylene are examples of alkylene.

Unsaturated alkyl is, for example, alkenyl such as vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl, or alkynyl such as ethynyl, 1-propynyl or propargyl. Unsaturated alkylene groups, ie alkenylene and alkynylene groups (=alkenediyl and alkynediyl) can likewise be straight-chain or branched. Examples of alkenylene are 1,2-ethenylene or propenylene, examples of alkynylene are ethynylene or propynylene. Alkyl groups can also be unsaturated when they are substituted. In the alkyl moiety, an example of unsaturated arylalkyl is styryl (=2-phenylethenyl).

Unless specifically stated otherwise, cycloalkyl groups can be monocyclic, bicyclic or tricyclic, ie they can be monocycloalkyl, bicycloalkyl and tricycloalkyl provided they have the appropriate number of carbon atoms. Monocycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclododecyl, cyclo Tetradecyl, cyclooctadecyl, which can also be substituted eg by (C ₁ -C ₄ )-alkyl. Examples of substituted cycloalkyl groups that may be mentioned are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.

Bicycloalkyl and tricycloalkyl groups can be unsubstituted or in any desired suitable position, for example via one or more oxo groups and/or one or more identical or different (C ₁ -C ₄ ) -Alkyl such as methyl or isopropyl, preferably methyl substituted. The free bond by which the bicyclic or tricyclic groups are attached can be positioned at any desired position in the molecule; the groups can thus be attached via a bridge terminal atom or an atom on a bridge. The free bond can also be positioned in any desired stereochemical position, for example in the exo-position or in the endo-position. Examples of bicycloalkyl and tricycloalkyl groups are camphanyl, bornyl, adamantyl such as 1-adamantyl and 2-adamantyl, caronyl, epiisobornyl, epiisobornyl, Borneoyl, norbornyl (norbornyl) and norpineyl.

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

(C ₅ -C ₁₄ )-aryl includes heterocyclic (C ₅ -C ₁₄ )-aryl (=(C ₅ -C ₁₄ )-heteroaryl), wherein of the 5 to 14 ring carbon atoms One or more are replaced by heteroatoms such as nitrogen, oxygen or sulfur and carbocyclic (C ₆ -C ₁₄ )-aryl groups. Examples of carbocyclic (C ₆ -C ₁₄ )-aryl groups are phenyl, naphthyl, biphenyl, anthracenyl or fluorenyl, with 1-naphthyl, 2-naphthyl and phenyl being preferred. If not stated otherwise, aryl groups, especially phenyl groups, may be unsubstituted or substituted by one or more groups, preferably one, two or three identical or different groups. In particular aryl can consist of identical or different groups selected from (C ₁ -C ₈ )-alkyl (in particular (C ₁ -C ₄ )-alkyl), (C ₁ -C ₈ )-alkoxy ( In particular (C ₁ -C ₄ )-alkoxy), halogens such as fluorine, chlorine and bromine, nitro, amino, trifluoromethyl, hydroxy, methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C ₁ -C ₄ )-Alkoxycarbonyl, phenyl, phenoxy, benzyl and benzyloxy radical substitution. In the compounds of the formula I according to the invention generally only up to two nitro groups can occur as substituents.

In monosubstituted phenyl groups, the substituents can be positioned in the 2-position, 3-position or 4-position, preferably the 3- and 4-position. If the phenyl group is disubstituted, the substituent can be in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In a disubstituted phenyl group, the two substituents are preferably arranged at the 3,4-position relative to the attachment position. In trisubstituted phenyl, the substituents can be at 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6 -bit or 3, 4, 5-bit. Similarly, naphthyl and other aryl groups can be substituted at any desired position, for example 1-naphthyl at the 2-, 3-, 4-, 5-, 6-, 7- and 8-positions, 2- Naphthyl is substituted at the 1-, 3-, 4-, 5-, 6-, 7- and 8-positions.

In addition to carbocyclic ring systems, (C ₅ -C ₁₄ )-aryl can also be monocyclic or polycyclic, for example bicyclic or tricyclic, in which 1, 2, 3, 4 or 5 ring carbon atoms are replaced by heteroatoms, especially by The same or different heteroatom substituted aromatic ring systems selected from nitrogen, oxygen and sulfur. Examples of heterocyclic (C ₅ -C ₁₄ )-aryl and (C ₅ -C ₁₄ )-heteroaryl groups are pyridyl like 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrrolyl like 2- Pyrrolyl and 3-pyrrolyl, furyl like 2-furyl and 3-furyl, thienyl like 2-thienyl and 3-thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, Thiazolyl, isothiazolyl, tetrazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, 2,3-diazinyl, quinolinyl, iso Quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, β-carbolinyl or benzo-fused, cyclopentane-fused, cyclohexane-fused or cycloheptane-fused Derivatives of these groups. The heterocyclic ring systems can be substituted in all suitable positions by the same substituents as mentioned above for the carbocyclic aryl systems.

Among these heteroaryl groups in the series, preference is given to monocyclic or bicyclic aromatic ring systems having 1, 2 or 3 heteroatoms, in particular 1 or 2 heteroatoms, selected from N, O and S, which may be Substituted or by 1, 2 or 3 selected from (C ₁ -C ₆ )-alkyl, (C ₁ -C ₆ )-alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxyl , (C ₁ -C ₄ )-alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl substituents. Particular preference is given here to monocyclic or bicyclic aromatic 5- to 10-membered ring systems having 1 to 3 heteroatoms selected from N, O and S, in particular 1 or 2 heteroatoms, which can be replaced by 1 to Substitution with 2 substituents selected from (C ₁ -C ₄ )-alkyl, (C ₁ -C ₄ )-alkoxy, phenyl, phenoxy, benzyl and benzyloxy. More particularly preferred are 5- or 6-membered monocyclic heteroaryls and 9- or 10-membered bicyclic heteroaryls containing 1 or 2, in particular 1, heteroatom selected from N, O and S, which are Unsubstituted or substituted as previously described.

If the two groups R ¹ - and R ² - together represent a divalent saturated or unsaturated (C ₂ -C ₉ )-alkylene group, these two groups and the two nitrogen atoms to which they are attached The central carbon atom of the guanidine group connected to these two nitrogen atoms forms a monocyclic 1,3-diazaheterocyclic ring, and the _heterocyclic ring is in the _2- position is attached to the nitrogen atom. An example of said 1,3-diazaheterocyclic group which may be substituted as indicated on the (C ₂ -C ₉ )-alkylene group and also on the nitrogen atom of the guanidino group is 2-imidazole base, 4,5-dihydro-2-imidazolyl, 1,4,5,6-tetrahydro-2-pyrimidinyl or the 4,5,6,7-tetrahydro-1H-1,3-di Azepine-2-yl. If the 5- to 7-membered ring is fused to a carbon-carbon bond on a (C ₂ -C ₉ )-alkylene group, then the two groups R ¹ and R ² with the two nitrogen atoms to which they are attached and The central carbon atoms of the guanidino group to which these two nitrogen atoms are bonded together form a bicyclic heterocycle which is bonded to the nitrogen atom of the group ( _CH2 ) ₂ -CO-NH and which can be substituted as indicated. The fused (or condensed) 5- to 7-membered ring may be saturated, mono- or di-unsaturated or aromatic. Thus, for example, a cyclopentane ring, cyclohexane ring, cyclohexene ring, cyclohexadiene ring, cycloheptane ring or benzene ring can be condensed. An example of such a bicyclic heterocyclic group capable of being attached to the nitrogen atom of the group (CH ₂ ) ₂ —CO—NH is 1,3a,4,5,6,6a-hexahydro-1,3-di Azapenten-2-yl, 1H-benzimidazol-2-yl, 3a, 4, 5, 6, 7, 7a-hexahydro-1H-benzimidazol-2-yl, 4, 5, 6, 7-tetrahydro-1H-benzimidazol-2-yl, 4,7-dihydro-1H-benzimidazol-2-yl or 1H-imidazo[4,5-b]pyridin-2-yl. If the condensed rings are substituted and/or if the (C ₂ -C ₉ )-alkylene groups are substituted, they are preferably mono- or disubstituted independently of one another by identical or different radicals R ³ . If the alkyl groups representing R ¹ and/or R ² are substituted, they are preferably mono- or di-substituted, in particular mono-substituted independently of each other, by identical or different radicals R ³ .

The optically active carbon atoms present in the compounds of formula I can independently of each other have the R-configuration or the S-configuration. The compounds of formula I can be present in the form of pure enantiomers or pure diastereomers or in the form of mixtures of enantiomers, for example in the form of racemates or in the form of mixtures of diastereomers. The present invention relates to the pure enantiomers and enantiomeric mixtures as well as to the pure diastereomers and diastereomeric mixtures. The present invention includes two or more than two stereoisomers of formula I and all ratios of stereoisomers in mixtures. Compounds of formula I can optionally be present as E isomer or Z isomer. The present invention relates to pure E isomers and pure Z isomers and E/Z mixtures in all ratios. The invention also includes compounds of formula I in all tautomeric forms, for example, in addition to the forms shown in said formula I, also in which the acylguanidine unit is represented as -CO-N=C(NHR ¹ )-NR ² R ⁶ forms, and include all other forms that are distinguished by mobile hydrogen atoms in different positions. Diastereomers, including E/Z isomers, can be separated into individual isomers, for example, by chromatography. Racemates can be separated into the two enantiomers by conventional methods, for example by chromatography on chiral phases or by resolution. Stereochemically uniform compounds of formula I can also be obtained by using stereochemically uniform starting materials or by using stereoselective reactions.

Physiologically tolerable salts of the compounds of the formula I are the non-toxic salts of the physiologically acceptable, especially pharmaceutically usable salts. Such salts of compounds of the formula I containing acidic groups such as carboxyl groups are, for example, alkali metal salts or alkaline earth metal salts, such as sodium, potassium, magnesium and calcium salts, also in combination with physiologically tolerable quaternary ammonium ions. Salts and acid addition salts with ammonia and physiologically tolerable organic amines, for example triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine. Compounds of the formula I containing basic groups, for example, with mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid or with organic carboxylic and sulfonic acids, such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid Acid addition salts formed with acid or p-toluenesulfonic acid. Compounds of the formula I which contain basic groups and acidic groups such as guanidine and carboxyl groups can be present as zwitterions (betaines) and are likewise included in the present invention.

When ^R is an alkyl group substituted with a positively charged ammonium group, the physiologically tolerable anion Q contained in the compound of formula I ^is a non-toxic, physiologically acceptable monovalent anion or an equivalent polyvalent anion. Commercially available, especially also pharmaceutically available inorganic or organic acids, for example anions or anion equivalents of one of the above-mentioned acids which are suitable for the formation of acid addition salts. Thus, Q ^- may be selected from, for example, chlorides, sulfates, phosphates, acetates, citrates, benzoates, maleates, fumarates, tartrates, methanesulfonates and One of said anions (or anion equivalents) of p-toluenesulfonate.

Compounds of formula I can be prepared by conventional methods known to those skilled in the art, for example by combining compounds of formula I with inorganic or organic acids or bases in solvents or dispersions, or by cation exchange or anion exchange from other salts of salt. The invention also includes all salts of the compounds of the formula I which are not directly suitable for use in medicaments due to their low physiological tolerability, but which are suitable, for example, as intermediates for carrying out other chemical modifications of the compounds of the formula I or as Starting material for the preparation of physiologically tolerated salts.

Furthermore, the invention includes all solvates of the compounds of the formula I, such as hydrates or adducts with alcohols, and also derivatives of the compounds of the formula I, such as esters, prodrugs and other physiologically tolerable Derivatives of and active metabolites of compounds of formula I. The present invention relates in particular to prodrugs of compounds of formula I which are capable of being converted into compounds of formula I under physiological conditions. Suitable prodrugs of the compounds of the formula I, ie chemically modified derivatives of the compounds of the formula I having properties improved in the desired manner, are known to the person skilled in the art. More detailed information concerning prodrugs is found in, for example, Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115-130; Prodrug Design , H. Bundgaard, Ed., Elsevier, 1985; H. Bundgaard, Future Drugs 16 (1991 ) 443; Saulnier et al., Bioorg. Med. Chem. Lett. 4 (1994) 1985; Safadi et al., Pharmaceutical Res. 10 (1993) 1350, which are incorporated herein by reference. Suitable prodrugs of compounds of formula ^I are in particular ester prodrugs of carboxylic acid groups, especially when R in the group COOR ⁴ is hydrogen, a COOH group is present, for example an alkyl ester of this group like (C ₁ -C ₆ )-Alkyl esters or (C ₁ -C ₄ )-Alkyl esters, and also acyl prodrugs and carbamate prodrugs of acylated nitrogen-containing groups such as amino groups and in particular Guanidino. In the acyl or carbamate prodrugs, the hydrogen atoms located on the nitrogen atoms in these groups are substituted one or more times, for example twice, by an acyl group or a carbamate group. Suitable acyl and carbamate groups for said acyl prodrugs and carbamate prodrugs are, for example, the groups R ¹⁰ —CO and R ¹¹ O—CO, where R ¹⁰ is hydrogen, (C ₁ -C ₁₈ )-Alkyl, (C ₃ -C ₁₄ )-Cycloalkyl, (C ₃ -C ₁₄ )-Cycloalkyl-(C ₁ -C ₈ )-Alkyl-, (C ₅ -C ₁₄ )-aryl, wherein 1 to 5 carbon atoms can be replaced by heteroatoms such as N, O or S, or (C ₅ -C ₁₄ )-aryl-(C ₁ -C ₈ )-alkyl-, wherein 1 to 5 carbon atoms in said aryl moiety can be replaced by heteroatoms such as N, O or S, and wherein R ¹¹ has the meaning indicated for R ¹⁰ except hydrogen.

In compounds of formula I, the radicals R ¹ and R ² are preferably hydrogen or together are saturated or unsaturated, in particular saturated divalent (C ₂ -C ₅ )-alkylene, in particular (C ₂ - C ₄ )-Alkylene, especially (C ₂ -C ₃ )-Alkylene, which is unsubstituted or consists of one or two identical or different halogens, (C ₁ -C ₆ )- Alkyl, (C ₁ -C ₆ )-alkoxy, (C ₆ -C ₁₄ )-aryl, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₆ )-alkyl-, ( C ₅ -C ₁₄ )-heteroaryl, (C ₅ -C ₁₄ )-heteroaryl-(C ₁ -C ₆ )-alkyl-, (C ₃ -C ₁₂ )-cycloalkyl, (C ₃ -C ₁₂ )-cycloalkyl-(C ₁ -C ₆ )-alkyl- and oxo-substituted, here unsubstituted or substituted by R ³ , in particular by one or two radicals R ³ 5-membered to 7-membered saturated or unsaturated rings which are carbocyclic or heterocyclic containing one or two ring nitrogen atoms can be fused to a carbon-carbon bond in the alkylene group . In the compounds of formula I, the radicals R ^{and R} are particularly preferably hydrogen or a radical in which p is the number 2, 3, 4 or 5, preferably 2, 3 or 4, particularly preferably 2 or 3, -( CH ₂ ) _P -, and it is unsubstituted or consists of one or two identical or different selected from halogen, (C ₁ -C ₆ )-alkyl, (C ₁ -C ₆ )-alkoxy, (C ₆ -C ₁₄ )-aryl, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₆ )-alkyl-, (C ₅ -C ₁₄ )-heteroaryl, (C ₅ - C ₁₄ )-heteroaryl-(C ₁ -C ₆ )-alkyl-, (C ₃ -C ₁₂ )-cycloalkyl, (C ₃ -C ₁₂ )-cycloalkyl-(C ₁ -C ₆ )-alkyl- and oxo-substituted groups, here unsubstituted or substituted by R ³ especially by one or two groups R ³ , and which are carbocyclic or contain one or two ring nitrogen atoms The 5- to 7-membered saturated or unsaturated ring of the heterocycle can be fused to a carbon-carbon bond in the group -(CH ₂ ) _P -. The radicals R ¹ and R ² are more particularly preferably together a radical -(CH ₂ ) _P -, where p is the number 2, 3, 4 or 5, preferably 2, 3 or 4, particularly preferably 2 or 3 , which is preferably unsubstituted. The groups R ¹ - and R ² - are particularly preferably together the divalent group -CH ₂ -CH ₂ -CH ₂ -, ie R ¹ and R ² are connected to the nitrogen atom to which they are attached and to the two nitrogens The central carbon atoms of the guanidine group connected by the atoms together form 1,4,5,6-tetrahydro-2-pyrimidinyl;

R ³ is preferably (C ₁ -C ₁₀ )-alkyl, (C ₃ -C ₂₀ )-monocycloalkyl, (C ₅ -C ₂₀ )-bicycloalkyl, (C ₅ -C ₂₀ )-tricyclic Alkyl, (C ₁ -C ₈ )-alkoxy, (C ₆ -C ₁₄ )-aryl, (C ₅ -C ₁₄ )-heteroaryl, (C ₆ -C ₁₄ )-aryl-( C ₁ -C ₄ )-alkyl-, (C ₅ -C ₁₄ )-heteroaryl-(C ₁ -C ₄ )-alkyl-, halogen, trifluoromethyl, cyano, oxo, -N ((C ₁ -C ₄ )-Alkyl) ₂ or -NH-CO-(C ₁ -C ₄ )-Alkyl. R ³ is more preferably (C ₁ -C ₄ )-alkyl, (C ₃ -C ₁₀ )-monocycloalkyl, (C ₅ -C ₁₂ )-bicycloalkyl, (C ₅ -C ₁₂ )-tricycloalkyl Cycloalkyl, (C ₁ -C ₄ )-alkoxy, (C ₆ -C ₁₄ )-aryl, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₄ )-alkyl-, Halogen, trifluoromethyl, cyano, oxo, -N((C ₁ -C ₄ )-alkyl) ₂ or -NH-CO-(C ₁ -C ₄ )-alkyl. R ³ is particularly preferably (C ₁ -C ₄ )-alkyl, (C ₃ -C ₁₀ )-monocycloalkyl, (C ₅ -C ₁₂ )-bicycloalkyl, (C ₅ -C ₁₂ )-tricycloalkyl Cycloalkyl, (C ₁ -C ₄ )-alkoxy, (C ₆ -C ₁₄ )-aryl, halogen, trifluoromethyl, cyano, oxo, -N((C ₁ -C ₄ ) -alkyl) ₂ or -NH-CO-(C ₁ -C ₄ )-alkyl.

R ⁴ is preferably hydrogen or unsubstituted or substituted (C ₁ -C ₆ )-alkyl, particularly preferably hydrogen or a group selected from (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ ) -Alkyl-S(O) ₂ - and -NR ⁷ R ^7' group substituted (C ₁ -C ₆ )-alkyl, wherein R ⁷ and R ^7' are independently hydrogen or (C ₁ -C ₄ )-Alkyl. R ⁴ is very particularly preferably hydrogen or unsubstituted or substituted (C ₁ -C ₄ )-alkyl, furthermore preferably hydrogen or unsubstituted or substituted (C ₁ -C ₄ )-alkyl as indicated above .

R ⁵ is preferably (C ₁ -C ₂₀ )-alkyl, (C ₃ -C ₂₀ )-monocycloalkyl, (C ₅ -C ₂₀ )-bicycloalkyl, (C ₅ -C ₂₀ )-tricyclic Alkyl, (C ₆ -C ₁₄ )-aryl, (C ₅ -C ₁₄ )-heteroaryl, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₆ )-alkyl- or ( C ₅ -C ₁₄ )-heteroaryl-(C ₁ -C ₆ )-alkyl-, wherein the aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl Each of is unsubstituted or substituted by one, two or three identical or different groups R ³ . R ⁵ is more preferably (C ₁ -C ₁₀ )-alkyl, (C ₃ -C ₁₅ )-monocycloalkyl, (C ₅ -C ₁₅ )-bicycloalkyl, (C ₅ -C ₁₅ )-tricycloalkyl Cycloalkyl, (C ₆ -C ₁₄ )-aryl, (C ₅ -C ₁₄ )-heteroaryl, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₆ )-alkyl- or (C ₅ -C ₁₄ )-heteroaryl-(C ₁ -C ₆ )-alkyl-, wherein said aryl, said heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricyclic Each of the alkyl groups is unsubstituted or substituted by one, two or three identical or different groups R ³ . In addition to these preferred groups, one class of preferred groups R ⁵ consists of groups (C ₃ -C ₂₀ )-monocycloalkyl, (C ₅ -C ₂₀ )-bicycloalkyl and (C ₅ -C ₂₀ )-tricycloalkyl are formed, and are more preferably formed from (C ₅ -C ₁₅ )-monocycloalkyl, (C ₅ -C ₁₅ )-bicycloalkyl, (C ₅ -C ₁₅ )-Tricycloalkyl formation. Another preferred group R ⁵ consists of the groups (C ₁ -C ₂₀ )-alkyl, (C ₆ -C ₁₄ )-aryl, (C ₅ -C ₁₄ )-heteroaryl, (C ₆ - C ₁₄ )-aryl-(C ₁ -C ₆ )-alkyl- or (C ₅ -C ₁₄ )-heteroaryl-(C ₁ -C ₆ )-alkyl- forms, wherein (C ₆ -C ₁₄ )-Aryl and (C ₅ -C ₁₄ )-heteroaryl are preferred, which can be substituted or otherwise modified as indicated above. A particularly preferred class of radicals ^R5 is formed from the radicals phenyl and naphthyl, ie from phenyl, 1-naphthyl and 2-naphthyl which may be unsubstituted or substituted as specified above.

R ⁶ is preferably hydrogen or (C ₁ -C ₆ )-alkyl-O-CO—, particularly preferably hydrogen or (C ₁ -C ₄ )-alkyl-O—CO—, especially hydrogen.

Preferred compounds of formula I are those in which one or more radicals have a preferred meaning or have one particular or some particulars of their respective meanings, all combinations of such preferred meanings or special meanings being the object of the present invention. Particularly preferred compounds of formula I are those in which R ^{and R} are hydrogen or together a saturated or unsaturated divalent (C ₂ -C ₅ )-alkylene group, in particular hydrogen or together in which p is the number 2 , 3, 4 or 5 of the group -(CH ₂ ) _p -compounds, where (C ₂ -C ₅ )-alkylene and the group -(CH ₂ ) _p - are unsubstituted or are selected from halogen , (C ₁ -C ₆ )-alkyl, (C ₁ -C ₆ )-alkoxy, (C ₆ -C ₁₄ )-aryl, (C ₆ -C ₁₄ )-aryl-(C ₁ - C ₆ )-Alkyl-, (C ₅ -C ₁₄ )-Heteroaryl, (C ₅ -C ₁₄ )-Heteroaryl-(C ₁ -C ₆ )-Alkyl-, (C ₃ -C ₁₂ )-cycloalkyl, (C ₃ -C ₁₂ )-cycloalkyl-(C ₁ -C ₆ )-alkyl- and oxo-substituted, and here unsubstituted or by R ³ in particular by one or two groups R ³ substituted, and a carbocyclic or heterocyclic 5-membered to 7-membered saturated or unsaturated ring containing one or two ring nitrogen atoms can be fused to (C ₂ -C ₅ )-alkylene and the group -(CH ₂ ) _P -on the carbon-carbon bond;

R ³ is (C ₁ -C ₁₀ )-alkyl, (C ₃ -C ₂₀ )-monocycloalkyl, (C ₅ -C ₂₀ )-bicycloalkyl, (C ₅ -C ₂₀ )-tricycloalkane radical, (C ₁ -C ₈ )-alkoxy, (C ₆ -C ₁₄ )-aryl, (C ₅ -C ₁₄ )-heteroaryl, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₄ )-alkyl-, (C ₅ -C ₁₄ )-heteroaryl-(C ₁ -C ₄ )-alkyl-, halogen, trifluoromethyl, cyano, oxo, -N( (C ₁ -C ₄ )-alkyl) ₂ or -NH-CO-(C ₁ -C ₄ )-alkyl;

R ⁴ is hydrogen or it is unsubstituted or consists of (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ )-alkyl-S(O) ₂ - and NR ⁷ R ^7' (C ₁ -C ₆ )-alkyl group substituted, wherein R ⁷ and R ^7' are independently hydrogen or (C ₁ -C ₄ )-alkyl;

R ⁵ is (C ₁ -C ₂₀ )-alkyl, (C ₃ -C ₂₀ )-monocycloalkyl, (C ₅ -C ₂₀ )-bicycloalkyl, (C ₅ -C ₂₀ )-tricycloalkane radical, (C ₆ -C ₁₄ )-aryl, (C ₅ -C ₁₄ )-heteroaryl, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₆ )-alkyl- or (C ₅ -C ₁₄ )-heteroaryl-(C ₁ -C ₆ )-alkyl-, wherein each of the aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl one is unsubstituted or substituted by one, two or three groups ^R3 ;

R ⁶ is hydrogen or (C ₁ -C ₆ )-alkyl-O-CO-;

All stereoisomeric forms and mixtures thereof in all proportions and their physiologically tolerable salts and their prodrugs.

Very particularly preferred compounds of formula I are those in which

R ¹ and R ² are hydrogen or together a saturated or unsaturated divalent (C ₂ -C ₄ )-alkylene group, in particular hydrogen or together a group in which p is the number 2, 3 or 4 -( CH ₂ ) _p -, where (C ₂ -C ₄ )-alkylene and the group -(CH ₂ ) _p - are unsubstituted or are formed from the group consisting of halogen, (C ₁ -C ₆ )-alkyl, ( C ₁ -C ₆ )-alkoxy, (C ₆ -C ₁₄ )-aryl, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₆ )-alkyl-, (C ₅ -C ₁₄ )-heteroaryl, (C ₅ -C ₁₄ )-heteroaryl-(C ₁ -C ₆ )-alkyl-, (C ₃ -C ₁₂ )-cycloalkyl, (C ₃ -C ₁₂ ) -Cycloalkyl-(C ₁ -C ₆ )-alkyl- and oxo-substituted groups, and here they are unsubstituted or substituted by R ³ in particular by one or two groups R ³ , and are carbon 5- to 7-membered saturated or unsaturated rings of rings or heterocycles containing one or two ring nitrogen atoms can be fused to (C ₂ -C ₄ )-alkylene and the group -(CH ₂ ) on the carbon-carbon bond in _P- ;

R ³ is (C ₁ -C ₄ )-alkyl, (C ₃ -C ₁₀ )-monocycloalkyl, (C ₅ -C ₁₂ )-bicycloalkyl, (C ₅ -C ₁₂ )-tricycloalkane radical, (C ₁ -C ₄ )-alkoxy, (C ₆ -C ₁₄ )-aryl, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₄ )-alkyl-, halogen, Trifluoromethyl, cyano, oxo, -N((C ₁ -C ₄ )-alkyl) ₂ or -NH-CO-(C ₁ -C ₄ )-alkyl;

R ⁴ is hydrogen or (C ₁ -C ₆ )-alkyl;

R ⁵ is (C ₁ -C ₁₀ )-alkyl, (C ₃ -C ₁₅ )-monocycloalkyl, (C ₅ -C ₁₅ )-bicycloalkyl, (C ₅ -C ₁₅ )-tricycloalkane radical, (C ₆ -C ₁₄ )-aryl, (C ₅ -C ₁₄ )-heteroaryl, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₆ )-alkyl- or (C ₅ -C ₁₄ )-heteroaryl-(C ₁ -C ₆ )-alkyl-, wherein each of the aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl one is unsubstituted or substituted by one, two or ^three R groups;

R ⁶ is preferably hydrogen or (C ₁ -C ₄ )-alkyl-O-CO-;

All stereoisomeric forms and mixtures thereof in all proportions and their physiologically tolerable salts and their prodrugs.

Particularly preferred compounds of formula I are those wherein:

R ¹ and R ² are hydrogen or together a saturated or unsaturated divalent (C ₂ -C ₃ )-alkylene group, in particular hydrogen or together a group in which p is the number 2 or 3 -(CH ₂ ) _p -, where (C ₂ -C ₃ )-alkylene and the group -(CH ₂ ) _p - are unsubstituted or are formed from the group consisting of halogen, (C ₁ -C ₆ )-alkyl, (C ₁ -C ₆ )-alkoxy, (C ₆ -C ₁₄ )-aryl, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₆ )-alkyl-, (C ₅ -C ₁₄ ) -heteroaryl, (C ₅ -C ₁₄ )-heteroaryl-(C ₁ -C ₆ )-alkyl-, (C ₃ -C ₁₂ )-cycloalkyl, (C ₃ -C ₁₂ )-cyclo Alkyl-(C ₁ -C ₆ )-alkyl- and oxo groups are substituted and here unsubstituted or substituted by R ³ especially by one or two R ³ groups and are carbocyclic or contain one A 5-membered to 7-membered saturated or unsaturated ring of a heterocyclic ring with two ring nitrogen atoms can be fused in a (C ₂ -C ₃ )-alkylene group and a group -(CH ₂ ) _P - on the carbon-carbon bond;

R ³ is (C ₁ -C ₄ )-alkyl, (C ₃ -C ₁₀ )-monocycloalkyl, (C ₅ -C ₁₂ )-bicycloalkyl, (C ₅ -C ₁₂ )-tricycloalkane radical, (C ₁ -C ₄ )-alkoxy, (C ₆ -C ₁₄ )-aryl, halogen, trifluoromethyl, cyano, oxo, -N((C ₁ -C ₄ )-alk base) ₂ or -NH-CO-(C ₁ -C ₄ )-alkyl;

R ⁴ is hydrogen or (C ₁ -C ₆ )-alkyl;

R ⁵ is (C ₁ -C ₁₀ )-alkyl, (C ₃ -C ₁₅ )-monocycloalkyl, (C ₅ -C ₁₅ )-bicycloalkyl, (C ₅ -C ₁₅ )-tricycloalkane radical, (C ₆ -C ₁₄ )-aryl, (C ₅ -C ₁₄ )-heteroaryl, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₆ )-alkyl- or (C ₅ -C ₁₄ )-heteroaryl-(C ₁ -C ₆ )-alkyl-, wherein each of the aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl one is unsubstituted or substituted by one, two or ^three R groups;

R ⁶ is hydrogen or (C ₁ -C ₆ )-alkyl-O-CO-;

All stereoisomeric forms and mixtures thereof in all proportions and their physiologically tolerable salts and their prodrugs.

Further preferred compounds of the formula I are those present in all their stereoisomeric forms and in the form of their mixtures in all proportions and their physiologically tolerable salts and their prodrugs, wherein R ⁵ is (C ₆ -C ₁₄ )-aryl or (C ₅ -C ₁₄ )-heteroaryl, preferably (C ₆ -C ₁₄ )-aryl, wherein each of aryl and heteroaryl is unsubstituted or substituted by one, two or three identical or different ^R3 groups, and preferably unsubstituted or substituted by one or two identical or different ^R3 groups. Even more preferred compounds of formula I are those in all their stereoisomeric forms and in the form of their mixtures in all proportions and their physiologically tolerable salts and their prodrugs, wherein R ^is Naphthyl such as 1-naphthyl or 2-naphthyl, which is unsubstituted or substituted by one, two or ^three R groups, and which is preferably unsubstituted such as unsubstituted 1-naphthyl or unsubstituted Substituted 2-naphthyl.

Preferred compounds of formula I are also those in which the carbon atom to which the two radicals R ⁴ O—CO— and R ⁵ —SO ₂ —NH— are attached has the S configuration, in all their stereoisomers Forms and their mixtures in all proportions and their physiologically tolerable salts and their prodrugs.

A special group of compounds of formula I is formed by compounds in which R and ^R independently of each other are hydrogen or unsubstituted or substituted by R ^{3 (} C ₁ -C ₆ )-alkyl,

or in which the radicals R ¹ - and R ² - together are saturated or unsaturated divalent (C ₂ -C ₉ )-alkylene groups, for example in which p is 2, 3, 4, 5, 6, 7, 8 or 9 groups -(CH ₂ ) _p -, which are unsubstituted or composed of one or more selected from halogen, (C ₁ -C ₆ )-alkyl, (C ₁ -C ₆ )-alkoxy , (C ₆ -C ₁₄ )-aryl, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₆ )-alkyl, (C ₅ -C ₁₄ )-heteroaryl, (C ₅ - C ₁₄ )-heteroaryl-(C ₁ -C ₆ )-alkyl, (C ₃ -C ₁₂ )-cycloalkyl and (C ₃ -C ₁₂ )-cycloalkyl-(C ₁ -C ₆ ) -Alkyl- and oxo-substituted groups, here unsubstituted or substituted by ^R3 in particular by one or two ^R3 groups, and carbocyclic or heterocyclic containing one or two ring nitrogen atoms A 5-membered to 7-membered saturated or unsaturated ring can be fused to a carbon-carbon bond in (C ₂ -C ₉ )-alkylene;

R ³ is (C ₁ -C ₈ )-alkyl, (C ₁ -C ₈ )-alkoxy, (C ₅ -C ₁₄ )-aryl, (C ₅ -C ₁₄ )-aryl-(C ₁ -C ₄ )-Alkyl, (C ₅ -C ₁₄ )-Heteroaryl, (C ₅ -C ₁₄ )-Heteroaryl-(C ₁ -C ₄ )-Alkyl, Halogen, Trifluoromethyl , hydroxy, oxo, nitro, amino, NH-(C ₁ -C ₄ )-alkyl, N-((C ₁ -C ₄ )-alkyl) ₂ , NH-CO-(C ₁ -C ₄ )-alkyl, CO-(C ₁ -C ₄ )-alkyl;

R ⁴ is hydrogen, unsubstituted or composed of hydroxyl, (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ )-alkyl-SO ₂ -, -NR ⁷ R ^7' and -N ⁺ R ⁷ R ^7' R ^7” Q ^- substituted (C ₁ -C ₆ )-alkyl-CO-O-(C ₁ -C ₄ )-alkyl or (C ₁ -C ₆ )- Alkyl, wherein R ⁷ , R ^7' and R ^7" are independently hydrogen, (C ₁ -C ₆ )-alkyl, (C ₅ -C ₁₄ )-aryl or (C ₅ -C ₁₄ )-aryl Group-(C ₁ -C ₆ )-alkyl and Q ^- is a physiologically tolerable anion, or wherein R ⁴ is one of said groups;

wherein the free bond through which the group is attached is indicated by a dashed line;

R ⁵ is (C ₁ -C ₂₀ )-alkyl, (C ₅ -C ₂₀ )-monocycloalkyl, (C ₅ -C ₂₀ )-bicycloalkyl, (C ₅ -C ₂₀ )-tricycloalkane radical, (C ₆ -C ₁₄ )-aryl, (C ₅ -C ₁₄ )-heteroaryl, (C ₆ -C ₁₄ )-aryl-(C ₁ -C ₆ )-alkyl- or (C ₅ -C ₁₄ )-heteroaryl-(C ₁ -C ₆ )-alkyl, wherein each of the aryl, heteroaryl, alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl is unsubstituted or substituted by one, two or ^three R groups, and wherein in said alkyl, monocycloalkyl, bicycloalkyl and tricycloalkyl, one or more carbon atoms, especially is one, two, three or four carbon atoms; can be replaced by the same or different atoms selected from nitrogen, oxygen and sulfur; R ⁶ is hydrogen, (C ₁ -C ₆ )-alkyl-O- CO, hydroxy, (C ₁ -C ₆ )-alkyl-O-CO-O or nitro; all stereoisomeric forms and mixtures thereof in all proportions and their physiologically tolerated salts and their prodrugs.

The present invention also relates to processes for the preparation of compounds of formula I. Said compounds can generally be prepared, for example, by linking two or more fragments capable of retrosynthetically derivatizing from formula I during a convergent synthesis. In the preparation of compounds of formula I, when introducing a functional group which can lead to undesirable reactions or side reactions in the respective synthetic steps, it is present in the form of a precursor which is then converted into the desired functional group or by means of a suitable Protecting Group Strategies for Synthetic Issues It is often beneficial or necessary to temporarily block functional groups during the synthesis described. Such strategies are well known to those skilled in the art (see eg Greene and Wuts, Protecting Groups in Organic Synthesis , Wiley, 1991). As examples of precursor groups, nitro and cyano groups may be mentioned, which can then be converted by reduction, for example by catalytic hydrogenation, into amino and aminomethyl groups, respectively.

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

wherein R ^{and R} are as defined above for formula I, or wherein additional functional groups are present in the form of precursors which are later converted to said groups present in compounds of formula I, or wherein the functional groups are present in protected form , and wherein X is a nucleophilically substituted leaving group of guanidine or a derivative of guanidine having formula III,

wherein R ¹ , R ² and R ⁶ are as defined above for said formula I, or additional functional groups are present in the form of precursors for their subsequent conversion into groups present in said formula I compounds, or functional groups are present in the form of The form of protection exists.

In formula II, the group COX is preferably a carboxylic acid group COOH or an activated carboxylic acid derivative. X is for example hydroxy or halogen especially chlorine or bromine, alkoxy, preferably methoxy or ethoxy, aryloxy such as phenoxy or pentafluorophenoxy, phenylthio, methylthio, 2- Pyridinethio or nitrogen heterocyclyl attached via a nitrogen atom, especially pyrrole, eg 1-imidazolyl. X can additionally be eg ((C ₁ -C ₄ )-alkyl)-O-CO-O- or tosyloxy, so the activated acid derivative can be a mixed anhydride.

If X is a hydroxyl group, ie if the guanidine of formula III is reacted with a carboxylic acid, then the carboxylic acid is first activated for convenience. For example, with dicyclohexylcarbodiimide (DCCI) or with O-((cyano(ethoxycarbonyl)-methylene)amino)-1,1,3,3-tetramethyluronium (uronium ) Tetrafluoroborate (TOTU; Konig et al., Proc. 21st Europ. Peptide Symp. 1990 (Eds. Giralt, Andreu), Escom, Leiden 1991, p. 143) or other activating reagents common in peptide chemistry enabling the activation.

In addition to the free guanidine of the formula III, guanidine salts can also be used in the reaction with compounds of the formula II, whereby the free guanidine can be prepared in situ or in a separate step with the aid of a base. In a manner known per se, the reaction of the activated carboxylic acid derivative of the formula II with the guanidine (derivative) of the formula III is preferably carried out in a protic or aprotic polar but inert organic solvent. In this case, at temperatures from 0° C. to the boiling point of these solvents, for example in the reaction of methyl esters (X = methoxy) or ethyl esters (X = ethoxy) with guanidine, it has been demonstrated that Solvents like methanol, isopropanol, tert-butanol, dimethylformamide or tetrahydrofuran are suitable. The reaction of COX compounds of said type with salt-free guanidine is advantageously carried out in an aprotic solvent such as dimethylformamide, tetrahydrofuran, dimethoxyethane or dioxane, if appropriate with the addition of a base such as t- potassium butoxide or sodium methoxide. However, water can also be used as solvent in the reaction of the compound of formula II with guanidine, eg when using a base such as sodium hydroxide. If X is eg chlorine, the reaction advantageously proceeds with the addition of an acid scavenger such as an additional base or in the presence of excess guanidine (derivative) for binding the hydrochloric acid formed. The reaction mixture is extracted and, if desired, the reaction product is then purified by conventional methods familiar to those skilled in the art.

The protecting group is optionally still present on the products obtained from compounds of formula II and III and is then removed by standard methods. For example, the tert-butyl ester group is converted to the carboxylic acid group by treatment with trifluoroacetic acid, the benzyl group is removed by hydrogenation or the fluorenylmethoxycarbonyl group is removed by a secondary amine. Further reactions, such as acylation or esterification, are then carried out by standard methods, if desired. In addition, conversion to physiologically tolerable salts or prodrugs can then be carried out by known methods.

The starting materials of the formulas II and III which are relevant to give the compounds of the formula I are commercially available or can be prepared according to or analogously to methods described in said literature. The preparation of the starting components of formula II is illustrated by means of the examples in Scheme 1 below, the invention not being limited to this synthesis or their starting components. Modifications of the shown syntheses, which are necessary for the preparation of the compounds of the invention, do not pose any problem to those skilled in the art.

Thus, for example in the presence of pyridine and piperidine, carboxybenzaldehydes of the formula IV can be reacted, for example, with malonate salts of the formula V to give cinnamic acid derivatives of the formula VI, for example after hydrogenation in the presence of palladium on carbon , to obtain the compound of formula VII. After activation of the carboxylic acid group, compounds of formula VII can be condensed with 2,3-diaminopropionic acid derivatives of formula VIII to give compounds of formula IX (Scheme 1). The condensation can be carried out in the presence of eg TOTU or another conventional reagent for activating carboxylic acids.

In formula VIII, Y can be the group R ⁵ -SO ₂ - which is present in the final compound of formula I of the invention and which can then remain in the molecule, or Y can be the temporarily protected amino group in the 2-position and is removed in a later step to give a free amino group which can then be prepared by standard methods for the preparation of sulfonamides, for example by combining said free amine with the formula R ⁵ —SO ₂ —Cl The sulfonyl chloride reaction converts to the R ⁵ -SO ₂ -NH group. An example of a protecting group representing Y is said benzyloxycarbonyl group (Z group) which can be removed by catalytic hydrogenation. Sulfonyl chlorides and other sulfonic acid derivatives of the formula R ⁵ -SO _{2 -Cl} suitable for introducing the group R ₅ -SO 2 are commercially available or can be followed or analogously to the procedures described in the literature Prepare. Instead of the tert-butyl ester present in the compounds of the formulas VIII and IX other esters may be present which only temporarily protect the acid group or which can also be present in the final compounds of the formula I according to the invention and can remain in the molecule . Compounds similar to compounds of VI can also be obtained by other methods of converting carbonyls to alkenes, for example by the Wittig reaction.

Process 1

Compounds of formula IX are examples of compounds of formula II wherein X is methoxy. These compounds and analogs derived from the above syntheses and containing activated carboxylic acid derivative groups can be reacted directly with compounds of formula III. However, under standard conditions, the compounds obtained in the above syntheses can also be converted firstly to the corresponding carboxylic acids by cleaving the methyl ester group or another ester group present in the relevant position of the compound of formula IX, which The guanidine of formula III is reacted after in situ activation, eg with TOTU or DCCI, or after conversion to an activated carboxylic acid derivative. If one intends to prepare, for example, carboxylic acid chloride derivatives (formula II, X=Cl) as activated acid derivatives, this transformation can be carried out, for example, by using thionyl chloride. If it is intended to prepare, for example, the methyl ester from the carboxylic acid (formula II, X = methoxy), this can be done by treatment with hydrogen chloride gas in methanol. In a manner known per se, other activated acid derivatives can be prepared from the carboxylic acid chlorides or directly from the carboxylic acids (formula II, X=OH) in which they are basified. Examples are their imidazoles (formula II, X = 1-imidazolyl) obtained by treating the acid with carbonyldiimidazole (cf. Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)), Or said mixed anhydride obtained by reaction with a chloroformate such as ethyl chloroformate or with toluenesulfonyl chloride in the presence of an amine such as triethylamine in an inert solvent. A number of suitable methods for the preparation of activated carboxylic acid derivatives are specified in J. March, Advanced Organic Chemistry , Third Edition, John Wiley & Sons, 1985, p. 350.

The compounds of the formula I are valuable pharmaceutically active ingredients which are suitable, for example, for the treatment and prophylaxis of bone disorders, neoplastic diseases or cardiovascular diseases. The compounds of the formula I and their physiologically tolerable salts and their prodrugs can be administered to animals, preferably mammals and especially humans, as therapeutic or prophylactic agents. They can be administered by themselves or in admixture with another drug or in the form of pharmaceutical preparations which allow enteral or parenteral administration and which contain, in addition to conventional pharmaceutically acceptable non-toxic carriers and/or additives, An effective amount of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs as active ingredient.

Accordingly, the present invention also relates to compounds of formula I and/or their physiologically tolerable salts and/or their prodrugs for use as medicaments, to compounds of formula I and/or their physiologically tolerable salts and /or the use of their prodrugs in the production of medicaments for the treatment and prevention of the diseases mentioned above or below, for example for the treatment and prevention of bone diseases, and also to compounds of the formula I and/or their physiological tolerability The use of salts and/or their prodrugs in the treatment and prevention of these diseases. The present invention further relates to pharmaceutical preparations or pharmaceutical preparations containing, in addition to conventional pharmaceutically acceptable carriers, an effective amount of at least one compound of formula I and/or their physiologically tolerable salts and/or their prodrugs combination.

The medicament can be administered orally, for example, in the form of pills, tablets, film tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures . However, the administration can also be administered rectally, for example in the form of suppositories or parenterally, for example in the form of injection or infusion solutions, microcapsules, implants or sticks, intravenous, intramuscular or subcutaneous, Alternatively, transdermally or topically, eg, in the form of an ointment, solution or tincture, or otherwise, eg, in the form of an aerosol or nasal spray.

The pharmaceutical formulations of the present invention are prepared by methods known per se and familiar to those skilled in the art, except that the compound of formula I and/or its (their) physiologically tolerable salts and/or its (their) In addition to prodrugs, pharmaceutical inert inorganic carriers or organic carriers are used. For the production of pills, tablets, coated tablets and hard gelatine capsules it is possible to use, for example, lactose, corn starch or their derivatives, talc, stearic acid or its salts and the like. Carriers for soft gelatine capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils and the like. Suitable carriers for producing solutions such as injections or emulsions or syrups are, for example, water, alcohols, glycerin, polyols, sucrose, invert sugar, glucose, vegetable oils and the like. Suitable carriers for microcapsules, implants or sticks are, for example, copolymers of gluconic and lactic acids. Said pharmaceutical preparations normally contain about 0.5 to 90% by weight of compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs. The amount of the active ingredient of formula I and/or its physiologically tolerable salt and/or its prodrug in the pharmaceutical preparation is normally 0.2 to 500 mg, preferably 1 to 200 mg.

In addition to the active ingredients and carriers, the pharmaceutical preparations may additionally contain additives such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, Coloring agents, flavoring or aromatic agents, thickeners, diluents, buffering substances, and also contain solvents or co-solvents for obtaining storage effects, and also contain salts, coating agents for changing the isotonic pressure or antioxidants. They can also contain two or more compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs. In addition, besides at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs, they can also contain one or more further therapeutically or prophylactically active ingredients.

Compounds of formula I are vitronectin receptor antagonists and cell adhesion inhibitors. They have, for example, the ability to inhibit the binding of osteoclasts to the bone surface and thereby inhibit bone resorption by osteoclasts. For example, the action of compounds of the formula I can be demonstrated in an assay in which the inhibition of vitronectin binding to cells containing said vitronectin receptor is determined. Details of such tests are given below. As vitronectin receptor antagonists, the compounds of formula I and their physiologically tolerable salts and their prodrugs are generally suitable for the treatment and prophylaxis of vitronectin-based Diseases in which protein receptors interact with their ligands, or can be inhibited by inhibiting this type of interaction, or the inhibition of this type of interaction is required for their prevention, alleviation or cure. As explained at the outset, such interactions play a part, for example, in bone resorption, in angiogenesis or in proliferation of vascular smooth muscle cells. The compounds of the formula I and their physiologically tolerable salts and their prodrugs are therefore suitable, for example, for alleviating or curing diseases which are caused at least in part by an undesirable degree of bone resorption, angiogenesis or proliferation of vascular smooth muscle cells.

Bone diseases which can be treated and prevented using the compounds of the formula I according to the invention are in particular osteoporosis, hypercalcemia, e.g. osteopenia caused by metastases, dental diseases, hyperparathyroidism, in rheumatoid arthritis and Periarticular erosions in Paget's disease. In addition, the compounds of formula I can be used to alleviate, avoid or treat bone diseases caused by glucocorticoid, steroid or corticosteroid therapy or by sex hormone deficiency. All of these diseases are characterized by bone loss based on a balance between bone formation and bone destruction, and which can be favorably influenced by the inhibition of bone resorption via osteoclasts. In combination with conventional osteoporosis therapy, e.g. with bisphosphonates, estrogens, estrogens/progestins, estrogen agonists/antagonists, calcitonin, vitamin In the combination therapy of D analogs, parathyroid hormone, growth hormone secretagogue or sodium fluoride, the compound of formula I and/or its physiologically tolerable salt and/or its prodrug can also be advantageously used As a bone resorption inhibitor. The compound of formula I and/or its physiologically tolerable salt and/or its prodrug can be used in any order simultaneously with the other active ingredients listed above that are effective in the treatment or prevention of osteoporosis-like diseases Continuously, jointly or separately. For use in such combined therapy or prophylaxis, the compounds of formula I and/or their physiologically tolerable salts and/or their prodrugs and one or more other drugs like those previously listed The active ingredients can be presented together in a single pharmaceutical formulation, such as tablets and granules, or they can be presented in two or more separate pharmaceutical formulations contained in a single package or in two or more separate packages middle. The use of the compounds of formula I and/or their physiologically tolerable salts and/or their prodrugs in such combination therapy or prevention and their use in the production of medicaments for such combination therapy or prevention is also subject to the present invention. purpose of the invention. The present invention additionally relates to the treatment or prevention of osteoporosis comprising an effective amount of at least one compound of formula I and/or its physiologically tolerable salt and/or its prodrug and at least one of the drugs listed above Pharmaceutical formulations of other active ingredients effective in inhibiting bone resorption and conventional pharmaceutically acceptable carriers. The above explanations regarding pharmaceutical preparations apply correspondingly to such pharmaceutical combination preparations.

In addition to their use as inhibitors of bone resorption by osteoclasts, the compounds of formula I and their physiologically tolerable salts and their prodrugs can be used as inhibitors of tumor growth and tumor metastasis, as anti-inflammatory drugs , for the treatment or prevention of cardiovascular diseases such as arteriosclerosis or restenosis, or for the treatment or prevention of nephropathy or retinopathy such as diabetic retinopathy. As inhibitors of tumor growth or tumor metastasis, the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs can also advantageously be administered in combination with conventional cancer therapies. Examples of conventional cancer therapies are given in Bertino (Ed.), Encyclopedia of Cancer, Academic Press, 1997, which is incorporated herein by reference. All statements made above in connection with the use of the compounds of the formula I in combination therapy with conventional osteoporosis, such as possible modes of administration and pharmaceutical combination preparations, apply correspondingly to the combination therapy of the compounds of formula I with conventional cancers.

When using compounds of the formula I, the dosage can vary within wide limits and is customary, being adapted to the individual conditions in each individual case. It depends, for example, on the compound used, on the nature and severity of the disease being treated, and on whether acute or chronic disease is being treated or prevented. In the case of oral administration, the daily dosage is generally 0.01 to 100 mg/kg, preferably 0.1 to 50 mg/kg, especially 0.1 to 5 mg/kg, for example 0.3 to 0.5 mg/kg (in each case expressed as per kg body weight mg) effective results were obtained in adults weighing approximately 75 kg. In the case of intravenous administration, the daily dosage is also generally about 0.01 to 100 mg/kg, preferably 0.05 to 10 mg/kg (per kg body weight in each case). Especially in the case of relatively large doses, the daily dose can be divided into several doses, for example 2, 3 or 4 doses. In general, depending on individual behaviour, it may be necessary to vary upwards or downwards from the indicated daily dose.

In addition to being used as pharmaceutically active ingredients, the compounds of formula I can also be used as vehicles or carriers for active ingredients to transport them specifically to the site of action (=drug targeting; see e.g. Targeted drug delivery , RCJuliano , Handbook of Experimental Pharmacology , Vol. 100, Ed. Born, GVR et al., Springer Verlag, which is incorporated herein by reference). The active ingredients to be delivered are in particular those which can be used in the treatment of the diseases mentioned above.

The compounds of formula I and their salts can additionally be used for diagnostic purposes, for example in vitro diagnostics and as an aid in biochemical research, where blocking the vitronectin receptor or influencing cell-cell or cell-matrix interactions is desirable of. They can additionally be used as synthesis intermediates for the preparation of other compounds, in particular other pharmaceutically active ingredients, which can be obtained from compounds of the formula I, for example by modifying or introducing groups or functional groups.

Example

The products are identified by means of mass spectroscopy (MS) and/or NMR spectroscopy. Depending on the last synthetic step and/or the method of processing (e.g. freeze-drying), in some cases the compounds are obtained partly or completely in the form of salts, e.g. as acetates, trifluoroacetates or hydrochlorides get.

Example 1

(2S)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzene Formylamino)-propionic acid

a) 4-(2-methoxycarbonyl-vinyl)benzoic acid

Suspend 18.74g (0.12mol) potassium monomethyl malonate in 18ml of pyridine, add 15.01g (0.1mol) of 4-carboxybenzaldehyde and 0.85g (0.01mol) of piperidine at room temperature with stirring . The mixture was refluxed until complete _CO2 evolution (approximately 2 hours), then another 60 ml of pyridine was added and the mixture was stirred at reflux for another 1 hour. With stirring, the reaction mixture was treated with 500 ml of ice and 110 ml of concentrated hydrochloric acid. After the addition was complete, the reaction mixture was stirred for a further 20 minutes, and the product was filtered off with suction, washed with water and recrystallized from isopropanol. Yield: 12.85g.

¹ H-NMR (200MHz, d ₆ -DMSO): δ=3.75 (s, 3H, OCH ₃ ), 6.76 (d, J=15Hz, 1H, CHCOOCH ₃ ), 7.73 (d, J=15Hz, 1H, Ar -CH), 7.84 (d, J=9Hz, 2H, Ar-H), 7.98 (d, J=9Hz, 2H, Ar-H), 13.11 (s, broad, 1H, COOH). MS (Cl ⁺ ): m/e = 207.2 (M+H ⁺ ).

HPLC: RP18, Nucleosil 300-5-C18, 250×4mm; Buffer A: H ₂ O, 0.1% trifluoroacetic acid (TFA); Buffer B: Acetonitrile (80% v/v)/H ₂ O (20 % v/v), 0.1% TFA; Gradient: 90% Buffer A/10% Buffer B for the first 5 minutes, then to 90% Buffer B during 20 minutes, then 90% Buffer B for 5 minutes; Flow rate 1 ml/min; _Rt = 18.05 min.

b) 4-(2-Methoxycarbonyl-ethyl)benzoic acid

8 g (38.8 mmol) of 4-(2-methoxycarbonyl-vinyl)benzoic acid were suspended in 250 ml of dioxane and heated over Pd/C (10% conc. ) hydrogenated for 7 hours. The mixture was filtered and the solvent was removed under vacuum. Yield: 8.05 g.

¹ H-NMR (200MHz, d ₆ -DMSO): δ = 2.67 (t, J = 8Hz, 2H, CH ₂ -COOCH ₃ ), 2.93 (t, J = 8Hz, 2H, Ar-CH ₂ ), 3.59 ( s, 3H, _OCH3 ), 7.35 (d, 2H, Ar-H), 7.86 (d, J=9Hz, 2H, Ar-H), 12.80 (s, broad, 1H, COOH).

MS (Cl ⁺ ): m/e = 209.2 (M+H ⁺ ).

HPLC: RP18, Nucleosil 300-5-C18, 250×4mm; Buffer A: H ₂ O, 0.1% TFA; Buffer B: Acetonitrile (80% v/v)/H ₂ O (20% v/v) , 0.1% TFA; gradient: first 5 minutes 90% buffer A, 10% buffer B, then to 90% buffer B during 20 minutes, then 90% buffer B for 5 minutes; flow rate 1ml/min; _Rt = 17.03 minutes.

c) (2S)-tert-butyl 2-benzyloxycarbonylamino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)propionate

Dissolve 354mg (1.7mmol) of 4-(2-methoxycarbonyl-ethyl)benzoic acid and 500mg (1.7mmol) of (2S)-3-amino-2-benzyloxycarbonylaminopropionic acid tert-butyl ester In 3ml of dimethylformamide and with 557mg (1.7mmol) of O-((cyano-(ethoxycarbonyl)-methylene)amino)-1,1,3,3-tetramethyluronium Tetrafluoroborate (TOTU) was treated with 204 mg (1.7 mmol) diisopropylethylamine and the mixture was stirred at pH 7-8 at room temperature for 7 hours. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate and the solution was washed 3 times each with KHSO ₄ solution and NaHCO ₃ solution until neutral. The organic phase is separated off and dried and the solvent is distilled off in vacuo. Yield: 770 mg. MS (ES ⁺ ): m/e = 485.2 (M + H ⁺ ).

d) (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester

Dissolve 6.88g (14.2mmol) of (2S)-2-benzyloxycarbonylamino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester in 200ml methanol and add 852mg (14.2mmol) acetic acid. The mixture was hydrogenated over Pd/C (5% strength) under 1 bar of hydrogen at room temperature for 7 hours. The mixture was filtered and the solvent was removed in vacuo. The residue was washed with n-heptane and dried in vacuo. Yield: 6.9 g. MS (ES ⁺ ): m/e = 351.2 (M+H ⁺ ).

e) (2S)-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-2-(naphthalene-1-sulfonylamino)-propionic acid tert-butyl ester

Dissolve 0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester in 2 ml of dimethyl formamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.159 g (0.7 mmol) of 1-naphthalenesulfonyl chloride. The solution was stirred at room temperature for 4 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on a silica gel column eluting with n-heptane/ethyl acetate (1/1). Yield: 47 mg. MS (ES ⁺ ): m/e = 541.3 (M+H ⁺ ).

f) (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl) -Benzoylamino)-tert-butyl propionate

47 mg (0.087 mmol) of (2S)-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-2-(naphthalene-1-sulfonylamino)-propionic acid tert-butyl The ester was dissolved in 2 ml of dimethylformamide and 86 mg (0.87 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine was added. The reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue was chromatographed on a silica gel column eluting with dichloromethane/methanol (1/1) followed by dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5) elute. Yield: 46 mg. MS (ES ⁺ ): m/e = 608.3 (M+H ⁺ ).

g) (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl) -benzoylamino)-propionic acid

45 mg (0.074 mmol) of (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl )-Ethyl)-benzoylamino)-tert-butyl propionate was dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid was added. The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water (1/1) and lyophilized. Yield: 50 mg. MS (ES ⁺ ): m/e = 552 (M+H ⁺ ).

Example 2

(2S)-2-(quinoline-8-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)- Benzoylamino)-propionic acid

a) (2S)-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-2-(quinoline-8-sulfonylamino)-propionic acid tert-butyl ester

Dissolve 0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester in 2 ml of dimethyl formamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.159 g (0.7 mmol) of 8-quinolinesulfonyl chloride. The solution was stirred at room temperature for 4 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on a silica gel column, eluting with n-heptane/ethyl acetate (1/1), yield: 67 mg. MS (ES ⁺ ): m/e = 542.2 (M+H ⁺ ).

b) (2S)-2-(quinoline-8-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl )-benzoylamino)-tert-butyl propionate

65 mg (0.12 mmol) of (2S)-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-2-(quinoline-8-sulfonylamino)-propionic acid tert The butyl ester was dissolved in 1 ml of dimethylformamide and 59 mg (0.6 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine was added. The reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue was chromatographed on a silica gel column eluting with dichloromethane/methanol (1/1) followed by dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5) elute. Yield: 72 mg. MS (ES ⁺ ): m/e = 609.3 (M+H ⁺ ).

c) (2S)-2-(quinoline-8-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl )-benzoylamino)-propionic acid

72 mg (0.11 mmol) of (2S)-2-(quinoline-8-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylaminomethyl) Acyl)-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid was added. The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water (1/1) and lyophilized. Yield: 54 mg. MS (ES ⁺ ): m/e = 553 (M+H ⁺ ).

Example 3

(2S)-2-(4-Acetamido-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl) -benzoylamino)-propionic acid

a) (2S)-2-(4-acetylamino-benzenesulfonylamino)-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester

Dissolve 0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester in 2 ml of dimethyl formamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.164 g (0.7 mmol) of 4-acetamido-benzenesulfonyl chloride. The solution was stirred at room temperature for 4 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on a silica gel column, eluting with n-heptane/ethyl acetate (1/2), yield: 90 mg. MS (ES ⁺ ): m/e = 548 (M+H ⁺ ).

b) (2S)-2-(4-acetylamino-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl base)-benzoylamino)-tert-butyl propionate

87 mg (0.16 mmol) of (2S)-2-(4-acetylamino-benzenesulfonylamino)-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid The tert-butyl ester was dissolved in 1 ml of dimethylformamide and 79 mg (0.8 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine was added. The reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue was chromatographed on a silica gel column eluting with dichloromethane/methanol (1/1) followed by dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5) elute. Yield: 57 mg. MS (ES ⁺ ): m/e = 615.3 (M+H ⁺ ).

c) (2S)-2-(4-acetylamino-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl base)-benzoylamino)-propionic acid

57mg (0.09mmol) of (2S)-2-(4-acetylamino-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylamino Formyl)-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid was added. The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water (1/1) and lyophilized. Yield: 42 mg. MS (ES ⁺ ): m/e = 559.2 (M+H ⁺ ).

Example 4

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

a) 2-((1S)-1-tert-butoxycarbonyl-2-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-ethylsulfamoyl)-benzoic acid methyl ester

Dissolve 0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester in 2 ml of dimethyl formamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.164 g (0.7 mmol) of 2-(methoxycarbonyl)-benzenesulfonyl chloride. The solution was stirred at room temperature for 4 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on a silica gel column, eluting with n-heptane/ethyl acetate (1/1), yield: 75 mg. MS (ES ⁺ ): m/e = 549 (M+H ⁺ ).

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

75 mg (0.13 mmol) of 2-((1S)-1-tert-butoxycarbonyl-2-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-ethylsulfamoyl )-methyl benzoate was dissolved in 1 ml dimethylformamide and 68 mg (0.69 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine was added. The reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue was chromatographed on a silica gel column eluting with dichloromethane/methanol (1/1) followed by dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5) elute. Yield: 54 mg. MS (ES ⁺ ): m/e = 683.3 (M+H ⁺ ).

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

54 mg (0.08 mmol) of (2S)-2-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-benzenesulfonylamino)-3-(4-(2 -(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-tert-butyl propionate was dissolved in 2ml of dichloromethane and added 2ml of trifluoroacetic acid . The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water (1/1) and lyophilized. Yield: 34 mg. MS (ES ⁺ ): m/e = 627 (M+H ⁺ ).

General Method 1 (Synthesis of Compounds of Examples 5 to 24)

Step a: Reaction with Sulfonyl Chloride

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

Step b: Formation of acylguanidine

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

Step c: Cleavage of tert-butyl ester

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

Example 5

(2S)-2-(4-tert-butyl-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl )-benzoylamino)-propionic acid

The title compound was synthesized following General Procedure 1 using 4-tert-butylbenzenesulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 83mg 547.2(M+H) ⁺

Product of step b 85mg 614.3(M+H) ⁺

Product of step c (title compound) 75mg 558.3(M+H) ⁺

Example 6

(2S)-2-(Propane-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzene Formylamino)-propionic acid

The title compound was synthesized following General Procedure 1 using propane-1-sulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 54mg 457.3(M+H) ⁺

Product of step b 55mg 524.3(M+H) ⁺

Product of step c (title compound) 45 mg 468.3 (M+H) ⁺

Example 7

(2S)-2-(2-Phenyl-ethanesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl )-benzoylamino)-propionic acid

The title compound was synthesized following General Procedure 1 using trans-β-styrenesulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 49mg 517.1(M+H) ⁺

Product of step b 45mg 584.3(M+H) ⁺

Product of step c (title compound) 37mg 528.3(M+H) ⁺

Example 8

(2S)-2-(4-Propyl-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl) -benzoylamino)-propionic acid

The title compound was synthesized following General Procedure 1 using 4-(n-propyl)-benzenesulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 78mg 533.2(M+H) ⁺

Product of step b 73mg 600.4(M+H) ⁺

Product of step c (title compound) 55 mg 544.3 (M+H) ⁺

Example 9

(2S)-2-(2-Methyl-propane-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)- Ethyl)-benzoylamino)-propionic acid

The title compound was synthesized following General Procedure 1 using 2-methyl-propane-1-sulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 21mg 471.3(M+H) ⁺

Product of step b 10mg 538.4(M+H) ⁺

Product of step c (title compound) 13 mg 482.3 (M+H) ⁺

Example 10

(2S)-2-(4-Butoxy-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl )-benzoylamino)-propionic acid

The title compound was synthesized following General Method 1 using 4-(n-butoxy)-benzenesulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 83mg 563.2(M+H) ⁺

Product of step b 83mg 630.4(M+H) ⁺

Product of step c (title compound) 63mg 574.3(M+H) ⁺

Example 11

(2S)-2-(2-cyano-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl) -benzoylamino)-propionic acid

The title compound was synthesized following General Procedure 1 using 2-cyano-benzenesulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 91mg 516.2(M+H) ⁺

Product of step b 71mg 583.3(M+H) ⁺

Product of step c (title compound) 73mg 527.3(M+H) ⁺

Example 12

(2S)-2-(7,7-Dimethyl-2-oxo-bicyclo[2.2.1]hept-1-ylmethylsulfonylamino)-3-(4-(2-(1,4 , 5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid

The title compound was synthesized following General Method 1 using 10-camphorsulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 85mg 565.3(M+H) ⁺

Product of step b 88mg 632.4(M+H) ⁺

Product of step c (title compound) 71 mg 576.4 (M+H) ⁺

Example 13

(2S)-2-(4-Chloro-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)- Benzoylamino)-propionic acid

The title compound was synthesized following General Method 1 using 4-chloro-benzenesulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 91mg 525.1(M+H) ⁺

Product of step b 82mg 592.3(M+H) ⁺

Product of step c (title compound) 64mg 536.3(M+H) ⁺

Example 14

(2S)-2-(3-Chloro-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)- Benzoylamino)-propionic acid

The title compound was synthesized following General Procedure 1 using 3-chloro-benzenesulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 65mg 525.2(M+H) ⁺

Product of step b 58mg 592.3(M+H) ⁺

Product of step c (title compound) 52mg 536.3(M+H) ⁺

Example 15

(2S)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-2-(3-trifluoro Methyl-benzenesulfonylamino)-propionic acid

The title compound was synthesized following General Procedure 1 using 3-trifluoromethyl-benzenesulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 86mg 559.2(M+H) ⁺

Product of step b 94mg 626.3(M+H) ⁺

Product of step c (title compound) 84mg 570.3(M+H) ⁺

Example 16

(2S)-2-(4-methoxy-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl )-benzoylamino)-propionic acid

The title compound was synthesized following General Procedure 1 using 4-methoxy-benzenesulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 66mg 521.1(M+H) ⁺

Product of step b 71mg 588.3(M+H) ⁺

Product of step c (title compound) 49 mg 532.3 (M+H) ⁺

Example 17

(2S)-2-Benzenesulfonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)- propionic acid

The title compound was synthesized following General Procedure 1 using benzenesulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 76mg 491.2(M+H) ⁺

Product of step b 77mg 558.3(M+H) ⁺

Product of step c (title compound) 64mg 502.3(M+H) ⁺

Example 18

(2S)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-2-(thiophene-2- Sulfonylamino)-propionic acid

The title compound was synthesized following General Method 1 using 2-thiophenesulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 87mg 497.1(M+H) ⁺

Product of step b 74mg 564.2(M+H) ⁺

Product of step c (title compound) 64mg 508.2(M+H) ⁺

Example 19 (2S)-2-(biphenyl-4-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)- Ethyl)-benzoylamino)-propionic acid

The title compound was synthesized following General Method 1 using 4-biphenylsulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 39mg 567.1(M+H) ⁺

Product of step b 40mg 634.4(M+H) ⁺

Product of step c (title compound) 33mg 578.3(M+H) ⁺

Example 20

(2S)-2-(Naphthalene-2-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzene Formylamino)-propionic acid

The title compound was synthesized following General Procedure 1 using 2-naphthalenesulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 76mg 541.2(M+H) ⁺

Product of step b 74mg 608.3(M+H) ⁺

Product of step c (title compound) 62mg 552.3(M+H) ⁺

Example 21

(2S)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-2-(2,4, 6-Trimethyl-benzenesulfonylamino)-propionic acid

The title compound was synthesized following General Procedure 1 using 2,4,6-trimethylbenzenesulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 68mg 533.2(M+H) ⁺

Product of step b 71mg 600.4(M+H) ⁺

Product of step c (title compound) 54mg 544.3(M+H) ⁺

Example 22

(2S)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-2-(4-trifluoro Methyl-benzenesulfonylamino)-propionic acid

The title compound was synthesized following General Procedure 1 using 4-trifluoromethyl-benzenesulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 105mg 559.3(M+H) ⁺

Product of step b 93mg 626.4(M+H) ⁺

Product of step c (title compound) 70mg 570.3(M+H) ⁺

Example 23

(2S)-2-(Butane-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)- Benzoylamino)-propionic acid

The title compound was synthesized following General Procedure 1 using butane-1-sulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 87mg 471.4(M+H) ⁺

Product of step b 60mg 538.4(M+H) ⁺

Product of step c (title compound) 57mg 482.3(M+H) ⁺

Example 24

(2S)-2-Methanesulfonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)- propionic acid

The title compound was synthesized following General Procedure 1 using methanesulfonyl chloride in step a.

Yield MS(ES ⁺ ): m/e

Product of step a 87.8mg 429.3(M+H) ⁺

Product of step b 98mg 496.4(M+H) ⁺

Product of step c (title compound) 74mg 440.3(M+H) ⁺

General Method 2 (Synthesis of Compounds of Examples 25 to 27)

Step a: Reaction with Sulfonyl Chloride

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

Step b: Formation of acylguanidine

The product of step a was dissolved in 2 ml 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)-1,1,3,3-tetramethyluronium hexafluorophosphate. The reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate, and the solution was washed twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The organic phase was dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5) followed by dichloromethane/methanol/acetic acid/water (9/1/0.1 /0.1) elution.

Step c: Cleavage of tert-butyl ester

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

Example 25

(2S)-2-(propane-2-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzene Formylamino)-propionic acid

The title compound was synthesized following General Method 2 using propane-2-sulfonyl chloride in step a.

                                                                                             MS: m/e

Product of step a 17mg 443.2(M+H) ⁺ (FAB ⁺ )

Product of step b 7mg 524.2(M+H) ⁺ (ES ⁺ )

Product of step c (title compound) 7.2 mg 468.2 (M+H) ⁺ (ES ⁺ )

Example 26

(2S)-2-Chloromethylsulfonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino) -propionic acid

The title compound was synthesized following General Method 2 using chloromethanesulfonyl chloride in step a.

                                                                                             MS: m/e

Product of step a 94mg 449.1(M+H) ⁺ (FAB ⁺ )

Product of step b 28mg 530.2(M) ⁺ (ES ⁺ )

Product of step c (title compound) 34 mg 474.2 (M+H) ⁺ (ES ⁺ )

Example 27

(2S)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-2-(2,2, 2-Trifluoro-ethanesulfonylamino)-propionic acid

The title compound was synthesized following General Method 2 using 2,2,2-trifluoroethanesulfonyl chloride in step a.

                                                                        MS: m/e

Product of step a 43mg 483.2(M+H) ⁺ (FAB ⁺ )

Product of step b 24mg 564.2(M+H) ⁺ (ES ⁺ )

Product of step c (title compound) 22 mg 508.2 (M+H) ⁺ (ES ⁺ )

Example 28

(2S)-2-(4-tert-butyl-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl )-benzoylamino)-propionic acid ethyl ester

700mg of (2S)-2-(4-tert-butyl-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)- Ethyl)-benzoylamino)-propionic acid was dissolved in 100 ml ethanol and 15 drops of concentrated sulfuric acid were added. The reaction solution was boiled for 3.5 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with saturated aqueous sodium bicarbonate. The aqueous phase was extracted once with dichloromethane and the combined organic phases were washed twice with saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The hydrochloric acid was removed in vacuo, the residue was dissolved in acetonitrile and water was added. The mixture was lyophilized. Yield: 480mg. MS (ES ⁺ ): m/e = 586.4 (M+H) ⁺ .

Example 29

(2S)-2-(4-tert-butyl-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl )-benzoylamino)-isopropyl propionate

700mg of (2S)-2-(4-tert-butyl-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)- Ethyl)-benzoylamino)-propionic acid was dissolved in 100 ml of isopropanol and 15 drops of concentrated sulfuric acid were added. The reaction solution was boiled for 2.5 days. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with saturated aqueous sodium bicarbonate. The aqueous phase was extracted once with dichloromethane and the combined organic phases were washed twice with saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The hydrochloric acid was removed in vacuo, the residue was dissolved in acetonitrile and water was added. The mixture was lyophilized. Yield: 444mg. MS (ES ⁺ ): m/e = 600.4 (M+H) ⁺ .

Example 30

(2S)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzene Formylamino)-ethyl propionate

590 mg of (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl) -Benzoylamino)-propionic acid was dissolved in 80 ml of ethanol and 12 drops of concentrated sulfuric acid were added. The reaction solution was boiled for 3 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with saturated aqueous sodium bicarbonate. The aqueous phase was extracted once with dichloromethane and the combined organic phases were washed twice with saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The hydrochloric acid was removed in vacuo, the residue was dissolved in acetonitrile and water was added. The mixture was lyophilized. Yield: 381 mg. MS (ES ⁺ ): m/e = 580.3 (M+H) ⁺ .

Example 31

(2S)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzene Formylamino)-isopropyl propionate

1.5g (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl )-benzoylamino)-propionic acid was dissolved in 250 ml of isopropanol and 1 ml of concentrated sulfuric acid was added. The reaction solution was boiled for 3 days. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with saturated aqueous sodium bicarbonate. The aqueous phase was extracted once with dichloromethane and the combined organic phases were washed twice with saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The hydrochloric acid was removed in vacuo, the residue was dissolved in acetonitrile and water was added. The mixture was lyophilized. Yield: 950mg. MS (ES ⁺ ): m/e = 594.4 (M+H) ⁺ .

Example 32

(2S)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzene Formylamino)-isobutyl propionate

600mg of (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl) -Benzoylamino)-propionic acid was dissolved in 12 ml of isobutanol and 0.1 ml of concentrated sulfuric acid was added. The reaction solution was boiled for 24 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with dichloromethane/methanol/acetic acid/water (9/1/0.1/0.1). The product was dissolved in acetic acid/water and lyophilized. Yield: 250 mg. MS (ES ⁺ ): m/e = 608.5 (M+H) ⁺ .

pharmacological test

For example, the inhibitory effect of compounds of the invention on bone resorption can be determined by means of, for example, an osteoclast resorption assay ("PIT ASSAY") similar to WO-A-95/32710, which is incorporated herein by reference.

For example, compounds of the invention can be assayed for inhibition of vitronectin receptor [alpha] _v [beta] ₃ as described below.

293 Cell Inhibition Assay for Measuring Binding to Human Vitronectin (Vn/293 Cell Assay)

1. Purification of Human Vitronectin

Human vitronectin was isolated from human plasma and purified by affinity chromatography according to the method of Yatohyo et al. ( Cell Structure and Function , 1988, 23, 281-292).

2. Cell Assay

Following the FACS method, 293 cells (human embryonic kidney cell line) co-transfected with DNA sequences for the _{αv and β3} subunits of the vitronectin receptor _αvβ3 were selected for high ratio expression (> 500,000 α _v β ₃ receptors/cell). Selected cells were cultured and re-sorted by FACS to obtain a stable cell line (15D) with expression of _αvβ3 at a _ratio of >1,000,000 template per cell.

Linbro 96-well tissue culture plates with flat bottoms were coated overnight at 4°C with human vitronectin (0.01 mg/ml, 0.05 ml/well) in phosphate-buffered saline (PBS), and then incubated with 0.5 % concentration of BSA (bovine serum albumin) blocking. 10 ^-10 mol/l to 2 x 10 ^-3 mol/l solutions of the test substance in DMEM culture fluid containing glucose were prepared, and 0.05 ml/well of the solution was added to the plate in each case superior. Cells expressing high levels of α _v β ₃ (eg, 15D) were suspended in DMEM culture fluid containing glucose, and the suspension was adjusted to a content of 25,000 cells/0.05 ml of culture fluid. 0.05 ml of this cell suspension was added to each well, and the plate was incubated at 37°C for 90 minutes. The plates were washed three times with warm PBS to remove unbound cells. The bound cells were frozen in citrate buffer (25 mM, pH 5.0) containing 0.25% Triton X-100. The hexosamidase substrate p-nitrophenyl-N-acetyl-β-D-glucosaminidase was then added and the plate was incubated at 37°C for 90 minutes. The reaction was stopped with glycine (50 mM)/EDTA (5 mM) buffer (pH 10.4) and the absorbance of each well was measured at 405-650 nm. The data were analyzed according to standard methods.

The test results (inhibitory concentration IC ₅₀ ) described below were obtained.

Example number IC ₅₀ Vn/293 cell test

1 6nM

2 52nM

3 27nM

5 18nM

6 32nM

7 28nM

8 20nM

9 69nM

10 29nM

11 24nM

12 27nM

13 27nM

14 10nM

15 6nM

16 26nM

17 9nM

18 14nM

19 38nM

20 5nM

21 21nM

22 10nM

23 30nM

24 100nM

Claims (16)

1. formula I compound, the salt that can tolerate on the stereoisomer form that they are all and the form of mixtures of all proportions thereof and their physiology

Wherein

Radicals R ¹-and R ²-be saturated or unsaturated divalence (C together ₂-C ₉)-alkylidene group; R ⁴Be hydrogen, (C ₁-C ₆)-alkyl-CO-O-(C ₁-C ₄)-alkyl-or (C ₁-C ₆)-alkyl, it is for unsubstituted or by being selected from hydroxyl, (C ₁-C ₄)-alkoxyl group, (C ₁-C ₄)-alkyl-S (O) ₂-,-NR ⁷R ^{7 '}With-N ⁺R ⁷R ^{7 '}R ^{7 "}Q ^-Group replace R wherein ⁷, R ^{7 '}And R ^{7 "}Independently of one another is hydrogen, (C ₁-C ₆)-alkyl, (C ₅-C ₁₄)-aryl or (C ₅-C ₁₄)-aryl-(C ₁-C ₆)-alkyl-and Q ^-Be the negatively charged ion that can tolerate on the physiology, perhaps R wherein ⁴Be one of following groups

Wherein said group indicates by a dotted line so as to the key that connects;

R ⁵Be (C ₁-C ₂₀)-alkyl, (C ₃-C ₂₀)-monocycle alkyl, (C ₅-C ₂₀)-bicyclic alkyl, (C ₅-C ₂₀)-tricyclic alkyl, (C ₆-C ₁₄)-aryl, (C ₅-C ₁₄)-heteroaryl, (C ₆-C ₁₄)-aryl-(C ₁-C ₆)-alkyl-or (C ₅-C ₁₄)-heteroaryl-(C ₁-C ₆)-alkyl-, each is unsubstituted or by one, two or three R in wherein said aryl, heteroaryl, alkyl, monocycle alkyl, bicyclic alkyl and the tricyclic alkyl ³Group replaces, and wherein in described alkyl, monocycle alkyl, bicyclic alkyl and tricyclic alkyl, one or more carbon atoms can be replaced by the identical or different atoms that are selected from nitrogen, oxygen and sulphur;

R ³Be (C ₁-C ₁₀)-alkyl, (C ₃-C ₂₀)-monocycle alkyl, (C ₅-C ₂₀)-bicyclic alkyl, (C ₅-C ₂₀)-tricyclic alkyl, (C ₁-C ₈)-alkoxyl group, (C ₆-C ₁₄)-aryl, (C ₆-C ₁₄)-aryl-(C ₁-C ₄)-alkyl-, (C ₅-C ₁₄)-heteroaryl, (C ₅-C ₁₄)-heteroaryl-(C ₁-C ₄)-alkyl-, halogen, trifluoromethyl, cyano group, hydroxyl, oxo, nitro, amino ,-NH-(C ₁-C ₄)-alkyl ,-N ((C ₁-C ₄)-alkyl) ₂,-NH-CO-(C ₁-C ₄)-alkyl ,-CO-(C ₁-C ₄)-alkyl;

R ⁶Be hydrogen, (C ₁-C ₆)-alkyl-O-CO-, hydroxyl, (C ₁-C ₆)-alkyl-O-CO-O-or nitro; Described aryl is selected from phenyl, naphthyl, xenyl, anthryl or fluorenyl; And described heteroaryl is selected from pyridyl, pyrryl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazyl, pyridazinyl, pyrazinyl, pyrimidyl, indyl, pseudoindoyl, indazolyl, 2 base, quinolyl, isoquinolyl, quinoxalinyl, quinazolyl, cinnolines base, β-Ka Lin base or benzo is thick and, pentamethylene is thick and, hexanaphthene is thick and or suberane is thick and the derivative of these groups.

2. the claimed formula I compound of claim 1, the salt that can tolerate on the form of the stereoisomer form that they are all and the mixture of all proportions thereof and their physiology, wherein R ¹And R ²For hydrogen or be saturated or unsaturated divalence (C together ₂-C ₅)-alkylidene group; R ³Be (C ₁-C ₁₀)-alkyl, (C ₃-C ₂₀)-monocycle alkyl, (C ₅-C ₂₀)-bicyclic alkyl, (C ₅-C ₂₀)-tricyclic alkyl, (C ₁-C ₈)-alkoxyl group, (C ₆-C ₁₄)-aryl, (C ₅-C ₁₄)-heteroaryl, (C ₆-C ₁₄)-aryl-(C ₁-C ₄)-alkyl-, (C ₅-C ₁₄)-heteroaryl-(C ₁-C ₄)-alkyl-, halogen, trifluoromethyl, cyano group, oxo ,-N ((C ₁-C ₄)-alkyl) ₂Or-NH-CO-(C ₁-C ₄)-alkyl;

R ⁴For hydrogen or its for unsubstituted or by being selected from (C ₁-C ₄)-alkoxyl group, (C ₁-C ₄)-alkyl-S (O) ₂-and NR ⁷R ^{7 '}(the C that replaces of group ₁-C ₆)-alkyl, wherein R ⁷And R ^{7 '}Independently of one another is hydrogen or (C ₁-C ₄)-alkyl;

R ⁵Be (C ₁-C ₂₀)-alkyl, (C ₃-C ₂₀)-monocycle alkyl, (C ₅-C ₂₀)-bicyclic alkyl, (C ₅-C ₂₀)-tricyclic alkyl, (C ₆-C ₁₄)-aryl, (C ₅-C ₁₄)-heteroaryl, (C ₆-C ₁₄)-aryl-(C ₁-C ₆)-alkyl-or (C ₅-C ₁₄)-heteroaryl-(C ₁-C ₆)-alkyl-, each is unsubstituted or by one, two or three R in wherein said aryl, heteroaryl, alkyl, monocycle alkyl, bicyclic alkyl and the tricyclic alkyl ³Group replaces;

R ⁶Be hydrogen or (C ₁-C ₆)-alkyl-O-CO-.

3. claim 1 or 2 claimed formula I compounds, the salt that can tolerate on the stereoisomer form that they are all and the form of mixtures of all proportions thereof and their physiology, wherein R ¹And R ²For hydrogen or be saturated or unsaturated divalence (C together ₂-C ₄)-alkylidene group; R ³Be (C ₁-C ₄)-alkyl, (C ₃-C ₁₀)-monocycle alkyl, (C ₅-C ₁₂)-bicyclic alkyl, (C ₅-C ₁₂)-tricyclic alkyl, (C ₁-C ₄)-alkoxyl group, (C ₆-C ₁₄)-aryl, (C ₆-C ₁₄)-aryl-(C ₁-C ₄)-alkyl-, halogen, trifluoromethyl, cyano group, oxo ,-N ((C ₁-C ₄)-alkyl) ₂Or-NH-CO-(C ₁-C ₄)-alkyl;

R ⁴Be hydrogen or (C ₁-C ₆)-alkyl;

R ⁵Be (C ₁-C ₁₀)-alkyl, (C ₃-C ₁₅)-monocycle alkyl, (C ₅-C ₁₅)-bicyclic alkyl, (C ₅-C ₁₅)-tricyclic alkyl, (C ₆-C ₁₄)-aryl, (C ₅-C ₁₄)-heteroaryl, (C ₆-C ₁₄)-aryl-(C ₁-C ₆)-alkyl-or (C ₅-C ₁₄)-heteroaryl-(C ₁-C ₆)-alkyl-, each is unsubstituted or by one, two or three R in wherein said aryl, heteroaryl, alkyl, monocycle alkyl, bicyclic alkyl and the tricyclic alkyl ³Group replaces;

R ⁶Be hydrogen or (C ₁-C ₆)-alkyl-O-CO-.

4. claim 1 or 2 claimed formula I compounds, the salt that can tolerate on the form of the stereoisomer form that they are all and the mixture of all proportions thereof and their physiology, wherein R ¹And R ²For hydrogen or be saturated or unsaturated divalence (C together ₂-C ₃)-alkylidene group;

R ³Be (C ₁-C ₄)-alkyl, (C ₃-C ₁₀)-monocycle alkyl, (C ₅-C ₁₂)-bicyclic alkyl, (C ₅-C ₁₂)-tricyclic alkyl, (C ₁-C ₄)-alkoxyl group, (C ₆-C ₁₄)-aryl, halogen, trifluoromethyl, cyano group, oxo ,-N ((C ₁-C ₄)-alkyl) ₂Or-NH-CO-(C ₁-C ₄)-alkyl;

R ⁴Be hydrogen or (C ₁-C ₆)-alkyl;

R ⁵Be (C ₁-C ₁₀)-alkyl, (C ₃-C ₁₅)-monocycle alkyl, (C ₅-C ₁₅)-bicyclic alkyl, (C ₅-C ₁₅)-tricyclic alkyl, (C ₆-C ₁₄)-aryl, (C ₅-C ₁₄)-heteroaryl, (C ₆-C ₁₄)-aryl-(C ₁-C ₆)-alkyl-or (C ₅-C ₁₄)-heteroaryl-(C ₁-C ₆)-alkyl-, each is unsubstituted or by one, two or three R in wherein said aryl, heteroaryl, alkyl, monocycle alkyl, bicyclic alkyl and the tricyclic alkyl ³Group replaces;

R ⁶Be hydrogen or (C ₁-C ₄)-alkyl-O-CO-.

5. claim 1 or 2 claimed formula I compound, wherein R ⁵Be (C ₆-C ₁₄)-aryl or (C ₅-C ₁₄Each is unsubstituted or by one, two or three identical or different R in the)-heteroaryl, wherein said aryl and heteroaryl ³Group replaces, the salt that can tolerate on the stereoisomer form that they are all and the form of mixtures of all proportions thereof and their physiology.

6. claim 1 or 2 claimed formula I compounds, the salt that can tolerate on the form of the stereoisomer form that they are all and the mixture of all proportions thereof and its physiology, wherein R ⁵Be naphthyl.

7. claim 1 or 2 claimed formula I compounds, it is 2-(R ⁵-sulfuryl amino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidine-2-base formamyl)-ethyl)-benzoyl-amido) propionic acid, wherein R ⁵-sulfuryl amino substituting group is selected from benzenesulfonyl amino; 4-(n-propyl) benzenesulfonyl amino; 4-tert.-butylbenzene sulfuryl amino; 2; 4; 6-Three methyl Benzene sulfuryl amino; 4-anisole sulfuryl amino; 4-(n-butoxy) benzenesulfonyl amino; 3-chlorobenzene sulfuryl amino; 4-chlorobenzene sulfuryl amino; 3-trifluoromethylbenzene sulfuryl amino; 4-trifluoromethylbenzene sulfuryl amino; 4-P-acetamido benzene sulfonyl base amino; 2-cyano group benzenesulfonyl amino; naphthalene-1-sulfuryl amino; naphthalene-2-sulfuryl amino; xenyl-4-sulfuryl amino; thiophene-2-sulfuryl amino; quinoline-8-sulfuryl amino; methylsulfonyl amino; propane-1-sulfuryl amino; propane-2-sulfuryl amino; butane-1-sulfuryl amino; 2-methylpropane-1-sulfuryl amino; the chloromethane sulfuryl amino; 2; 2; 2-trifluoro ethylsulfonylamino; 7; 7-dimethyl-2-oxo-dicyclo [2.2.1] heptan-the amino and 2-phenyl ethylsulfonylamino of 1-base methylsulfonyl, the salt that can tolerate on the stereoisomer form that they are all and the form of mixtures of all proportions thereof and their physiology.

8. claim 1 or 2 claimed formula I compounds, it is the salt that can tolerate on (2S)-2-(naphthalene-1-sulfuryl amino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidine-2-base formamyl)-ethyl) benzoyl-amido) propionic acid and its physiology.

9. claim 1 or 2 claimed formula I compounds, it is (2S)-2-(naphthalene-1-sulfuryl amino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidine-2-base formamyl)-ethyl)-benzoyl-amido) propionic acid or its (C ₁-C ₄The salt that can tolerate on)-alkyl ester and its physiology.

10. claim 1 or 2 claimed formula I compounds; it is that (2S)-2-(naphthalene-1-sulfuryl amino)-((2-(1 for 4-for 3-; 4,5,6-tetrahydropyrimidine-2-base formamyl)-and ethyl) benzoyl-amido) salt that can tolerate on ethyl propionate or its physiology.

11. the method for claimed formula I compound in any one of the claim 1 to 10 of preparation, this method comprises carboxylic acid or the carboxylic acid derivative that makes formula II,

R wherein ⁴And R ⁵Such as in any one of claim 1 to 10 definition or other functional group exist with precursor forms or with the form of protection, and X is the commutable leavings group of nucleophilicity, with the guanidine or the guanidine derivative reaction of formula III,

R wherein ¹, R ²And R ⁶Such as in any one of claim 1 to 10 definition, perhaps other functional group exists with precursor forms or with the form of protection.

12. a medicinal preparations, it comprises pharmaceutically harmless carrier, and comprises the salt that can tolerate on any claimed formula I compound of at least a claim 1 to 10 and/or its physiology.

13. the purposes of salt in the preparation Vitronectic receptor antagonist that can tolerate on claimed formula I compound and/or its physiology in any one of the claim 1 to 10.

14. the salt that can tolerate on formula I compound that claim 13 is claimed and/or its physiology the preparation inhibitors of bone resorption or preparation be used for the treatment of or the medicine of preventing osteoporosis disease in purposes.

15. the purposes of the salt that can tolerate on formula I compound that claim 13 is claimed and/or its physiology in the inhibitor of preparation tumor growth or metastases.

16. the salt that can tolerate on formula I compound that claim 13 is claimed and/or its physiology the preparation antiphlogiston or preparation be used for the treatment of preventing cardiovascular disease, restenosis, arteriosclerosis, ephrosis become or the medicine of retinopathy in purposes.