CZ20002246A3 - Acylguanidine derivative functioning as inhibitor of bone resorption and as antagonist of vitronectin receptor - Google Patents

Abstract

The acylguanidine derivative of the general formula (I) wherein R1 is a R 2 H, C 1-6 alkyl optionally substituted, or R 1 and R 2 together together a saturated or unsaturated bivalent group C 2-9 alkylene, optionally substituted; R 4 H, C 1-6 alkyl-CO-OC 1-4 alkyl, which is optionally substituted or is R4 group (s) where the links are linked indicated by a dashed line; R 5 is C 1-8 alkyl, C 6-14 arylC 1-6 alkyl or heteroC 5-14 aryl-C 1-6 alkyl, wherein the aryl or heteroaryl is optionally substituted with 1, 2 or 3 R 3; R 6 H, C 1-5 alkyl-O-Co-, OH, C 1-6 alkyl-O-CO-O- or NO 2; and CH 2, O, S or NH; m 1, 2 or 3; n 0 or 1 and all stereoisomeric forms a mixtures thereof in any ratio and physiologically thereof acceptable salts and prodrugs thereof are suitable vitronectin receptor antagonist, resorption inhibitor bone, tumor growth inhibitor, or tumor metastasis, and an anti-inflammatory agent for the manufacture of pharmaceutical compositions for the treatment or prophylaxis of cardiovascular disorders, restenosis, arteriosclerosis, nephropathy, retinopathy and osteoporosis

Description

Technical field

The invention relates to acylguanidine derivatives of the general formula I

wherein R ¹ , R ² , R ³ , R ⁴ , R =>, R 0, A, n and n are further defined for their physiologically acceptable salts and prodrugs thereof. The compounds of formula (I) are valuable pharmaceutically active compounds. They are antagonists at the itronectin receptors and inhibitors of bone resorption by osteoclasts and are useful, for example, in the treatment and prophylaxis of diseases that are caused, at least in part, by the undesirable extent of bone resorption, such as osteoporosis. The invention further relates to processes for the preparation of compounds of formula I, their use, in particular as pharmaceutically active ingredients and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Human bones undergo a sustained dynamic renovation process involving bone resorption and formation. These processes are controlled by the type of cells specialized for this purpose. Bone resorption is based on the destruction of the bone matrix by osteoclasts. The majority of bone diseases consist in disturbing the balance between bone formation and bone resorption. Osteoporosis is a disease characterized by low bone mass and easy bone fracture resulting in an increased risk of fractures. It comes from a lack of new bone formation versus bone loss in the ongoing bone remodeling process.

Osteoporosis treatment commonly includes, for example, administration of bisphosphonates, estrogens, estrogen / progesterone combinations (hormone replacement therapy or HRT), estrogen agonists / antagonists (selective estrogen receptor modulators SERM), calcitonin, vitamin D analogs, parathyroid hormone, growth hormone secretagogues or sodium fluoride (Jardin et al., Annual Reports in Medicinal Chemistry 31, 211 (1996)).

Activated osteoclasts are polynucleic cells having a diameter of up to 400 µm that remove the bone matrix. Activated osteoclasts adhere to the surface of the bone matrix and secrete proteolytic enzymes and acids into the so-called sealing zone, the region between their cell membrane and the bone matrix. Acidic environments and proteases cause bone degradation. The compounds of formula I inhibit bone resorption by osteoclasts.

Studies have shown that adherence of osteoclasts to bones is controlled by integrin receptors on the cell surface of osteoclasts. Integrins are a superior family of receptors. containing, for example, the platelet fibrinogen receptor platelet and the vitronectin receptor ΗνΠ3. The vitronectin h receptor _in H3 is a membrane glycoprotein that is expressed on the cell surface of a number of cells, such as endothelial cells, vascular smooth muscle cells, osteoclasts, and tumor cells. The vitronectin receptor π _ν π3, which is expressed on the osteoclast membrane, controls the process of adhering to and absorbing bone, thus contributing to osteoporosis. In this case, Η _ν Π3 binds to the bone matrix proteins such as osteopontin, bone sialoprotein and thrombospontin, which contain the tripeptide motif Arg-Gly-Asp (or

RGD).

Horton and coworkers disclose RGD peptides and an anti-v itronectin (23C6) receptor antibody that inhibit tooth destruction by osteoclasts and osteoclast migration (Horton et al., Exp. Cell Res. 195, p. 368, 1991). Sato et al. (J. Cell. Biol. 111, p. 1713, 1990) discloses echistatin and snake venom RGD 2 peptide as potent inhibitors of bone resorption in tissue culture and as an inhibitor of osteoclast adhesion to bone. Fischer et al. (Endocrinology 132, p. 1411, 1993) demonstrated in rats that echiostatin also inhibits bone resorption in vivo.

Furthermore, the vitronectin receptor ΗνΠ3 on human aortic vascular smooth muscle cells has been shown to stimulate the migration of these cells to the neointima (new vessel walls), ultimately leading to arteriosclerosis and restenosis after angioplasty (Brown et al., Cardiovascular Res. 28, p. 1815, 1994). Yue et al. (Pharmacology Reviews and Communications 10, pp. 9-18, 1998) demonstrated inhibition of neointima formation by a istνΠ3 antagonist.

Brooks et al. (Cell 79, 1157, 1994) demonstrated that antibodies against βνΠ3 or H _V n3 antagonists can cause tumor shrinkage by causing the death (apoptosis) of blood vessel cells during angiogenesis. The vitronectin receptor H _n3 is also involved in the progression of many other types of cancer, and is overexpressed in malignant melanoma cells (Engleman et al., Annual Reports in Medicinal Chemistry 31, p. 191, 1996). Invasion of vita melanoma is associated with this overexpression (Stracke \

et al., Encyclopedia of Cancer, Vol. III, 1955, Academic Press, 1997; Hillis et al., Clinical Science 91, 639 (1996). Carron et al. (Cancer Res. 58, 1930, 1998) describes the inhibition of tumor growth and the inhibition of the malignancy of hypercalcemia (excessive calcium in the blood) using a ΗνΠ3 antagonist.

• · · · · · · φ φ φ

Cheresh et al.

antibodies against ΗνΠ3 angiogenesis processes property that can be patiated (retinal diseases (Science 270, p.

or antagonists induced by bFGF (therapeutically used).

1500,

ΗνΠ3, rat at

1995) which eye,

The treatment describes inhibiting the retention of the vitronectin receptor or the interactions in which it is involved provides the opportunity to influence various disease states for which there is a constant need for suitable pharmaceutically active agents for treatment and prophylaxis.

WO-A-94/12181 discloses substituted aromatic ring systems and WO-A 94/09577 describes substituted heterocycles as fibrinogen receptor antagonists and platelet aggregation inhibitors. EP-A-528 586 and EP-A-528 587 relate to phenyl and amino derivatives substituted with aminoalkyl or heterocyclyl. WO-A-95/32710 relates to aryl derivatives as inhibitors of bone resorption by osteoclasts. WO-A-96/00574 describes benzodiazepines and WO-A-96/00730 discloses fibrinogen receptor antaagonist matrices, particularly benzodiazepines, which are bound to a nitrogen-containing four-membered ring as a vitronectin receptor antagonist. WO-A-97/21726 discloses bone-promoting agents belonging to different classes of compounds, including tyrosine derivatives containing an unsubstituted guanidine group. Other researchers have shown that the acylguanidines of formula I are particularly potent inhibitors of the vitronectin receptor and bone resorption by osteoclasts.

SUMMARY OF THE INVENTION

The present invention relates to an acylguanidine derivative of the formula I according to the invention.

where it means

R ¹ and R ² are independently hydrogen, alkyl having 1 to 6 carbon atoms optionally substituted with R ³ with the proviso that R ¹ and R ² are not both simultaneously hydrogen, or

R ¹ and R ² together are a saturated or unsaturated bivalent alkylene group having 2 to 9 carbon atoms, for example - (CH 2) p - wherein p is 2, 3, 4, 5, 6, 7, 8 or 9 which is optionally substituted by one or more halogen, C1-C6alkyl, C1-C6alkoxy, C6-C14 aryl, C6-C14 arylalkyl in an aryl moiety of about 1 to about 6 carbon atoms; up to 6 carbon atoms in the alkyl moiety, heteroaryl of 5 to 14 carbon atoms, heteroarylalkyl of 5 to 14 carbon atoms in the aryl moiety of up to 6 carbon atoms in the alkyl moiety, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl and oxo of 3 to 12 carbon atoms in the cycloalkyl moiety of up to about 6 carbon atoms in the alkyl moiety, wherein the 5- to 7-membered ring is saturated or unsaturated and is optionally substituted with R ³ , especially once or the two R ³ groups and the carbocyclic or heterocyclic ring contains one or two ring nitrogen atoms and is optionally fused to a carbon-carbon bond in the C 2 -C 9 alkylene group; * 4 · 4 · · · · · · · · · · · · ·

R ³ is C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 5 -C 14 aryl, C 5 -C 14 arylalkyl of aryl and C 1 -C 4 alkyl, halogen , tri fluoromethyl, hydroxyl, nitro or amino,

R ( ⁴⁾ is hydrogen, (C 1 -C 6) -alkyl-CO-O- (C 1 -C 4) alkyl or C 1 -C 6 alkyl optionally substituted with hydroxyl, C 1 -C 4 alkoxy carbon a1ky1 -S (O) 2 group with 1 to 4 carbon atoms, NRR ', and N ⁺ R ⁷ R ^7' R ⁷ '' Q, where R ^7, R ⁷ 'and R ^7' independently denote hydrogen, C 1 -C 6 -alkyl, C 5 -C 14 -aryl, C 5 -C 14 -alkylalkyl and C 1 -C 6 -aryl and C 1 -C 6 -alkyl, and Q is a physiologically acceptable anion, or R ⁴ is formulas

in which the bonds to which the shares are linked are indicated by a dashed line,

R @ ⁵ is alkyl of 1 to 8 carbon atoms, arylalkyl of 6 to 14 carbon atoms in the aryl moiety of up to about 6 carbon atoms in the alkyl moiety or heteroarylalkyl of 5 to 14 carbon atoms in the aryl moiety and of 1 to 6 carbon atoms in the alkyl moiety; wherein the a7 -flflflflflflflflflflyl or heteroaryl moiety is optionally substituted with one, two or three R ³ groups,

R ( ⁶⁾ is hydrogen, alkyl-O-C0- (C1-C6) -alkyl, hydroxyl, alkyl-O-C0-O- (C1-C6) -alkyl or nitro,

A is CH 2, O, S or NH, m 1, 2 or 3, n O or 1 and all stereoisomeric forms thereof and mixtures thereof in any ratio, and physiologically acceptable salts thereof and prodrugs thereof.

All symbols in the general formula I occur more than once, for example R ³ are independently the same or different. Similarly, all groups that are said to be independent of one another are the same or different from each other.

The alkyl groups have a straight or branched chain and are saturated or monounsaturated or polyunsaturated. This also applies if they have substituents or are substituents of other groups, for example in the case of alkoxy, alkoxycarbonyl or arylalkyl groups. The same applies to alkylene (alkanediyl) groups. Examples of suitable alkyl groups having 1 to 9 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and n-isomers, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, and the like. -methylpentyl, 2,3,4-trimethylhexyl, sec.butyl, ·· ······ · φ · φ · φ · φ · φφφ · φφφφφφφφ

Ter · Φ ·· φφφφ ·· ·· ·· φ ·· Φ · t-butyl, t-pentyl group. Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The bivalent groups correspond to the aforementioned monovalent groups, and are exemplified by methylene, ethylene, 1,3-propylene, 1,2-propylene, (= 1-methylethylene), 2,3-butylene (= 1,2-dimethylethylene), 1-propylene, 1-methylene, , 4-butylene, 1,6-hexylene.

Unsaturated alkyl groups include, for example, alkenyl groups such as vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl or alkynyl groups such as ethynyl, 1-propynyl or propargyl. Unsaturated alkylene groups, i.e. alkenylene groups (= alkenediyl groups) and alkynylene groups (= alkindiyl groups) have a straight or branched chain. Examples of alkenylene groups include vinylene, propenylene and examples of alkynylene groups include ethinylene or propynylene.

Cycloalkyl groups are, for example, monocyclic, bicyclic or tricyclic. Monocyclic groups which may be mentioned are, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl groups, which are optionally substituted, for example, by C1 -C4 alkyl. Examples of substituted cycloalkyl groups include 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.

The halogen atoms include fluorine, chlorine, bromine and iodine.

C 5 -C 14 aryl includes C 5 -C 14 heterocyclic aryl groups (= C 5 -C 14 -heteroaryl)

9 99 4 4449

9 9 9 9999

44 44 44 44 49 9

4 4444 4444

94 94 9 9 9 44 groups) in which one or more of the 5 to 14 ring atoms are replaced by heteroatoms such as nitrogen, oxygen or sulfur and carbocyclic aryl groups of 6 to 14 carbon atoms. The phenyl, naphthyl, biphenylyl, anthryl or fluorenyl group is mentioned, with 1-naphthyl, 2-naphthyl and especially phenyl being particularly preferred. Unless otherwise indicated, an aryl group, in particular a phenyl group, is optionally substituted with one or more groups, preferably one, two or three groups. Aryl groups are especially substituted by the same or different groups from the group consisting of alkyl of 1 to 8 carbon atoms, especially alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 8 carbon atoms, especially alkoxy of 1 to 4 carbon atoms, halogen atom such as fluorine, chlorine or bromine, nitro, amino. trifluoromethyl, hydroxyl, methylenedioxy, cyano, hydroxycarbonyl, C1 -C4 aminocarbonyl alkoxycarbonyl, phenyl, phenoxy, benzyl and benzyloxy. Generally, only up to two nitro groups can be substituents of a compound of formula I according to the invention.

In the case of a monosubstituted phenyl group, the substituent is in the 2-, 3- or 4-position, with the 3- and 4-positions being preferred. In the case of a disubstituted phenyl group, the substituents are in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-position.

Preferably, in the case of a disubstituted phenyl group, the two substituents are in the 3,4-position with respect to the bond site. In the case of the trisubstituted phenyl group, the substituent is in the 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-position. .

In addition to carbocyclic systems, aryl groups of 5 to 14 carbon atoms, monocyclic or polycyclic aromatic ring systems are also possible in which 1, 2, 3, 4 or 10 are not suitable.

4 or 5 of 5 to 14 ring carbon atoms are replaced by heteroatoms, particularly the same or different heteroatoms from the group consisting of nitrogen, oxygen and sulfur. Examples of heterocyclic aryl groups of 5 to 14 carbon atoms and heteroaryl groups of 5 to 14 carbon atoms include 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, zolyl, thiazolyl isothiazolyl, dyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, n-carbolinyl or benzo-fused, cyclopentacondensated, cyclopentacondensated, cyclopentacondensated groups. The heterocyclic systems optionally have the same substituents as above for the carbocyclic aryl systems.

isooxatetrazolyl, pyrrole heteroaryl groups, monocyclic or bicyclic aromatic ring systems with one, two or three heteroatoms, in particular one or two heteroatoms selected from nitrogen, oxygen and sulfur are optionally substituted with one, two or three substituents from the group consisting of preferably C1 -C6 alkyl, C1 -C6 alkoxy, fluorine and chlorine, nitro, amino, trifluoromethyl, hydroxyl, C1 -C4 alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl group. Particularly preferred are monocyclic or bicyclic aromatic 5- to 10-membered ring systems having one to three heteroatoms, in particular one or two heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with one to two substituents from the alkyl group. C 1 to C 4 alkoxy, C 1 to C 4 alkoxy, phenyl, phenoxy, benzyl and benzyloxy.

<· 00 · «0 0 0 0 0 0 0 0 0

t • · e ·

Where two R ¹ and R ² taken together are a bivalent saturated or unsaturated C 2 -C 9 alkylene group, the two groups, together with the two nitrogen atoms to which they are attached, and the central carbon atom of the guanidine group to which they are attached the two nitrogen atoms are bonded to form a monocyclic 1,3-diazaheterocyclic group that is bonded to the nitrogen atom in the group (CH 2 m -CO-NH through its position 2).

The 1,3-diazaheterocyclic groups which are optionally substituted, as indicated for the C 2 -C 9 alkylene group, and also on the guanidine nitrogen atom, are more recently 1H-imidazol-2-yl, 4,5-dihydro-1H-iraidazole -2-yl,

1,4,5,6-tetrahydropyrimidin-2-yl and 4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl. If a 5- to 7-membered ring is fused to a carbon-carbon bond in the C 2 -C 9 alkylene moiety, the two R ¹ and R ² groups together with the two nitrogen atoms to which they are attached and the central carbon atom of the guanidine group to which the two nitrogen atoms are bonded to form a bicyclic heterocyclic group which is bonded to the nitrogen atom in the (CH 3) m -CO-NH group and which is optionally substituted as described above. The fused 5- to 7-membered ring is optionally saturated, unsaturated, or unsaturated or aromatic. For example, a cyclopentane, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane or benzene ring may be condensed. Examples of groups of such bicyclic heterocycles that may be attached to the nitrogen atom of the (CH 2) m -CO-NH group include 1,3a, 4,5,6,6a-hexahydro-1,3-thiazapentalen-2-yl, 1H- benzimidazol-2-yl, 3a, 4, 5, 6, 7, 7-hexahydro-1H-benzimidazol-2-yl, 4,5,6,7-tetrahydro-1H-benzimidazol-2-yl, 4,7-dihydro- 1H-benzimidazol-2-yl and 1H-imidazole-4,5-b] pyridin-2-yl. When the fused ring is substituted and / or if the C 2 -C 9 alkylene group is substituted, preferably the same monosubstituted or disubstituted independently of one another are the same

4444

4444 or a different R ³ group. If there are symbol groups

R ¹ and / or R ^{2 are} substituted, preferably monosubstituted or disubstituted independently of one another, especially monosubstituted with the same or different R ³ .

• σ 4 · · 44 44 4 4 4 4 4 4 4 4

4 44 44 4 • 4 44 4 4 4 · · 4 4 4 4

4 4 4

4 44

The optically active carbon atoms in the compound of formula I independently of one another have the R or S configuration. The configuration at the different centers may be the same or different. The compounds of formula I may be 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 diastereomeric mixtures. The invention includes pure enantiomers and enantiomeric mixtures, for example, racemates, diastereomers, and diastereomeric mixtures. The invention includes mixtures of two or more than two stereoisomers of formula I and all ratios of stereoisomers in the mixture. The compounds of formula I may exist as E isomers and Z isomers. The invention includes both pure E isomers and pure Z isomers and E / Z mixtures in all ratios. The invention also includes tautomeric forms of the compounds of formula I. For example, in addition to formula I, the form in which the acylguanidine units are included as -CO-N = C (NHR ¹ ) -NR ² R ⁶ and all other forms which different positions of mobile hydrogen atoms. Diastereomers, including E / Z isomers, can be separated into the individual isomers, for example, by chromatography. The racemates can be separated into two enantiomers by methods known per se, for example by chiral phase chromatography or resolution. Stereochemically uniform compounds can also be obtained by using stereochemically uniform starting materials or by using stereoselective reactions.

Physiologically acceptable salts of the compounds of formula (I) are non-toxic, physiologically acceptable, and especially pharmaceutically usable salts. Such salts of the compounds of the general formula

I which contain acidic groups, for example carboxylic acid groups, are, for example, salts with alkali metals or

9 9 9

9 • ·

Alkaline earth metals such as sodium, potassium, magnesium and calcium salts as well as salts with physiologically acceptable quaternary ammonium ions and acid addition salts with ammonia and physiologically acceptable organic amines such as triethylamine, ethanolamine or tris- (2-hydroxyethyl) amine. The compounds of formula I which contain basic groups form acid addition salts with, for example, inorganic acids such as hydrochloric, sulfuric or phosphoric acid, or with organic carboxylic and sulfonic acids such as acetic, citric, benzoic, maleic, fumaric acids. , tartaric, methanesulfonic and p-toluenesulfonic acids. Compounds of formula I that contain both basic and acidic groups, for example guanidino and carboxyl, may be zwitterions (betaines), which are also encompassed by the invention.

As a physiologically acceptable anion Q - contained in a compound of formula I when R ^{4 is a} positively charged ammonium alkyl group, mention may be made in particular of a monovalent anion or a polyvalent anion equivalent of a non-toxic, physiologically acceptable and especially a pharmaceutically usable inorganic or organic acids, for example an anion or an anionic equivalent of any of the above acids suitable for forming an acid addition salt. Thus, for example, Q may be an anion (or anionic equivalent) of chloride, sulfate, phosphate, acetate, citrate, benzoate, meleate, fumarate, tartrate, methanesulfonate or p-toluenesulfonate.

Salts of compounds of formula (I) may be prepared by methods known to those skilled in the art, for example by combining a compound of formula (I) with an inorganic or organic acid or base in a solvent or dispersant or from other salts by cationic or anionic exchange. The invention also encompasses all salts of the compounds of general formula (I).

However, due to poor physiological suitability, they are not directly suitable for use in pharmaceutical compositions, but are useful as intermediates for further chemical modification of the compounds of Formula I or as starting materials for the preparation of physiologically acceptable salts.

The invention furthermore includes solvates of the compounds of the formula I for example hydrates or adducts with alcohols and also derivatives of the compounds of the formula I for example esters and other prodrugs and other physiologically acceptable derivatives as well as active metabolites of the compounds of the formula I. I, i.e., the chamically modified derivatives of the compounds of formula I, having the properties improved in a desirable manner, as known to those skilled in the art. Prodrugs are described in detail in the literature (e.g., Fleisher et al., Advanced Drug Delivery Reviews 19, 115-130, 1996; Design of Prodrugs, H. Bundgaard, eds. Elsevier, 1985; H. Bundgaard, Drugs of the Future 16 443 (1991); Saulbier et al., Bioorg. Med. Chem. Lett. 4 (1986), 1994; Safadi et al., Pharmaceutical Res. 10, 1350 (1993). Suitable prodrugs for the compounds of formula I are especially ester prodrugs for example an alkyl ester having 1 to 4 carbon atoms, carboxylic acids, in particular of the COOH group which is present when R ⁴ in the group COOR ⁴ is hydrogen, and also acyl prodrugs and carbamate prodrugs acy1ovate1ných nitrogen-containing groups such as amino and especially guanidino. In acyl prodrugs or carbamate prodrugs, one or two, for example, two hydrogen atoms on a nitrogen atom in these groups is replaced by an acyl or carbamate group. Suitable acyl groups and carbamate groups for acyl prodrugs and carbamate prodrugs are, for example the group R ^lo and R ¹¹ -C0- 0-C0- wherein R ¹⁰ is hydrogen, alkyl having 1 to 18 carbon atoms, cycloalkyl having 3 to 14 carbon atoms C 3 -C 14 cycloalkylalkyl of 1 to 8 carbon atoms in the alkyl moiety, aryl of 5 to 14 carbon atoms in which one to 5 carbon atoms may be replaced by heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or arylalkyl group of 5 to 14 carbon atoms in the aryl portion of about 8 to 8 carbon atoms in the alkyl portion in which one to 5 carbon atoms can be replaced by heteroatoms from the group consisting of nitrogen, oxygen and sulfur; ¹¹ is as defined for rio _{with the} exception of hydrogen.

In the compound of formula (I ⁾ , R @ ¹ and R @ ² preferably together are a saturated or unsaturated, preferably saturated, bivalent alkylene group having from 2 to 5 carbon atoms, in particular an alkylene group having from 2 to 4 carbon atoms, in particular an alkylene group having from 2 to 3 atoms. carbon which is unsubstituted or substituted by one or two of the same or different groups from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, aryl of 6 to 14 carbon atoms, arylalkyl of 6 from 1 to 6 carbon atoms in the aryl portion and from 1 to 6 carbon atoms in the alkyl portion, heteroaryl of 5 to 14 carbon atoms, heteroaryl and 1-alkyl with 5 to 14 carbon atoms in the aryl portion and from 1 to 6 carbon atoms in the alkyl portion, cycloalkyl C 3 to C 12, cycloalkylalkyl, and C 3 to C 12 oxo in a cycloalkyl moiety of up to 6 carbon atoms in the alkyl wherein the five- to seven-membered ring is saturated or unsaturated and is optionally substituted with R ³ , especially one or two R ³ groups, and the carbocyclic or heterocyclic ring contains one or two ring nitrogen atoms and is optionally fused to a carbon-carbon bond in an alkylene group. In the compound of the formula I, R @ ¹ and R @ ^{2 are} particularly preferably - (CH2) p -, where p is 2, 3, 4 or 5, in particular 2, 3 or 4, in particular 2 or 3, which is unsubstituted or substituted by one or two of the same or different groups selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, (C 1 -C 6) alkoxy, (C 6 -C 14) -aryl, (C 6 -C 14) -aryl, (C 6 -C 14) -aryl, (C 6 -C 14) -aryl, (C 5 -C 14) Heteroaryl C 5 -C 14 heteroarylalkyl of aryl and C 1 -C 6 alkyl, C 3 -C 12 cycloalkylalkyl, C 3 -C 12 cycloalkylalkyl and C 3 -C 12 cycloalkyl of up to 6 C-alkyl share membered up to seven membered ring is saturated or unsaturated and optionally substituted by R ^3, especially one or two groups R ³ and the carbocyclic or heterocyclic ring comprising one or two ring nitrogen atoms and optionally fused to a carbon-carbon bond in the group - (CH Preferably, R ^{3 is} C 1 -C 4 alkyl or C 1 -C 4 alkoxy.

Preferably, R ⁴ is hydrogen, C 1 -C 6 alkyl which is unsubstituted or substituted by C 1 -C 4 alkoxy, and C 1 -C 4 -alkyl (S) O-C 1-4 alkyl. carbon atoms and MR ^{S * 7} R ⁷ ', where R ⁷ , R ⁷ ' are independently hydrogen or C 1 -C 4 alkyl. R @ ⁴ is particularly preferably hydrogen or C1 -C4 -alkyl which is unsubstituted or substituted, in particular R @ 1 or C1 -C4 -alkyl which is unsubstituted or substituted by an alkoxy group selected from the group consisting of C 1 -C 4 alkyl, S-O (O) 2 -C 1 -C 4 alkyl and NR ⁷ R ⁷ ', wherein R ⁷ , R ⁷ ' are independently hydrogen or C 1 -C 4 alkyl carbon.

Preferably, R is an alkyl group ^having 1 to 8 carbon atoms or a group of the formula II • · · ·

wherein R ³ is independently the same or different in any desired position of the phenyl group, q is 0, 1 or 2, preferably 0 or 1, particularly preferably R ⁵ is C 1 -C 4 alkyl or a group of the formula Wherein q is 0 or 1, and in particular R ^{5 is a} group of formula II. wherein q is 0 or 1, i.e. unsubstituted benzyl or benzyl monosubstituted in ortho, meta or para position by R ³ .

Preferably, R ^D represents a hydrogen atom, an alkyl-O-CO- group having from 1 to 6 carbon atoms in the alkyl moiety, in particular a hydrogen atom, an alkyl-O-C0- group having from 1 to 4 carbon atoms in the alkyl moiety and in particular a hydrogen atom.

Preferably A is CH2 or O.

Preferred are compounds of formula (I) wherein one or more of the symbols are as defined above or particularly preferred, and the invention includes all such combinations of preferred meanings. Particularly preferred are the compounds of formula I where they are

R ¹ and R ² together are a saturated or unsaturated, bivalent C 2 -C 5 alkylene group, in particular - (CH ₂ ) _p -, wherein p is 2, 3, 4 or 5, wherein the C 2 -C 5 alkylene group the carbon atoms and - (CH 2) p - are unsubstituted or substituted by halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 6 -C 14 -aryl, arylalkyl C 6 -alkyl; up to 14 carbon atoms in the aryl portion of up to about 6 carbon atoms in the alkyl portion, heteroaryl of 5 to 14 carbon atoms, heteroarylalkyl of 5

- 18 with 1 to 6 carbon atoms, up to 12 carbon atoms, cycloalkylene atoms up to 14 carbon atoms in the aryl and alkyl moieties, cycloalkyl with cycloalkylalkyl and an oxo group having from 3 to 12 keel atoms of up to 6 carbon atoms in the an alkyl moiety wherein the 5- to 7-membered ring is saturated or unsaturated and is optionally substituted with R ³ , especially one or two R ³ groups, and the carbocyclic or heterocyclic ring contains one or two ring nitrogen atoms and is optionally fused to a carbon-carbon bond C 2 -C 5 alkylene or - (CH 2) p -;

R ^{3 is} C 1 -C 4 alkyl or C 1 -C 4 alkoxy;

R @ ⁴ is hydrogen, C1 -C6 alkyl which is unsubstituted or substituted by C1 -C4 alkoxy, C1 -C4 alkyl-S (O) and NR @ 4 R @ 8; ⁷ ', wherein R ⁷ and R ^z ' independently of one another are hydrogen or C 1 -C 4 alkyl;

R &lt; 6 ^&gt; is alkyl of 1 to 8 carbon atoms or a group of formula II (R &lt; ³ &gt;) q

wherein q is 0 or 1 and R ³ can be at any position of the phenyl group;

R ⁶ is hydrogen, C 1 -C 6 alkyl-O-CO-;

A is CH2 or O;

m is 1, 2 or 3;

n the number 0 or 1, and all stereoisomeric forms thereof, and mixtures thereof in any ratio, and their physiologically acceptable salts and prodrugs.

Very preferred are compounds of formula I, wherein i

R ¹ and R ^and R together are a saturated or unsaturated divalent alkylene group having 2 to 4 carbon atoms, particularly a group -CCH3) p-, in which p is the numbers 2, 3 or 4, wherein the alkylene group with 2-4 carbon atoms and R - (CH 2) p - are unsubstituted or substituted by halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 6 -C 14 -aryl, C 6 -C 14 -arylalkyl in the aryl moiety of up to 6 carbon atoms in the alkyl moiety, heteroaryl of 5 to 14 carbon atoms, heteroaryl alkyl of 5 to 14 carbon atoms in the aryl moiety of about 6 carbon atoms in the alkyl moiety, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl and oxo having from 3 to 12 carbon atoms in the cycloalkyl moiety of up to about 6 carbon atoms in the alkyl moiety, wherein the 5- to 7-membered ring is saturated or unsaturated and is optionally substituted alkylated by R ^3, especially one or two groups R ³ and the carbocyclic or heterocyclic ring comprising one or two ring nitrogen atoms and optionally fused to a carbon-carbon bond in the alkylene group with 2-4 carbon atoms or a group - (CHslp- :

R ³ is alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms;

R ( ⁴⁾ is hydrogen or (C1-C6) -alkyl;

R ⁵ is C 1 -C 4 alkyl or a group of formula II

wherein q is 0 or 1 and R ³ may be at any position of the phenyl group:

R @ ⁶ is hydrogen, C1 -C4 alkyl-O-CO-- • flfl flfl flfl • flfl ·

in an alkyl moiety;

A is CH2 or O; m is 1, 2 or 3;

n the number 0 or 1 and all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts and prodrugs.

Particularly preferred are the compounds of formula I where they are

R ( ¹⁾ and R ( ²⁾ together are a saturated or unsaturated, bivalent alkylene group having 2 to 3 carbon atoms, in particular - (CH2) p-, where p is 2 or 3, the alkylene group having 2 to 3 carbon atoms and - (CH 2) p - are unsubstituted or substituted by halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, aryl. 6 to 14 carbon atoms, arylalkyl of 6 to 14 carbon atoms in the aryl moiety and of 1 to 6 carbon atoms in the alkyl moiety, heteroaryl of 5 to 14 carbon atoms, heteroaryl and 1-alkyl of 5 to 14 carbon atoms in the aryl moiety of 1 to 6 C 3 -C 12 alkyl, C 3 -C 12 cycloalkyl, and C 3 -C 12 cycloalkyl of up to 6 carbon atoms in the alkyl moiety, wherein the 5- to 7-membered ring is saturated or unsaturated and is optionally substituted with R 10 ³ , in particular one or two R ³ groups, and the carbocyclic or heterocyclic ring contains one or two ring nitrogen atoms and is optionally fused to a carbon-carbon bond in an alkylene group having 2 to 3 carbon atoms or - (CH 2) _p -;

R ^{3 is} C 1 -C 4 alkyl or C 1 -C 4 alkoxy;

R ( ⁴⁾ is hydrogen or (C1-C4) -alkyl;

R ⁵ is C 1 -C 4 alkyl or a group of formula II

(II)

9444

444 ·

wherein q is 0 or 1 and R ³ may be in any position of the phenyl group;

R &lt; 6 &gt; is hydrogen, C1-C4 alkyl-O-C0- alkyl;

A is CH 3; m number 1;

n number 1 and all slereoisomeric forms thereof and mixtures thereof in any ratio, and their physiologically acceptable salts and prodrugs.

Particularly preferred are also the compounds of formula I where they are

R ¹ and R ² together are a saturated or unsaturated, bivalent C 2 -C 3 alkylene group, in particular - (CH ₂ ) _p -, wherein p is 2 or 3, wherein the C 2 -C 3 alkylene group and - (CH ₂ ) p - are unsubstituted or substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 14 aryl, C 6 -C 14 arylalkyl C 1 -C 6 aryl, C 5 -C 14 heteroaryl, C 5 -C 14 heteroarylalkyl, C 1 -C 6 aryl, C 3 -C 12 cycloalkyl, cycloalkylalkyl and an oxo group having from 3 to 12 carbon atoms in the cycloalkyl moiety of up to about 6 carbon atoms in the alkyl moiety, wherein the 5- to 7-membered ring is saturated or unsaturated and is optionally is substituted by R ³ , in particular by one or two R ³ groups, and the carbocyclic or heterocyclic ring contains one or two ring nitrogen atoms and is optionally fused to a carbon-carbon bond in an alkylene group with an alkylene group.

Up to 3 carbon atoms or - (CH2) p ~:

R ³ is alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms;

R ( ⁴⁾ is hydrogen or (C1-C4) -alkyl:

R ⁵ is C 1 -C 4 alkyl or a group of formula II

where q is 0 or 1 and R ^{3 can} be in any position of the phenyl group:

R ⁶ is hydrogen, alkyl-O-CO- having 1 to 4 carbon atoms in the alkyl moiety:

And an oxygen atom to: number 1:

and their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts and prodrugs.

Particularly preferred are also the compounds of formula I where they are

R ( ¹⁾ and R ( ²⁾ together are a saturated or unsaturated, bivalent alkylene group having 2 to 3 carbon atoms, in particular - (CH2) p- where p is 2 or 3, the alkylene group having 2 to 3 carbon atoms and - (CH 2) p - are unsubstituted or substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 14 aryl, C 6 -C 14 arylalkyl aryl moiety of up to 6 carbon atoms in the alkyl moiety, heteroaryl of 5 to 14 carbon atoms, heteroarylalkyl of 5 to 14 carbon atoms in the aryl moiety and of 1 to 6 carbon atoms in the alkyl moiety, cycloalkyl of 3 to 12 carbon atoms, φφ φφφφ φ Cycloalkylalkyl and an oxo group having from 3 to 12 carbon atoms in the cycloalkyl moiety of up to about 6 carbon atoms in the alkyl moiety, wherein: the 5- to 7-membered ring is saturated or unsaturated and is optionally substituted with R ³ , especially one or two R ³ groups, and the carbocyclic or heterocyclic ring contains one or two ring nitrogen atoms and is optionally fused to a carbon-carbon bond in the 2-alkylene group up to 3 carbon atoms or - (CH 3> p -);

R ^{3 is} C 1 -C 4 alkyl or C 1 -C 4 alkoxy;

R ( ⁴⁾ is hydrogen, (C1-C4) -alkyl;

R ⁵ is C 1 -C 4 alkyl or a group of formula II

wherein q is 0 or 1 and R ³ can be at any position of the phenyl group;

R (0) is hydrogen or alkyl-O-C0- (C1-C4) alkyl;

A is an oxygen atom; m number 3;

n number 0 and all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts and prodrugs.

Most preferred are compounds of formula I, wherein i

R ¹ and R ² together are a saturated or unsaturated, bivalent C 2 -C 3 alkylene group which is unsubstituted by a particularly unsubstituted group - (CH 2> 2- or

- (CH ₂ ) 3 -;

R ( ⁴⁾ is hydrogen or (C1-C4) -alkyl;

• · '

9 <

· «· · · · # ·· ··

R ^{5 is} unsubstituted bensyl;

R ⁶ hydrogen atom:

And the oxygen atom:

m with 1 o 3;

and their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts and prodrugs.

Further preferred are compounds of formula I in which the carbon atom to which the R ⁴ O-CO and R ⁵ OCO-NH- groups are bonded has the S configuration.

The invention also relates to processes for the preparation of compounds of formula I. The compounds are usually prepared, for example, during convergent synthesis by coupling two or more fragments, which may be retrosynthetically derived from formula I. It may usually be convenient or necessary to introduce them during synthesis functional groups which can lead to undesired reactions or side reactions at the appropriate stage of the synthesis, in the form of their precursors, which are later converted to the desired functional groups, or temporarily block functional groups by introducing protecting groups suitable for the preparation method as known to those skilled in the art (Greene and Kuts, Protective Groups in Organic Synthesis, kiley, 1991).

The compounds of the formula I can be prepared, for example, by the known coupling of a carboxylic acid or a carboxylic acid derivative of the formula III

where R ⁴ , R ⁵ ,

A, n and m have the aforementioned (III) meaning, or a1 ternφ φφφφ Φ ···· outside, the functional groups may be contained in the form of their precursors, which are later converted to the groups of compounds of formula I, or protected form and X represents a nucleophilically substitutable release group, with guanidine or a guanidine derivative of the formula (IV).

«· · · · · · · · ·

wherein R ¹ , R ² and R ⁵ are as defined above, or alternatively, the functional groups may be present in the form of a precursor, which are later converted to the groups in the compound of formula 1, or the functional groups may be present in protected form.

The COX group of formula III is preferably a carboxylic acid group COOH or an activated carboxylic acid derivative group. X represents, for example, a hydroxyl group or a halogen atom, in particular chlorine or bromine, an alkoxy group, preferably a methoxy group, or an ethoxy group, an aryloxy group, for example such as a 1-imidazolyl group. X may further be, for example, an alkyl-O-CO-O- group having from 1 to 4 carbon atoms in the alkyl moiety or tolylsulfonyloxy and the activated derivative of the acid may thus be a mixed anhydride

When X is a hydroxyl group, i.e. when the guanidine of formula IV is reacted with a carboxylic acid, it is preferable to activate the carboxylic acid beforehand appropriately. Activation can be performed, for example, with dicyclohexylcarbodiimide (DCCl) or O - ((cyano (ethoxycarbonyl) methylene) amino-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU; Konig et al.)

4 • 4

4

9

9 · · 9 9 4 4

9 4 ·

Why. 21st Europ. Peptide Symp. 1990 (eds. Giralt, Andreu), Escoa, Leiden str. 143, 1991) or other activating agents common in peptide chemistry.

In addition to the free guanidine of formula IV, guanidine salts can also be used for the reaction with compounds of formula III, from which free guanidines can then be prepared in situ or in a separate step by means of a base. The reaction of the activated carboxylic acid derivatives of the formula III with guanidine (or a derivative thereof) of the formula IV is preferably carried out in a manner known per se in a protic or aprotic polar but inert organic solvent. In this case, methanol, isopropanol, tert-butanol, dimethylformamide or tetrahydrofuran at 0 DEG C. to the boiling point of these solvents have proven useful, for example in the reaction of methyl esters (X = methoxy) or ethyl esters (X = ethoxy) with guanidines. The reactions of the compounds of formula COX with salts free of guanidines are preferably carried out in aprotic inert solvents such as dimethylformamide, tetrahydrofuran, dimethoxyethane or dioxane, optionally with an addition of a base such as potassium tert-butoxide or sodium methoxide. However, water can also be used as a solvent in the reaction of the compounds of formula III with guanidines, for example using sodium hydroxide as the base. When X is a chlorine atom, the reaction is preferably carried out using an acid binding agent, for example an added base, or in the presence of an excess of guanidine (or a derivative thereof) to bind the resulting hydrohalic acid. The reaction mixture is worked up and the reaction product is optionally purified in a manner well known to those skilled in the art.

The protecting group, possibly still contained in the products obtained by the reaction of the compounds of formula III and compounds of formula IV, is removed in a manner known per se, for example tert-butyl groups are converted to carboxylic acid groups by treatment with trifluoroacetic acid, benzyl groups.

9 9 9

9 9 9

9 · · *

9 9 9 • 9 <9 * 9 9 9 9 99 99 J 9 9 9 9 9

The pins are removed by hydrogenation or fluorophenylmethoxycarbonyl groups are removed by secondary amines and further reactions are carried out per se by methods such as acylation. Optionally, the product is converted into physiologically acceptable salts or prodrugs by known methods.

The starting compounds of the formulas III and IV which are reacted to obtain the acylguanidine derivatives of the formula I are commercially available or can be prepared by methods similar to those described in the literature. The preparation of the starting compounds of the general formula (III) is illustrated, for example, by the following schemes, which, however, are not to be construed as limiting the invention with respect to either the process or the starting materials. Those skilled in the art will not have difficulty modifying the methods for preparing the compounds of the invention.

The carboxybensaldehyde of formula V can be reacted in the presence of pyridine or piperidine with a malonic acid ester salt of formula VI to give a cinnamic acid derivative of formula VII which, after hydrogenation in e.g. palladium on charcoal, provides a compound of formula VIII. a 2,3-diaminopropionic acid derivative of Formula IX to give a compound of Formula X (Scheme 1). The condensation can be carried out, for example, in the presence of TOTU or another carboxylic acid activating agent. In formula X, Z is a benzyloxycarbonyl group, but other Z groups may also be present on the nitrogen atom which either temporarily protects the amino group at the 2-position or which may be present in the compounds of formula I according to the invention and thus remain in the molecule. Similarly, instead of the tert-butyl ester group, other ester groups may either temporarily protect the acid group or may be present in the compounds of formula I of the invention and may thus remain in the molecule. Compounds similar to the compound of formula (VII) may also be obtained by other methods

999 »• 8 · ·»

9 9 · ·

9

# 9

99 99 * 9 9 9 9

9 9>

9 · 9 9

9 9 9

Methods for converting a carbonyl group to an alkene, for example, by a Wittig reaction.

Scheme 1

Vlil

H ₃ C ch / —o ch ₃

ÍX /

O-ch ₃

The p-hydroxybenzoic acid of formula XI can be condensed with a 2,3-diaminopropionic acid derivative of formula IX to give a compound of formula XII as described above. The compound of formula (XII) may be alkylated with a halo-carboxylic acid derivative under known conditions, for example using a bromoacetic acid ester of formula (XIII) to give a compound of formula (XIII) to give a compound of formula (XIII). The compound of formula XIV (Scheme 2). The p-aminobenzoic acid and the p-mercaptobenzoic acid can be reacted accordingly.

Scheme 2

The tyrosine derivatives of the general formula XV can be alkylated under known conditions by halogenated carboxylic acid derivatives, for example using a bromobutyric acid ester of the formula

XVI to give a compound of formula XVII (Scheme 3).

44

9 4 4

4 4 9 4

4 4 4

94

9944 · «49 · 4 · · · · · ··· ·

In formula (XV), it is 2 benzyloxycarbonyl, but instead of Z, other groups may be bonded to a nitrogen atom which either temporarily protects the amino group or may be present in the compound of formula (I) and thus may remain in the molecule. Similarly, instead of the tert-butyl ester, other ester groups can either protect only temporarily an acidic group or may be present in a compound of formula I and may thus remain in the molecule. Analogues of compounds of formula XVII can also be obtained in the same or analogous manner.

Scheme 3

XVII

Examples of compounds of formula III wherein X is methoxy or ethoxy include compounds of formula X, XIV, and XVII. These compounds and analogous compounds obtained as described above, containing a group which is an activated carboxylic acid derivative group, can be reacted directly with compounds of formula IV. Compounds obtained in the above manner: · · · · · · získané získané získané získané získané získané získané získané získané získané získané získané získané získané získané získané získané získané získané However, they can also be converted at first to the corresponding carboxylic acids, which are then reacted with a compound of formula (X), (XIV) and (XVII) under known conditions by cleavage of the methyl ester or ethyl ester group or another ester group. guanidines of formula II after in situ activation, for example by reaction with TOTU or DCCl or after conversion to an activated carboxylic acid derivative. If it is intended to prepare activated acid derivatives of, for example, carboxylic acid chlorides (a compound of formula III wherein X is chlorine), thionyl chloride may be used. If, for example, it is intended to prepare carboxylic acid methyl esters (a compound of formula III wherein X is methoxy), the carboxylic acids can be reacted with hydrogen chloride gas in methanol. Other activated acid derivatives can be prepared in a manner known per se from carboxylic acid chlorides or directly from carboxylic acids (X = hydroxyl group), for example imidazolides (X = 1-imidazolyl group) can be prepared by reacting the acid with carbonyldiimidazole ( Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962) or mixed anhydrides can be prepared by reacting chloroformic acid esters, for example ethyl chloroformate, with tosyl chloride in the presence of amines such as triethylamine in an inert solvent. Numerous suitable methods for preparing activated carboxylic acid derivatives are described in detail in the literature (J. March, Advanced Organic Chemistry, 3rd Edition, p. 350, John Wiley & Sons. 1985).

The compounds of formula (I) are valuable pharmaceutically active substances which are suitable, for example, for the treatment and prophylaxis of bone diseases, cardiovascular disorders or cancer. The compounds of formula (I) and their physiologically acceptable salts and prodrugs can be administered to animals, especially mammals, and in particular to humans, as therapeutics for both therapy and prophylaxis. They may be administered as such, in admixture with other active ingredients, or in the form of pharmaceutical compositions which allow for

They also contain enteral or parenteral administration and which contain, together with the usual pharmaceutically acceptable carriers or additives, an effective dose of at least one compound of the formula I and / or its physiologically acceptable salts and / or its progrogs as active ingredient.

The invention therefore relates to compounds of formula I and / or their physiologically acceptable salts and / or prodrugs thereof for use as medicaments, to the use of compounds of formula I &lt; / RTI &gt; or their physiologically acceptable salts and / or prodrugs for the manufacture of medicaments for therapy and prophylaxis of diseases as mentioned above, for example for the therapy and prophylaxis of bone or tumor diseases, as well as the use of the compounds of the formula I or their physiologically acceptable salts and / or prodrugs thereof for the therapy and prophylaxis of such diseases. The invention further relates to pharmaceutical compositions comprising an effective amount of at least one compound of the formula I and / or its physiologically acceptable salts and / or prodrugs thereof together with customary pharmaceutically acceptable carriers.

The pharmaceutical compositions may be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard or soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. Administration can also be rectal, for example in the form of suppositories, or parenteral, for example, intravenous, intramuscular or subcutaneous in the form of injectable solutions or infusion solutions, microcapsules, implants or sticks or percutaneous, or topical in the form of ointments, solutions or tinctures or for example in the form of aerosols or nasal sprays.

The pharmaceutical compositions of the invention are prepared in a manner known per se using one or more pharmaceutically inert inorganic and / or organic carriers used in conjunction with the compounds of formula (I) and / or with a compound of formula (I).

their physiologically acceptable salts and / or their prodrugs. For example, lactose, corn starch and derivatives thereof, talc, stearic acid or salts thereof can be used to make pills, tablets, coated tablets and hard gelatin capsules. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-liquid and liquid polyols, natural or hardened oils. Suitable carriers for the preparation of solutions, for example, injectable solutions or emulsions or syrups, are, for example, water, alcohols, glycerol, polyols, sucrose, invert sugar, glucose and vegetable oils. Suitable carriers for microcapsules, implants or sticks are, for example, copolymers of glycolic and lactic acid. The pharmaceutical compositions generally contain from about 0.5 to 90% by weight of the compounds of the formula I and / or their physiologically acceptable salts and / or their progrogs. The amount of active compound of the formula I and / or its physiologically acceptable salts and / or prodrugs thereof in the pharmaceutical compositions is generally 0.2 to 500 mg, preferably 1 to 200 mg.

In addition to the active ingredients and carriers, the pharmaceutical compositions may additionally contain one or more additives such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavoring or flavoring agents, thickeners, diluents, buffers as well as solvents or solubilizing agents or depot agents, as well as salts for the treatment of osmosis coating agents or antioxidants. They may contain or several compounds of the formula I and / or their physiologically acceptable salts and / or prodrugs thereof. In addition to at least one compound of the formula I or its physiologically acceptable salts and / or prodrugs thereof, they may also contain other therapeutically or prophylactically active substances.

pressure, reaching also

The compounds of formula (I) are vitronecti34 antagonists of the novel receptor and have, for example, ability to inhibit osteoclast binding to bone surface and thereby bone resorption by osteoclasts. The activity of the compounds of formula I can be demonstrated, for example, by an assay which detects the inhibition of vitronectin binding to cells containing the vitronectin receptor. This test is described in detail below. In general, the compounds of formula I or their physiologically acceptable salts and / or prodrugs thereof for the treatment and prophylaxis of diseases which depend on the interaction between vitronectin receptors and their ligands in the cell-to-cell or matrix-to-matrix interaction process are suitable as vitronectin receptor antagonists. , or which may be affected by the inhibition of interactions of this type, or by their prevention, relief or treatment, where inhibition of interactions of this type is desirable. As explained above, such interactions play a role, for example, in bone resorption, angiogenesis, or vascular smooth muscle cell proliferation. The compounds of formula I and their physiologically acceptable salts and prodrugs thereof are therefore suitable, for example, for the alleviation and treatment of diseases caused at least in part by the undesirable extent of bone resorption, angiogenesis or vascular smooth muscle cell proliferation.

Bone diseases for the treatment and prevention of which the compounds of the formula I according to the invention can be used are, in particular, osteoporosis, hypercalcemia, osteopenia caused, for example, by metastasis, dental disorders, hyperparathyroidism, periarticular erosion in rheumatoid arthritis and Paget's disease. In addition, the compounds of formula (I) may be used to alleviate, prevent or treat bone diseases caused by treatment with glucocorticoids, steroids or corticosteroids or in the absence of sexual hormones. All of these diseases are characterized by bone loss, which is an imbalance between bone formation and destruction, and which can be favorably influenced by inhibition of bone resorption by osteoclasts. The compounds of formula I and / or their physiologically acceptable salts and / or prodrugs thereof can also be successfully used as bone resorption inhibitors, for example in the therapy and prophylaxis of osteoporosis in combination with conventional osteoporosis treatment, for example in combination with bisphosphonates, estrogens, estrogen. progesterone, estrogen agonists / antagonists, with calcitonin, D-Vitamin analogs, parathyroid hormone, growth hormone secretagogues, or sodium fluoride. The administration of the compounds of the formula I and / or their physiologically acceptable salts and / or prodrugs thereof and the other compounds mentioned above effective in the treatment or prophylaxis of osteoporosis, can occur simultaneously or sequentially, in any sequence and together or separately. For use in such combination therapy or prophylaxis, the compounds of formula (I) and / or their physiologically acceptable salts and / or prodrugs thereof and one or more of the other active ingredients mentioned above may be present together in a single pharmaceutical composition, for example tablets or granules; they may be contained in two or more separate pharmaceutical compositions, which may be packaged in a multipack or in two or more separate packs. The invention also relates to the use of the compounds of formula I and / or their physiologically acceptable salts and / or prodrugs thereof in such combination therapy or prophylaxis and their use in the manufacture of medicaments for such combination therapy or prophylaxis. The invention furthermore relates to pharmaceutical compositions comprising effective amounts of at least one compound of the formula I and / or its physiologically acceptable salts and / or prodrugs thereof with at least one of the aforementioned active substances effective in the treatment or prophylaxis of osteoporosis or inhibition of bone resorption. along with the usual harmless carrier. The above discussion of pharmaceutical compositions applies accordingly to such pharmaceutical combination compositions.

In addition to being used as osteoclast bone resorption inhibitors, compounds of formula I and / or theirs are used

0 0 00 0

00 • 0 · 0

physiologically acceptable salts and / or prodrugs thereof as inhibitors of tumor metastasis growth, as anti-inflammatory agents for the treatment or prophylaxis of cardiovascular diseases such as arteriosclerosis or restenosis, or for the treatment or prophylaxis of nephropathy or retinopathies such as diabetic retinopathy. As inhibitors of tumor growth or tumor metastasis, the compounds of formula I and / or their physiologically acceptable salts and / or prodrugs thereof can be successfully used in combination with conventional cancer therapy. Examples of conventional cancer therapy are in Encyclopedia of Cancer, Academic Press, Bertino, 1997. All of the above data regarding the use of compounds of Formula I in combination with conventional osteoporosis therapy, such as possible routes of administration and pharmaceutical combination formulations, is valid. correspondingly for the use of compounds of formula I in combination with conventional cancer therapy.

When using the compounds of formula I, the dosage may vary within wide limits according to the individual conditions of each individual case. It depends, for example, on the compound used, which may be physiologically active by itself, or may be a prodrug which is first metabolically activated, or on the nature and severity of the disease being treated, or whether an acute or chronic disease is being treated or prophylaxis. In the case of oral administration, the daily dose is generally 0.01 to 100 mg / kg, preferably 0.1 to 50 mg / kg, in particular 0.1 to 5 mg / kg, for example 0.3 to 0.5 mg / kg, to achieve effective results for adults weighing approximately 75 kg (in each case in mg per kg body weight). Also in the case of intravenous administration, the daily dose is generally about 0.01 to 100 mg / kg, preferably 0.05 to 10 mg / kg (in each case in mg per kg body weight). The daily dose may be divided, especially in cases of administration of relatively large amounts, for example 2, 3 or 4 administrations. If necessary, the indicated daily dose may need to be increased or decreased depending on individual behavior.

»· ····

In addition to its use as a pharmaceutically active ingredient, a compound of formula (I) may be used as an active ingredient carrier to deliver the active ingredient specifically to a drug targeting site, for example Targeted Drug Delivery, R.C. Juliano, Handbook of Experimental Pharmacology, Vol. 100, ed. Ed. Born, G.V.R. et al., Springer Verlag). In particular, the active transferred ingredients are those which can be used to treat the above diseases.

The compounds of formula I and their salts may further be used for diagnostic purposes, for example in the diagnosis of cell or tissue samples in vitro, or as adjuncts in biochemical research where blocking the vitronectin receptor or influencing cell-to-cell or matrix-cell interactions . Furthermore, they can be used as blanks in the preparation of other compounds, in particular other pharmaceutically active substances obtainable from the compounds of formula I, for example by modification or incorporation of substituents or functional groups.

The invention is illustrated by the following examples. Percentages are by weight. unless otherwise stated.

DETAILED DESCRIPTION OF THE INVENTION

The products were identified by mass spectra (HS) or NMR spectra. Compounds, purified by chromatography using an eluent containing, for example, acetic or trifluoroacetic acid and freeze-dried, or in the final step using, for example, trifluoroacetic acid to remove the tert-butyl protecting group, still contain, depending on how The freeze-drying is performed by the acid originating from the eluent or from the last step of the synthesis when obtained partly or completely in the form of a salt of the acid used, for example in the form of an acetic or trifluoroacetic acid salt.

Example 1 (2S) -2-Benzyloxycarbonylamino-3- (4- (3- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) propyloxy) phenyl) propionic acid

O

a) Target. Butyl (2S) -2-benzyloxycarbonylamino-3- (4- (3-ethoxycarbonylpropyloxy) phenyl) propionate

7.42 g (0.02 mol) of H-benzyloxycarbonyl-L-tyrosine t-butyl ester were reacted under reflux for six hours with 9.77 g (0.03 mol) of cesium carbonate and 3.9 g (0, 02 mol) of ethyl 4-bromobutyrate in about 60 ml of acetone. After cooling the reaction mixture, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and water (1/1). After phase separation, the organic phase is washed twice each time with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The oily crude product was purified by flash chromatography on silica gel (dichloromethane / acetonitrile 25/1). Yield: 9.4 g (97% of theory) of a viscous oil.

R f = 0.36 (silica gel, dichloromethane / methanol 99/1).

b) tert -Butyl (2S) -2-benzyloxycarbonylamino-3- (4- (3- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) propyloxy) phenyl) propionate

99

I 9 9 <

»9 · <9 9»

To a solution of potassium tert-butoxide (6.72 g, 0.06 mol) was added a solution of 1-amino- (1,4,5,6-tetrahydropyrimidine hydrochloride (8.13 g, 0.06 mol) in absolute DMF (100 ml). 7.2 g (0.015 mol) of tert-butyl (2S) -2-benzyloxycarbonylamino-3- (4- (3-ethoxycarbonylpropyloxy) phenyl) propionate are added to the solution and the mixture is stirred for 30 minutes at room temperature. After removal of the solvent in vacuo, the residue is treated with 300 ml of ethyl acetate and 100 ml of water and the organic phase is separated, washed twice with saturated sodium chloride solution, dried over sodium sulfate and concentrated. immediately purified by chromatography on silica gel (dichloromethane / methanol / glacial acetic acid 100/5/1) to give 5.4 g (60.6% of theory) of the amorphous product.

c) (2S) -2-Benzyloxycarbonylamino-3- (4- (3- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) propyl oxy) phenyl) propionic acid

Dissolve 5.4 g (0.009 mol) of tert-butyl (2S) -2-benzyloxycarbonyl-amino-3- (4- (3- (1-methyl) -benzyloxycarbonyl) salt in 20 ml of a solution of trifluoroacetic acid in water (95/5). (4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl) -propyloxy) -phenyl) propionate in the form of the acetic acid salt. The reaction mixture was stirred at room temperature for 30 minutes and concentrated in vacuo. The residue was dissolved in water and the solution was freeze-dried. Yield 5.2 g (98% of theory). MS (ES ⁺ ): mlz = 483.3 (M + H ⁺ , 100%).

EXAMPLE 2 (2S) -2-Benzyloxycarbonylamino-3- (4- (2- (1,4,5,6-trahydropyrrolidine)

• 4 · · 4

4 4 · 4

4 4 • 4 «4 4 ** 4 w

• 4 • 4

4 4 4

4 4 4

44

444 * • 4 • 4

4

4

4

a) 4- (2-Methoxycarbonylvinyl) benzoic acid

18.74 g (0.12 mol) of the monomethyl malonate potassium salt are suspended in 18 ml of pyrimidine. 15.01 g (0.1 mol) of 4-carboxybenzaldehyde and 0.85 g (0.01 mol) of piperidine are added with stirring at room temperature. The mixture was refluxed until carbon dioxide evolution had ceased (approximately 2 hours), an additional 60 mL of pyridine was added and the mixture was stirred at reflux for a further 1 hour. The reaction mixture was treated with stirring with 500 ml of ice and 110 ml of concentrated hydrochloric acid. After the addition was complete, the mixture was stirred for 20 minutes and the product was filtered on a suction filter, washed with water and crystallized from isopropanol. Yield: 12.85 g (62% of theory).

H-NMR (200 MHz, DMSO-da) = «= 3.75 (s, 3H, 0CH _3), 6.76 (d, J = 15Hz,

1 H, CHCOOCH 3), 7.73 (d, J = 15 Hz, 1H, Ar-CH), 7.84 (d, J = 9 Hz, 2H, Ar-H) 7.98 (d, J = 9 Hz, 2H, Ar-H), 13.11 (s, broad 1H, COOH).

MS (CI) &lt; + &gt;: m / e = 207.2 (M + H &lt; + &gt;, 100%).

HPLC = RP18, Nucleosil 300-5-C18, 250x4mm; buffer A = H ₂ 0, 0,1% trifluoroacetic acid (TFA), buffer B ^: acetonitrile by volume

%) / water (20% v / v), 0.1% TFA; gradient: first 5 min% buffer A / 10% buffer B, then for 20 minutes to 90% buffer

B, then 5 minutes 90% buffer B; flow rate 1 ml / min;

R t = 18.05 min.

b) 4- (2-Methoxycarbonylethyl) benzoic acid

8 g (38.8 mmol) of 4- (2-methoxycarbonylvinyl (benzoic acid) are suspended in 250 ml of dioxane and hydrogenated to 10% palladium on carbon at 10 psi hydrogen for 7 hours at room temperature. Yield: 8.05 g (100% of theory). @ 1 H-NMR (200 MHz, d6 -DMSO): .delta. = 2.67 (t, J = 8 Hz, 2H, CH2 COOCH3), 2.93 (t, J = 8Hz, 2H, Ar-CH2), 3.59 (s, 3H, 0CH _3), 7.35 (d, 2H, Ar-H), 7.86 (d, J = 9Hz, 2H, Ar-H), 12.80 (s, broad 1H, COOH).

• ·

MS (CI) &lt; + &gt;: m / e = 209.2 (M + H &lt; + & gt ^; , 100%).

HPLC: RP18, Nucleosil 300-5-C18, 250x4mm; buffer A = water, 0.1% trifluoroacetic acid (TFA); buffer B ^; acetonitrile (80% v / v) / water (20% v / v) 0.1% TFA; gradient: first 5 min 90% buffer A, 10% buffer B, then for 20 min to 90% buffer B, then 5 min 90% buffer B; flow rate 1 ml / min;

R t = 17.03 min.

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

354 mg (1.7 mmol) of 4- (2-methoxycarbonylethyl) benzoic acid are dissolved in 3 ml of dimethylformamide and 500 mg (1.7 mmol) of butyl (2S) -3-amino-2-benzyloxycarbonylaminopropionate are treated and the solution is worked up. 557 mg (1.7 mmol) of O - ((cyano (ethoxycarbonyl) methylidene) amino-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) and 204 mg (1.7 mmol) of diisopropylethylamine and the mixture is stirred for seven hours at The solvent is removed in vacuo, the residue is dissolved in ethyl acetate, and the solution is washed three times with potassium hydrogen sulphate solution and sodium bicarbonate solution until neutral, and the organic phase is separated, dried and the solvent is removed by distillation. Yield: 770 mg (93% of theory).

MS (ES) &lt; + &gt;: m / e = 485.2 (M + H &lt; + & gt ^; , 100%).

d) target; Butyl (2S) -2-benzyloxycarbonylamino-3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionate

1.25 g (9.2 mmol) of 2-amino- (1,4,5,6-tetrahydropyrimidine hydrochloride) and 1.03 g (9.2 mmol) of potassium tert-butoxide are dissolved in 3 ml of absolute dimethylformamide and the mixture is stirred for 2 hours. After stirring for 30 minutes at room temperature, 740 mg (1.53 mmol) of tert-butyl (2S) -2-benzyloxycarbonylamino-3- (4- (2-methoxycarbonylethyl) benzoyl amino) propionate in 1 ml was added. dimethylformamide

and the mixture is stirred for four hours at room temperature. The pH is adjusted to 4 with glacial acetic acid, the solvent is removed in vacuo and the residue is chromatographed on silica gel, eluting with dichloromethane / methanol / glacial acetic acid / water (9: 1: 0.1: 0.1). ). Yield: 190 mg (38% of theory).

MS (ES) &lt; + &gt;: m / e = 552.3 (M + H &lt; + & gt ^; , 100%).

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

190 mg (0.34 mmol) of tert-butyl (2S) -2-benzyloxycarbonylamino-3- (4- (2 (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)) are dissolved in 5 ml of 95% trifluoroacetic acid. ethyl) benzoylamino) propionate and stirred for one hour at room temperature. The trifluoroacetic acid was removed by distillation in vacuo and co-evaporated with toluene and the residue was dissolved in glacial acetic acid, diluted with water and freeze-dried. Yield: 170 mg (100%).

MS (ES) &lt; + &gt;: m / e = 496.3 (M + H &lt; + &gt;, 100%).

Example 3 (2S) -2-Benzyloxycarbonylamino-3- (4 - ((1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) methyloxy) benzoylamino) propionic acid

a) Benzyl 4- (methoxycarbonylmethyloxy) benzoate

4.5 g (0.02 mol) of benzyl p-hydroxybenzoate together with 9.7 g (0.03 mol) of cesium carbonate are suspended in approximately 60 ml of acetone and treated with 2.3 ml (0.025 mol) of ethyl bromoacetate. The mixture is maintained at reflux until the reaction is complete. For work-up, the reaction solution was filtered through a clarifying layer and the filtrate was evaporated to dryness. The residue was taken up in ethyl acetate and washed three times with 10% citric acid solution and saturated sodium chloride solution each time. The organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was recrystallized from diisopropyl ether / heptane. Yield 5.5 g.

b) 4- (Methoxycarbonylmethoxy) benzoic acid

5 g of benzyl 4- (methoxycarbonylmethoxy) benzoate are dissolved in the methanol / ethyl acetate system and hydrogenated in the presence of 600 mg of catalyst (10% palladium on carbon). After purging with inert gas, the catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was triturated with diisopropyl ether / heptane (9/1) and suction filtered. Yield 3.3 g.

c) tert -Butyl (2S) -2-benzyloxycarbonylamino-3- (4- (methoxycarbonylmethoxy) benzoylamino) propionate

420 mg (0.002 mol) of 4- (methoxycarbonylmethyloxy) benzoic acid, 270 mg (0.002 mol) of 1-hydroxybenztriazole and 588 mg (0.002 mol) of tert-butyl (2S) -3-amino-2-benzyloxycarbonylaminopropionate are dissolved in 5 ml of dimethylformamide. . The solution was cooled to 0 ° C and treated with 453 mg (0.0022 mol) of N, N dicyclohexylcarbodiimide and stirred for 10 minutes at 0 ° C for 2 hours at room temperature. For work-up, the urea was filtered off and the filtrate was evaporated to dryness. The pure compound is obtained by chromatography of the crude product on silica gel (dichloromethane / acetonitrile 20/1). Yield: 820 mg.

• • •

d) tert -Butyl (2S) -2-benzyloxycarbonylamino-3- (4 - ((1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) methyloxy) benzoylamino) propionate

438 mg of tert-butyl (2S) -2-benzyloxycarbonylaminopropionate, 606 mg of potassium tert-butoxide and 732 mg of 2-amino-1,4,5,6-tetrahydropyrimidine hydrochloride are dissolved in 10 ml of absolute dimethylformamide and the solution is stirred for for 14 hours at room temperature and evaporated to dryness in vacuo. The residue was dissolved in ethyl acetate and the solution was extracted with water. The organic phase was dried and concentrated in vacuo and the crude product was subjected to silica gel chromatography (dichloromethane / methanol 100 / 7.5). Yield: 370 mg.

e) (2S) -2-Benzyloxycarbonylamino-3- (4 - ((1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) methyloxy) benzoylamino) propenoic acid

87 mg of the tert-butyl ester obtained in step d) are stirred for 15 minutes at room temperature in 2 ml of 95% trifluoroacetic acid. After concentration in vacuo, the mixture was triturated with ether and the residue was filtered off and dried. Yield: 79 mg. MS (ES +) m / e = 498.2 (M + H) ⁺ .

Example 4

Isopropyl (2S) -2-benzyloxycarbonylamino-3- (4- (3- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) propyloxy) phenyl) propionate hydrochloride

23.88 g (0.04 mol) of the compound of Example 1 (as the trifluoroacetic acid salt) are suspended in 400 ml of isopropanol. To this suspension is added at -15 ° C and the previously prepared thionyl chloride solution is added dropwise in an inert gas medium.

C and inert in isopropanol (to prepare thionyl chloride at -10 to -15 ml of gas for five minutes to 160 ml, stirred for 20 minutes at -10 isopropanol and the mixture with C). After completion of the additive, the temperature is raised to room temperature within 30 minutes. The clarified solution is heated to 60 DEG C. and maintained at this temperature for seven hours with stirring. Stirring was continued without heating overnight. TLC indicated the reaction to be complete. The solvents were removed by distillation on a vacuum rotary evaporator. The residue was suspended in 100 ml of isopropanol and the isopropanol was removed in vacuo. The solid residue was triturated with diethyl ether and collected by suction filtration. The crude product is suspended in 120 ml of isopropanol, heated to reflux with 2.4 g of charcoal and filtered. After cooling, the colorless product was collected by filtration. Yield: 16.2 g of off-white solid.

MS (ES ⁺ ): m / e = 525 (M + H ⁺ , 100%).

Elemental analysis: calculated% C 59.9 H 6.6 found% 59.3 6.7

N 10.0 Cl 6.3

6. 6

10.0 @ 1 H-NMR (200 MHz, d6 -DMSO): w = 1.1 (dd, 6H, J = 7 Hz), 1.8. 1.95 and 2.5 (m, each 2H), 2.85 (m, 2H), 3.35 (t, 4H, J = 3-4 Hz), 3.95 (t, 2H, J = 3 -4Hz), 4.15 (m, 1H), 4.9 (sep., 1H, J = 7Hz), 5.0 (s, 2H), 6.9 and

7.1 (d, each 2H, J = 7 Hz), 7.3 (m, 5H), 7.7 (d, 1H, J = 7 Hz).

Example 5

Ethyl (2S) -2-benzyloxycarbonylamino-3- (4- (3-1,4,5,6-tetrahydropyrimidin-2-ylcarbaraoyl) propyloxy) phenyl) propionate hydrochloride

Add 0.14 mL (1.15 eq) of thionyl chloride at c

-10 DEG C. to 5 ml of ethanol and the reaction mixture is stirred for 10 minutes at this temperature. 1 g (1.66 mmol) of the compound of Example 1 is added as a suspension in 10 ml of ethanol. While stirring, the mixture was allowed to warm to room temperature and stirred for an additional five hours. The solution which had become clear in the meantime was evaporated in vacuo, the residue dissolved in water and lyophilized after filtration. Yield: 0.85 g of a colorless amorphous solid. US (ESO = 1 / e / e = 511 (M + H ⁺ , 100%)).

Example 6 (2S) -2-Benzyloxycarbonylamino-3- (4- (3- (4,5-dihydro-1H-imidazol-2-ylcarbamoyl) propyloxy) phenyl) propionic acid

a) tert -Butyl (2S) -2-benzyloxycarbonylamino-3- (4- (3- (4,5-dihydro-1H-imidazol-2-ylcarbamoyl) propyloxy) phenyl) propionate

340 mg of 4,5-dihydro-1H-imidazol-2-ylamine, 13.6 mg of imidazole and 26.8 mg of lithium iodide are added to a solution of 970 mg of tert-butyl (2S) -2-benzyloxycarbonylamino-3- (4). - (3-ethoxycarbonylpropyloxy) phenyl) propionate (Example 1a) in 5 ml of absolute dimethylformamide. The solution was stirred at 40 ° C for four hours, an additional 170 mg of 4,5-dihydro-1H-imidazol-2-ylamine was added, and the solution was stirred for a further three hours at 55 ° C. The reaction was treated with ethyl acetate, filtered, extracted with 10% aqueous potassium bicarbonate solution, dried over magnesium sulfate, filtered, concentrated in vacuo and precipitated with diisopropyl ether. The crude product was purified by silica gel chromatography (dichloromethane / methanol / glacial acetic acid 90/10/1) to give 250 mg of an amorphous product.

MS (ES ^{& lt ; +} & gt ^; ) ^; m / e = 525.2 (M + H ⁺ , 100%).

b) (2S) -2-Benzyloxycarbonylamino-3- (4- (3- (4,5-dihydro-1H-imidazol-2-ylcarbamoyl) propyloxy) phenyl) propionic acid.

Dissolve 200 mg of tert-butyl (2S) -2-benzyloxycarbonylamino-3- (4- (3- (4,5-dihydro-1H-imidazol-2-ylcarbamoyl) propoxy) phenyl) propionate in 5 ml of trifluoroacetic acid mixture and water (95/5) and the solution was stirred at room temperature for 15 minutes. The reaction solution was concentrated in vacuo. The residue was dissolved in water and the solution was freeze-dried. Yield 100% of theory,

MS (ES ⁺ ): mlz = 469.2 (M + H ⁺ , 100%).

Pharmacological tests

Inhibition of bone resorption by the compounds of the invention can be determined, for example, by the osteoblast resorption assay (PIT ASSAY '), for example according to WO-A-95/32710.

The inhibitory effect of the compounds of the invention on the vitronectin receptor ΠνΠ3 can be determined, for example, as described below.

• flflflfl flflflfl flflflfl flflflfl flflflfl flflflfl

to human plasma vitronectin and purified

Measurement of 293 cell binding inhibition assay (Vn / 293 cell assay).

1. Purification of human vitronectin

Human vitronectin is isolated from affinity chromatography as described by Yatohyo et al. (Cell Structure and Function 23, pp. 281 to 292, 19S8).

2. Cell test

293 cells, a human erabryonal kidney cell line, are co-transfected with the DNA sequences for the h _v and Π3 subunits in the itronect of the novel ΗνΠ3 receptor for high expression (> 500,000 _ν Π3 receptors / cell) according to the FACS method. The selected cells are cultured and sorted again by FACS to obtain a stable cell line (15D) with an expression rate of more than 1,000,000 copies of ΠνΠ3 per cell.

The flat bottom 96-well Linbro tissue plate is coated overnight at 4 ° C with human in itronectin (0.01 mg / ml, 0.05 ml / well) in phosphate buffered saline (PBS) and blocked with 0.5% BSA (bovine serum albumin). Test solutions from 10 * ¹⁰ mol / l to 2x10 ^-3 mol / l are prepared in DMEM containing glucose and 0.05 ml / well of solution is added to the plate in each case. Cells expressing high amounts of ΠνΠ3 (e.g. 15D) are suspended in glucose-containing DMEM and the suspension is adjusted to 25,000 cells / 0.05 ml medium. 0.05 ml of this suspension is added to each well and the plate is incubated for 90 minutes at 37 ° C. The plate is washed three times with warm PBS to remove unbound cells. Bound cells are lysed in citrate buffer (25 mM, pH 5.0) containing 0.25% Triton X-100. Then, the hexosamidase substrate of p-nitrophenyl-N-acetyl-n-D-glucosamine is added and the plate is incubated for 90 minutes at 37 ° C. The reaction is terminated with glycine buffer (50 mM) / EDTA (5 mM, pH 10.4) and the absorption of each is measured at 405 to 650 nm.

9 4 4 8

4 4 9 4

4 9 9 9 4 5

4 9 4

45 99 9

99 • 4 4 9 4

4 4 9 4

9 4 4

94 dimple. Data se

Results obtained Compound

Example 1 Example 2

Example 3

Example 6 are analyzed in a conventional manner

Vn / 293 cell trick

IC 50 (liM)

O, 028.0.017 1.35 O, 032

Industrial applicability

An acylguanidine derivative as a vitronectin receptor antagonist, a bone resorption inhibitor, an inhibitor of tumor growth or tumor metastasis, and an anti-sleigh agent for the manufacture of pharmaceutical compositions for the treatment or prophylaxis of cardiovascular disorders, restenosis, arteriosclerosis, nephropathy, retinopathy and osteoporosis.

Claims (17)

PATENT CLAIMS An acylguanidine derivative of the general formula I wherein is R ¹ and R ³ independently itorn hydrogen, alkyl having I to 6 carbon atoms optionally substituted with R ^3, provided that ^R; and R ^{2 are} not both hydrogen or R ¹ and R ² together taken together are a saturated or unsaturated bivalent C 2 -C 9 alkylene group optionally substituted by one or more of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy , aryl of 6 to 14 carbon atoms, arylalkyl of 6 to 14 carbon atoms in the aryl moiety of about 6 to 6 carbon atoms in the alkyl moiety, heteroaryl of 5 to 14 carbon atoms, heteroarylalkyl of 5 to 14 carbon atoms in the aryl moiety and 1 to 6 carbon atoms. (C až-C až cyk) cycloalkyl, (C až-C až cyk) cycloalkyl, (C ox-C cyk cyk) cycloalkyl and (C až-C ox ox) cycloalkyl group having 1 to 6 carbon atoms in the alkyl group, the 5- to 7-membered ring being saturated or unsaturated and optionally substituted a R ³ group, in particular one or two R ³ groups, and the carbocyclic or heterocyclic ring comprises them day or two ring nitrogen atoms and is optionally fused to a carbon-carbon bond in an alkylene group of 2 to 9 carbon atoms, R ³ is C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 5 -C 14 aryl, C 5 -C 14 arylalkyl and C 1 -C 4 alkyl, halogen , trifluoromethyl, hydroxyl, nitro or amino, R ⁴ is hydrogen, (C 1 -C 6) -alkyl-CO-O- (C 1 -C 6) alkyl or C 1 -C 6 alkyl optionally substituted with hydroxyl, C 1 -C 6 alkoxy 4-carbon atoms, alkyl-S (O) 2-C 1 -C 4 -group, NR ⁷ R ⁷ 'and N ⁺ R ⁷ R' ^Z 'R ⁷ ''Q-, wherein R ⁷ , R ⁷ ' and R ⁷ 'independently of one another is hydrogen, C 1 -C 6 -alkyl, C 5 -C 14 -aryl, C 5 -C 14 -aryl-aryl-C 1 -C 14 -aryl and C 1 -C 8 -alkylalkyl and Q-physiologically an acceptable anion, or R ⁴ represents a group of the formula wherein the bonds to which the moieties are attached are indicated by a dashed line, R @ ⁵ is C1 -C8 alkyl, arylalkyl having 6 32 14 carbon atoms in the aryl moiety and having 1 to 6 carbon atoms in the alkyl moiety or heteroarylalkyl having 5 to 14 carbon atoms in the aryl moiety and having 1 to 6 carbon atoms the carbon atoms in the alkyl moiety, wherein the aryl or heteroaryl moiety is optionally substituted with one, two or three R ³ groups, R ^s is hydrogen, and to in the alkyl moiety, and 1ky1 -0-CO-O- having 1 to 6 lu or nitro; A is a CH3, O, S or m 1,2 or 3, n0 or 1-O-CO- group having from 1 to 6 carbon atoms; mixtures thereof in any ratio; and physiologically acceptable salts thereof and prodrugs thereof The acylguanidine derivative according to claim 1, wherein it is R ¹ and R ^and R together are a saturated or unsaturated divalent alkylene group having 2 to 5 carbon atoms unsubstituted or substituted by halogen, alkyl having 1 to β carbon atoms, alkoxy having 1 to 6 carbon atoms, by aryl (C 6 -C 14) aryl, (C 6 -C 14) arylalkyl with 1 to 6 carbon atoms in the alkyl moiety, C 5 -C 14 heteroaryl, (C 5 -C 14) heteroarylalkyl in the aryl moiety of up to 6 carbon atoms C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkyl and C 3 -C 12 cycloalkyl of up to 6 carbon atoms in the alkyl moiety, wherein the 5- to 7-membered ring is saturated or unsaturated and is optionally substituted with R ³ , especially one or two R ³ groups, and the carbocyclic or heterocyclic ring contains one or two ring nitrogen atoms and is optionally fused to a carbon-carbon bond in the C 2 -C 5 alkylene group, R- ⁵ alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms. R ⁴ is hydrogen, C 1 -C 6 alkyl which is unsubstituted or substituted by C 1 -C 4 alkoxy, C 1 -C 4 alkyl-S (O) and MR ⁷ R ⁷ ', wherein R ⁷ R ⁷ ' independently of one another is hydrogen or C 1 -C 4 alkyl, ^R is alkyl having 1-8 carbon atoms or a group of the formula II in which q is 0 or 1 and R ³ may be at any position of the phenyl group. R ° is hydrogen, alkyl-O-C0- (C 1 -C 6) alkyl; A is a CHa or oxygen atom, m is 1, 2 or 3, n is 0 or 1, and all stereoisomeric forms thereof and mixtures thereof in any ratio, and their physiologically acceptable salts and prodrugs. An acylguanidine derivative according to claim 1 and / or 2 of the general formula I, wherein it is R ¹ and R ² taken together are a saturated or unsaturated, bivalent C 2 -C 4 alkylene group, unsubstituted or substituted by a group selected from the group consisting of and ha. 54: - Logene, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 14 aryl, C 6 -C 14 arylalkyl an aryl of 1 to 6 carbon atoms in the alkyl portion, a heteroaryl of 5 to 14 carbon atoms, a heteroarylalkyl of 5 to 14 carbon atoms in an aryl portion of up to 6 carbon atoms in an alkyl portion, a cycloalkyl of 3 to 12 carbon atoms, C 3 -C 12 cycloalkyl and C 3 -C 12 oxo in a cycloalkyl group of up to 6 carbon atoms in the alkyl moiety, wherein the 5- to 7-membered ring is saturated or unsaturated and is optionally substituted with R ³ , especially one or two R ³ groups and a carbocyclic or heterocyclic ring it contains one or two nitrogen atoms in the ring and is optionally fused to a carbon-carbon bond in an alkylene group having 2 to 4 carbon atoms, R ³ is alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, R ⁴ is hydrogen, alkyl having 1 to 6 carbon atoms, R ⁵ is C 1 -C 4 alkyl or a group of formula II (R ³ )? CH, (II) wherein g is 0 or 1 and R ³ may be at any position of the phenyl group, R ° is hydrogen, alkyl-O-CO- having 1 to 4 carbon atoms in the alkyl moiety, A is a CH 2 group or an oxygen atom, m is 1, 2 or 3, n is 0 or 1, and all stereoisomeric forms thereof and mixtures thereof in any ratio, and their physiologically acceptable salts and prodrugs. 4. Acy1guanidinu derivative according to claim 1 to 3 of ·· ··> »· '> ¹ ·> · ♦ 4 4 Of formula I, where is R ¹ and R ³ together are a saturated or unsaturated, bivalent C 2 -C 3 alkylene group, unsubstituted or substituted by a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an aryl group C 6 -C 14 arylalkyl of 6 to 14 carbon atoms in the aryl moiety and of 1 to 6 carbon atoms in the alkyl moiety, heteroaryl C 5 to 14 carbon atoms, heteroarylalkyl of 5 to 14 carbon atoms in the aryl moiety of up to about 6 carbon atoms C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkyl and C 3 -C 12 cycloalkyl of up to 6 carbon atoms in the alkyl moiety, the 5- to 7-membered ring being saturated or unsaturated and optionally substituted with R ³ , in particular one or two R ^j groups and the carbocyclic or heterocyclic ring contains one or two nitrogen atoms and is optionally fused to a carbon-carbon bond in the C 2 -C 3 alkylene group. R ³ is alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, R ( ⁴⁾ is hydrogen, (C1-C4) -alkyl; R &lt; 1 ^&gt; is C1-C4alkyl or II (R &lt; ³ &gt;) _c -CH, c II) wherein q is 0 or 1 and R ³ may be in any position of the phenyl group, R ^o is hydrogen, alkyl-0-C0- having 1 to 4 carbon atoms in the alkyl moiety, A group CHz, m number 1, n number 1 • 9 9 · 9 And their all stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts and prodrugs. 5. An acylguanidine derivative according to any one of claims 1 to 3 of the general formula (I), wherein it is R ¹ and R ^and R together are a saturated or unsaturated divalent alkylene group having 2 to 3 carbon atoms, unsubstituted or substituted by halogen, alkyl having 1 to C 6 -C 6 alkoxy, C 1 -C 6 alkoxy, C 6 -C 14 aryl, C 6 -C 14 arylalkyl and C 1 -C 6 alkyl, heteroaryl C 5 -C 14 heteroarylalkyl (C až-C 14) aryl moiety of up to about 6 carbon atoms in the alkyl moiety, (C až-C cyk) cycloalkyl, (Clo-Clo) cycloalkylalkyl, and (C 12-C ox) cycloalkyl group (C až-C až) carbon in the alkyl moiety, wherein the 5- to 7-membered ring is saturated or unsaturated and is optionally substituted with R ³ , in particular one or two R ³ groups, and the carbocyclic or heterocyclic ring contains one or two ring nitrogen atoms and is optionally fused to a carbon bond -carbon in the C 2 -C 3 alkylene group, R ³ is alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, R ( ⁴⁾ is hydrogen, alkyl of up to 4 carbon atoms, R @ ⁵ is C1 -C4 alkyl or a group of formula II (R @ ³ ) _c CH (II) wherein q is 0 or 1 and R ³ may be in any position of the phenyl group, R ⁶ hydrogen atom, a C 1 -C 4 alkyl-O-C 0 - group in the alkyl moiety, ,φ podí · · ·, * * * * * * * * v v v v v v · v φ v v A is an oxygen atom, m is number 1, n is number 1 and all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts and prodrugs. The acylguanidine derivative according to any one of claims 1 to 3, wherein is R ^x and R ^and R together are a saturated or unsaturated divalent alkylene group having 2 to 3 carbon atoms, unsubstituted or substituted groups selected from halogen, alkyl having 1 to 6 carbon atoms, alkoxy of 1-6 carbon atoms, aryl of from 6 to 14 carbon atoms. arylalkyl of 6 to 14 carbon atoms in the aryl moiety and of 1 to 6 carbon atoms in the alkyl moiety, heteroaryl of 5 to 14 carbon atoms, heteroarylalkyl of 5 to 14 carbon atoms in the aryl moiety of up to about 6 carbon atoms in the alkyl moiety, cycloalkyl of 3 up to 12 carbon atoms, cycloalkyl and alkyl groups having from 3 to 12 carbon atoms in the cycloalkyl moiety of up to about 6 carbon atoms in the alkyl moiety, the 5- to 7-membered ring being saturated or unsaturated and optionally substituted by R ³ , especially one or two R groups ³ and the carbocyclic or heterocyclic ring contains one or two ring nitrogen atoms and is optionally fused to a carbon-carbon bond in an alkylene group having 2 to 3 carbon atoms, R ³ is alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, R ( ⁴⁾ is hydrogen, (C1-C4) -alkyl, ^R is alkyl having 1 to 4 carbon atoms or a group of the formula II (R ³⁾ q CH, (II) • φ φφ ♦ ·· · · φ φ φ φ φ φ φ · φ φ φ φφ φφ φ φ φ φ φ φφ · where q is 0 or 1 and R ³ may be at any position of the phenyl group , R @ 0 is hydrogen, C1 -C4 alkyl-O-CO--; A is an oxygen atom, m is number 3, n is number 0, and all stereoisomeric forms thereof and mixtures thereof in any ratio, and their physiologically acceptable salts and prodrugs. 7. An acylguanidine derivative according to claim 1, wherein R &lt; ⁵ &gt; is unsubstituted benzyl and all its stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts and prodrugs. The acylguanidine derivative according to any one of claims 1 to 7, wherein is R ¹ and R ² taken together are a saturated bivalent unsubstituted alkylene group having 2 to 3 carbon atoms, R ( ⁴⁾ is hydrogen, (C1-C4) -alkyl; R ^{5 is} unsubstituted benzyl; R ° is hydrogen; A is an oxygen atom; m number 3; n number 0 and all its stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts and prodrugs. 9. A compound according to claim 1, which is (2S) -2-benzyloxycarbonylamino-3- (4- (3- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) propyloxy) phenyl). propionic acid and its physiologically acceptable salts and prodrugs. 10. An acylguanidine derivative according to any one of claims 1 to 7 which is (2S) -2-benzyl-oxycarbonyl-amino-3- (4- (2- (1-carboxylic acid)). · ♦♦ · - 59: -: · 44 ·· ♦ · 4 · · · 4 · · 4 9 4 9 4 4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl-ethyl-benzoylamino-pionic acid and its physiologically acceptable salts and prodrugs. 11. A compound according to claim 1, which is (2S) -2-benzyloxycarbonylamino-3- (4 - ((1,45,6-tetrahydropyrimidin-2-ylcarbamoyl) methyl). oxy) benzoyl and amino) propionic acid and its physiologically acceptable salts and prodrugs. 12. A compound according to claim 1, which is (2S) -2-benzyloxycarbonylamino-3- (4- (3- (4,5-dihydro-1H-imidazol-2-yl) carbamoyl). (propyloxy) phenyl) propionic acid and its physiologically acceptable salts and prodrugs. and: A process for the preparation of an acylguanidine derivative according to up to 12 of the formula I, 1 to 12, characterized in that it is bound by one or wherein the individual symbols have two fragments which can be derived retrospectively from the compound of the formula I according to claim 1. 14. three, derivate The process according to claim 13, characterized in that the carboxylic carboxylic acids of the general formula III are reacted with an acid or a carboxylic acid H H (N-C), N- _{A - (C} H ₂ ) _m -U (III) wherein R ⁴ , R ⁵ , A, _{n and m} are as defined above, or alternatively the functional groups may be present in the form of their precursors which are later converted to groups of compounds of general formula of formula I, or the functional groups may be in protected form and X represents a nucleophilically substitutable release group, with guanidine or a guanidine derivative of formula IV N - R ¹ h ₂ n (IV) 4 9 44 4 44 9449 • · · 9 9 4 4 8 . 9 4 4 4 4 4 4 4 4 Wherein R @ ¹ , R @ ² and R @ ⁵ are as defined in claims 1 to 12 in the form of precursors or in protected form Acylguanidine derivative according to claims 1 to 12 and / or its physiologically acceptable salts and / or prodrugs as a medicament. A pharmaceutical composition comprising at least one acylguanidine derivative according to claims 1 to 12 and / or its physiologically acceptable salts and / or prodrugs together with a pharmaceutically acceptable non-toxic carrier. An acylguanidine derivative according to a physiologically acceptable salt and / or a novel receptor antagonist. A prodrug as claimed in claim 1 and / or a prodrug thereof as claimed in claims 1 to 12 and / or a prodrug thereof as an inhibitor of the prophylaxis of osteoporosis. 18. An acylguanidine derivative according to a physiologically acceptable salt and / or bone resorption or therapy; or The acylguanidine derivative according to claims 1 to 12 and / or its physiologically acceptable salts and / or prodrugs as an inhibitor of tumor growth or tumor metastasis. The acylguanidine derivative according to claims 1 to 12 and / or its physiologically acceptable salts and / or prodrugs as an anti-inflammatory agent or for the therapy or prophylaxis of cardiovascular disorders, restenosis, arteriosclerosis, nephropathy or retinopathy.