JP2002501054A - Novel sulfonamide derivatives as inhibitors of bone resorption and as inhibitors of cell adhesion - Google Patents

Abstract

(57) Abstract: The present invention relates to a sulfonamide derivative represented by the formula (I) wherein R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ have the meanings indicated in the claims, and their physiologically acceptable It relates to salts and their prodrugs. 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. They are suitable, for example, for the treatment and prevention of diseases at least partially caused by an undesirable degree of bone resorption, for example osteoporosis. The invention further relates to a process for the preparation of the compounds of the formula (I), their use, in particular as pharmaceutically active ingredients, and pharmaceutical preparations containing them. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the following formula I:

Embedded image Wherein R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ have the meanings given below, their physiologically acceptable salts and their prodrugs. The compounds of the formula I are valuable pharmaceutically active compounds. These are vitronectin receptor antagonists and cell adhesion inhibitors, which inhibit bone resorption by osteoclasts. They are suitable, for example, for the treatment and prevention of diseases caused, for example, by osteoporosis, at least partially by an undesirable degree of bone resorption. The invention further relates to a process for the preparation of the compounds of the formula I, their use in particular as pharmaceutically active ingredients, and pharmaceutical preparations (medicines) containing them.

[0002] Human bones undergo a certain dynamic regeneration process, including bone resorption and bone formation. These processes are controlled by several types of cells that specialize in their purpose. Bone resorption is based on the destruction of bone matrix by osteoclasts. Most bone disorders are based on an imbalance between bone formation and bone resorption. Osteoporosis has low bone mass,
A disease characterized by increased bone brittleness, thereby increasing the risk of fracture. This occurs as a result of the lack of new bone formation for bone resorption during the course of the remodeling (remodeling) process. Conventional treatments for osteoporosis include, for example, bisphosphonates, estrogens, estrogen / progesterone (hormone replacement therapy, HRT), estrogen agonists / antagonists (selective estrogen receptor modulators, SERMs), calcitonin, vitamin D analogs, Including administration of parathyroid hormone (parathyroid hormone), growth hormone secretagogue or sodium fluoride (Jardine et al., Annual Reports in Medical Chemistry, 19
96, 31, 211).

[0003] Active osteoclasts are multinucleated cells having a diameter of up to 400 μm and remove bone matrix. Activated osteoclasts become attached to the surface of the bone matrix and secrete proteolytic enzymes and acids into the so-called "sealing zone", the area between their cell membranes and the bone matrix. The acidic environment and the proteases (protease) cause bone destruction. Compounds of formula I inhibit bone resorption by osteoclasts.

[0004] Previous studies have shown that osteoclast adhesion to bone is controlled by integrin receptors on the cell surface of osteoclasts. Integrins are a superfamily of receptors, specifically including fibrinogen receptor α _IIb β ₃ on platelets and vitronectin receptor α _V β ₃ . The vitronectin receptor α _v β ₃ is a membrane glycoprotein and is expressed on the cell surface of many cells such as endothelial cells, vascular smooth muscle cells, osteoclasts and tumor cells. The vitronectin receptor α _v β ₃ expressed on the osteoclast membrane regulates the process of adhesion to bone and bone resorption, thus contributing to osteoporosis. Α _V β _{3 in} this case binds to bone matrix proteins such as osteopontin, bone saliva protein and thrombospontin, which contain the tripeptide moiety Arg-Gly-Asp (or RGD).

Report that RGD peptide and an anti-vitronectin receptor antibody (23C6) inhibit tooth destruction and osteoclast migration by osteoclasts (Horton
Et al., Exp. Cell. Res., 1991, 195, 368). Sato et al., In J. Cell Biol., 1990, 111, 1713, described echistatin, an RGD peptide from snake venom ( echist
atin). Fischer et al. (Endocrinology, 1993, 132, 1411) were able to show in rats that exstatin also inhibits bone resorption in vivo.

In addition, the vitronectin receptor α _V β ₃ on human cells of aortic vascular smooth muscle is
It has been shown to stimulate the penetration of these cells into the neointima, eventually leading to restenosis and arteriosclerosis after angioplasty (Brown et al., Cardiovascular
Res., 1994, 28, 1815).

[0007] Brook et al (Cell, 1994,79,1157), the antibody or alpha _V beta ₃ antagonists for alpha _V beta ₃ causes shrinkage of tumors by inducing the apoptotic vascular cells during angiogenesis It indicates that you can do it. The vitronectin receptor α _v β ₃ is also involved in the progression of various other types of cancer and is overexpressed in malignant melanoma cells (Engleman et al., Annual Reports in Medicinal Chemistry, 1).
996, 31, 191). Melanoma invasion was associated with this overexpression (Stracke et al., Enc
yclopedia of Cancer, Volume III, 1855, Academic Press, 1997; Hillis et al., Clin.
ical Science, 1996, 91, 639). Carron et al. (Cancer Res., 1998, 58, 1930) report the inhibition of tumor growth and inhibition of hypercalcemia of malignant tumors using α _v β ₃ antagonists.

[0008] Cheresh et al. (Science, 1995,270,1500) have reported that anti-alpha _V beta ₃ antibody or alpha _V beta ₃ antagonists inhibit bFGF-induced angiogenesis processes in the rat eye. This property can be used therapeutically in the treatment of retinopathy.
Thus, the effects of the vitronectin receptor and its associated interactions have the potential to affect a variety of medical conditions that continue to require suitable pharmaceutically active ingredients for treatment and prevention.

[0009] WO 94/12181 describes substituted aromatic ring systems and WO 94/08577 describes substituted heterocycles as fibrinogen receptor antagonists and inhibitors of platelet aggregation. EP-A-528586 and EP-A-528587 disclose aminoalkyl-substituted or heterocyclic-substituted phenylalanine derivatives and are disclosed in International Publication WO 9
No. 5/32710 discloses aryl derivatives as inhibitors of bone resorption by osteoclasts. WO 96/00574 describes benzodiazepines and WO 96/00730 describes a fibrinogen receptor antagonist template, particularly a benzodiazepine bound to a nitrogen-containing 5-membered ring, as a vitronectin receptor antagonist. I have. International Publication WO98 / 00395 pamphlet (German Patent Application No. 196533382)
No.) describes a vitronectin receptor antagonist derived from a tyrosine skeleton. European Patent Publication No. 820991 (German Patent Application No. 196)
29816.4) describe cycloalkyl derivatives and EP-A-97-122520.6 describes carbamate derivatives.
These are vitronectin receptor antagonists. Further studies have shown that the sulfonamide derivatives of formula I are particularly potent inhibitors of the vitronectin receptor and of bone resorption by osteoclasts.

The present invention relates to compounds in the form of all stereoisomers of the formula I and their mixtures in all ratios, and their physiologically acceptable salts, and their prodrugs:

Embedded image[Wherein, R¹And R^TwoIs R¹And R^TwoAre independently of one another hydrogen or unsubstituted or R^Three(C₁~ C₆) -Alkyl, or¹And R^TwoTogether with saturated or unsaturated divalent (C_Two~ C₉) -Alkylene group,
For example, the group-(CH_Two)_p-(Where p is 2, 3, 4, 5, 6, 7, 8 or 9
ア ル キ レ ン The alkylene group is halogen, (C₁~ C₆) -Al
Kill, (C₁~ C₆) -Alkoxy, (C₆~ C₁₄) -Aryl, (C₆~ C₁₄)-
Aryl- (C₁~ C₆) -Alkyl-, (C_Five~ C₁₄) -Heteroaryl, (C_Five ~ C₁₄) -Heteroaryl- (C₁~ C₆) -Alkyl-, (C_Three~ C₁₂) -Cycloalkyl, (C_Three~ C₁₂) -Cycloalkyl- (C₁~ C₆) -Alkyl- and oxo, optionally substituted with one or more groups selected from the group consisting of:
And a 5- to 7-membered saturated or unsaturated ring may be substituted with R^Three(Especially one or two groups R^Three), And may be a carbocyclic ring or a heterocyclic ring containing one or two ring nitrogen atoms._Two~ C₉) -A
Can also be condensed with the carbon-carbon bond in the alkylene group.^ThreeIs (C₁~ C_Ten) -Alkyl, (C_Three~ C₂₀) -Monocycloalkyl, (C_Five ~ C₂₀) -Bicycloalkyl, (C_Five~ C₂₀) -Tricycloalkyl, (C₁~ C ₈ ) -Alkoxy, (C₆~ C₁₄) -Aryl, (C₆~ C₁₄) -Aryl- (C₁ ~ C_Four) -Alkyl-, (C_Five~ C₁₄) -Heteroaryl, (C_Five~ C₁₄) -Heteroaryl- (C₁~ C_Four) -Alkyl-, halogen, trifluoromethyl, shea
, Hydroxyl, oxo, nitro, amino, -NH- (C₁~ C_Four) -Alkyl
, -N-((C₁~ C_Four) -Alkyl)_Two, -NH-CO- (C₁~ C_Four) -Alkyl or -CO- (C₁~ C_Four) -Alkyl; R^FourIs hydrogen, (C₁~ C₆) -Alkyl-CO-O- (C₁~ C_Four) -Alkyl- or (C₁~ C₆) -Alkyl ｛which, even if unsubstituted, is hydroxyl, (C₁~ C_Four) -Alkoxy,
(C₁~ C_Four) -Alkyl-S (O)_Two-, NR⁷R⁷’And N⁺R⁷R⁷'R⁷"Q^- (Where R⁷, R⁷’And R⁷"Are independently hydrogen, (C₁~ C₆) -Alkyl, (C_Five~ C₁₄) -Aryl or (C_Five~ C₁₄) -Aryl- (C₁~ C₆)
-Alkyl, Q^-Is a physiologically acceptable anion), or may be substituted with a group selected from the group consisting of:

Embedded image(Where the dashed line indicates the bond to which this group is attached)
Or R^FiveIs (C₁~ C₂₀) -Alkyl, (C_Three~ C₂₀) -Monocycloalkyl, (C_Five ~ C₂₀) -Bicycloalkyl, (C_Five~ C₂₀) -Tricycloalkyl, (C₆~ C ₁₄ ) -Aryl, (C_Five~ C₁₄) -Heteroaryl, (C₆~ C₁₄) -Aryl-
(C₁~ C₆) -Alkyl- or (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆) -Alkyl-, wherein an aryl group, a heteroaryl group, an alkyl group,
Nocycloalkyl group, bicycloalkyl group and tricycloalkyl group are
1, 2 or 3 unsubstituted groups R^ThreeAnd an alkyl group, a monocycloalkyl group, a bicycloalkyl group and a tricycloalkyl group.
One or more carbon atoms in the alkyl group (especially 1, 2, 3 or 4 carbon atoms)
At the same or different atoms selected from the group consisting of nitrogen, oxygen and sulfur
May be replaced, R⁶Is hydrogen, (C₁~ C₆) -Alkyl-O-CO-, hydroxyl, (C₁~ C ₆ ) -Alkyl-O-CO-O- or nitro].

All radicals which can occur more than once in the compounds of the formula I (for example the radical R ³ ) each have the abovementioned meanings independently of one another and may in each case be the same or different . The groups which can have the abovementioned meanings independently of one another may in each case be the same or different.

The alkyl group may be straight-chain or branched, and may be saturated, mono-unsaturated or poly-unsaturated. This also applies if they have a substituent or appear as substituents on another group (for example in an alkoxy, alkoxycarbonyl or arylalkyl group). 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 include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl and eicosyl, The n-isomers of all these groups, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, isodecyl, 3-methylpentyl, 2,3,4-trimethylhexyl, sec-butyl, t-butyl, t-butyl
There is a pentyl. A preferred group of alkyl groups is methyl, ethyl, n-propyl,
Consists of isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl groups. A divalent group corresponding to the above monovalent group, for example, methylene, 1,1-ethylene (=
Methylmethylene), 1,2-ethylene, 1,3-propylene, 1,2-propylene (= 1-methylethylene and 2-methylethylene), 2,3-butylene (= 1
, 2-dimethyl-1,2-ethylene), 1,4-butylene, 1,6-hexylene are examples of alkylene groups.

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

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

The bicycloalkyl and tricycloalkyl groups may be unsubstituted and may be substituted at any desired suitable position, for example, with one or more oxo groups and / or 1
Or two or more identical or different (C ₁ -C ₄ ) -alkyl groups (eg methyl or isopropyl, preferably methyl). The free bond to which the bicyclic or tricyclic group is attached can be located at any desired position in the molecule. Thus, the group can be attached via the bridgehead atom or an atom in the bridge. The free bond can also be located at any desired stereochemical position, for example, an exo position or an end position. Examples of bicycloalkyl and tricycloalkyl groups include camphanyl, bornyl, adamantyl (eg, 1-adamantyl and 2-adamantyl), caranyl, epiisobornyl, epibornyl, norbornyl and norpinanyl.

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

(C_Five~ C₁₄) -Aryl includes heterocyclic (C) wherein one or more of 5 to 14 ring carbon atoms are replaced by a heteroatom such as nitrogen, oxygen or sulfur._Five~ C₁₄ ) -Aryl group (= (C_Five~ C₁₄) -Heteroaryl)) and carbocyclic (C₆~
C₁₄) -Aryl groups are included. Carbocyclic (C₆~ C₁₄Examples of) -aryl groups include phenyl, naphthyl, biphenylyl, anthryl or fluorenyl,
1-Naphthyl, 2-naphthyl and phenyl are preferred. Unless otherwise stated,
The reel group, especially the phenyl group, may be unsubstituted and may have one or more groups, preferably
Alternatively, it may be substituted with one, two or three identical or different groups.
In particular, the aryl group is (C₁~ C₈) -Alkyl (especially (C₁~ C_Four) -Alkyl),
(C₁~ C₈) -Alkoxy (especially (C₁~ C_Four) -Alkoxy), halogen (eg,
For example, fluorine, chlorine and bromine), nitro, amino, trifluoromethyl, hydroxyl
, Methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C ₁ ~ C_Four) -Alkoxycarbonyl, phenyl, phenoxy, benzyl and ben
Substituted with the same or different groups selected from the group consisting of ziroxy
Can be. In general, only two nitro groups can be present as substituents in the compounds of the formula I according to the invention.

In a monosubstituted phenyl group, the substituent can be located at the 2-, 3- or 4-position, with the 3- and 4-positions being preferred. When the phenyl is disubstituted, the substituent is 2
, 3,2,4,2,5,2,6,3,4 or 3,5. In a disubstituted phenyl group, it is preferred that the two substituents are located at the 3- and 4-positions relative to the binding site. In a trisubstituted phenyl group, these substituents are 2,2
3,4,2,3,5,2,3,6,2,4,5,2,4,6 or 3,
Can be in fourth or fifth place. Similarly, naphthyl and other aryl groups are
It can be substituted at any desired position, for example, the 1-naphthyl group is at the 2-, 3-, 4-, 5-, 6-, 7- and 8-position, the 2-naphthyl group is at the 1-position, It can be substituted at the 3-, 4-, 5-, 6-, 7- and 8-positions.

In addition to carbocyclic systems, (C ₅ -C ₁₄ ) -aryl groups also have 1, 2, 3, 4 or 5 ring carbon atoms more than heteroatoms, especially nitrogen, oxygen and sulfur. It can also be a monocyclic or polycyclic (eg bicyclic or tricyclic) aromatic ring system replaced by the same or different heteroatoms selected from the group consisting of: Heterocyclic (C ₅ ~C ₁₄₎ - aryl and (C ₅ ~C ₁₄₎ - Examples of heteroaryl groups include 2-pyridyl, 3-pyridyl, such as pyridyl and 4-pyridyl, 2-pyrrolyl and Pyrrolyl such as 3-pyrrolyl, furyl such as 2-furyl and 3-furyl, thienyl such as 2-thienyl and 3-thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridazinyl, pyrazinyl, There are pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, β-carbolinyl, or benzo-, cyclopenta-, cyclohexa-, or cyclohepta-fused derivatives of these groups. These heterocyclic systems can be substituted at all suitable positions with the same substituents as those described above for carbocyclic aryl systems.

Within these series of heteroaryl groups, monocyclic having 1, 2 or 3 heteroatoms (particularly 1 or 2 heteroatoms) selected from the group consisting of N, O and S Or a bicyclic aromatic ring system (which may be unsubstituted, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, 1,2 selected from the group consisting of hydroxyl, (C ₁ -C ₄ ) -alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl
Or may be substituted with three substituents). A mono- or bicyclic aromatic 5- to 10-membered ring system having 1 to 3 heteroatoms (especially 1 or 2 heteroatoms) selected from the group consisting of N, O and S, which are , (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, phenyl, phenoxy, benzyl and benzyloxy, which may be substituted with one or two substituents. Is particularly preferred. 5- or 6-membered monocyclic heteroaryl groups having 1 or 2 heteroatoms (particularly 1 heteroatom) selected from the group consisting of N, O and S and 9 or 10-membered bicyclic heteroaryl Groups (unsubstituted or substituted as described above) are particularly preferred.

When the two radicals R ¹ -and R ^2- together represent a saturated or unsaturated divalent (C ₂ -C ₉ ) -alkylene radical, these two radicals are the two Together with the central carbon atom of the guanidino group to which these two nitrogen atoms are attached to form a monocyclic 1,3-diazaheterocycle. The monocyclic 1,3 Jiazahetero ring is attached to the nitrogen atom of the group (CH ₂₎ in ₂ -CO-NH in its 2-position. The 1,3 Jiazahetero ring, (C ₂ ~C ₉₎ - may be substituted, and on the guanidino nitrogen atom may be substituted as indicated in the alkylene group. Examples of such 1,3-diazaheterocyclic groups include a 2-imidazolyl group, 4,5-
There are a dihydro-2-imidazolyl group, a 1,4,5,6-tetrahydro-2-pyrimidinyl group and a 4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl group. When a 5- to 7-membered ring is fused with a carbon-carbon bond in a (C ₂ -C ₉ ) -alkylene group, the _two groups R ¹ and R ² are the two nitrogen atoms to which they are bonded and the two nitrogen atom are taken together with the central carbon atom of the guanidino group attached to form a bicyclic heterocycle, the bicyclic heterocycle, the nitrogen atom of the group (CH ₂₎ in ₂ -CO-NH And may be substituted as described above. The fused 5- to 7-membered ring may be saturated, mono-unsaturated, di-unsaturated or aromatic. Thus, for example, cyclopentane, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane or benzene rings can be fused. Examples of such bicyclic heterocyclic groups that can be attached to a nitrogen atom in the group (CH ₂ ) ₂ —CO—NH include 1,3a, 4,5,6,6a-hexahydro-1,3
-Diazapentalen-2-yl group, 1H-benzimidazol-2-yl group, 3
a, 4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl group, 4,5,6,7-tetrahydro-1H-benzimidazol-2-yl group, 4,7-dihydro- There is a 1H-benzimidazol-2-yl group or a 1H-imidazo [4,5-b] pyridin-2-yl group. The fused ring is substituted and / or
When the (C ₂ -C ₉ ) -alkylene groups are substituted, they are preferably mono- or disubstituted independently of one another by the same or different radicals R ³ ; The groups R ³ may be the same or different. When the alkyl groups represented by R ¹ and / or R ² are substituted, they are independently mono- or di-substituted (especially mono-substituted) by the same or different groups R ³ . In the case of disubstitution, the two groups R ³ may be the same or different.

The optically active carbon atoms present in the compounds of the formula I can have, independently of one another, the R or S configuration. The compounds of formula I may be in the form of pure enantiomers or pure diastereomers, or in the form of a mixture of enantiomers (eg racemic
Form) or diastereomeric mixtures. The present invention
Pure enantiomers and enantiomeric mixtures and pure diastereomers
And both diastereomeric mixtures. The present invention includes mixtures of two or more stereoisomers of the formula I and all ratios of the stereoisomers in the mixture. Compounds of formula I can optionally exist as E or Z isomers. The invention is pure
It relates to both the E isomer and the pure Z isomer and to E / Z mixtures of all ratios.
The present invention also includes all tautomeric forms of the compounds of formula I, for example, as shown in formula I
In addition to the modified form, the acylguanidine unit has -CO-N = C (NHR¹) -NR^TwoR ⁶ It also includes the form present as the group and all other forms which depend on the various positions of the mobile hydrogen atom. Diastereomers including E / Z isomers include, for example,
The individual isomers can be separated by chromatography. Racemic, conventional
In a conventional manner, for example, by chromatography or resolution on a chiral phase, the two
Can be separated into enantiomers. Use a stereochemically uniform starting material.
By using a stereoselective reaction
Can also be obtained.

Physiologically acceptable salts of the compounds of the formula I are non-toxic, physiologically acceptable, especially physiologically usable salts. Such salts of compounds of Formula I containing an acidic group, for example, a carboxyl group, include, for example, alkali metal or alkaline earth metal salts, such as sodium, potassium, magnesium, and calcium salts, and physiologically acceptable salts There are salts with quaternary ammonium ions and acid addition salts with ammonia and physiologically acceptable organic amines such as triethylamine, ethanolamine or tris- (2-hydroxyethyl) amine. Compounds of formula I containing a basic group can be prepared from acid addition salts, e.g. inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-acid. Form acid addition salts with organic carboxylic acids and sulfonic acids, such as toluenesulfonic acid. Compounds of formula I containing basic and acidic groups, such as guanidino and carboxyl groups, can exist as zwitterions (zwitterions) (betaines) and are also included in the present invention.

When R ⁴ is an alkyl group substituted with a positively charged ammonium group,
Anion can be physiologically acceptable contained in the compounds of the Q ^- is particularly nontoxic raw pharmacologically available, especially monovalent anion or a polyvalent anion equivalent pharmaceutically available inorganic or organic acids, for example Anion or anion equivalents of one of the acids suitable for the formation of the above-mentioned acid addition salts. Thus, Q ^- is, for example, an anion selected from the group consisting of chloride, sulfuric acid, phosphoric acid, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid anion (
Or an anion equivalent).

The salts of the compounds of the formula I can be prepared by customary methods well known to those skilled in the art, for example by combining the compounds of the formula I with inorganic or organic acids or bases in solvents or dispersants, or By cation exchange or anion exchange. The invention also relates to compounds which are not directly suitable for use in medicine due to their poor physiological acceptability, but for example as intermediates for carrying out further chemical modifications of the compounds of the formula I or which are physiologically acceptable. Starting materials for the preparation of the possible salts also include all salts of the compounds of the formula I which are suitable.

The invention further relates to all solvates of the compounds of the formula I, such as hydrates or alcohol adducts, as well as derivatives, such as esters, prodrugs and other physiologically acceptable compounds of the compounds of the formula I Also encompassed are derivatives, as well as active metabolites of the compounds of formula I. The invention especially relates to prodrugs of a compound of formula I that can be converted under physiological conditions to a compound of formula I. Suitable pro-forms for compounds of formula I
Drugs, ie, chemically modified derivatives of the compounds of formula I, which have improved properties in the desired manner, are well known to those skilled in the art. Learn more about prodrugs
Detailed information is, for example, Fisher et al., Advanced Drug Delivery Reviews, 19, (1996),
115-130; Design of Prodrugs, edited by H. Bundgaard, Elsevier, 1985; H. Bundg
aard, Drugs of the Future, 16, (1991), 443; Saulnier et al., Bioorg. Med. Che.
m. Lett., 4, (1994), 1985; Safadi et al., Pharmaceutical Res., 10, (1993), 13
Found in 50. Please refer to these if necessary. Suitable prodrugs for the compounds of the formula I are, in particular, carboxylic acid groups, in particular the group COOR^FourR in^FourIs hydrogen
Ester prodrugs of the optionally present COOH group (eg (C₁~ C₆) -A
Alkyl ester or (C₁~ C_Four) -Alkyl esters), and amino groups and
Acyl prodrugs of acylatable nitrogen-containing groups such as guanidino groups
It is a rubamate prodrug. Acyl prodrug or carbamate prodola
In these groups, the hydrogen atom located on the nitrogen atom in these groups is more than once,
For example, it is substituted twice with an acyl group or a carbamate group. Acyl prodrugs and
Suitable acyl and carbamate groups for and carbamate prodrugs are
For example, the group R^Ten-CO- and R¹¹—O—CO—: where R^TenIs hydrogen, (C₁~ C₁₈) -Alkyl, (C_Three~ C₁₄) -Cycloal
Kill, (C_Three~ C₁₄) -Cycloalkyl- (C₁~ C₈) -Alkyl-, (C_Five-C ₁₄ ) -Aryl wherein 1-5 carbon atoms are replaced by heteroatoms such as N, O or S
Or (C_Five~ C₁₄) -Aryl- (C₁~ C₈) -Alkyl- (where 1-5 carbon atoms in the aryl portion are heteroatoms such as N, O or S)
R may be replaced by¹¹Is R^Tenの も の has a meaning other than hydrogen within the meaning indicated for｝.

In the compounds of the formula I, the radical R¹And R^TwoIs hydrogen or saturated or unsaturated (especially saturated) divalent (C_Two~ C_Five) -Alkylene groups, especially (C_Two~ C_Four)-Archi
Len groups, especially (C_Two~ C_Three) -Alkylene group These alkylene groups may be halogen, (C₁~ C₆) -A
Luquil, (C₁~ C₆) -Alkoxy, (C₆~ C₁₄) -Aryl, (C₆~ C₁₄)
-Aryl- (C₁~ C₆) -Alkyl-, (C_Five~ C₁₄) -Heteroaryl, (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆) -Alkyl-, (C_Three~ C₁₂) -S
Chloroalkyl, (C_Three~ C₁₂) -Cycloalkyl- (C₁~ C₆1) or two identical or different groups selected from the group consisting of -alkyl- and oxo
Wherein the 5- to 7-membered saturated or unsaturated ring is substituted
R even if not^Three(Especially one or two groups R^Three) May be substituted with a carbocyclic ring
A heterocyclic ring containing one or two ring nitrogen atoms, even a formula ring,
It is also preferable that the compound can be condensed with the carbon-carbon bond in the alkylene group. In the compounds of formula I, the group R¹And R^TwoIs hydrogen or a group-(CH _Two )_p-(Where p is a number 2, 3, 4 or 5, preferably a number 2, 3 or 4, especially
(Preferably the number 2 or 3) {This group is a halogen, (C₁~ C₆) -Alkyl, (C ₁ ~ C₆) -Alkoxy, (C₆~ C₁₄) -Aryl, (C₆~ C₁₄) -Aryl-
(C₁~ C₆) -Alkyl-, (C_Five~ C₁₄) -Heteroaryl, (C_Five~ C₁₄)-
Heteroaryl- (C₁~ C₆) -Alkyl-, (C_Three~ C₁₂) -Cycloalkyl, (C_Three~ C₁₂) -Cycloalkyl- (C₁~ C₆) -Alkyl- and oxo, substituted by one or two identical or different groups selected from the group consisting of
Wherein the 5- to 7-membered saturated or unsaturated ring is an unsubstituted R ^Three (Especially one or two groups R^Three) May be substituted with a carbocyclic ring,
May also be a heterocyclic ring containing one or two ring nitrogen atoms,
(CH_Two)_pParticularly preferred is a compound which can be condensed with a carbon-carbon bond in the formula. More particularly, the group R¹And R^TwoAre together a group-(CH_Two)_p-(Where p is the number 2, 3, 4 or 5, preferably the number 2, 3 or 4, particularly preferably
Is preferably the number 2 or 3, which is preferably unsubstituted. Group R¹And R^TwoIs
Together form a divalent radical -CH_Two-CH_Two-CH_TwoIs particularly preferred, ie R¹ And R^TwoTogether with the nitrogen atom to which they are attached and the central carbon atom of the guanidino group to which these nitrogen atoms are attached is 1,4,5,6-tetrahydro-2-pyrimido
It is particularly preferred to form a dinyl group.

R^ThreeIs (C₁~ C_Ten) -Alkyl, (C_Three~ C₂₀) -Monocycloalkyl, (C_Five~ C₂₀) -Bicycloalkyl, (C_Five~ C₂₀) -Tricycloalkyl, (C₁ ~ C₈) -Alkoxy, (C₆~ C₁₄) -Aryl, (C_Five~ C₁₄) -Heteroaryl, (C₆~ C₁₄) -Aryl- (C₁~ C_Four) -Alkyl-, (C_Five~ C₁₄)-
Heteroaryl- (C₁~ C_Four) -Alkyl-, halogen, trifluoromethyl,
Cyano, oxo, -N-((C₁~ C_Four) -Alkyl)_TwoOr -NH-CO- (C₁~
C_Four) -Alkyl. R^ThreeIs (C₁~ C_Four) -Alkyl, (C_Three ~ C_Ten) -Monocycloalkyl, (C_Five~ C₁₂) -Bicycloalkyl, (C_Five~ C ₁₂ ) -Tricycloalkyl, (C₁~ C_Four) -Alkoxy, (C₆~ C₁₄) -Allyl, (C₆~ C₁₄) -Aryl- (C₁~ C_Four) -Alkyl-, halogen, trifluoromethyl, cyano, oxo, -N ((C₁~ C_Four) -Alkyl)_TwoOr -NH-CO- (C₁~ C_Four) -Alkyl. R^ThreeIs (C₁ ~ C_Four) -Alkyl, (C_Three~ C_Ten) -Monocycloalkyl, (C_Five~ C₁₂) -Bicycloalkyl, (C_Five~ C₁₂) -Tricycloalkyl, (C₁~ C_Four) -Alkoxy, (C₆~ C₁₄) -Aryl, halogen, trifluoromethyl, cyano, oxo, -N ((C₁~ C_Four) -Alkyl)_TwoOr -NH-CO- (C₁~ C_Four) -Alkyl.

R ⁴ is preferably hydrogen or substituted or unsubstituted (C ₁ -C ₆ ) -alkyl, hydrogen or unsubstituted or (C ₁ -C ₄ ) -alkoxy, (C _1- C ₄₎ - (- 'in (wherein, R ⁷ and R ^7' and NR ⁷ R ⁷ are each independently of the other hydrogen or _{(C 1 -C 4 O) 2} ) - alkyl -S group consisting of alkyl as) Particularly preferred is (C ₁ -C ₆ ) -alkyl substituted with a group selected from R ⁴ is particularly preferably hydrogen or substituted or unsubstituted (C ₁ -C ₄ ) -alkyl, hydrogen or unsubstituted or substituted as above-mentioned (C ₁ -C ₄ ) -alkyl. Is more preferred.

R^FiveIs (C₁~ C₂₀) -Alkyl, (C_Three~ C₂₀) -Monocycloalkyl, (C_Five~ C₂₀) -Bicycloalkyl, (C_Five~ C₂₀) -Tricycloalkyl, (C₆ ~ C₁₄) -Aryl, (C_Five~ C₁₄) -Heteroaryl, (C₆~ C₁₄)-Ally
Lu- (C₁~ C₆) -Alkyl- or (C_Five~ C₁₄) -Heteroaryl- (C₁~ C ₆ ) -Alkyl- (where, aryl group, heteroaryl group, alkyl group, monocycloalkyl group
, A bicycloalkyl group and a tricycloalkyl group each have 1
Two or three identical or different radicals R^ThreeMay be substituted). R^FiveIs (C₁~ C_Ten) -Alkyl, (C_Three~ C₁₅) -Monocycloalkyl, (C_Five~ C₁₅) -Bicycloalkyl, (C_Five~ C₁₅) -Trisik
Loalkyl, (C₆~ C₁₄) -Aryl, (C_Five~ C₁₄) -Heteroaryl, (C ₆ ~ C₁₄) -Aryl- (C₁~ C₆) -Alkyl- or (C_Five~ C₁₄)-Heteroa
Reel-(C₁~ C₆) -Alkyl- (where, aryl group, heteroaryl group, alkyl group, monocycloalkyl group
, A bicycloalkyl group and a tricycloalkyl group are each unsubstituted
Also one, two or three identical or different radicals R^ThreeIs even more preferable. In addition to these preferred ones, a preferred group of groups
R^FiveIs (C_Three~ C₂₀) -Monocycloalkyl group, (C_Five~ C₂₀) -Bicycloalkyl group and (C_Five~ C₂₀) -Tricycloalkyl groups, which may be substituted or modified as described above, and_Five~ C₁₅) -Monocycloalkyl, (C_Five~ C₁₅) -Bicycloalkyl, (C_Five~ C₁₅) -Tricyclo
More preferably, it is alkyl. Another preferred group of radicals R^FiveIs (C₁~ C₂₀)
-Alkyl, (C₆~ C₁₄) -Aryl, (C_Five~ C₁₄) -Heteroaryl, (C ₆ ~ C₁₄) -Aryl- (C₁~ C₆) -Alkyl- or (C_Five~ C₁₄)-Heteroa
Reel-(C₁~ C₆) -Alkyl, which are substituted or modified as described above.
May be included), among which (C₆~ C₁₄) -Aryl and (C_Five~
C₁₄) -Heteroaryl (including substituted or modified) is preferred. Especially good
Group R^FiveIs composed of phenyl and naphthyl groups, that is, phenyl, 1-naphthyl and 2-naphthyl groups, which may be unsubstituted,
May be substituted.

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

Preferred compounds of the formula (I) are those in which one or more groups have the preferred meanings or their respective meanings.
A compound having one or several of its explicit meanings
Accordingly, all combinations of such preferred meanings or specific explicit meanings are subject to the present invention.
It is a title. Particularly preferred compounds of formula I are¹And R^TwoIs hydrogen or, together with saturated or unsaturated divalent (C_Two~ C_Five) -Alkylene groups, especially the group-(CH_Two)_p-(Where p is the number 2, 3, 4, or 5);_Two~ C_Five) -Alkylene group and group-(CH_Two)_p-Is not substituted
Also halogen, (C₁~ C₆) -Alkyl, (C₁~ C₆) -Alkoxy, (C₆~ C₁₄) -Aryl, (C₆~ C₁₄) -Aryl- (C₁~ C₆) -Alkyl-, (C_Five~ C₁₄) -Heteroaryl, (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆)
-Alkyl-, (C_Three~ C₁₂) -Cycloalkyl, (C_Three~ C₁₂) -Cycloalkyl
Lu- (C₁~ C₆) -Alkyl- and oxo substituted with a group selected from the group consisting of:
Wherein the 5-7 membered saturated or unsaturated ring is unsubstituted
Also R^Three(Especially one or two groups R^Three) May be substituted with a carbocyclic ring
Or a heterocyclic ring containing one or two ring nitrogen atoms,
(C_Two~ C_Five) -Alkylene group and group-(CH_Two)_p-Condensation with carbon-carbon bonds in
You can also^ThreeIs (C₁~ C_Ten) -Alkyl, (C_Three~ C₂₀) -Monocycloalkyl, (C_Five ~ C₂₀) -Bicycloalkyl, (C_Five~ C₂₀) -Tricycloalkyl, (C₁~ C ₈ ) -Alkoxy, (C₆~ C₁₄) -Aryl, (C_Five~ C₁₄) -Heteroaryl, (C₆~ C₁₄) -Aryl- (C₁~ C_Four) -Alkyl-, (C_Five~ C₁₄)-Hete
Lower aryl- (C₁~ C_Four) -Alkyl-, halogen, trifluoromethyl, shea
No, oxo, -N-((C₁~ C_Four) -Alkyl)_TwoOr -NH-CO- (C₁~ C_Four ) -Alkyl; R^FourIs hydrogen or (C₁~ C₆) -Alkyl, wherein the alkyl is (C)₁~ C_Four) -Alkoxy, (C₁~ C_Four) -Alkyl-S
(O)_Two-And NR⁷R⁷’(Where R⁷And R⁷′ Independently of one another are hydrogen or (C₁~ C_Four) -Alkyl
R) may be substituted with a group selected from the group consisting of^FiveIs (C₁~ C₂₀) -Alkyl, (C_Three~ C₂₀) -Monocycloalkyl, (C_Five ~ C₂₀) -Bicycloalkyl, (C_Five~ C₂₀) -Tricycloalkyl, (C₆~ C ₁₄ ) -Aryl, (C_Five~ C₁₄) -Heteroaryl, (C₆~ C₁₄) -Aryl-
(C₁~ C₆) -Alkyl- or (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆) -Alkyl-, wherein an aryl group, a heteroaryl group, an alkyl group,
Nocycloalkyl group, bicycloalkyl group and tricycloalkyl group are
1, 2 or 3 unsubstituted groups R^ThreeMay be substituted with⁶Is hydrogen or (C₁~ C₆) -Alkyl-O-CO-, compounds in the form of all stereoisomers and of their mixtures in all ratios, and their physiology
Pharmaceutically acceptable salts and their prodrugs.

More particularly preferred compounds of formula I are¹And R^TwoIs hydrogen or, together with saturated or unsaturated divalent (C_Two~ C_Four) -Alkylene groups, especially the group-(CH_Two)_p-(Where p is the number 2, 3 or 4);_Two~ C_Four) -Alkylene group and group-(CH_Two)_p-Is not substituted
Also halogen, (C₁~ C₆) -Alkyl, (C₁~ C₆) -Alkoxy, (C₆~ C₁₄) -Aryl, (C₆~ C₁₄) -Aryl- (C₁~ C₆) -Alkyl-, (C_Five~ C₁₄) -Heteroaryl, (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆)
-Alkyl-, (C_Three~ C₁₂) -Cycloalkyl, (C_Three~ C₁₂) -Cycloalkyl
Lu- (C₁~ C₆) -Alkyl- and oxo substituted with a group selected from the group consisting of:
Wherein the 5-7 membered saturated or unsaturated ring is unsubstituted
Also R^Three(Especially one or two groups R^Three) May be substituted with a carbocyclic ring
Or a heterocyclic ring containing one or two ring nitrogen atoms,
(C_Two~ C_Four) -Alkylene group and group-(CH_Two)_p-Condensation with carbon-carbon bonds in
You can also^ThreeIs (C₁~ C_Four) -Alkyl, (C_Three~ C_Ten) -Monocycloalkyl, (C_Five ~ C₁₂) -Bicycloalkyl, (C_Five~ C₁₂) -Tricycloalkyl, (C₁~ C _Four ) -Alkoxy, (C₆~ C₁₄) -Aryl, (C₆~ C₁₄) -Aryl- (C₁ ~ C_Four) -Alkyl-, halogen, trifluoromethyl, cyano, oxo, -N-((C₁~ C_Four) -Alkyl)_TwoOr -NH-CO- (C₁~ C_Four) -Alkyl;^FourIs hydrogen or (C₁~ C₆) -Alkyl; R^FiveIs (C₁~ C_Ten) -Alkyl, (C_Three~ C₁₅) -Monocycloalkyl, (C_Five ~ C₁₅) -Bicycloalkyl, (C_Five~ C₁₅) -Tricycloalkyl, (C₆~ C ₁₄ ) -Aryl, (C_Five~ C₁₄) -Heteroaryl, (C₆~ C₁₄) -Aryl-
(C₁~ C₆) -Alkyl- or (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆) -Alkyl-, wherein an aryl group, a heteroaryl group, an alkyl group,
Nocycloalkyl group, bicycloalkyl group and tricycloalkyl group are
1, 2 or 3 unsubstituted groups R^ThreeMay be substituted with⁶Is hydrogen or (C₁~ C_Four) -Alkyl-O-CO-, compounds in the form of all stereoisomers and of their mixtures in all ratios, and their physiology
Pharmaceutically acceptable salts and their prodrugs.

Particularly preferred compounds of formula I are¹And R^TwoIs hydrogen or together is saturated or unsaturated divalent (C_Two ~ C_Three) -Alkylene groups, especially the group-(CH_Two)_p-(Where p is the number 2 or 3);_Two~ C_Three) -Alkylene and the group-(CH_Two)_p-The group is not substituted
Also halogen, (C₁~ C₆) -Alkyl, (C₁~ C₆) -Alkoxy, (C₆~ C₁₄) -Aryl, (C₆~ C₁₄) -Aryl- (C₁~ C₆) -Alkyl-, (C_Five~ C₁₄) -Heteroaryl, (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆)
-Alkyl-, (C_Three~ C₁₂) -Cycloalkyl, (C_Three~ C₁₂) -Cycloalkyl
Lu- (C₁~ C₆) -Alkyl- and oxo substituted with a group selected from the group consisting of:
Wherein the 5-7 membered saturated or unsaturated ring is unsubstituted
Also R^Three(Especially one or two groups R^Three) May be substituted with a carbocyclic ring
Or a heterocyclic ring containing one or two ring nitrogen atoms,
(C_Two~ C_Three) -Alkylene group and group-(CH_Two)_p-Condensation with carbon-carbon bonds in
You can also^ThreeIs (C₁~ C_Four) -Alkyl, (C_Three~ C_Ten) -Monocycloalkyl, (C_Five ~ C₁₂) -Bicycloalkyl, (C_Five~ C₁₂) -Tricycloalkyl, (C₁~ C _Four ) -Alkoxy, (C₆~ C₁₄) -Aryl, halogen, trifluoromethyl,
Cyano, oxo, -N-((C₁~ C_Four) -Alkyl)_TwoOr -NH-CO- (C₁~
C_Four) -Alkyl; R^FourIs hydrogen or (C₁~ C₆) -Alkyl; R^FiveIs (C₁~ C_Ten) -Alkyl, (C_Three~ C₁₅) -Monocycloalkyl, (C_Five ~ C₁₅) -Bicycloalkyl, (C_Five~ C₁₅) -Tricycloalkyl, (C₆~ C ₁₄ ) -Aryl, (C_Five~ C₁₄) -Heteroaryl, (C₆~ C₁₄) -Aryl-
(C₁~ C₆) -Alkyl- or (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆) -Alkyl-, wherein an aryl group, a heteroaryl group, an alkyl group,
Nocycloalkyl group, bicycloalkyl group and tricycloalkyl group are
1, 2 or 3 unsubstituted groups R^ThreeMay be substituted with⁶Is hydrogen or (C₁~ C_Four) -Alkyl-O-CO-, compounds in the form of all stereoisomers and of their mixtures in all ratios, and their physiology
Pharmaceutically acceptable salts and their prodrugs.

Further preferred compounds of formula I are R^FiveIs (C₆~ C₁₄) -Aryl or (C_Five~ C ₁₄ ) -Heteroaryl, preferably (C₆~ C₁₄) -Aryl, wherein the aryl group and the heteroaryl group are unsubstituted in one, two or three
The same or different groups R^ThreeCompounds in the form of all stereoisomers and of their mixtures in all ratios, optionally substituted with
And their prodrugs. Further preferred compounds of formula I are^FiveIs a naphthyl group such as a 1-naphthyl group or a 2-naphthyl group (this is an unsubstituted group having 1, 2 or 3 groups R^ThreeMay be substituted, but is preferably unsubstituted like an unsubstituted 1-naphthyl group or an unsubstituted 2-naphthyl group.
Of all stereoisomeric forms and their mixtures in all ratios
And their physiologically acceptable salts, and their prodrugs.
You.

Preferred compounds of the formula I additionally have two groups R ⁴ O—CO— and R ⁵ —SO ₂ —
Compounds in the form of all stereoisomers and their mixtures in all ratios, and the physiologically acceptable salts thereof, wherein the carbon atom to which NH- is bonded has the S configuration.
And their prodrugs.

A specific group of compounds of formula I is that wherein R ¹ and R ² are such that: R ¹ and R ² independently of one another are hydrogen or unsubstituted or substituted by R ³ (C _1- Represents a C ₆ ) -alkyl, or R ¹ and R ² together represent a saturated or unsaturated divalent (C ₂ -C ₉ ) -alkylene group,
For example group - (CH _{2) p} - (wherein, p is a is 2,3,4,5,6,7,8 or 9) {the alkylene group representing the can be unsubstituted or substituted, 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₎ - a cycloalkyl, (C ₃ ~C ₁₂₎ - cycloalkyl - (C ₁ -C ₆₎ - alkyl - and may be substituted with one or more groups selected from the group consisting of oxo, Here, the 5- to 7-membered saturated or unsaturated ring may be unsubstituted or substituted with R ³ (particularly one or two groups R ³ ), and may be a carbocyclic ring. It may be a heterocyclic ring containing one or two ring nitrogen atoms, and may be condensed with the carbon-carbon bond in the (C ₂ -C ₉ ) -alkylene group. 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 Le -, halogen, trifluoromethyl, hydroxyl, oxo, nitro, amino, -NH- (C ₁ -C ₄₎ - _{alkyl, -N - ((C 1 ~C} 4) - alkyl) _{2, -N H-CO- (C 1 ~C} 4) - alkyl or -CO- (C ₁ ~C ₄₎ - alkyl, R ⁴ is hydrogen, (C ₁ ~C ₆₎ - alkyl -CO-O- (C ₁ -C ₄ ) -alkyl- or (C ₁ -C ₆ ) -alkyl, which, even if unsubstituted, is hydroxyl, (C ₁ -C ₄ ) -alkoxy,
(C ₁ -C ₄ ) -alkyl-S (O) ₂ —, NR ⁷ R ⁷ ′ and N ⁺ R ⁷ R ⁷ ′ R ⁷ ″ Q ⁻ (where R ⁷ , R ⁷ ′ and R ⁷ ″ are Independently of one another, 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 acceptable anion) or a group selected from the group consisting of:

Embedded image(Where the dashed line indicates the bond to which this group is attached)
Or R^FiveIs (C₁~ C₂₀) -Alkyl, (C_Five~ C₂₀) -Monocycloalkyl, (C_Five ~ C₂₀) -Bicycloalkyl, (C_Five~ C₂₀) -Tricycloalkyl, (C₆~ C ₁₄ ) -Aryl, (C_Five~ C₁₄) -Heteroaryl, (C₆~ C₁₄) -Aryl-
(C₁~ C₆) -Alkyl- or (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆) -Alkyl-, wherein an aryl group, a heteroaryl group, an alkyl group,
Nocycloalkyl group, bicycloalkyl group and tricycloalkyl group are
1, 2 or 3 unsubstituted groups R^ThreeAnd an alkyl group, a monocycloalkyl group, a bicycloalkyl group and a tricycloalkyl group.
One or more carbon atoms in the alkyl group (especially 1, 2, 3 or 4 carbon atoms)
At the same or different atoms selected from the group consisting of nitrogen, oxygen and sulfur
May be replaced, R⁶Is hydrogen, (C₁~ C₆) -Alkyl-O-CO-, hydroxyl, (C₁~ C ₆ ) -Alkyl-O-CO-O- or nitro compounds in all stereoisomeric forms and in their mixtures in all ratios, and their physiologically acceptable
And their prodrugs.

The present invention also relates to a process for preparing a compound of formula I. The compounds can generally be prepared by linking two or more fragments that can be derived retrosynthetically from Formula I, for example, in a convergent synthesis. In the preparation of the compounds of the formula I, during the course of the synthesis, functional groups which may lead to undesired reactions or side reactions in the respective synthesis steps are introduced in the form of precursors which are subsequently converted into the desired functional groups. Alternatively, it may be generally advantageous or necessary to either protect the functional group temporarily with a protecting group strategy appropriate for the synthesis problem. Such strategies are well known to those skilled in the art (eg, Greens and Wuts, Pr.
otective Groups in Organic Synthesis, Willey, 1991). Examples of precursor groups include nitro and cyano groups, which can later be converted to amino and aminomethyl groups, respectively, by reduction (eg, catalytic hydrogenation).

Compounds of formula I are for example of the formula II:

Embedded image (Can wherein, R ⁴ and R ⁵ are defined as described above for formula I, also, the functional groups may be present in the form of a precursor which is converted to groups present in the compound of Formula I after, The functional group can also be present in protected form, X being a nucleophilically displaceable leaving group) in a manner known per se of the formula III:

Embedded image (Wherein R ¹ , R ² and R ⁶ are as defined above for Formula I, and the functional group is present in the form of a precursor which can be subsequently converted to a group present in the compound of Formula I. Or the functional group can be present in a protected form) can be prepared by conjugation with guanidine or a guanidine derivative.

The group COX in the formula II is preferably a carboxylic acid group COOH or an activated carboxylic acid derivative. X is for example hydroxyl or a halogen, especially chlorine or bromine, alkoxy, preferably methoxy or ethoxy, aryloxy, for example phenoxy or pentafluorophenoxy, phenylthio, methylthio, 2-pyridylthio or a group of nitrogen heterocycle linked by a nitrogen atom And especially azoles such as 1-imidazolyl. X further represents, for example, ((C ₁ -C ₄ )
-Alkyl) -O-CO-O- or tolylsulfonyloxy,
Thus, the activated acid derivative can be a mixed anhydride.

When X is hydroxyl, ie when reacting a guanidine of the formula III with a carboxylic acid, the carboxylic acid is conveniently first activated. This activation is carried out, for example, by dicyclohexylcarbodiimide (DCCI) or O-((cyano (ethoxycarbonyl) methylene) amino) -1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) {Konig et al., Proc. . 21st Europ. Peptide Symp. 1
990 (Giralt, edited by Andreu), Escom, Leiden 1991, p. 143｝ or other activation reagents conventional in peptide chemistry.

In addition to the free guanidine of the formula III, guanidinium salts can also be used for the reaction with the compounds of the formula II, from which free guanidine is prepared in situ or in a separate step with a base. You. 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 manner known per se in a protic or aprotic polar (but inert) organic solvent. In this case, for example, in the reaction of a methyl ester (X = methoxy) or an ethyl ester (X = ethoxy) with a guanidine, a solvent such as methanol, isopropanol, t-butanol, dimethylformamide or tetrahydrofuran is heated to 0 ° C. to the boiling point of these solvents. It has been found suitable at temperatures up to. The reaction of a COX-type compound with a salt-free guanidine can be carried out in an aprotic inert solvent such as dimethylformamide, tetrahydrofuran, dimethoxyethane or dioxolane with a base such as potassium t-butoxide or sodium methoxide. It is advantageous to carry out with appropriate addition. However, when using a base such as, for example, sodium hydroxide, water can also be used as the solvent in the reaction of the compound of formula II with guanidine. When X is, for example, chlorine, the reaction is carried out with the addition of an acid scavenger (eg an additional base) or in the presence of an excess of guanidine (derivative) in order to couple with the resulting hydrohalic acid. It is advantageous. The reaction mixture is assembled and, if desired, the reaction product is then purified by conventional methods well known to those skilled in the art.

The protecting groups optionally still present in the products obtained from the compounds of the formulas II and III are then removed by standard methods. For example, a t-butyl ester group is converted to a carboxylic acid group by treatment with trifluoroacetic acid, a benzyl group is removed by hydrogenation, and a fluorenylmethoxycarbonyl group is removed by a secondary amine. If desired, a further reaction, such as an acylation reaction or an esterification reaction, is then carried out by standard methods. Furthermore, the conversion to a physiologically acceptable salt or prodrug can then be carried out by known methods.

The starting compounds of the formulas II and III, which are combined to give the compounds of the formula I, are also commercially available and can be prepared by methods described in the literature or by analogous forms thereof. The preparation of the starting compound of Formula II is illustrated by way of example in Scheme 1, but the invention is not limited to this synthesis or these starting components. Making the necessary changes to the indicated synthesis for the preparation of another compound according to the invention will not present any problem to those skilled in the art.

[0045]

Embedded image

Thus, the carboxybenzaldehyde of the formula IV is reacted with a malonic ester salt of the formula V, for example in the presence of pyridine and piperidine, to give a cinnamic acid derivative of the formula VI, for example in the presence of palladium on carbon. To give a compound of formula VII. After activating the carboxylic acid group, the compound of formula VII can be condensed with a 2,3-diaminopropionic acid derivative of formula VIII to give a compound of formula IX (Scheme 1). The condensation can be carried out, for example, in the presence of TOTU or other conventional carboxylic acid activators.

In formula VIII, Y can also be a group R ⁵ —SO ₂ — which can be present in the final compound of formula I according to the invention and subsequently remain in the molecule, temporarily protecting the amino group, after the standard procedures for the preparation of the removed with the free amino groups {which then sulfonamide in step (such as free amine of formula R ⁵ -SO ₂ -Cl It can also be a group that provides｝, which can be converted to R ⁵ —SO ₂ —NH (by reacting with sulfonyl chloride). One example of a protecting group represented by Y is a benzyloxycarbonyl group (Z group), which can be removed by catalytic hydrogenation. Sulfonyl chlorides of the formula R ⁵ —SO ₂ —Cl and other sulfonic acid derivatives suitable for introducing the groups R ⁵ —SO ₂ are also commercially available and can be obtained from procedures described in the literature or analogs thereof. Can also be prepared according to Instead of the t-butyl ester present in the compounds of the formulas VIII and IX, it can also be present in another ester which only protects the acid group temporarily or in the final compound of the formula I according to the invention. Another ester can be present which can remain in the molecule. Alternatively, analogous compounds of the compound of formula VI can be obtained by another method for converting a carbonyl group to an alkene, such as the Wittig reaction.

Compounds of formula IX are examples of compounds of formula II wherein X is methoxy. These compounds and analogous compounds obtained from the above synthesis and containing groups that are activated carboxylic acid derivatives can be reacted directly with compounds of formula III. However, the compounds obtained in the above synthesis are first converted to the corresponding carboxylic acids by cleaving under standard conditions the methyl ester group or another ester group present at the point of interest in the compound of formula IX. It can also be reacted with a guanidine of formula III after it has been activated in situ (eg by TOTU or DCCI) or converted to an activated carboxylic acid derivative. If it is intended to prepare, for example, carboxylic acid chlorides (formula II, X = Cl) as activated acid derivatives, this conversion can be carried out, for example, with thionyl chloride. If it is intended to prepare, for example, methyl esters (formula II, X = methoxy) from carboxylic acids, this can be carried out by treatment with hydrogen chloride gas in methanol. Other activated acid derivatives are derived from carboxylic acid chlorides or directly from their underlying carboxylic acids (Formula II, X = OH)
It can be prepared in a manner known per se. For example, treatment of an acid with carbonyldiimidazole affords imidazolides (Formula II, X = 1-imidazolyl). See Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962). Most often, mixed anhydrides are obtained, for example, by reaction with tosyl chloride in the presence of an amine such as triethylamine in an inert solvent or by reaction with a chloroformate such as ethyl chloroformate. A number of suitable methods for preparing activated carboxylic acid derivatives are described in J. March, Advanced Org.
Anic Chemistry, 3rd Edition, John Wiley & Sons, 1985, p. 350, along with details of the bibliography.

The compounds of the formula I are valuable pharmaceutically active ingredients and are suitable, for example, for the treatment and prevention of bone disorders, tumor diseases or cardiovascular disorders. The compounds of formula I and their physiologically acceptable salts and their prodrugs can be administered to animals, preferably mammals, especially humans, as therapeutic or prophylactic medicaments. They can be administered alone, in a mixture with one another, or in the form of pharmaceutical preparations. The pharmaceutical preparations may contain, in addition to conventional pharmaceutically harmless carriers and / or excipients, efficacious doses of at least one compound of the formula I and / or a physiologically acceptable salt and / or It contains the prodrug as an active ingredient and allows enteral or parenteral administration.

Accordingly, the present invention also relates to compounds of the formula I and / or their physiologically acceptable salts and / or their prodrugs for use as medicaments, and also to the above or below mentioned. And / or their physiologically acceptable salts and / or their prodrugs for the manufacture of a medicament for the treatment and prevention of diseases of the type described above, for example for the treatment and prevention of bone disorders or tumor diseases. It also relates to the use of the compounds of the formula I and / or their physiologically acceptable salts and / or their prodrugs for the treatment and prevention of these diseases. The invention further relates to pharmaceutical preparations comprising an effective amount of at least one compound of the formula I and / or a physiologically acceptable salt thereof and / or a prodrug thereof together with conventional pharmaceutically harmless carriers. It relates to a pharmaceutical composition.

These medicaments can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. However, by the rectal route, for example, in the form of suppositories, or parenterally, for example, by the intravenous, intramuscular or subcutaneous route, for example, in the form of injection or infusion solutions, microcapsules, implants or rods.
Or the administration can be effected transdermally or topically, for example in the form of an ointment, solution or tincture, or in other ways, for example in the form of an aerosol or nasal spray.

The pharmaceutical compositions according to the invention may be prepared in a manner known per se and well-known to the person skilled in the art, comprising a compound of the formula I and / or its (the) physiologically acceptable salts and / or its In addition to the (drug) prodrugs, pharmaceutically inert, inorganic and / or organic carriers are used. For the production of pills, tablets, coated tablets and hard gelatin capsules, for example, lactose, corn starch or derivatives thereof, talc,
Stearic acid or a salt thereof can be used. Soft gelatin capsules and suppository carriers include, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils, and the like. Suitable carriers for the production of solutions (eg injectable solutions) or emulsions or syrups include, for example, water, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oil and the like. Suitable carriers for microcapsules, implants or rods include, for example, copolymers of glycolic acid and lactic acid. Pharmaceutical formulations generally contain from about 0.5 to 90% by weight of the compounds of formula I and / or their physiologically acceptable salts and / or their prodrugs. The amount of the active ingredient of the formula I and / or its physiologically acceptable salts and / or its prodrugs in a pharmaceutical preparation is generally between 0.2 and 500 mg and between 1 and 200 mg Is preferred.

In addition to the active ingredient and carrier, pharmaceutical formulations include, for example, bulking agents, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorings, flavors or Fragrances, thickeners, diluents, buffering substances and solvents or solubilisers or additives to achieve a storage effect, and salts to alter the osmotic pressure, coatings,
Alternatively, an additive such as an antioxidant can be additionally contained. They can also contain two or more compounds of the formula I and / or their physiologically acceptable salts and / or their prodrugs. Furthermore, in addition to at least one compound of the formula I and / or its physiologically acceptable salts and / or its prodrugs, they can also contain one or more other therapeutically or prophylactically active ingredients. .

The compounds of formula I are antagonists of the vitronectin receptor and are inhibitors of cell adhesion. These have the ability, for example, to inhibit osteoclasts from binding to the bone surface, thereby inhibiting bone resorption by osteoclasts. The activity of the compounds of formula I can be demonstrated, for example, in assays measuring the inhibition of vitronectin binding to cells containing the vitronectin receptor. Details of such an analysis will be given later. Compounds of formula I and their physiologically acceptable salts and their prodrugs as vitronectin receptor antagonists are useful in cell-cell interaction processes or cell-cell interactions.
For the treatment and prevention of diseases based on the interaction between vitronectin receptors and their ligands in the substrate interaction process or diseases that can be affected by inhibition of this type of interaction, or inhibition of this type of interaction It is generally suitable for preventing, alleviating or treating the desired disease. As explained at the outset, such interactions play a role, for example, in bone resorption, angiogenesis or the proliferation of vascular smooth muscle cells. Thus, the compounds of formula I and their physiologically acceptable salts and their prodrugs may, for example, alleviate or alleviate diseases caused at least in part by undesired degrees of bone resorption, angiogenesis or vascular smooth muscle cell proliferation. Suitable for treatment.

Bone diseases in which the compounds of the formula I according to the invention can be used for the treatment and prevention include, in particular, osteoporosis, hypercalcemia, osteopenia (eg caused by metastasis), tooth disorders Periarticular erosion and Paget's disease in hyperparathyroidism, rheumatoid arthritis (rheumatoid arthritis). In addition, the compounds of formula I can be used for alleviating, avoiding or treating bone disorders caused by glucocorticoid, steroid or corticosteroid treatment or by deficiency of sex hormones. All of these disorders are characterized by bone loss, which is based on the imbalance between bone formation and bone destruction, which has an advantageous effect by inhibiting bone resorption by osteoclasts. Can exert. The compounds of the formula I and / or their physiologically acceptable salts and / or their prodrugs can also be used in combination with conventional osteoporosis treatments, for example in the treatment or prevention of osteoporosis, for example bisphosphonates, estrogens, estrogens / Progesterone, estrogen agonists / antagonists, calcitonin, vitamin D analogs, parathyroid hormone, growth hormone secretagogue or sodium fluoride can also be used advantageously as inhibitors of bone resorption. The administration of the compounds of formula I and / or their physiologically acceptable salts and / or their prodrugs and other active ingredients effective for treating or preventing osteoporosis, such as those listed above, may be concurrent or simultaneous. It can be performed sequentially in any order and can be performed together or separately. For use in such combination therapy or prophylaxis, compounds of formula I and / or their physiologically acceptable salts and / or their prodrugs and one or more other active ingredients such as those listed above Can be present together in a single pharmaceutical formulation (eg a tablet or a granule) or in two or more separate pharmaceutical formulations, in which case they are in a single package Or in two or more separate packages. The use of the compounds of formula I and / or their physiologically acceptable salts and / or their prodrugs in such combination therapy or prophylaxis and their use in the manufacture of a medicament for such combination therapy or prophylaxis is also described in the present invention. Covered by the invention. The invention further relates to the treatment or prevention of osteoporosis, such as those listed above for effective amounts of at least one compound of formula I and / or a physiologically acceptable salt thereof and / or a prodrug thereof. Or a pharmaceutical formulation comprising at least one other active ingredient effective in inhibiting bone resorption and a conventional pharmaceutically harmless carrier. The above description for pharmaceutical formulations applies analogously to such pharmaceutical combination formulations.

In addition to their use as inhibitors of bone resorption by osteoclasts, the compounds of formula I and their physiologically acceptable salts and their prodrugs are useful as inhibitors of tumor growth and metastasis. It can also be used as an inflammatory agent for the treatment or prevention of cardiovascular disorders such as arteriosclerosis or restenosis, or for the treatment or prevention of nephropathy or retinopathy such as diabetic retinopathy. The compounds of formula I and / or their physiologically acceptable salts and / or their prodrugs as inhibitors of tumor growth and metastasis can also be used to advantage in combination with conventional cancer treatments. Examples of conventional cancer treatments can be found in Bertino (Editor), Encyclopedia of Cance
r, given to Academic Press, 1997, please refer to this if necessary. All the foregoing statements regarding the use of compounds of formula I in combination with conventional treatments for osteoporosis, such as those relating to possible modes of administration and pharmaceutical combinations, are similar to the use of compounds of formula I in combination with conventional cancer treatments. Applied to

When using the compounds of the formula I, the dosages can be varied within wide limits and, as a rule, should in each case be adapted to the individual conditions. The dosage will depend, for example, on the compound employed, the nature and severity of the condition to be treated, whether to treat an acute condition, a chronic condition, or to prevent. In the case of oral administration, in order to achieve effective results in adults weighing about 75 kg, the daily dose is generally 0.01 to 100 mg / kg, and 0.1 to 50 mg / kg. Preferably, it is made 0.1 kg to 5 mg / kg, for example, 0.3 to 0.5 mg / kg (in each case, mg / kg of body weight). In the case of intravenous administration, the daily dose is generally about 0.01 to 100 mg / kg, and 0.05 to 10 mg / kg.
It is preferably mg / kg (in each case per kg of body weight).
The daily dose can be divided into several, for example 2, 3 or 4, divided doses, especially in the case of relatively large doses. As usual, depending on the individual behavior, the indicated 1
It may be necessary to increase or decrease the daily dose as appropriate.

In addition to their use as pharmaceutical active ingredients, the compounds of formula I can also be used as vehicles or carriers for the active ingredient to transport the active ingredient specifically to the site of action (targeting agents: eg Targeted Drug Delivery, RC Juliano, Handboo
k of Experimental Pharmacology, Volume 100, edited by GVR Born et al., Springer V
erlag). The active ingredients to be transported are those which can be used, in particular, for the treatment of the aforementioned diseases.

The compounds of the formula I and their salts can furthermore be used for diagnostic purposes in in vitro diagnostics and also in biochemistry where it is desired to block the vitronectin receptor or to influence cell-cell or cell-substrate interactions. Can be used as an aid in a technical investigation. They can also be used as synthetic intermediates for preparing other compounds, in particular other pharmaceutically active ingredients, which can be obtained from the compounds of the formula I, for example, by modification or introduction of substituents or functional groups.

EXAMPLES The products were identified by mass spectra (MS) and / or NMR spectra.
Depending on how the last synthesis step and / or work-up procedure (eg lyophilisation) were carried out, in some cases the compound may be partly or wholly in the form of a salt, for example acetate, trifluoroacetate or Obtained in the form of the hydrochloride.

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

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(A) 4- (2-methoxycarbonylvinyl) benzoic acid 18.74 g (0.12 mol) of malonic acid monomethyl potassium salt was added to pyridine 18
Suspended in milliliter. 15.01 g of 4-carboxybenzaldehyde (
0.1 mol) and 0.85 g (0.01 mol) of piperidine were added at room temperature with stirring. The mixture was refluxed until the evolution of CO ₂ was complete (about 2 hours), then a further 60 ml of pyridine were added and the mixture was stirred under reflux for a further hour. The reaction mixture was treated with 500 ml of ice and 110 ml of concentrated hydrochloric acid while stirring. After the addition was complete, the mixture was stirred for a further 20 minutes, the product was filtered off with suction, washed with water and recrystallized from isopropanol. Yield 12.85 g. ¹ H-NMR (200 MHz, d ₆ -DMSO): δ = 3.75 (s, 3 H, O
_{CH 3); 6.76 (d,} J = 15Hz, 1H, C H COOCH 3); 7.73 (
d, J = 15Hz, 1H, Ar-C H); 7.84 (d, J = 9Hz, 2H, A
7.98 (d, J = 9 Hz, 2H, Ar-H); 13.11 (s, wide, 1H, COOH). MS (CI ^<+> ): m / e = 207.2 (M + H ^< + ^> ). HPLC: RP18, Nucleosil 300-5-C18, 250 × 4 mm; 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: First 90% 5 minutes buffer A / 10% buffered agent B, then 90% buffer during 20 min B, then 5
Min 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
Suspend in 250 ml of dioxane and room temperature on Pd / C (10% concentration)
At 1 bar of hydrogen for 7 hours. The mixture is filtered and the solvent is removed under vacuum
Removed. Yield 8.05 g.¹H-NMR (200 MHz, d₆-DMSO): δ = 2.67 (t, J = 8H
z, 2H, CH _Two-COOCH_Three); 2.93 (t, J = 8 Hz, 2H, Ar-C) H _Two ); 3.59 (s, 3H, OCH)_Three); 7.35 (d, 2H, Ar-H);
. 86 (d, J = 9 Hz, 2H, Ar-H); 12.80 (s, wide, 1H, C
OOH). MS (CI⁺): M / e = 209.2 (M + H)⁺). HPLC: RP18, Nucleosil 300-5-C18, 250 × 4 mm; Buffer A: H_Two O, 0.1% TFA; buffer B: acetonitrile (80% v / v) / H_TwoO (20% v / v), 0.1% TFA; Gradient: 90% buffer A, 10% buffer for first 5 minutes
Impact B, then 90% Buffer B for 20 minutes, then 90% Buffer B for 5 minutes;
Flow rate 1 ml / min; R_t= 17.03 minutes.

(C) t-butyl (2S) -2-benzyloxycarbonylamino-3- (4- (2-methoxycarbonylethyl) benzoylamino) propionate 354 mg of 4- (2-methoxycarbonylethyl) benzoic acid ( 1.7 mmol) and 500 mg (1.7 mmol) of t-butyl (2S) -3-amino-2-benzyloxycarbonylaminopropionate are dissolved in 3 ml of dimethylformamide, and O-((cyano- (ethoxy) Carbonyl) -methylidene) amino) -1,1,3,3-tetramethyluronium tetrafluoroborate (T
OTU) 557 mg (1.7 mmol) and diisopropylethylamine 204
mg (1.7 mmol) and the mixture was stirred at room temperature at pH 7-8 for 7 hours. The solvent was removed under vacuum, the residue was dissolved in ethyl acetate, and the solution was washed three times with KHSO ₄ and NaHCO ₃ until neutral, respectively. The organic phase was separated, dried and the solvent was removed by distillation under vacuum. Yield 7
70 mg. MS (ES ^<+> ): m / e = 485.2 (M + H ^< + ^> ).

(D) (2S) -2-amino-3- (4- (2-methoxycarbonylethyl)
Benzoylamino) propionic acid t-butyl ester (2S) -2-benzyloxycarbonylamino-3- (4- (2-methoxycarbonylethyl) benzoylamino) propionic acid t-butyl 6.88 g (1
4.2 mmol) was dissolved in 200 ml of methanol, and 852 ml of acetic acid were dissolved.
g (14.2 mmol) was added. The mixture was hydrogenated over Pd / C (5% strength) at room temperature and 1 bar of hydrogen for 7 hours. The mixture was filtered and the solvent was removed under vacuum. The residue was washed with n-heptane and dried under vacuum. Yield @ Amount 6. 9g. MS (ES ^<+> ): m / e = 351.2 (M + H ^< + ^> ).

(E) (2S) -3- (4- (2-methoxycarbonylethyl) benzoylamino) -2- (naphthalene-1-sulfonylamino) propionic acid t-butyl ester (2S) -2-amino- 0.123 g (0.35 mmol) of 3- (4- (2-methoxycarbonylethyl) benzoylamino) propionic acid t-butyl ester was dissolved in 2 ml of dimethylformamide to give 0.1 ml of triethylamine.
Treated with 196 ml (1.4 mmol) 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 under vacuum, 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 under vacuum. The residue was chromatographed on silica gel, 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) propionic acid t-butyl ester (2S) -3- (4- (2-methoxycarbonylethyl) benzoylamino)
47 mg (0.087 mmol) of 2- (naphthalene-1-sulfonylamino) propionic acid ester was dissolved in 2 ml of dimethylformamide, and 86 mg of 2-amino-1,4,5,6-tetrahydropyrimidine ( 0.
87 mmol) was added. The reaction was stirred at room temperature for 20 hours. The solvent is removed under vacuum and the residue is chromatographed on silica gel, eluting with dichloromethane / methanol (1/1), then with dichloromethane / methanol /
Eluted with vinegar @ acid / water (85/15 / 1.5 / 1.5). 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 (2S) -2- (naphthalene-1-sulfonylamino) -3- (4- (2- (
45 mg (0.074 mmol) of 1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid were dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid were added. . The solution was stirred at room temperature for 3 hours. The solvent was removed under vacuum, toluene was added to the residue, which was then removed under vacuum. 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

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(A) (2S) -3- (4- (2-methoxycarbonylethyl) benzoylamino) -2- (quinoline-8-sulfonylamino) propionic acid t-butyl ester (2S) -2-amino- 0.123 g (0.35 mmol) of 3- (4- (2-methoxycarbonylethyl) benzoylamino) propionic acid t-butyl ester was dissolved in 2 ml of dimethylformamide to give 0.1 ml of triethylamine.
196 ml (1.4 mmol) and 8-quinoline sulfonyl chloride 0
. Treated with 159 g (0.7 mmol). The solution was stirred at room temperature for 4 hours. The solvent was removed under vacuum, 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 under vacuum. The residue was chromatographed on silica gel, 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) propionic acid t-butyl ester (2S) -3- (4- (2-methoxycarbonylethyl) benzoylamino)
-2- (quinoline-8-sulfonylamino) propionic acid t-butyl ester 6
5 mg (0.12 mmol) 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 is removed under vacuum and the residue is chromatographed on silica gel with dichloromethane / dichloromethane.
Elution with methanol (1/1) followed by dichloromethane / methanol / acetic acid /
Eluted with water (85/15 / 1.5 / 1.5). 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 (2S) -2- (quinoline-8-sulfonylamino) -3- (4- (2- (1
72 mg (0.11 mmol) of 4,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid t-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 under vacuum, toluene was added to the residue, which was then removed under vacuum. 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-acetylaminobenzenesulfonylamino) -3- (4-
(2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid

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(A) (2S) -2- (4-acetylaminobenzenesulfonylamino) -3
-(4- (2-methoxycarbonylethyl) benzoylamino) propionic acid t
-Butyl ester (2S) -2-Amino-3- (4- (2-methoxycarbonylethyl) benzoylamino) propionic acid 0.123 g (0.35 mmol) is dissolved in 2 ml of dimethylformamide. , Triethylamine 0.
Treated with 196 ml (1.4 mmol) and 0.164 g (0.7 mmol) of 4-acetylaminobenzenesulfonyl chloride. The solution was stirred at room temperature for 4 hours. The solvent was removed under vacuum, 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 under vacuum. The residue was chromatographed on silica gel, eluting with n-heptane / ethyl acetate (1/2). Yield 90 mg. MS (ES ^<+> ): m / e = 548 (M + H ^< + ^> ).

(B) (2S) -2- (4-acetylaminobenzenesulfonylamino) -3
-(4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid t-butyl ester (2S) -2- (4-acetylaminobenzenesulfonylamino) -3- (4
87 mg (0.16 mmol) of-(2-methoxycarbonylethyl) benzoylamino) propionic acid ester were dissolved in 1 ml of dimethylformamide, and 79 mg of 2-amino-1,4,5,6-tetrahydropyrimidine was dissolved.
g (0.8 mmol) was added. The reaction was stirred at room temperature for 20 hours. The solvent is removed under vacuum and the residue is chromatographed on silica gel, eluting with dichloromethane / methanol (1/1), then dichloromethane / methanol / acetic acid / water (85/15 / 1.5 / 1.5). Eluted. Yield 57 mg. MS (ES ^<+> ): m / e = 615.3 (M + H ^< + ^> ).

(C) (2S) -2- (4-acetylaminobenzenesulfonylamino) -3
-(4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid (2S) -2- (4-acetylaminobenzenesulfonylamino) -3- ( 4
-(2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)
Ethyl) benzoylamino) propionic acid t-butyl ester 57 mg (0.0
9 mmol) was dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid were added. The solution was stirred at room temperature for 3 hours. The solvent was removed under vacuum, toluene was added to the residue, which was then removed under vacuum. The residue was dissolved in acetonitrile / water (1/1) and lyophilized. Yield 42mg
. 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

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(A) 2-((1S) -1-t-butoxycarbonyl-2- (4- (2-methoxycarbonylethyl) benzoylamino) ethylsulfamoyl) benzoic acid methyl ester (2S) -2- 0.123 g (0.35 mmol) of amino-3- (4- (2-methoxycarbonylethyl) benzoylamino) propionic acid t-butyl ester was dissolved in 2 ml of dimethylformamide to give 0.1 ml of triethylamine.
Treated with 196 ml (1.4 mmol) 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 under vacuum, 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 under vacuum. The residue was chromatographed on silica gel, eluting with n-heptane / ethyl acetate (1/1). Yield 75mg
. MS (ES ^<+> ): m / e = 549 (M + H ^< + ^> ).

(B) (2S) -2- (2- (1,4,5,6-tetrahydropyrimidine-2)
-Ylcarbamoyl) benzenesulfonylamino) -3- (4- (2- (1,4
, 5,6-Tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid t-butyl ester 2-((1S) -1-t-butoxycarbonyl-2- (4- (2-methoxycarbonylethyl) 75 mg (0.13 mmol) of benzoylamino) ethylsulfamoyl) benzoic acid methyl ester was dissolved in 1 ml of dimethylformamide, and 68 mg of 2-amino-1,4,5,6-tetrahydropyrimidine (
0.69 mmol) was added. The reaction was stirred at room temperature for 20 hours. The solvent is removed under vacuum and the residue is chromatographed on silica gel, eluting with dichloromethane / methanol (1/1), then dichloromethane / methanol / acetic acid / water (85/15 / 1.5 / 1.5). Eluted. Yield 54 mg. MS (ES ^<+> ): m / e = 683.3 (M + H ^< + ^> ).

(C) (2S) -2- (2- (1,4,5,6-tetrahydropyrimidine-2)
-Ylcarbamoyl) benzenesulfonylamino) -3- (4- (2- (1,4
, 5,6-Tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid (2S) -2- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) benzenesulfonylamino) -3- (4- (2- (1,4,5,
54 mg (0.08 mmol) of 6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid were dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid were added. The solution was stirred at room temperature for 3 hours. The solvent was removed under vacuum, toluene was added to the residue, which was then removed under vacuum. The residue was treated with acetonitrile / water (
1/1) and lyophilized. Yield 34 mg. MS (ES ^<+> ): m / e = 627 (M + H ^< + ^> ).

General Procedure 1 (Synthesis of Compounds of Examples 5 to 24) Step a: Reaction with Sulfonyl Chloride (2S) -2-Amino-3- (4- (2-methoxycarbonylethyl) benzoylamino) propionic acid t 0.2 g of -butyl ester was dissolved 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 under vacuum, 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 under vacuum. The residue was chromatographed on silica gel with n-heptane /
Eluted with ethyl acetate (1/1).

Step b: Production 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 is removed in vacuo and the residue is chromatographed on silica gel in dichloromethane / methanol (1.
/ 1) followed by dichloromethane / methanol / acetic acid / water (85/15).
/1.5/1.5).

Step c: cleavage of t-butyl ester The product of step b was dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid were added. The solution was stirred at room temperature for 3 hours. The solvent was removed under vacuum, toluene was added to the residue, which was then removed under vacuum.
The residue was dissolved in acetonitrile / water (1/1) and lyophilized.

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

Embedded image

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

[Table 1]

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

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

[Table 2]

Example 7 (2S) -2- (2-phenylethenesulfonylamino) -3- (4- (2- (
1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid

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

[Table 3]

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

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

[Table 4]

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

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

[Table 5]

Example 10 (2S) -2- (4-butoxybenzenesulfonylamino) -3- (4- (2-
(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl)
Benzoylamino) propionic acid

Embedded image

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

[Table 6]

Example 11 (2S) -2- (2-cyanobenzenesulfonylamino) -3- (4- (2- (
1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid

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

[Table 7]

Example 12 (2S) -2- (7,7-Dimethyl-2-oxobicyclo [2.2.1] heptane-1-ylmethanesulfonylamino) -3- (4- (2- (1, 4,5,6-
Tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino)
Propionic acid

Embedded image

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

[Table 8]

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

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

[Table 9]

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

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

[Table 10]

Example 15 (2S) -3- (4- (2- (1,4,5,6-tetrahydropyrimidine-2-
Ilcarbamoyl) ethyl) benzoylamino) -2- (3-trifluoromethylbenzenesulfonylamino) propionic acid

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

[Table 11]

Example 16 (2S) -2- (4-methoxybenzenesulfonylamino) -3- (4- (2-
(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl)
Benzoylamino) propionic acid

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

[Table 12]

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

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

[Table 13]

Example 18 (2S) -3- (4- (2- (1,4,5,6-tetrahydropyrimidine-2-
Ilcarbamoyl) ethyl) benzoylamino) -2- (thiophen-2-sulfonylamino) propionic acid

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

[Table 14]

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

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

[Table 15]

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

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

[Table 16]

Example 21 (2S) -3- (4- (2- (1,4,5,6-tetrahydropyrimidine-2-
Ilcarbamoyl) ethyl) benzoylamino) -2- (2,4,6-trimethylbenzenesulfonylamino) propionic acid

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

[Table 17]

Example 22 (2S) -3- (4- (2- (1,4,5,6-tetrahydropyrimidine-2-
Ilcarbamoyl) ethyl) benzoylamino) -2- (4-trifluoromethylbenzenesulfonylamino) propionic acid

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

[Table 18]

Example 23 (2S) -2- (butane-1-sulfonylamino) -3- (4- (2- (1,4
, 5,6-Tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid

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

[Table 19]

Example 24 (2S) -2-methanesulfonylamino-3- (4- (2- (1,4,5,6-
Tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino)
Propionic acid

Embedded image

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

[Table 20]

General Procedure 2 (Synthesis of Compounds of Examples 25-27) Step a: Reaction with Sulfonyl Chloride (2S) -2-Amino-3- (4- (2-carboxyethyl) benzoylamino) propionic acid t- 0.1 g of butyl ester hydrochloride was added to dimethylformamide 3
Dissolved in milliliters and treated at 0 ° C. with 3 molar equivalents of diisopropylethylamine and 2 molar equivalents of the appropriate sulfonyl chloride. 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 hydrogen sulfate solution and once with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and the solvent was removed under vacuum. The residue was chromatographed on silica gel with dichloromethane / methanol / ethyl acetate / water (97.5 / 2.5 / 0.25 / 0.2).
Eluted in 5).

Step b: Formation of Acylguanidine The product of step a is dissolved in 2 ml of tetrahydrofuran and 1.2 molar equivalents of 2-amino-1,4,5,6-tetrahydropyrimidine, 4 molar equivalents of diisopropyl Ethylamine and 1.1 molar equivalents of O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate were added. The reaction was stirred at room temperature for 20 hours. The solvent was removed under vacuum, 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 under vacuum. The residue was chromatographed on silica gel with dichloromethane / methanol / acetic acid / water (8
5/15 / 1.5 / 1.5), then dichloromethane / methanol /
Eluted with acetic acid / water (9/1 / 0.1 / 0.1).

Step c: cleavage of t-butyl ester The product of step b was dissolved in 1.5 ml of trifluoroacetic acid / water (95/5). The solution was stirred at room temperature for 1 hour. The solvent is removed under vacuum,
Toluene was added to the residue, which was then removed under vacuum. The residue was dissolved in acetonitrile / water (1/1) and lyophilized.

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

Embedded image

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

[Table 21]

Example 26 (2S) -2-Chloromethanesulfonylamino-3- (4- (2- (1,4,5
, 6-Tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid

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The title compound was synthesized according to General Procedure 2 using chloromethanesulfonyl chloride in step a.

[Table 22]

Example 27 (2S) -3- (4- (2- (1,4,5,6-tetrahydropyrimidine-2-
Ilcarbamoyl) ethyl) benzoylamino) -2- (2,2,2-trifluoroethanesulfonylamino) propionic acid

Embedded image

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

[Table 23]

Example 28 (2S) -2- (4-t-butylbenzenesulfonylamino-3- (4- (2-
(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl)
Benzoylamino) propionic acid ethyl ester

Embedded image

(2S) -2- (4-t-butylbenzenesulfonylamino) -3- (4- (
700 mg of 2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid were dissolved in 100 ml of ethanol and 15 drops of concentrated sulfuric acid were added. The reaction solution was boiled for 3.5 hours. The solvent was removed under vacuum and 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 solution. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed under vacuum. The residue was dissolved in 2N hydrochloric acid. The hydrochloric acid was removed under vacuum and the residue was dissolved in acetonitrile and added to water. This mixture was lyophilized. Yield 480 mg. ^{MS (ES +): m /} e = 586.4 (M + H) +.

Example 29 (2S) -2- (4-t-butylbenzenesulfonylamino-3- (4- (2-
(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl)
Benzoylamino) propionic acid isopropyl ester

Embedded image

(2S) -2- (4-t-butylbenzenesulfonylamino) -3- (4- (
700 mg of 2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid were 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 under vacuum and 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 solution. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed under vacuum. The residue was dissolved in 2N hydrochloric acid. The hydrochloric acid was removed under vacuum and the residue was dissolved in acetonitrile and added to water. This mixture was lyophilized. Yield 444 mg. 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) benzoylamino) propionic acid ethyl ester

Embedded image

(2S) -2- (Naphthalene-1-sulfonylamino) -3- (4- (2- (
590 mg of 1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid were 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 under vacuum and 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 solution. The organic phase is dried over sodium sulfate,
Filter and remove the solvent under vacuum. The residue was dissolved in 2N hydrochloric acid. The hydrochloric acid was removed under vacuum and the residue was dissolved in acetonitrile and added to water. This mixture was lyophilized. Yield 381 mg. MS (ES ^<+> ): m / e = 580.3 (M + H) ^<+> .

Example 31 (2S) -2- (Naphthalene-1-sulfonylamino-3- (4- (2- (1,1
4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid isopropyl ester

Embedded image

(2S) -2- (Naphthalene-1-sulfonylamino) -3- (4- (2- (
1.5 g of 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 under vacuum and 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 solution. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed under vacuum. The residue was dissolved in 2N hydrochloric acid. The hydrochloric acid was removed under vacuum and the residue was dissolved in acetonitrile and added to water. This mixture was lyophilized. Yield 950 mg. MS (ES ^<+> ): m / e = 594.3 (M + H) ^<+> .

Example 32 (2S) -2- (Naphthalene-1-sulfonylamino-3- (4- (2- (1,
4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid isobutyl ester

Embedded image

(2S) -2- (Naphthalene-1-sulfonylamino) -3- (4- (2- (
600 mg of 1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid were 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 under vacuum and the residue was chromatographed on silica, 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 tests

The inhibition of bone resorption by the compounds according to the invention is described, for example, in WO 95/327.
It can be measured by an osteoclast resorption test (PIT ASSAY) similar to that described in pamphlet No. 10 (see if necessary).

The inhibitory activity of the compounds according to the invention on the vitronectin receptor α _v β ₃ can be determined, for example, as described below.

Tests to determine inhibition of 293 cell binding to human vitronectin (V
n / 293 cell test)

[0147] 1. Purification of human vitronectin Isolation of human vitronectin from human plasma and the method of Yatoyo et al. (Cell Structur
Purify by affinity chromatography according to e and Function, 1988, 23, 281-292).

[0148] 2. 293 cells, a cell test human embryonic kidney cell line, resulted in a co-transfected with DNA sequences for alpha _V and beta ₃ subunits of the vitronectin receptor alpha _V beta _3, high-speed expressed in accordance with FACS method (> 500000α _V β ₃ (Receptor / cell). Culturing the selected cells, obtained was fractionated again by FACS, stable cell lines with high expression rate than alpha _V beta ₃ 1000000 copies per cells (15D).

A flat-bottomed Linbro 96-well tissue culture plate was coated with human vitronectin in phosphate buffered saline (PBS) at 4 ° C. overnight (0.01 mg / min).
Ml, 0.05 ml / hole) and then 0.5% B
Block with SA (bovine serum albumin). Prepare a solution of 10 ⁻¹⁰ mol / l to 2 × 10 ⁻³ mol / l of test substance in DMEM medium containing glucose and in each case add this solution to the plate in an amount of 0.05 ml / well. I do. Cells expressing the alpha _V beta ₃ of high levels (e.g., 15D) are suspended in glucose-containing DMEM medium and adjusted to a cell 25000 content per medium 0.05 ml of this suspension. Add 0.05 milliliters of this cell suspension to each well and incubate the plate at 37 ° C for 90 minutes. The plate is washed three times with warm PBS to remove unbound cells. Unbound cells were treated with a citrate buffer (25 mM, pH 5.0) containing 0.25% Triton X-100.
Dissolve in 0). Then the hexose amidase substrate p-nitrophenyl-N
-Acetyl-β-D-glucosaminide is added and the plate is incubated at 37 ° C. for 90 minutes. The reaction was stopped with a glycine (50 mM) / EDTA (5 mM) buffer (pH 10.4), and the absorbance of each well was reduced to 405-6.
Measure at 50 nm. Data is analyzed according to standard methods.

The following results were obtained.

[Table 24]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 9/10 101 A61P 9/10 101 13/12 13/12 19/10 19/10 27/02 27 / 02 29/00 29/00 35/00 35/00 43/00 111 43/00 111 C07D 401/12 C07D 401/12 409/12 409/12 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU) , TJ, TM), AL, AM, AT, A U, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID , IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Anne Sylvain Payman Germany Day 65779 Kerkheim, Zeilsheimerstrasse 46 (72) Inventor David William Will Germany Day 65824 Schwa Lubach, Taunusstrasse 9a (72) Inventor Jochen Knorr Germany Republic of Germany Day 65830 Cliftel, Heechsterstrasse 21 (72) Inventor Karl Heinz Schoinemann Germany Day 65835 Leader Bach, Im Kohlurs 11 (72) Inventor Doni Carniato France F 91460 Markusi, Abnu de Retanneuf, 10 (72) Inventor Jean-François Gourbest France 77140 Clay Suiy, Rue de la Biblonne, 12 (72) Inventor Thomas Gadek United States 94611 California, Auckland, Chelsea Drive 2838 (72) Inventor Robert McDauer United States 94114 California, San Francisco , Church Street 1264 (72) Inventor Ceila Catherine Bordery United States 94066 California, San Bruno, Crestmoor Drive 3530 (72) Inventor Robert Andrew Cuthbertson Australia 3068 Victoria, North Fitzroy, Ray Street 75 F term (reference) 4C063 AA01 BB07 CC29 CC92 DD14 DD29 EE01 4C086 AA01 AA02 AA03 BC42 GA04 GA07 NA14 ZA33 ZA36 ZA45 ZA81 ZA97 ZB11 ZB26 AA FAB MA04 NA14 ZA33 ZA36 ZA45 ZA81 ZA97 ZB11 ZB26 ZC42

Claims (18)

[Claims] 1. Compounds of the formula I in the form of all stereoisomers or of their mixtures in all ratios, or their physiologically acceptable salts, or their prostheses.
Lodrug:[Wherein, R¹And R^TwoIs R¹And R^TwoAre independently of one another hydrogen or unsubstituted or R^Three(C₁~ C₆) -Alkyl, or¹-And R^Two-Together with a saturated or unsaturated divalent (C_Two~ C₉)-Alkyre
This alkylene group is halogen, (C₁~ C₆) -Al
Kill, (C₁~ C₆) -Alkoxy, (C₆~ C₁₄) -Aryl, (C₆~ C₁₄)-
Aryl- (C₁~ C₆) -Alkyl-, (C_Five~ C₁₄) -Heteroaryl, (C_Five ~ C₁₄) -Heteroaryl- (C₁~ C₆) -Alkyl-, (C_Three~ C₁₂) -Cycloalkyl, (C_Three~ C₁₂) -Cycloalkyl- (C₁~ C₆) -Alkyl- and oxo, optionally substituted with one or more groups selected from the group consisting of:
And a 5- to 7-membered saturated or unsaturated ring may be substituted with R^ThreeAnd may be a carbocyclic ring or a heterocyclic group containing one or two ring nitrogen atoms.
A cyclic ring;_Two~ C₉A) a carbon-carbon bond in the alkylene group;
Can also be condensed.^ThreeIs (C₁~ C_Ten) -Alkyl, (C_Three~ C₂₀) -Monocycloalkyl, (C_Five ~ C₂₀) -Bicycloalkyl, (C_Five~ C₂₀) -Tricycloalkyl, (C₁~ C ₈ ) -Alkoxy, (C₆~ C₁₄) -Aryl, (C₆~ C₁₄) -Aryl- (C₁ ~ C_Four) -Alkyl-, (C_Five~ C₁₄) -Heteroaryl, (C_Five~ C₁₄) -Heteroaryl- (C₁~ C_Four) -Alkyl-, halogen, trifluoromethyl, shea
, Hydroxyl, oxo, nitro, amino, -NH- (C₁~ C_Four) -Alkyl
, -N-((C₁~ C_Four) -Alkyl)_Two, -NH-CO- (C₁~ C_Four) -Alkyl or -CO- (C₁~ C_Four) -Alkyl; R^FourIs hydrogen, (C₁~ C₆) -Alkyl-CO-O- (C₁~ C_Four) -Alkyl- or (C₁~ C₆) -Alkyl ｛which, even if unsubstituted, is hydroxyl, (C₁~ C_Four) -Alkoxy,
(C₁~ C_Four) -Alkyl-S (O)_Two-, NR⁷R⁷’And N⁺R⁷R⁷'R⁷"Q^- (Where R⁷, R⁷’And R⁷"Are independently hydrogen, (C₁~ C₆) -Alkyl, (C_Five~ C₁₄) -Aryl or (C_Five~ C₁₄) -Aryl- (C₁~ C₆)
-Alkyl-, Q^-Is a physiologically acceptable anion), or may be substituted with a group selected from the group consisting of:(Where the dashed line indicates the bond to which this group is attached)
Or R^FiveIs (C₁~ C₂₀) -Alkyl, (C_Three~ C₂₀) -Monocycloalkyl, (C_Five ~ C₂₀) -Bicycloalkyl, (C_Five~ C₂₀) -Tricycloalkyl, (C₆~ C ₁₄ ) -Aryl, (C_Five~ C₁₄) -Heteroaryl, (C₆~ C₁₄) -Aryl-
(C₁~ C₆) -Alkyl- or (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆) -Alkyl-, wherein an aryl group, a heteroaryl group, an alkyl group,
Nocycloalkyl group, bicycloalkyl group and tricycloalkyl group are
1, 2 or 3 unsubstituted groups R^ThreeAnd an alkyl group, a monocycloalkyl group, a bicycloalkyl group and a tricycloalkyl group.
One or more carbon atoms in the alkyl group is selected from the group consisting of nitrogen, oxygen and sulfur.
R may be replaced by the same or different atoms⁶Is hydrogen, (C₁~ C₆) -Alkyl-O-CO-, hydroxyl, (C₁~ C ₆ ) -Alkyl-O-CO-O- or nitro]. 2. R¹And R^TwoIs hydrogen or, together with saturated or
Saturated divalent (C_Two~ C_Five) -Alkylene group;_Two~ C_Five) -Alkylene groups are unsubstituted, halogen, (C ₁ ~ C₆) -Alkyl, (C₁~ C₆) -Alkoxy, (C₆~ C₁₄) -Aryl, (C₆~ C₁₄) -Aryl- (C₁~ C₆) -Alkyl-, (C_Five~ C₁₄) -Hetero
Aryl, (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆) -Alkyl-, (C_Three ~ C₁₂) -Cycloalkyl, (C_Three~ C₁₂) -Cycloalkyl- (C₁~ C₆)-May be substituted with a group selected from the group consisting of alkyl- and oxo;
Here, the 5- to 7-membered saturated or unsaturated ring may be substituted with R^ThreeAnd may be a carbocyclic ring even if it contains one or two ring nitrogen atoms.
The ring may be a telocyclic ring,_Two~ C_Five) -Carbon-carbon bond in alkylene group
Can also be condensed with^ThreeIs (C₁~ C_Ten) -Alkyl, (C_Three~ C₂₀) -Monocycloalkyl, (C_Five ~ C₂₀) -Bicycloalkyl, (C_Five~ C₂₀) -Tricycloalkyl, (C₁~ C ₈ ) -Alkoxy, (C₆~ C₁₄) -Aryl, (C_Five~ C₁₄) -Heteroaryl, (C₆~ C₁₄) -Aryl- (C₁~ C_Four) -Alkyl-, (C_Five~ C₁₄)-Hete
Lower aryl- (C₁~ C_Four) -Alkyl-, halogen, trifluoromethyl, shea
No, oxo, -N-((C₁~ C_Four) -Alkyl)_TwoOr -NH-CO- (C₁~ C_Four ) -Alkyl; R^FourIs hydrogen or (C₁~ C₆) -Alkyl, wherein the alkyl is (C)₁~ C_Four) -Alkoxy, (C₁~ C_Four) -Alkyl-S
(O)_Two-And NR⁷R⁷’(Where R⁷And R⁷′ Independently of one another are hydrogen or (C₁~ C_Four) -Alkyl
R) may be substituted with a group selected from the group consisting of^FiveIs (C₁~ C₂₀) -Alkyl, (C_Three~ C₂₀) -Monocycloalkyl, (C_Five ~ C₂₀) -Bicycloalkyl, (C_Five~ C₂₀) -Tricycloalkyl, (C₆~ C ₁₄ ) -Aryl, (C_Five~ C₁₄) -Heteroaryl, (C₆~ C₁₄) -Aryl-
(C₁~ C₆) -Alkyl- or (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆) -Alkyl-, wherein an aryl group, a heteroaryl group, an alkyl group,
Nocycloalkyl group, bicycloalkyl group and tricycloalkyl group are
1, 2 or 3 unsubstituted groups R^ThreeMay be substituted with⁶Is hydrogen or (C₁~ C₆2. A compound according to claim 1, which is in the form of all stereoisomers of formula I or a mixture thereof in all ratios, or a physiologically acceptable salt thereof, or) -alkyl-O-CO-. Prodrugs of them. 3. R¹And R^TwoIs hydrogen or, together with saturated or
Saturated divalent (C_Two~ C_Four) -Alkylene group;_Two~ C_Four) -Alkylene groups are unsubstituted, halogen, (C ₁ ~ C₆) -Alkyl, (C₁~ C₆) -Alkoxy, (C₆~ C₁₄) -Aryl, (C₆~ C₁₄) -Aryl- (C₁~ C₆) -Alkyl-, (C_Five~ C₁₄) -Hetero
Aryl, (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆) -Alkyl-, (C_Three ~ C₁₂) -Cycloalkyl, (C_Three~ C₁₂) -Cycloalkyl- (C₁~ C₆)-May be substituted with a group selected from the group consisting of alkyl- and oxo;
Here, the 5- to 7-membered saturated or unsaturated ring may be substituted with R^ThreeAnd may be a carbocyclic ring even if it contains one or two ring nitrogen atoms.
The ring may be a telocyclic ring,_Two~ C_Four) -Carbon-carbon bond in alkylene group
Can also be condensed with^ThreeIs (C₁~ C_Four) -Alkyl, (C_Three~ C_Ten) -Monocycloalkyl, (C_Five ~ C₁₂) -Bicycloalkyl, (C_Five~ C₁₂) -Tricycloalkyl, (C₁~ C _Four ) -Alkoxy, (C₆~ C₁₄) -Aryl, (C₆~ C₁₄) -Aryl- (C₁ ~ C_Four) -Alkyl-, halogen, trifluoromethyl, cyano, oxo, -N-((C₁~ C_Four) -Alkyl)_TwoOr -NH-CO- (C₁~ C_Four) -Alkyl;^FourIs hydrogen or (C₁~ C₆) -Alkyl; R^FiveIs (C₁~ C_Ten) -Alkyl, (C_Three~ C₁₅) -Monocycloalkyl, (C_Five ~ C₁₅) -Bicycloalkyl, (C_Five~ C₁₅) -Tricycloalkyl, (C₆~ C ₁₄ ) -Aryl, (C_Five~ C₁₄) -Heteroaryl, (C₆~ C₁₄) -Aryl-
(C₁~ C₆) -Alkyl- or (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆) -Alkyl-, wherein an aryl group, a heteroaryl group, an alkyl group,
Nocycloalkyl group, bicycloalkyl group and tricycloalkyl group are
1, 2 or 3 unsubstituted groups R^ThreeMay be substituted with⁶Is hydrogen or (C₁~ C_FourOr a physiologically acceptable salt thereof, wherein the compound is in the form of all stereoisomers of formula I or a mixture thereof in all ratios, or a physiologically acceptable salt thereof. Or their prodrugs. 4. R¹And R^TwoIs hydrogen or, together with saturated or
Saturated divalent (C_Two~ C_Three) -Alkylene group;_Two~ C_Three) -Alkylene groups are unsubstituted, halogen, (C ₁ ~ C₆) -Alkyl, (C₁~ C₆) -Alkoxy, (C₆~ C₁₄) -Aryl, (C₆~ C₁₄) -Aryl- (C₁~ C₆) -Alkyl-, (C_Five~ C₁₄) -Hetero
Aryl, (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆) -Alkyl-, (C_Three ~ C₁₂) -Cycloalkyl, (C_Three~ C₁₂) -Cycloalkyl- (C₁~ C₆)-May be substituted with a group selected from the group consisting of alkyl- and oxo;
Here, the 5- to 7-membered saturated or unsaturated ring may be substituted with R^ThreeAnd may be a carbocyclic ring even if it contains one or two ring nitrogen atoms.
The ring may be a telocyclic ring,_Two~ C_Three) -Carbon-carbon bond in alkylene group
Can also be condensed with^ThreeIs (C₁~ C_Four) -Alkyl, (C_Three~ C_Ten) -Monocycloalkyl, (C_Five ~ C₁₂) -Bicycloalkyl, (C_Five~ C₁₂) -Tricycloalkyl, (C₁~ C _Four ) -Alkoxy, (C₆~ C₁₄) -Aryl, halogen, trifluoromethyl,
Cyano, oxo, -N-((C₁~ C_Four) -Alkyl)_TwoOr -NH-CO- (C₁~
C_Four) -Alkyl; R^FourIs hydrogen or (C₁~ C₆) -Alkyl; R^FiveIs (C₁~ C_Ten) -Alkyl, (C_Three~ C₁₅) -Monocycloalkyl, (C_Five ~ C₁₅) -Bicycloalkyl, (C_Five~ C₁₅) -Tricycloalkyl, (C₆~ C ₁₄ ) -Aryl, (C_Five~ C₁₄) -Heteroaryl, (C₆~ C₁₄) -Aryl-
(C₁~ C₆) -Alkyl- or (C_Five~ C₁₄) -Heteroaryl- (C₁~ C₆) -Alkyl-, wherein an aryl group, a heteroaryl group, an alkyl group,
Nocycloalkyl group, bicycloalkyl group and tricycloalkyl group are
1, 2 or 3 unsubstituted groups R^ThreeMay be substituted with⁶Is hydrogen or (C₁~ C_Four4) Compounds in the form of all stereoisomers of formula I or their mixtures in all ratios, or their physiological properties, according to any of claims 1 to 3, which are -alkyl-O-CO-. Acceptable salts or their pros
drag. 5. R ⁵ is (C ₆ -C ₁₄ ) -aryl or (C ₅ -C ₁₄ ) -heteroaryl, wherein the aryl and heteroaryl groups are 1, 2 even if they are unsubstituted. Or in the form of all stereoisomers of formula I or their mixtures in all ratios according to any of claims 1 to 4, which may be substituted by ^three groups R3. A compound, or a physiologically acceptable salt thereof, or a prodrug thereof. 6. The compound according to claim 1, wherein R ⁵ is a naphthyl group, or a compound thereof in the form of all stereoisomers of the formula I or mixtures thereof in all ratios. Physiologically acceptable salts or prodrugs thereof. 7. (2- (R ⁵ -sulfonylamino) -3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid (wherein , 2- (R ⁵ - sulfonylamino) substituent, benzenesulfonyl amino, 4-(n-propyl) benzenesulfonylamino, 4-t-butyl-benzenesulfonylamino, 2,4,6-trimethylbenzene sulfonylamino, 4-methoxybenzenesulfonylamino, 4- (n-butoxy) benzenesulfonylamino, 3-chlorobenzenesulfonylamino, 4-chlorobenzenesulfonylamino, 3-trifluoromethylbenzenesulfonylamino, 4-trifluoromethylbenzenesulfonylamino, 4-acetylaminobenzenesulfonylamido No, 2-cyanobenzenesulfonylamino, naphthalene-1-sulfonylamino,
Naphthalene-2-sulfonylamino, biphenyl-4-sulfonylamino, thiophen-2-sulfonylamino, quinoline-8-sulfonylamino, methanesulfonylamino, propane-1-sulfonylamino, propane-2-sulfonylamino, butane-1- Sulfonylamino, 2-methylpropane-1-sulfonylamino, chloromethanesulfonylamino, 2,2,2-trifluoroethanesulfonylamino, 7,7-dimethyl-2-oxobicyclo [2.2.1] heptane-
Selected from the group consisting of 1-ylmethanesulfonylamino and 2-phenylethanesulfonylamino) or any of the stereoisomers of formula I according to any of claims 1-4. A compound in the form of their mixture in ratio, or a physiologically acceptable salt thereof,
Or its prodrug. 8. (2S) -2- (naphthalene-1-sulfonylamino) -3
- (4- (2- (1,4,5,6-tetrahydronaphthalen-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid or its (C ₁ -C ₄₎ - alkyl ester, according to claim 1 A compound of the formula I according to any one of the above, or a physiologically acceptable salt thereof, or a prodrug thereof. 9. (2S) -2- (naphthalene-1-sulfonylamino) -3
A compound of formula I according to any of the preceding claims, which is-(4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid. Or a physiologically acceptable salt thereof. 10. (2S) -2- (naphthalene-1-sulfonylamino)-
Formula I according to any of the preceding claims, which is 3- (4- (2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) benzoylamino) propionic acid ethyl ester. Or a physiologically acceptable salt thereof. 11. A process for the preparation of a compound of formula I according to any of the preceding claims, comprising combining two or more fragments which can be derived retrosynthetically from formula I. 12. The following formula II: (Where R ⁴ and R ⁵ are defined as in any of claims 1 to 10 and the functional group can be present in precursor form or in protected form; A carboxylic acid or a carboxylic acid derivative of the formula: (Where R ¹ , R ² and R ⁶ are defined as in any of claims 1 to 10 and the functional groups can be present in precursor form or in protected form The method according to claim 11, wherein the reaction is carried out with guanidine or a guanidine derivative. 13. A compound of formula I or a physiologically acceptable salt thereof or a prodrug thereof according to claim 1 for use as a medicament. 14. A composition according to claim 1, comprising at least one compound of the formula I and / or a physiologically acceptable salt thereof and / or a prodrug thereof together with a pharmaceutically harmless carrier. Pharmaceutical formulations. 15. A compound of formula I or a physiologically acceptable salt thereof or a prodrug thereof according to any one of claims 1 to 10, for use as a vitronectin receptor antagonist. 16. A compound of the formula I according to any one of claims 1 to 10, or a physiologically acceptable salt thereof or a prodrug thereof, for use as an inhibitor of bone resorption or for treating or preventing osteoporosis. . 17. A compound of formula I or a physiologically acceptable salt thereof or a prodrug thereof according to any one of claims 1 to 10, for use as an inhibitor of tumor growth or metastasis. 18. An anti-inflammatory agent or as a cardiovascular disorder, restenosis, arteriosclerosis,
A compound of formula I or a physiologically acceptable salt thereof or a prodrug thereof according to any one of claims 1 to 10, for use in treating or preventing nephropathy or retinopathy.