NO314583B1 - Substituted purine derivatives, methods of preparation and pharmaceutical compositions containing them - Google Patents

Description

The present invention relates to compounds of formula I

where X, Y, W and G have the given meanings, as well as their physiologically tolerable salts, preparation thereof and pharmaceutical preparations containing these.

Compounds of formula I are valuable active pharmaceutical ingredients. They are particularly vitronectin receptor antagonists and are suitable for therapy and prophylaxis of diseases that depend on the interaction between vitronectin receptors and their ligands at cell

cell or cell-matrix infarct processes or which by means of the influence of this interaction can be prevented, alleviated or cured. The invention relates, among other things, to the use of compounds of formula I as well as their physiologically tolerable salts and pharmaceutical preparations thereof, which contain such compounds, as medicine for the prevention, alleviation or treatment of diseases, which are at least partially conditioned by an undesirable measure of bone resorption, angiogenesis or proliferation of cells in vascular smooth muscle, or for therapy or prophylaxis in terms of influencing these processes. Compounds of formula I are particularly suitable, for example, as inhibitors of bone resorption, as inhibitors of tumor growth and tumor metastasis, as inflammation inhibitors, for the treatment or prophylaxis of cardiovascular diseases, such as arteriosclerosis or restenosis, or for the treatment or prophylaxis of nephropathies and retinopathies, such as for example diabetic retinopathies.

The compounds according to the invention with formula I inhibit bone resorption through osteoclasts. Bone diseases, against which the compound of formula I can be used, are above all osteoporosis, hypercalcemia, osteopenia, as for example accentuated by metastases, dental diseases, hyperparathyroidism, periarticular erosions in rheumatoid arthritis and Paget's disease. Furthermore, the compound of formula I can be used for the alleviation, avoidance or therapy of bone diseases, which become necessary with glucocorticoid, steroid or corticosteroid therapy or with a lack of sex hormones. All of these diseases are characterized by bone loss, which is due to a lack of balance between bone formation and bone breakdown.

Human bones are subject to a constantly dynamic remodeling process that includes bone resorption and bone building. These processes are controlled by specialized cell types. Bone formation depends on the deposition of the bone matrix through osteoblasts, bone resorption depends on the breakdown of bone matrix through osteoclasts. The majority of bone diseases are due to a disturbed balance between bone formation and bone resorption. Osteoporosis is characterized by a loss of bone matrix. Activated osteoclasts are multinucleated cells with an average of up to 400 µm that remove the bone matrix. Activated osteoclasts deposit on the surface of the bone matrix and secrete the proteolytic enzyme and acid in the so-called "sealing zone", the area between their cell membrane and the bone matrix. The acidic environment and the protease cause the breakdown of bone.

Studies have shown that the deposition of osteoclasts on bone is controlled by integrin receptors on the cell surface of osteoclasts. Integrin is a superfamily of receptors to which, among other things, fibrinogen receptor ambp3 on platelets and vitronectin receptor ayp3 belong.

The vitronectin receptor avp3 is a membrane-containing glycoprotein that is expressed on the cell surface of a number of cells such as endothelial cells, vascular smooth muscle cells, osteoclasts and tumor cells. The vitronectin receptor avp3, which is expressed on the osteoclast membrane, controls the process of bone deposition and bone resorption and leads to osteoporosis. ayp3 consequently binds to bone matrix proteins such as osteopontin, bensialo-protein and thrombospontin that contain the tripeptide motif Arg-Gly-Asp (or RGD).

Horton et al have described RGD peptides and antivitronectin receptor antibody (23C6) which inhibit the tooth formation of osteoclasts and the migration of osteoclasts (Horton et al, Exp. Cell. Rest. 1991,195,368). Sato et al describe in J. Cell Biol. 1990, 111,1713 Echistatin, an RGD peptide from snake venom, as potent inhibitors of bone resorption in a tissue culture and as inhibitor of osteoclast attachment on bone. Fischer et al (Endocrinology 1993,132,1411) have shown in rats that echistatin inhibits bone resorption also in vivo. Wayne et al (J. Clin. Invest. 1997, 99, 2284) have shown in rats the in vivo activity of inhibiting bone resorption through a vitronectin receptor antagonist.

Vitronectin receptor avPj on human aortic vascular smooth muscle cells stimulates migration of these cells into the neointima, which ultimately leads to arteriosclerosis and restenosis after angioplasty (Brown et al, Cardiovascular Res. 1994,28, 1815).

Brooks et al (Cell 1994,79,1157; J. Clin. Invest. 96 (1995) 1815) as well as Mitjans et al, J. Cell Science 1995,108,2825) show that antibodies against avfb or avP3 antagonists cause a shrinkage of tumors, as they induce the apoptosis of blood vessel cells during angiogenesis. Cheresh et al (Science 1995,270,1500) describe anti-avP3 antibodies avp3 antagonists that inhibit bFGF-induced angiogenesis processes in rat eyes, and this can be exploited therapeutically in the treatment of retinopathies.

From EP-A-0 528 586 and EP-A-0 528 587 aminoalkyl- or hetercyclyl-substituted phenylalanine derivatives, from EO 95/32710 aryl derivatives as inhibitors of bone resorption through osteoclasts are known. IWO 95/28426 RGD peptides are described as inhibitors of bone resorption, angiogenesis and restenosis. In WO 96/00574 and WO 96/26190, benzodiazepines are described, among other things, as vitronectin receptor antagonists and integrin receptor antagonists, respectively. In EO 96/00730, fibrinogen receptor antagonist templates, in particular benzodiazepines, which are linked to pure nitrogen-bearing 5-rings, are described as vitronectin receptor antagonists. In EP-A-0 531 883, condensed 5-membered heterocycles are described and these inhibit fibrinogen binding to thrombocytes.

Subject matter according to the present invention are compounds with the formulas I

where: G means a residue of formula II

W means a residue of formula III

A means -CH 2 -or where X means phenyl or adamantyl; R<4> means NHR<3> where R<3> means or dihydroimidazolyl; or CO2R<2> where D means -A-, -C3-C7-cycloalkylene-, -phenylene-,

E means hydrogen, C1-C6-alkyl, phenyl-C1-C6-alkyl, dihydroimidazolyl,

benzimidazolyl or tetrahydropyrimidyl;

n means 0, 1, 2, 3, 4 or 5;

m means 0, 1, 2, 3, 4 or 5;

and their physiologically tolerable salts.

All residues and indices, which may occur several times in the compounds of formula I, may independently have the indicated meanings. They can be the same or different. Likewise, substituents in residues, which may be present several times, can independently have the indicated meanings and be the same or different.

The alkyl radicals present in the substituents can be linear or branched, saturated or one or more times unsaturated. This also applies when they carry substituents or act as substituents of other residues. The same applies to divalent alkyl residues.

Examples of suitable (Ci-CéJ alkyl residues are: methyl, ethyl, propyl, butyl, pentyl, hexyl, the n-isomers of these residues, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, sec-butyl, tert- butyl, tert-pentyl Preferred alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

Unsaturated alkyl radicals are, for example, alkenyl radicals such as vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl or alkynyl radicals such as ethynyl, 1-propynyl or propargyl. The alkylene and alkylene residues can be linear and branched. Examples of alkylene residues are vinylene or propylene, for alkynyl residues ethynylene or propynylene.

The cycloalkyl residues can be monocyclic, bicyclic or tricyclic. Monocyclic cycloalkyl radicals are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The compounds according to the invention with the formula I are optionally available as E/Z isomers. Both pure E isomers and pure Z isomers and also E/Z isomer mixtures in all ratios are the subject of the present invention. The compounds of formula I may contain optically active carbon atoms, which may independently have R or S configuration. They can exist in the form of pure enantiomers or pure diastereomers or in the form of enantiomer mixtures, for example in the form of racemates, or diastereomer mixtures. Both pure enantiomers and enantiomer mixtures in all ratios and also diastereomers and diastereomer mixtures in all ratios are the subject of the present invention. Diastereomers, including E/Z isomers, can for example be separated by chromatography into single isomers. Racemates can, for example, be separated by chromatography in chiral phases or by racemate resolution into both enantiomers. In the presence of mobile hydrogen atoms, the present origin also includes all tautomeric forms of compounds with formula I.

Physiologically tolerable salts of compounds of formula I are particularly pharmaceutically usable or non-toxic physiologically usable salts.

Of compounds with formula I, which contain acid groups, for example carboxy, such salts are for example alkali metal salts or alkaline earth metal salts such as sodium salts, potassium salts, magnesium salts and calcium salts as well as salts with physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines, such as triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine.

Compounds of formula I, which contain basic groups, for example one or more amino groups, amidino groups or guanidino groups, form acid addition salts, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic acids and sulphonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid , tartaric acid, methanesulfonic acid or p-toluenesulfonic acid.

Salts can be obtained according to methods known to those skilled in the art from compounds with

formula I, for example by combining compounds of formula I with an inorganic or organic acid or base in a solvent or dispersant, or also by cation exchange or anion exchange from other salts. The present invention also includes all salts of compounds of formula I, which, due to poor physiological tolerance, do not

are directly suitable for use in pharmaceuticals, but as, for example, intermediate products for carrying out further chemical modifications of compounds of formula I or as starting materials for the production of physiologically tolerable salts.

The compounds according to the present invention can exist as all possible solvates of the compounds of formula I, for example hydrates or adducts with alcohols, as well as derivatives of the compounds of formula I, for example esters, prodrugs and metabolites that act like the compounds of formula I. Subject matter according to the invention is particularly prodrugs of some compounds of formula I which are converted under physiological conditions to compounds of formula I. Suitable prodrugs for compounds of formula I, i.e. chemically modified derivatives of the compounds of formula I with desired improved properties, are known to the person skilled in the art. Further details regarding prodrugs are, for example, described by Fleisher et al, Advanced Drug Delivery Reviews 10 (1996) 115-130; Design of Prodrugs, H. Bundgaaard, Ed Elsevier, 1985; H. Bundgaard, Drugs of the Future 16 (1991) 443; Saulnier et al., Bioorg. With. Chem. Easy. 4 (1994) 1985; Safadi et al., Pharmaceutical Res. 10 (1993) 1350. As prodrugs for the compounds with the formulas I and Ia, ester prodrugs of acid groups, for example carboxylic acid groups, especially the COOH group standing for R4, as well as acyl prodrugs and carbamate prodrugs of acylatable nitrogen-containing groups such as amino groups, amidino groups or guanidino groups come into consideration in particular. In acyl pro-drugs or carbamate pro-drugs, one or more times, for example twice, in this group one hydrogen atom present at the nitrogen atom is replaced by an acyl group or carbamate group. As acyl groups and carbamate groups for the acyl prodrugs and carbamate prodrugs, for example, the groups R<6->CO and R<6>0-CO come into consideration, where R6 has the meaning hydrogen, (Ci-CigJ-alkyl, (C3-C14)-cycloalkyl , (C3-Ci4)-cycloalkyl-(Ci-Cg)-alkyl, (Cs-CuJ-aryl, where 1 to 5 carbon atoms may be replaced by heteroatoms such as N, O, S, or (C5-Ci4)-aryl- (C1-C8)-alkyl, where the aryl part can be replaced with 1 to 5 carbon atoms by heteroatoms such as N, O, S, combinations of the substituent meanings which in individual cases lead to unstable compounds, for example to unstable free carbamic acids, not taken into account Preparation of these prodrugs can be carried out according to conventional methods for the preparation of acylamines and carbamates known to those skilled in the art.

A preferred group of compounds according to the invention is formed by compounds of formula I, where:

G means a residue of formula II

W means a residue of formula III

where X means phenyl or adamethyl

R<4> means CO2R2, where R2 means H or C1-C6-alkyl,

B means -S-, -NH-, a direct bond or a piperidyl or imidazolyl group;

D means -A-, -C3-C7-cycloalkylene-, -phenylene-, -1

-CO2-, -CO-NH-(CH2)„-NH-, -NHCO- or -Ph-NH-CO-NH-; E means hydrogen or a residue from the series

n means 0, 1, 2, 3 or 4;

m means 0 or 1;

and physiologically tolerable salts.

A further group of preferred compounds is formed by compounds of formula I, where:

G means a residue of formula II

W means a residue of formula HI A means-CH2-or

where X is phenyl or adamantyl;

R<4> means CO2R2, where R2 means H or C1-C6 alkyl,

B means -S-, -NH-, a direct bond or a piperidyl or imidazolyl group;

D means a -NH-, -C(O)-NH- or -NH-C(O)-;

E means hydrogen or a residue from the series

n means 1,2,3 or 4;

m means 0 or 1;

and physiologically tolerable salts thereof.

Particularly preferred are compounds of formula I, in which:

G means a residue of formula II

W means a residue of formula nine

A means -CH2-;

R<4> means CO2R<2>, where R2 means H or C1-C4 alkyl,

B means 1,4-piperidinyl to which the nitrogen atom of the piperidine is attached

the purine lattice;

D means -NH-, -C(O)-NH- or -NH-C(O)-;

E means hydrogen or a residue from the series

n means 1, 2, 3 or 4;

m means 0 or 1;

and physiologically tolerable salts thereof.

Particularly preferred are further compounds of formula I where:

G means a residue of formula II

W means a residue of formula nine

A means - CH2-\

R<4> means CO2R<2>, where R2 means H or C1-C4 alkyl,

B means 1,4-piperidinyl, the nitrogen atom of the piperidine being bound to the purine lattice;

D means -NH-, -C(0)-NH-, the group -C(0)-NH- being the nitrogen atom bound to

group E;

E means a remainder from the series

n means 0 or 1;

m means 0;

and physiologically tolerable salts thereof.

Particularly preferred compounds according to the invention are compounds of formula Ih, where R<3> -NH-C(0)-0-CH2X where X means phenyl or adamantyl, Rh means the carboxylic acid group COOH or means a carboxylic acid derivative; in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts as well as their prodrugs thereof.

Compounds of formula I can generally, for example in the course of a convergent synthesis, be prepared by linking two or more fragments which can be retrosynthetically derived from formula I. When preparing the compounds of formula I, it can generally be advantageous during the synthesis or necessary and insert functional groups which during the synthesis step can lead to unwanted reactions or side reactions, in the form of advantages, which can later be transferred to desired functional groups, or functional groups which through a protecting group strategy adapted to the synthesis problem are temporarily blocked, as known for those skilled in the art (Greene, Wuts, Protective Groups in Organic Synthesis, Wiley, 1991).

The invention therefore relates to a method for producing a compound of formula I according to the invention, characterized by connecting one or more fragments which can be retrosynthetically derived from formula I.

The present invention also relates to a method for producing the compounds of formula I, which is characterized by one or more of the following steps for building up compounds of formula I are carried out.

al) A compound with formal V,

where

LI means a common leaving group known to those skilled in the art, for example chlorine, bromine,

iodine, OTos or OMes, preferably chlorine or bromine, and

is reacted with a compound of formula V,

where

A, n and m are defined as above,

R<10> is defined as the group R4 above, but is optionally protected with a protecting group, for example R<4> = COOH with a tert-butyl or a methyl or ethyl protecting group,

L2 means a leaving group known to the person skilled in the art, for example chlorine, bromine, iodine,

OTos, OMes or OTf,

to a compound of formula VI

in which

R<11> means -(CH2)n-A-(CH2)m-R<10> and otherwise the above meanings apply,

as the conversion takes place according to a method known to those skilled in the art (see Quellenlitaratur in J. March, Advanced Organic Chemistry, Fourth Edition, Wiley, 1992). It is being worked on

preferably in a suitable organic solvent or diluent, for example DCM, CHCh, THF, diethyl ether, n-heptane, n-hexane, n-pentane, cyclohexane, diisopropyl ether, methyl tert-butyl ether, acetonitrile, DMF, DMSO, dioxane, toluene , benzene, acetic acid ethyl ester or a mixture of these solvents, optionally with the addition of a base such as for example butyllithium, lithium diisopropylamide (LDA), sodium hydride, sodium amide, potassium tetrabutylate, CaCC>3, CS2CO3, triethylamine, diisopropylethylamine or complex bases (Sodium amide7R1 <2>ONa, where R<12> means (C2-C6)-alkyl or CH3CH2OCH2CH2). For L2 = OH, the reaction can for example take place according to the conditions described for the Mitsunobu reaction (Hughes, Organic Reactions 42 (1992) 335-656), for example by reaction with triphenylphosphine and DEAD in THF.

a2) The compound of formula VI is reacted with a compound of formula VII

wherein R<13> means -D-E or a group R<14>, which can be converted into D-E and which is optionally equipped with suitable protecting groups and which otherwise applies to the above meanings. R<14> means, for example, an optionally protected amino group -NHR<6>, with Boc protecting groups, a protected carboxylic acid ester, an aldehyde -C(0)H, a keto group -C(0)R<6> being used as a protecting group or a protected mercapto group.

Thus a compound of formula Vin is obtained

where

R15 means -B-(CH2)n-D-(CH2)m-R<13> and otherwise has the meanings given above.

The reaction takes place by methods known to those skilled in the art (see Quellenliteratur in J. March, Advanced Organic Chemistry, Fourth Edition, Wiley, 1992) preferably in a suitable organic solvent or diluent, for example DCM, CHCI3, THF, diethyl ether, n-heptane, n- hexane, n-pentane, cyclohexane, diisopropyl ether, methyl tert-butyl ether, acetonitrile, DMF, DMSO, dioxane, toluene, benzene, acetic acid ethyl ester or mixtures of these solvents, optionally with the addition of a base such as butyllithium, lithium diisopropylamide (LDA), sodium hydride, sodium amide, potassium tert-butylate, CaCO3, CS2CO3, triethylamine, diisopropylethylamine or complex bases (sodium amide/R<12>ONa, where R<12> means (C2-C6)-alkyl or CH3CH2OCH2CH2), since for B = NH a surplus of VE can serve as bases.

a3) Optionally, the protective groups in connection with formula VHI according to known methods (Greene, Wuts, Protective Groups in Organic Synthesis, Wiley, 1991) are cleaved off at R<13> and/or R<10>. If, for example, R13 stands for a Boc-protected amino group, the Boc group can, for example, be cleaved off by reaction with trifluoroacetic acid.

a4) Then, where appropriate, R<13> in connection with formula VIII is reacted according to known methods to the group D-E, for example according to one of the following methods.

a4.1) When reacting compounds where R<13> = NHR<6> with 1 H-pyrazole-1-carbox-amidine or cyanamide, a guanidine is obtained (see Bernatowicz et al, J. Org. Chem. 57 ( 1992) 2497). Where R<6> has the meaning of E or a group which can be converted to E.

a4.3) When reacting compounds where R = NHR with compounds of type

where L3 is a nucleophilic substitutable cleavable group such as halogen or SH, SCH3s SOCH3, SO2CH3 or HN-NO2, compounds with end groups are obtained (for methods see e.g. Miller, Synthesis 1986, 777; or Brimble, J. Chem. Soc, Perkin Trans. 1 (1990) 311). a4.9) Compounds which in themselves are not part of the invention, where -D-E means R6R6 N-C(=NR6)-NR6-C(0)- or the remainder of a cyclic acylguanidine of the type can for example be prepared, by reacting a compound, where R<1J> means -C(0)-L4 and IA means an easily nucleophilic substitutable leaving group, with corresponding guanidine (derivative) of the type or cyclic guanidine (derivative) of the type

The above-mentioned activated acid derivatives with the group L4(0)C-, where L4 can for example mean an alkoxy group, preferably a methoxy group, a phenoxy group, phenylthio group, methylthio group, 2-pyridylthio group or a nitrogen heterocyclis, preferably 1-imidazolyl, are preferably obtained by known way from the basic carboxylic acid chlorides (L4 = Cl), which can be prepared in a manner known per se from the basic carboxylic acids, for example with thionyl chloride. In addition to the carboxylic acid chlorides (L4 = Cl), it is also possible to prepare further activated acid derivatives with the group of the type 1A(0) C-, in a manner known per se, directly from the underlying carboxylic acids (L4 = OH), such as for example methyl ester (L4 = OCH3) by treatment with gaseous HC1 in methanol, imidazolides (L4 = 1-imidazolyl) by treatment with carbonyldiimidazole (cf. Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)) or mixed anhydrides (L4 = C2H5OC(0)O respectively TosO) where Cl-COOC2H5 respectively tosyl chloride in the presence of triethylamine in an inert solvent. Activation of the carboxylic acid can also take place with carbodiimides such as dicyclohexylcarbodiimide (DCCI) or with 0-((cyano(ethoxycarbonyl)methylene)amino)-l,l,3,3-tetramethyl-uronium tetrafluoroborate ("TOTU") (Kflnig et al, Proe . 2Ist Europ. Peptide Symp. 1990 (Eds. Giralt, Andreu), Scom, Leiden, 1991, p. 143) and other activation reagents applicable in peptide chemistry (a number of suitable methods for the preparation of activated carboxylic acid derivatives are indicated in the entry in Quellenliteratur in J .March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985) p. 350). Reaction of an activated carboxylic acid derivative with the group of the type L4(0)C- with the applicable guanidine (derivative) preferably takes place in a manner known per se in a protic or aprotic polar, inert organic solvent, the reaction of methyl ester (L4 = OMe) takes place with applicable guanidines preferably in methanol, isopropanol or THF at temperatures of from 20°C to the boiling temperature of this solvent. In most of the reactions of compounds with the group L4(0)C- with salt-free guanidines, the work is preferably done in aprotic inert solvents such as THF, dimethoxyethane, dioxane, whereas water can also be used when using a base such as NaOH as a solvent in reaction of compounds with the group L4(0)C- with guanidines. When L4 = Cl, you preferably work with the addition of acid scavengers, for example in the form of guanidine (derivative) in excess, for splitting off hydrohalic acid.

a4.10) Compounds where -D-E means R<6->C(=NR<6>)-NR<6->C(0)- or a monocyclic or polycyclic residue of the type

can be achieved analogously to a4.9).

a4.13) Compounds where -D- means -NH-C(O)- can, for example, be prepared by reacting a compound where R<13> = -NHH with a suitable carboxylic acid derivative, preferably phosgene, diphosgene (chloroformate trichloromethyl ester), triphosgene ( carboxylic acid bis-trichloromethyl ester), chloroformic acid ethyl ester, chloroformic acid i-butyl ester, bis-(1-hydroxy-1-H-benzotriazolyl)-carbonate or N,N'-carbonyldiirnidazole, in a solvent inert in relation to the reagents used, preferably DMF, THF or toluene, at temperatures between -20°C and the boiling point of the solvent, preferably between 0°C and 60°C, first to a compound where R<13> means

where L6 all carboxylic acid derivatives used for example means a hydroxy group, halogen such as chlorine, ethoxy, isobutoxy, benzotriazole-1-oxy or 1-imidazolyl. Corresponding reaction of this derivative with R R N-C(=NR )-NR H or R<6->C(=NR<6>)-NHR<6> or with a monocyclic or polycyclic obtained compound of the type

takes place as above for the production of acylguanidine (derivatives) as described in a4.9).

a4.15) Compounds of formula I where -D-E is a urea group can be prepared according to known methods, as for example summarized in C. Ferri, Reaktionen der organizchen Synthese, Georg Thieme Verlag, Stuttgart 1978, for example by reaction of corresponding amines with isocyanates respectively isothiocyanates.

a5) After reaction of R<13> in the compound of formula VIU to the group D-E, an additional protective group is possibly further cleaved off which can be removed according to known methods (see Greene, Wuts, s.o.).

a6) Optionally, the obtained compounds of formula I are transferred to salts thereof, especially in pharmaceutically usable or non-toxic physiologically tolerable salts and/or to prodrugs thereof.

In methods for preparing compounds of formula I, step a2) can also be carried out before al).

Introduction of the carbon substituent in the 6-position of the purine lattice can, for example, be carried out by Stille coupling, as for example described in Langli et al, Tetrahedron 52

(1996) 56225; Gundersen, Tetrahedron Lett. 35 (1994) 3152 or through Heck coupling, as described for example in Koyama et al, Nucleic Acid Res., Symp. Looking. 11

(1982) 41.

A substituent X in position 2 of the purine lattice is also possible to introduce at the end of the synthesis of compounds with the formulas I and Ia according to known methods, as for example described in D.A. Nugiel, J. Org. Chem. 62 (1997) 201-203; N. S. Gray, Tetrahedron Lett. 38 (1997) 1161 and also the literature cited therein.

It is possible to introduce a substituent for Y in the 8-position according to known methods, as for example described in E.J. REist et al, J. Org. Chem. 33 (1968) 1600; J. L. Kelley et al, J. Med. Chem. 33 (1990) 196; or E. Vanotti et al, Eur. J. Chem. 29(1994)287.

The compounds of formula I according to the invention and their physiologically tolerable salts can be administered to animals, preferably mammals, and especially humans as drugs alone, in mixtures with each other or in the form of pharmaceutical preparations, which replace an enteral or parenteral application and which contain as active component an effective dose of at least one compound of formula I or a salt thereof or a prodrug thereof in addition to usual pharmaceutical carriers and/or additives. The pharmaceutical preparations normally contain about 0.5 to 90% by weight of therapeutically active compounds.

The medicine can be administered orally, for example in the form of pills, tablets, lacquer tablets, dragées, granules, hard and loose gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. The administration can also take place rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions or infusion solutions, microcapsules or sticks, percutaneously, for example in the form of ointments or tinctures, or nasally, for example in the form of a nasal spray.

Production of the pharmaceutical preparations takes place in a manner known per se, as pharmaceutical inert inorganic or organic carriers are used. For the production of pills, tablets, dragées and hard gelatin capsules, you can for example use lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof, etc. Carriers for soft gelatin capsules and suppositories mean, for example, fat, wax, semi-solid and liquid polyols, natural or hardened oils, etc. As carriers for the production of solutions of syrups, for example, water, sucrose, invert sugar, glucose, polyols, etc. are suitable. As carriers for the production of injection solutions, water, alcohols, glycerin, polyols, vegetable oils, etc. are suitable. microcapsules, implants or rods, mixed polymers from glycolic acid and lactic acid are suitable.

In addition to active substances and carriers, the pharmaceutical preparations may also contain additives, such as fillers, stretching, bursting, binding, sliding, netting, stabilizing, emulsifying, preserving, sweetening, colouring, flavouring, , or aromatizing, thickening, diluting agent, buffer compounds, further solvent and/or dissolution agent or agent for achieving a depot effect, as well as salts for changing osmotic pressure, coating agent or antioxidants. They may also contain two or more compounds with the formulas I and/or physiologically tolerable salts thereof, further next to at least one compound with the formulas I or Ia or a salt thereof one or more other therapeutically active substances.

The doses can be varied widely and are in each case adapted to individual circumstances. By oral administration, the daily dose is generally about 0.01 to 100 mg/kg, preferably 0.1 to 5 mg/kg, especially 0.3 to 0.5 mg/kg body weight to achieve effective results. Also with intravenous application, the daily dose is generally approximately 0.01 to 100 mg/kg, preferably 0.05 to 10 mg/kg body weight. The daily dose can, especially when applying larger amounts, be divided into several, for example two, three or four partial administrations. Depending on individual circumstances, it may be necessary to deviate from the above or below stated daily doses.

Apart from being active pharmaceutical ingredients, the compounds of formula I and Ia can also be used for diagnostic purposes, for example in vitro diagnostics, and as an aid in biochemical investigations, where the purpose is inhibition of the vitronectin receptor or an effect on cell-cell or cell- matrix interactions. Furthermore, they can serve as intermediates for the production of other compounds, in particular other medicinal substances which can be obtained from the compounds of formula I, for example by transformation or introduction of residues or groups.

Accordingly, the invention further relates to compounds of the formula I and/or physiologically tolerable salts for use as medicine.

Furthermore, the invention includes compounds of formula I and/or physiologically tolerable salts thereof for use as inhibitors of bone resorption or osteoclasts, as inhibitors of tumor growth or tumor metastasis, as anti-inflammatory agents, for therapy or prophylaxis of cardiovascular diseases, for therapy or prophylaxis of nephropathies or retinopathies, or as vitronectin receptor antagonists for the therapy or prophylaxis of diseases, which depend on the interaction between vitronectin receptors and their ligands by cell-cell or cell-matrix interaction processes.

In addition, the invention relates to a pharmaceutical preparation, characterized by containing at least one compound of the formula I according to the invention and/or a physiologically tolerable salt thereof, alongside pharmaceutically tolerable carriers and/or additives.

Abbreviations used:

EXAMPLES

Compounds of formula I, which in the 6-position of the purine lattice contain an amino group, which is not a component of the ring, can also be considered as derived from adenines (=6 aminopurine) and be designated as such when naming the compounds. Substituents which are bound to the nitrogen atom in the amino group in the 6-position of the adenine are given the suffix N<6> in this designation. Substituents that are attached to the ring nitrogen atom in the 9-position are provided with the addition N9. When specifying the substituent, it is indicated at the beginning above which position in the substituent the substituent is bound in the chosen designation method to the nitrogen atom N6 or N<9>. The same applies to compounds that are designated as N<9->substituent derived from purine.

Example 1

Ne<->(1-(5-guanidinopentyl))-N<9->(3-(2S-(benzyloxycarbonylamino)propionic acid))-adenine la) ^--(S-CZS-CbenzyloxycarbonylaminoJ-tert-butylpropionaOJ-e -chloropurine.

2.63 g (17 mmol) of 6-chloropuriri and 4.46 g (16.5 mmol) of triphenylphosine were suspended under argon in 50 ml of absol. THF. To this mixture was added at RT 2.56 ml (16.3 mmol) of DEAD and stirred for 15 minutes at RT, forming a clear solution. To this solution was added 3.78 g (12.8 mmol) of N-benzyloxycarbonyl-L-serine-tert-butyl ester (prepared according to M. Schultz, H. Kunz, Tetrahedron: Asymmetry 4

(1993) 1205-1220), dissolved in 50 ml absol. THF during 1.5 hours. It was then stirred for a further 2 hours at RT. The solvent was evaporated, the residue treated with ether and chromatographed over silica gel (toluene:EE 98:2 to 7:3) to give 2.85 g (51%) of pure product.

1 H-NMR (200 MHz, DMSO): δ = 1.30 (s, )H, C(CH 3 ) 3 ); 4.48-4.73 (m, 3H, N<9->CH2-CHfNHZ)); 4.98 (s, 2H, CH 2 -aryl); 7.19-7.40 (m, 5H, aryl-H); 7.87 (d, 1H, NH); 8.61 + 8.77 (2 s, 2H,C6-H + C<8->H).

MS (FAB): m/e = 432.1 (100%; (M+H)<*>); 376.0 (60).

1 b) N6-( 1 -(5-(tert-butyoxycarbonylamino)pentyl))-N9-(3-(2S-(tensyloxycarbonyl-amino)-tert-butylpropionate))-adenine

To a solution of 431 mg (1 mmol) N<9->(3-(2S-(benzyloxycarbonylamino)-tert-butyl-propionate))-6-chloropurine (Example 1a) and 404 mg (2 mmol) 5-( tert-butyloxy-carbonylamino)-1-pentylamine in 5 ml absol. 0.170 ml (1 mmol) of DIPEA and 5 mg of potassium iodide were added to DMF and the mixture was stirred for 72 hours at 40°C. The solvent was evaporated and the residue chromatographed over silica gel (toluene:EE 7:3 to 1:2) to give 190 mg (32%) of pure product.

1 c) N*-( 1 -(5-aminopentyl))-N9-(3-(2-(benzyloxycarbonylamino)propionic acid))-adenine 190 mg (0.32 mmol) N<6->(l-(5 -(tert-butyloxycarbonylamino)pentyl))-N<9->(3-(2S-(benzyloxycarbonylamino)-tert-butylpropionate))-adenine (Example 1b) was dissolved in 2 ml of 90% trifluoroacetic acid and stirred for 2 hours at RT. It was evaporated to dryness and the residue was coevaporated twice with acetic acid. It was then dissolved in water and freeze-dried. Yield: 134 mg (95%). 1 d) N6-( 1 -(5-guanidinopentyl))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))-adenine 34 mg (0.077 mmol) N<6->(1-(5-aminopentyl) )-N<9->(3-(2S-(benzyloxycarbonylamino)-propionic acid))-adenine (Example 1c) was dissolved in 1.5 ml of water and 0.5 ml of DMF and reacted with 0.033 ml (0.193 mmol) of DIPEA and 13.5 mg (0.092 mmol) of 1H-pyrazole-1-carboxamidine hydrochloride and stirred for 40 hours at RT. The solvent was then evaporated, the residue taken up in water and freeze-dried. For further purification, it was chromatographed over silica gel (DCM:methanol:acetic acid:water 15:5:1:1). Substitute yield: 70%.

Example 2

^-(1-(4-guanidinobutyl))-N9-(3-(2S-(benzyloxycarbonyl).

2a) N6^ 1 -(4-(tert-butyloxycarbonylamino)butyl))-N9-(3-(2S-(benzyloxycarbonyl-amino)-tert-butylpropionate))-adenine

Synthesis analogous to 1b from 431 mg (1 mmol) N<9->(3-(2S-(benzyloxycarbonylamino)-tert-butyl-propionate))-6-chloropurine (Example 1a) and 376 mg (2 mmol) 4-( tert-butyloxy-carbonylamino)-1-butylamine. Yield: 214 mg (37%).

1 H-NMR (200 MHz, DMSO): δ = 1.30 (s, 9H, C(CH 3 ) 3 ); 1.38 (s, 9H, C(CH 3 ) 3 ); 1.41 (m, 2H, CH2); 1.57 (m, 2H, CH2); 3.46 (m, 2H, CH 2 -NH-Boc); 2.92 (t, 2H, C<2->NH-CH2); 4.31-4.58 (m, 3H, N'-CH 2 -CH(NH 2 )); 5.01 (s, 2H, CH 2 -aryl); 6.99 (t, 1H, C<2->NH); 7.10-7.38 (m, 5H, aryl-H); 7.75 (m, 1H, NH-Boc); 7.91 (d, 1H, NH-Z); 8.02 + 8.20 (2 s, 2H, C<6->H + C<8->H).

2b) N6-( 1 -(4-aminobutyl))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))-adenine

Synthesis analogous to example 1c from N<6->(1-(4-tert-butyloxycarbonylamino)butyl)-N<9->(3-(2S-(benzyloxycarbonylamino)-tert-butylpropionate))-adenine (Example 2a). Yield: 96%.

2c) N6-( 1 -(4-guanidinobutyl))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))-adenine

Synthesis analogous to example 1d from N<6->(1-(4-aminobutyl))-N<9->(3-(2S-(benzyloxy-carbonylamino)propionic acid))-adenine (example 2b). Yield: 76%.

Example 3

N6-(1-(3-guanidinoporpyl))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))-adenie

3a) N€-(1-(3-(tert-butoxycarbonylamino)porpyl))-N<9->(3-(2S-(benzyloxycarbonylamino)-tert-butylpropionate))-adenine

Synthesis analogous example 1d from 60 mg (0.14 mmol) N<9->(3-(2S-(benzyloxycarbonyl-amino)-tert-butyl-propionate))-6-chloropurine (example 1a) and 30 mg (0 .17 mmol) 3-(tert-butyloxycarbonylamino)-1-propylamine. Yield: 30 mg (38%).

■H-NMR (200 MHz, DMSO): δ = 1.28 (s, 9H, C(CH 3 ) 3 ); 1.36 (s, 9H, C(CH 3 ) 3 ); 1.68 (m, 2H, CH 2 -CH 2 -CH 2 ); 1.41 (m, 2H, CH2); 2.98 (t, 2H, C<2->NH-CH2), 3.46 (5.2H, CH2NH-BOC); 4.29-4.59 (m, 3H, I 2 -C 2 -CH 2 NH 2 )); 5.00 (s, 2H, CH2-aryl); 6.82 (t, 1H, C<2->NH); 7.21-7.40 (m, 5H, aryl-H); 7.72 (m, 1H, NH-Boc); 7.91 (d, 1H, NH-ZZ); 8.03 + 8.20 (2s, 2H, C<6->H + C<8->H).

3b) N<6->(1-(3-aminopropyl))-N<9->(3-(2S-(benzyloxycarbonylamino)propionic acid))-adenine

Synthesis analogous to lc from N<6->(1-(3-(tert-butyloxycarbonylamino)propyl))-N<9->(3-(2S-(benzyloxycarbonylamino)-tert-butylpropionate))-adenine (Example 3a). Yield: 100%.

3c) N6-( 1 -(3-guanidinopropyl))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))-adenine

Synthesis analogous to example 1d from N<6->(1-(3-aminopropyl))-N<9->(3-(2S-(benzyloxycarbonylamino)propionic acid))-adenine (Example 3b). Yield 66%.

Example 4

^-(1-(4-(4,5-dihydro-1H-imidazol-2-ylamino)butyl))-N9-(3-(2S-(benzyloxyamino)propionic acid))-adenine

153 mg (0.36 mmol) N<5-(1-(4-aminobutyl))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))-adenine (Example 2b) and 88 mg (0.36 mmol ) 2-(methylmercapto)-2-imidazoline hydroiodide was dissolved in 2 ml of water and adjusted with 1 N NaOH to pH 9.0. It was stirred for 100 hours at 50°C. Then the solution was brought to pH 1.5 with 1N HCl, the solvent was evaporated and the residue was chromatographed several times over silica gel (DCMMeOH 9:1 to 1:2, each time with 0.1% AcOH, 0.1% H2) , then (DCM:MeOH:H2O:AcOH 8:2:0.4:0.4.

Yield: 7 mg (4%).

Example 5

N<6->(1-(3-guanidinopropyl))-N<9->(4-(2S-(benzyloxycarbonylamino)butyric acid))-adenine 5a) N<9->(4-(2S-(benzyloxycarbonylamino) buty<y>re-tert-but<y>lester))-6-chloropurine

Synthesis analogous to example 1 a from 6-chloropurine and N-benzyloxycarbonyl-L-homoserine tert-butyl ester. Yield: 24%.

1 H-NMR (200 MHz, DMSO): δ = 1.34 (s, 9H, C(CH 3 ) 3 ); 2.08-2.43 (m, 2H, N-CH2-CH2-CH); 3.81-3.93 (m, 1H, CH-NHZ); 4.39 (t, 2H, N9-^); 5.02 (s, 2H, CH 2 -aryl); 7.26-7.42 (m, 5H, aryl-H); 7.87 (d, 1H, NH); 8.63 + 8.75 (2s, 2H, C<6->H + C<8->H).

5b) N<6->(1-(3-(tert-butyloxycarbonylamino)propyl))-N<9->(4-(2S-(benzyloxycarbonylamino)butyric acid tert-butylester))-adenine.

Synthesis analogous to example 1b from 50 mg (0.11 mmol) N<9->(4-(2S-(benzyloxycarbonyl-amino)butyric acid tert-butyl ester))-6-chloropurine (Example 5a) and 38 mg (0, 22 mmol) 3-(tert-butyloxycarbonylamino)-1-propylamine. Yield: 26 mg (41%).

5c) N6-(1-(3-aminopropyl))-N9-(4-(2-(benzyloxycarbonylamino)butyric acid)

Synthesis analogous example le from N<6->(1-(3-tert-butyloxycarbonylamino)propyl))-N<9->(4-(2S-(benzyloxycarbonylamino)butyric acid tert-butyl ester))-adenine (example 5b) . Yield: 94%.

5d) N+6?-(1 -(3-guanidinopropyl))-N9-(4-(2S-(benzyloxycarbonylamino)butyric acid))-adenine

Synthesis analogous to example 1d from N<6->(1-(3-aminopropyl))-N<9->(3-(2S-(benzyloxy-carbonylamino)butyric acid))-adenine (Example 5c). Yield: 71%.

5e) N-benzyloxycarbonyl-L-homoserine

6 g (50.4 mmol) of L-homoserine was thoroughly dissolved in 50 ml of DMF and portionwise reacted at 0°C with 12.56 g (50.4 mmol) of N-(benzyloxycarbonyloxy)-succinimide. It was stirred for 1 hour at 0°C, then for 48 hours at RT. The solvent was distilled off and the residue partitioned between EE and saturated NaCl solution. The organic phase was dried with saturated NaCl solution, with 5% citric acid and again with saturated NaCl solution, filtered and evaporated. The crystalline residue was stirred in ether, filtered off with suction, washed with ether and pentane. Yield: 9.55 g (75%). 1H-NMR (200 MHz, DMSO): δ = 1.61-1.95 (m, 2H, CH 2 -CH 2 -OH); 3.42 (m, 2H, CH 2 -OH); 4.08 (m, 1H, CH-NH-Z); 4.57 (s, broad, 1H, OH); 5.02 (s, 2H, CH2-Ph); 7.32 (m, 5H, aryl-H), 7.49 (d, 1H, NH-Z). 5 f) N-benzyloxycarbonyl-L-homoserine tert-butyl ester 3.8 g (15 mmol) of Z-L-homoserine and 3.42 g (15 mmol) of benzyltriethylammonium chloride were dissolved under argon in 110 ml of N-methyl-2-pyrrolidone and successively reacted with 53.9 g (390 mmol) K 2 CO 3 and 98.7 g (720 mmol) tert-butyl bromide. This was stirred for 22 hours at 55°C. The reaction mixture was poured into 1.5 ml of ice water, extracted twice with toluene, the organic phase was washed twice with saturated NaCl solution, dried, filtered and evaporated. The product was chromatographed over silica gel (N-heptane:EE 7:3 to 1:1) for further purification. Yield: 2.0 g (43.1%). 1 H-NMR (200 MHz, CDCl 3 ): δ = 1.45 (s, 9H, tBu); 1.51-3.74 + 2.03-2.26 (m, 2H, CH 2 -CH 2 -OH); 3.01 (s, broad, 1H, OH); 3.70 (m, 2H, CH 2 OH); 4.41 (m, 1H, CH-NH-Z); 5.12 (s, 2H, CH2-Ph), 5.60 (d, 1H, NH-Z); 7.36 (m, 5H, aryl-H).

Example 6

N<6->(1-(4-guanidomobutyl))-N<9->(4-(2S-(benzyloxycarbonylamino)butyric acid))-adenine

6a) N6-( 1 -(4-(tert-butyloxycarbonylamino)butyl)-N9-(4-(2S-(benzyloxycarbonyl-amino)butyric acid tert-butyl ester))-adenine

Synthesis analogous to lb from 50 mg (0.11 mmol) N<9->(4-(2S-(benzyloxycarbonylamino)butyric acid-tert-butyl ester))-6-chloropurine (Example 5a) and 41 mg (0.22 mmol) 4-(tert-butyl-oxycarbonylamino)-1-butylamine. Yield: 38 mg (58%).

6b) N*-( 1 -(4-aminobutyl))-N9-(4-(2-(benzyloxycarbonyl-amino)butyric acid))-adenine

Synthesis analogous example lc from N<6->(1-(4-(tert-butyloxycarbonylamino)butyl))-N<9->(4-(2S-(benzyloxycarbonylamino)butyric acid tert-butyl ester)-adenine (Example 6a) .Yield: 100%.

6c) N6-( 1 -(4-guanidinobutyl))-N9-(4-(2S-(benzyloxycarbonylamino)butyric acid))-adenine

Synthesis analogous to example 1d from N6-(1-(4-aminobutyl))-N9-(3-(2S-(benzyloxycarbonylamino)butyric acid))-adenine (Example 6b). Yield: 65%.

Example 7

N<6->(1-(3-guanidinopropyl))-N<9->(3-propionic acid)-adenine

7a) N<9->(3-propionic acid tert-butyl ester)-6-chloropurine

15.45 g (0.1 mol) 6-chloropurine, 43.5 ml (0.3 mol) tert-butyl acrylate and 1.34 ml (7 mmol) 5.22 N sodium methanolate (in MeOH) were dissolved in 400 ml absol. MeOH and during several additions of 2.6 ml (14 mmol) 5.22 N sodium methanolate (in MeOH) boiled for 4.5 h under reflux. For work-up, it was suctioned off, the solvent evaporated and the residue chromatographed over silica gel (+ 10% H20) (toluene: EE 3:1). Yield: 1.35 g (5%).

1H-NMR (200 MHz, DMSO): δ = 1.29 (s, 9H, C(CH3)3; 2.95 (t, 2H, CH2C(0)); 4.50 (t, 2H, N -CH 2 ); 8.70 + 8.79 (2 s, 2H, C<6>H + C<8>-H).

7b) N*-( 1 -(3-(tert-butyloxycarbonylamino)propyl))-N9-(3-propionic acid tert-butyl ester)-adenine

Synthesis analogous to lb from 282 mg (1.0 mmol) N<9->(3-propionic acid tert-butyl ester)-6-chloropurine (Example 7a) and 209 mg (1.2 mmol) 3-(tert-butyloxycarbonylamino) -1-propylamine. Yield: 160 mg (38%).

7c) N<6->(1-(3-aminopropyl))-N<9->(3-propionic acid)-adenine

Synthesis analogous to Example 1c from N6-(1-(3-(tert-butyloxycarbonylamino)propyl))-N9-(3-propionic acid tert-butyl ester)-adenine (Example 7b). Yield: 100%.

1H-NMR (200 MHz, DMSO): δ = 1.88 (t, 2H, CH 2 -CH 2 -CH 2 -); 2.80-2.93 (m, 4H, NH-CH2 + CH2-C(0)); 3.56 (m, 2H, CH 2 -NH 2 ); 4.38 (t, 2H, N<9->CH2); 7.72 (s, broad, 2H, NH2); 7.95 (t, 1H, NH); 8.15 + 8.23 (2 s, 2H, C<6->H + C<8->H).

7d) N<6->(1-(3-guanidinopropyl))-N<9->(3-propionic acid)-adenine

Synthesis analogous to example 1d from N6-(1-(3-aminopropyl))-N9-(3-propionic acid)-adenine (Example 7c). Yield: 41%.

1H NMR (200 MHz, D 2 O); δ = 1.95 (t, 2H, CH2-CH2-CH2-); 2.71 (t, 2H, CH 2 -C(O)); 3.24 (5.2H, Gua-CH 2 ); 3.65 (m, 2H, CH 2 -NH 2 ); 4.40 (5.2H, N<9->CH2); 8.00 + 8.15 (2s, 2H, C<6->H + C<8->H).

Example 8

N6-(1-(4-guanidinobutyl))-N9-(3-propionic acid)-adenine

8a) N<6->(1-(4-(tert-butyloxycarbonylamino)butyl))-N<9->(3-propionic acid tert-butyl ester)-adenine

Synthesis analogous to lb from 141 mg (0.5 mmol) N<9->(3-propionic acid tert-butyl ester)-6-chloropurine (Example 7a) and 104 mg (0.55 mmol) 4-(tert-butyloxycarbonylamino) -l-butylarnine. Yield: 130 mg (60%).

1 H-NMR (200 MHz, DMSO): δ = 1.32 (s, 9H, C(CH 3 ) 3 ); 1.35 (s, 9H, C(CH 3 ) 3 ); 1.40 (t, 2H, CH2); 1.57 (t, 2H, CH 2 ), 2.84 (t, 2H, -CH 2 -C(0)); 2.95 (t, 2H, C2-NH-CH2), 3.45 (m, 2H, CH2-NH-Boc); 4.34 (t, 2H, N<9->CH2); 6.78 (t, 1H, C<2->NH); 7.70 (m, 1H, NH-Boc); 8.08 + 8.19 (2 s, 2H, C<6->H + C<8->H).

8b) N*-( 1 -(4-aminobutyl))-N9-(3-propionic acid)-adenine

Synthesis analogous to example 1c fTaN<6->(1-(4-(tert-butyloxycarbonylamino)butyl)-N<9->(3-propionic acid tert-butyl ester)-adenine (Example 8a). Yield 100%.

1H-NMR (200 MHz, DMSO): δ = 1.50-1.70 (m, 4H, -CH 2 -CH 2 -); 2.74-2.91 (m, 4H, NH-CH2 + CH2-C(0)); 3.50 (m, 2H, CH2-NH2), 4.36 (t, 2H, N<9->CH2), 7.64 (s, broad, 2H, NH2); 7.90 (t, 1H, NH); 8.11 +8.21 (2 s, 2H, C<6->H + C<8->H).

8c) N*-( 1 -(4-guanidinobutyl))-N9-(3-propionic acid)-adenine

Synthesis analogous to example 1d from N<6->(1-(4-aminobut<y>1))-N<9->(3-propionic acid)adenine (Example 8b). Yield 65%.

Example 9

hf6-(1-(5-(tert-butyloxycarbonylamino)butyl))-N9-(3-propionic acid tert-butyl ester)-adenine

Synthesis analogous to 1b from 282 mg (1.0 mmol) of N^S-propionic acid tert-butyl ester)^-chloropurine (Example 7a) and 243 mg (1.2 mmol) of 5-(tert-butyloxycarbonylamino)-1-pentylamine. Yield: 219 mg (41%).

9b) N6-(1-(5-aminopentyl))-N9-(3-propionic acid)-adenine

Synthesis analogous to Example Ic from N6-(1-(5-(tert-butyloxycarbonylamino)pentyl))-N9-(3-propionic acid tert-butyl ester)-adenine (Example 9a). Yield: 100%.

1 H-NMR (200 MHz, DMSO): δ 1.39 (m, 2H, CH 2 ); 1.50-1.67 (m, 4H, 2 x CH 2 ); 2.79 (dt, 2H, NH-CH 2 ); 2.89 (m, 2H, CH 2 -C(O)); 3.48 (m, 2H, CH2-NH2), 4.37 (t, 2H, N<9->CH2); 7.67 (s, broad, 2H, NH2); 8.04 (t, 1H, NH); 8.13 + 8.25 (2 s, 2H, C<6->H + C<8->H).

9c) N6-( 1 -(S-guanidinopentyOJ-N^-fS-propionic acidJ-adenine

Synthesis analogous to example 1d from N<6->(1-(5-aminopentyl))-N<9->(3-propionic acid)-adenine (Example 9b). Yield: 37%.

1 H-NMR (200 MHz, DMSO): δ = 1.38-1.79 (m, 6H, 3 x CH 2 ); 2.80 (t, 2H, NH-CH 2 ); 3.12 (m, 2H, CH 2 -C(O)); 3.58 (m, 2H, CH 2 -Gua); 4.43 (t, 2H, N^-CH; ), 8.07 + 8.21 (2s, 2H, C<6->H + <C8-H>).

Example 10

N<6->(2-acetic acid)-N<9->(1-(5-aminopentyl))-adenine

10a) N<6->(2-acetic acid tert-butyl ester)-adenine

155 mg (1 mmol) of 6-chloropurine and 420 mg (2 mmol) of glycine tert-butyl ester hydrochloride (80%) were dissolved in 5 ml of absol. DMF and reacted with 0.17 ml of DIPEA and a spatula tip of potassium iodide and stirred for 6 hours at 50°C. The solvent was evaporated and the residue chromatographed over silica gel (toluene:EE 1:1 to 1:2). Yield: 76 mg (31%).

10b) N6-(2-acetic acid)-N9-(1-(5-(tert-butyloxycarbonylamino)pentyl))-adenine

75 mg (0.3 mmol) N<6->(2-acetic acid tert-butyl ester)-adenine (Example 10a), 214 mg (0.6 mmol) 4-toluenesulfonic acid-(5-tert-butyloxycarbonylamino)pentyl) ester and 42 mg (0.3 mmol) K2CO3 were dissolved in 6 ml absol. DMF and stirred for 5 days at RT. The solvent was evaporated and the residue chromatographed over silica gel (toluene.EE 7:3 to 1:2). Yield: 92 mg (71%).

10c) N6-(2-acetic acid)-N9-(1-(5-aminopentyl))-adenine

Synthesis analogous to example 1c from N<6->(2-acetic acid)-N<9->(1-(5-(tert-butyloxycarbonyl-amino)pentyl))-adenine (Example 10b). Yield: 93%.

Example 11

N<6->(2-(N-(2-aminoethyl)-acetamide))-N<9->(2-acetic acid)-adenine

1 la) N<9->(2-acetic acid tert-butyl ester)-adenine

6.76 g (0.05 mol) of adenine was suspended in 300 ml of absol. DMF under N 2 , then 2.4 g (0.06 mol) NaH dispersion was added and stirred for 2 h at RT. In the course of 30 min, 14.7 ml (0.1 mol) of bromoacetic acid tert-butyl ester was added and a clear solution was formed. It is further stirred for 5 hours at RT. The solvent was evaporated, the residue stirred with 500 ml of water, sucked off and crystallized from ethanol. Yield: 5.1 g (41%).

1 H-NMR (200 MHz, DMSO): δ = 1.42 (s, 9H, tBu); 4.95 (s, 2H, N<9->CH2); 7.22 (s, broad, 2H, N<*>H2); 8.10 + 8.15 (2 s, 2H, C<6->H + C<8->H).

11 b) N<6->(2-acetic acid ethyl ester)-N<9->(2-acetic acid tert-butyl ester)-adenine

978 mg (3 mmol) of NaH and 250 mg (1 mmol) of N<9-(2-acetic acid-tert-butyl ester)-adenine (Example 1 la) were suspended in 10 ml of absol. DMF and 0.12 ml of chloroacetic acid ethyl ester were added dropwise over 10 min. It was then stirred for 6 hours at 50°C, and then equal amounts of CSCO3 were further added and stirred for 6 hours at 50°C. The solvent was evaporated and the residue was partitioned between water and EE. The organic phase was dried and evaporated. Yield: 16%.

1H-NMR (200 MHz, DMSO): δ = 1.20 (t, 3H, CH 2 -CH 3 ); 1.41 (s, 9H, tBu); 4.00-4.28 (m, 4H, CH2-CH3 + N<*->CH2); 4.98 (s, 2H, N<9->CH2); 8.09 (s, broad, 1H, N<*>H); 8.15 + 8.21 (2 s, 2H, C6-H + C<8>-H).

1 lc) N<6->(2-acetic acid)-N<9->(2-acetic acid tert-butyl ester)-adenine

249 mg (0.74 mmol) of N<6->(2-acetic acid ethyl ester)-N<9->(2-acetic acid tert-butyl ester)-adenine (Example 11b) was dissolved in 6 ml of dioxane:water:triethylamine and stirred for 4 days at RT. The solvent was evaporated and the residue was chromatographed over silica gel (DCM:MeOH 95:5 to 90:10). Yield: 36%.

11 d) N6-(2-(N-(2-tert--butyloxycarbonylaminoethyl)-acetamide))-N9-(2-acetic acid-tert-butyl ester)-adenine 80 mg (0.26 mmol) N<6-> (2-acetic acid)-N<9->(2-acetic acid tert-butyl ester)-adenine (Example lic), 42 mg (0.26 mmol) of 2-tert-butyloxycarbonylaminoethylamine was dissolved under argon in 5 ml of absol. DMF and reacted at 0°C with 85 mg (0.26 mmol) TOTU and 0.13 ml (0.78 mmol) DIPEA and 10 min at 0°C and stirred at 2.5 h at RT. It was diluted with EE to 100 ml, then washed with saturated potassium hydrogen carbonate solution, dried and evaporated. This was chromatographed over silica gel (DCM:MeOH 98:2 to 90:10). Dividend: 5%

lie) N<6->(2-(N-(2-aminoethyl)-acetamide))-N<9->(2-acetic acid)-adenine

Synthesis analogous to example 1c from N<6->(2-(N-(2-tert-butyloxycarbonylaminoethyl)-acetamide))-N9-(2-acetic acid-tert-butyl ester)-adenine (example lid).

Yield: 80%.

Example 12

N<6->(4-(2S-(benzyloxycarbonylamino)butyric acid))-N<9->(1-(3-guanidinylpropyl))-adenine 12a)-(3-(tert-butyloxycarbonylamino)propyl))-6 -chloropurine 156 mg (1 mmol) of 6-chloropurine was dissolved in 2.5 ml absol. DMF and reacted with stirring with 331.7 mg (2.4 mmol) K2CO3 and 285.8 mg (1.2 mmol) N-(3-bromopropyl)carbamic acid tert-butyl ester. This was stirred for 11 h at RT, the solvent was evaporated, the residue was taken up in EE and washed twice with saturated NaHCO 3 solution, then with NaCl solution, dried, filtered and evaporated. The residue was chromatographed over silica gel (EE:n-heptane 8:2). Yield: 267 mg (86%).

1 H-NMR (200 MHz, DMSO): δ = 1.37 (s, 9H, tBu); 2.00 (tt, 2H, CH 2 -CH 2 -CH 2 ); 2.95 (dt, 2H, CH 2 -NH); 4.30 (t, 2H, N<9->CH2); 6.91 (t, broad, 1H, NH); 8.70 + 8.78 (2 s, 2H, C<6->H + C<8->H).

12b) N<6->(4-(2S-(benzyloxycarbonylamino)butyric acid))-N<9->(1-(3-(tert-butyloxycarbonylamino)propyl))-adenine 370 mg (1.19 mmol ) N<9->(1-(3-(tert-butyloxycarbonylamino)propyl))-6-chloropurine (Example 12a) was dissolved in 10 ml of absol. DMF and 5 ml DIPEA. At RT, 449 mg (1.8 mmol) of 2S-benzyloxycarbonylamino-4-aminobutyric acid were added and stirred for 50 hours at 65°C. The solvent was evaporated and the residue was partitioned between EE and saturated NaCl solution (20% KHSO<4>). The organic phase was washed with water, dried, filtered and evaporated. The residue was chromatographed over silica gel (EE:MeOH 8:2). Yield: 331 mg (53%). 1 H-NMR (200 MHz, DMSO): δ = 1.39 (s, 9H, tBu); 1.73-2.21 (m, 2H, CH2-CH(NH-Z)); 1.90 (m, 2H, CH 2 -CH 2 -CH 2 ); 2.92 (dt, 2H, CH 2 -NHBoc); 3.15 (dt, 2H, N<6>H-CH2); 3.88-4.10 (m, 1H, CH-NHZ); 4.14 (t, 2H, N^CH<2>), 5.03 (s, 2H, CH2-Ph); 6.91 (t, broad 1H, NH-Boc); 7.37 (s, 5H, Ar-H); 7.55-7.81 (m, 2H, NH-Z + N<6>H-CH 2 ); 8.13 + 8.19 (2s, 2H, C<6>H + C<8>-H). 12c) N6-(4-(2S-(benzyloxycarbonylamino)butyric acid))-N9-(1-(3-aminopropyl))-anedine 30 mg (0.06 mmol) N<6->(3-(2S-( benzyloxycarbonylamino)propionic acid))-N<9->(1-(3-(tert-butyloxycarbonylamino)propyl))-adenine (Example 12b) was dissolved in 2 ml of 90% trifluoroacetic acid, stirred for 70 min at RT, evaporated and the residue was stirred several times with ether. The remainder was dissolved in water and freeze-dried. Yield: 100%.

12d) N<6->(4-(2S-(benzyloxycarbonylamino)butyric acid))-N<9->(1-(3-guanidinopropyl))-adenine

Synthesis analogous to example 1d from N6-(3-(2S~(benzyloxycarbonylamino)propionic acid))-N<9->(1-(3-aminopropyl)-adenine (Example 12c). Yield: 77%.

Example 13

N<6->(4-(2S-(benzyloxycarbonylamino)butyric acid))-N<9->(1-(3-(4,5-dihydro-1H-imidazol-2-ylamino)propyl))-adenine

Synthesis analogous to example 4 from N<6->(3-(2S-(benzyloxycarbonylamino)propionic acid))-N<9->

(1-(3-aminopropyl))-adenine (Example 12c). Yield: 63%.

Example 14

N<6->(3-(2S-(benzyloxycarbonylamino)propionic acid))-N<9->(1-(5-guanidinylpentyl))-adenine 14a) N9-( 1 -(5-(tert-butyloxycarbonylamino)pentyl ))-6-chloropurine.

Synthesis analogous to example 12a from 6-chloropurine and N-(5-(tosyloxypentyl)carbamic acid tert-butyl ester. Yield: 66%.

1 H-NMR (200 MHz, DMSO): δ = 1.11-1.48 (m, 4H, 2 x CH 2 ); 1.35 (s, 9H, tBu); 1.87 (tt, 2H, CH2); 2.97 (dt, 2H, CH 2 -NHBoc); 4.28 (t, 2H, N<9->CH2); 6.72 (t, broad, 1H, NH); 8.71 + 8.78 (2 s, 2H, C<6>H + C<8>-H).

14b) N6-(3-(2S-(benzyloxycarbonylamino)propionic acid))-N9-(1-(5-(tert-butyloxycarbonylamino)pentyl))-adenine

Synthesis analogous to example 12b rraN<9->(1-(5-(tert-butyloxycarbonylamino)pentyl))-6-chloropurine and 2S-benzyloxycarbonylamino-3-aminopropionic acid. Yield: 23%.

1H-NMR (200 MHz, DMSO): δ = 1.10-1.49 (m, 4H, 2 x CH2; 1.36 (s, 9H, tBu); 1.62-1.88 (m, 2H, CH2), 2.87 (dt, 2H, CH2-NHBoc); 3.68-4.98 (m, 5H, N<9->CH2 + CH2-CH-NHZ); 5.00 (s, 2H, CH2-Ph); 6.75 (t, broad, 1H, NH); 8.02 + 8.20 (2 s, 2H, C<6->H + C<8->

H).

14c N S -(3-(2S-(benzyloxycarbonylamino)propionic acid))-N 0 -(1-(5-aminopentyl))-adenine

Synthesis analogous to example 12c from N<6->(3-(2S-(benzyloxycarbonylamino)propionic acid))-N<9->(1-(5-(tert-butyloxycarbonylamino)pentyl))-adenine (Example 14b). Exchange rate: 100%.

1H-NMR (200 MHz, DMSO): δ = 1.18-1.40 + 1.44-1.65 + 1.71-1.93 (2m, 6H, 3 x CH2), 2.77 ( dt(2H, CH2-NHBoc); 3.64-4.35 (m, 5H, N<9->CH2 + CH2CH-NHZ); 5.00 (s, 2H, CH2-Ph); 7.66 ( m, 3H, NH3<4>); 8.20 + 8.24 (2s, 2H, C<6->H + C<8->H).

14d) N<6->(3-(2S-(benzyloxycarbonylamino)propionic acid))-N<9->(1-(5-guanidinyl-pentyl))-adenine

Synthesis analogous example 1d from N<6->(3-(2S-(benzyloxycarbonylamino)propionic acid))-N<9->(1-(5-aminopentyl))-adenine (Example 14c). Yield: 90%.

Example 15

^-(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N9-(1-(5-(4,5-djih imidazol-2-ylamino)pentyl))-adenine

Synthesis analogous to example 4 from N<6->(3-(2S-(benzyloxycarbonylamino)propionic acid)-N<9->

(1-(5-aminopentyl))-adenine (Example 14c). Yield: 75%.

Example 16

N<6->(3-(2S-(benzyloxycarbonylamino)propionic acid))-N<9->(1-(3-(guanidinylpropyl))-adenine

16a) N6-(3-(2S-(benzyloxycarbonylamino)propionic acid))-N9-(1-(3-(tert-butyloxycarbonylamino)propyl))-adenine

Synthesis analogous to example 12b from N<9->(1-(3-(tert-butyloxycarbonylamino)propyl))-6-chloropurine (example 12a) and 2S-benzyloxycarbonylamino-3-aminopropionic acid. Yield: 27%.

1 H-NMR (200 MHz, DMSO): δ = 1.37 (s, 9H, tBu); 1.90 (m, 2H, CH 2 -CH 2 -CH 2 ); 2.92 (dt, 2H, CH 2 -NHBoc); 3.86 (m, broad, 2H, CH 2 CH(NH-Z)); 4.13 (t, 2H, N<9->CH2); 4.40 (m, 1H, CH-NHZ); 501 (s, 2H, CH2-Ph); 6.92 (t, broad, 1H, NH-Boc); 7.33 (s, 5H, Ar-H); 7.55-7.75 (m, 2H, NH-Z + N^H-CHa), 8.16 + 8.22 (2 s, 2H, C<6->H + C<8->H) .

16b) N6-(3-(2S-(benzyloxycarbonylamino)propionic acid))N9-(1-(3-aminopropyl))-adenine

Synthesis analogous to example 12c from N<6->(3-(2S-benzyloxycarbonylamino)propionic acid))-N<9->(1-(3-(tert-butyloxycarbonylamino)propyl))-adenine (Example 16a). Yield: 100%

16c) N6-(3-(2S-(benzyloxycaro^ adenine).

Synthesis analogous to example 1d from N<6->(3-(2S-(benzyloxycarbonylamino)propionic acid))-N<9->(1-(3-aminopropyl))-adenine (Example 16b). Yield 98%.

MS (ES+): m/e * 456.3 (40%; (M+H)<+>); 322.2 (100).

Example 17

N<6->(3-(2S-(benzyloxycarbonylamino)propionic acid))-N<9->(l-(4-guanidinylbutyl))-adenine 17a) N9-(l -(4-tert-butyloxycarbonylamino)butyl) )-6-chloropurine

Synthesis analogous to example 12a from 6-chloropurine and N-(4-tosyloxybutyl)carbamic acid tert-butyl ester. Yield: 66%.

1 H-NMR (200 MHz, DMSO): δ = 1.30 (m, 2H, CH 2 ); 1.35 (s, 9H, tBu); 1.86 (tt, 2H, CH2); 2.93 (dt, 2H, CH 2 -NHBoc); 4.31 (t, 2H, N<2->CH2); 6.79 (t, broad, 1H, NH); 8.72 + 8.78 (2 s, 2H, C<6->H + C<8->H).

MS (ES+): m/e = 326.2 (80%; (M+H)<*>); 270.1 (100).

17b) N6-(3-(2S-(benzyloxycarbonylamino)propionic acid))-N9-(1 -(4-(tert-butoxycarbonylamino)butyl))-adenine

Synthesis analogous to example 12b from N<9->(1-(4-tert-butyloxycarbonylamino)butyl))-6-chloropurine (example 17a) and 2S-benzyloxycarbonylamino-3-aminopropionic acid. Yield: 33%.

1 H-NMR (200 MHz, DMSO): δ = lm 30 (m, 2H, CH 2 ); 1.35 (s, 9H, tBu); 1.75 (m, 2H, CH2); 2.91 (dt(2H, CH2-NHBoc); 3.71-4.34 (m, 5H, CH2-CH(NH-Z) + N<9->^); 5.01 (s, 2H, CH2-Ph); 6.89 (t, broad, 1H, NH-Boc); 7.35 (s, 5H, Ar-H); 7.46-7.73 (m, 2H, NH-Z + N ^H-CHO; 8.10 (broad) + 8.20 (2 s, 2H, C<6->H + C<8->H).

MS (FAB): m/e = 528.4 (100%; (M+H)<+>).

17c) N6-(3-(2S-(benzyloxycarbonylamino)propionic acid))-N9-(1-(4-aminobutyl))-adenine

Synthesis analogous to example 12c from N<6->(3-(2S-(benzyloxycarbonylamino)propionic acid))-^-(1-(4-tert-butyloxycarbonylamino)propionic acid))-N9-(1-(4-tert-butyloxycarbonyl) -aminobutyl))-adenine (Example 17b). Yield: 100%.

1 H-NMR (200 MHz, DMSO): δ = 1.48 (m, 2H, CH 2 ); 1.87 (m, 2H, CH2); 2.80 (dt, 2H, CH 2 -NH 2 ); 3.69-4.02 (m, 2H, CH2-CH(NH-Z)); 4.20 (t, 2H, N<9->CH2); 4.36 (m, 1H, CH(NH-Z)); 5.01 (s, 2H, CH2-Ph); 7.33 (s, 5H, Ar-H); 7.64 (s, broad, 4H, NH3<+> + N^H-CH2); 8.10 (broad) + 8.20 (2 s, 2H, C<6->H + C<8->H).

17d) N6-(3-(2S-(benzyloxycarbonylamino)propionic acid))-N9-(1-(4-guanidinylbutyl))-adenine

Synthesis analogous example 1d from N<6->(3-(2S-(benzyloxycarbonylamino)propionic acid))-N<9->(1-(4-aminobutyl))-adenine (Example 17c). Yield: 78%.

Example 18

N6-(3-(2S-(benzyloxycarbonylamino)propionic acid))-N9-(1 -(4-(4,5-dihydro-1H-imidazol-2-yl)amino)butyl))-adenine

Synthesis analogous to example 4 from N<6->(3-(2S-(benzyloxycarbonylamino)propionic acid))-N<9->

(1-(4-aminobutyl))-adenine (Example 17c). Yield: 41%.

Example 19

2S-Benzyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-piperidin-1 -yl)-purin-9-yl)-propionic acid

19a) 2S-Benzyloxycarbonyl]amino-3-(6-(4-(carboxypiperidin-1-yl)-purin-9-yl)-propionic acid tert-butyl ester.

260 mg (0.6 mmol) 2S-benzyloxycarbonylamino-3-(6-chloropurin-9-yl)-propionic acid tert-butyl ester (Example 1a), 116.3 mg (0.9 mmol) piperidine-4-carboxylic acid and 310 mg (2.4 mmol) DIPEA in 4 ml absol. DMF was stirred for 16 hours at 60°C. 310 mg of DIPEA were then added and further stirred for 24 hours at 60°C. The solvent was evaporated and the residue partitioned between EE and water. The organic phase was washed once more with a KHSO 4 /K 2 SO 4 solution, then with NaCl solution, dried, filtered and evaporated. The residue was chromatographed over silica gel (EE). Yield: 219 mg (69%).

19b) 2S-Benzyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-piperidin-1-yl)-purin-9-yl)-propionic acid tert-butyl ester 126 mg (0.24 mmol) 2S-benzyloxycarbonylamino-3-(6-(4-carboxypiperidin-1-yl)-purin-9-yl)-propionic acid tert-butyl ester (Example 19a), 39.3 mg (0, 29 mmol) 2-amino-1,4,5,6-tetrahydropyrimidine hydrochloride, 86.6 mg (0.264 mmol) TOTU (O-((etholcoxycarbonyOcyanomethyleneaminoJ-N^.N^N-tetramethyluronium tetrafluoroborate) (W. Konig et al, Proceedings of the 2 Ist European Peptide Symposium, 1990, E. Giralt, D. Andreu, Eds. ESCOM, Leiden, P. 143) and 124 mg of DIPEA were added successively to 3 ml of absolute DMF. This was stirred for 3 hours at RT, then another 28 mg of DIPEA was added and stirred for 12 h at RT.The reaction mixture was adjusted with glacial acetic acid/toluene (1:1) to pH 6, the reaction solution was evaporated, the residue was partitioned between EE and saturated NaHCO 3 solution, the The organic phase was washed with NaCl, dried and evaporated.The residue was chromatographed above r silica gel (EE:MeOH:TEA 85:15:1.5). Yield: 70 mg 19c) 2S-Benzyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-piperidin-1-yl)-purin-9-yl)-propionic acid 80 mg 2S-Benzyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-piperidin-1-yl)-purin-9-yl)-propionic acid tert-butyl ester (example 19b) was dissolved in 16 ml of chilled 95% trifluoroacetic acid and first stirred for 30 min at 0°C, then 30 min at RT. Trifluoroacetic acid was sorted off, the residue coevaporated three times with toluene, stirred in ethanol/ether (1:2), washed with ether and dried in vacuo. Yield: 59 mg.

Example 20

2S-Benzyloxycarbonylamino-3-(1-(9-(2-guanidinoethyl)-9H-purin-6-yl)-1H-imidazol-4-yl)-propionic acid

20a) N9-( 1 -(2-(tert~butyloxycarbonylamino)ethyl))-6-chloropurine

The synthesis takes place analogously to example 12a from 6-chloropurine and N-(2-tosyloxyethyl)carbamic acid tert-butyl ester. Yield: 36%.

1 H-NMR (200 MHz, DMSO): δ = 1.24 (s, 9H, tBu); 3.40 (dt, 2H, CH 2 -NHBoc); 4.35 (t, 2H, N<9->CH2); 6.91 (t, broad, 1H, NH); 8.60 + 8.78 (2 s, 2H, C6-H + C8-H).

20b) 2S-benzyloxycarbonylamino-3-(1-(9-(2-tert-butyloxycarbonylamino)ethyl)-9H-purin-6-yl)-1H-imidazol-4-yl)-propionic acid

The synthesis takes place analogously to example 12b ftaN^O-^-tert-butyloxycarbonyl-amino)ethyl)-6-chloropurine (example 21 a) and N„-Z-L-hisitin. Yield: 33%.

20c) 3-( 1 -(9-(2-aminoethyl)-9H-purin-6-yl)-1H-imidazol-4-yl)-2S-benzoxycarbonyl-aminopropionic acid

The synthesis proceeds analogously to example 12c from 2S-benzyloxycarbonylamino-3-(1-(9-(2-(tert-butyloxycarbonylamino)ethyl)-9H-purin-6-yl)-1H-imidazol-4-yl)-propionic acid (example 20b). Yield: 100%.

1 H-NMR (200 MHz, DMSO): δ = 2.87-3.15 (m, 2H, Im-CH 2 ); 3.38-3.51 (m, 2H, CH2-

NH2); 4.36 (m, 1H, CH-NHZ); 4.60 (t, 2H, N<9->CH2); 5.00 (s, 2H, CH2-Ph); 7.28 (2,5H, Aryl-H); 7.62 (d, 1H, NH-Z); 8.23 + 9.05 (2s, 2H, Im-H); 8.71 + 8.88 (2s, 2H, C6-H +

C8-H).

20d) 2S-benzyloxycarbonylamino-3-(1-(9-(2-guanidinoethyl)-9H-purin-6-yl)-1H-imidazol-4-yl)-propionic acid

The synthesis takes place analogously to example 1d from 3-(1-(9-(2-aminoethyl)-9H-purin-6-yl)-1H-imidazol-4-yl)-2S-benzyloxycarbonylamino-propionic acid (example 20c).

Yield: 38%

Example 21

2R-Benzyloxycarbonylamino-3-(6-(N-(4-guanidinocyclohexyl)amino)-purin-9-yl)-propionic acid

21a) N<9->(3-(2R-(benzyloxycarbonylamino)-tert-butylpropionate))-6-chloropurine

The synthesis takes place analogously to example 1a from 6-chloropurine and N-benzyloxycarbonyl-D-serine-tert-butyl ester.

21 b) 2R-benzyloxycarbonylamino-3-(6-(N-(4-(tert-butyloxycarbonylamino)cyclohexyl)amino)-purin-9-yl)-propionic acid tert-butyl ester

The synthesis takes place analogously to example 1b from 4-amino-1-(tert-butyloxycarbonylamino)-cyclohexane and N9-(3-(2R-(benzyloxycarbonylamino)-tert-butylpropionate))-6-chloropurine (example 21a). Yield: 55%.

21 c) 3-(6-(N-(4-aminocyclohexyl)am propionic acid).

The synthesis takes place analogously to example 1c from 2R-benzyloxycarbonylamino-3-(6-(N-(4-(tert-butyloxycarbonylamino)cyclohexyl)amino)-purin-9-yl)-propionic acid tert-butyl ester (example 21b). Yield: 100%.

21d) 2R-benzyloxycarbonylamino-3-(6-(N-(4-guanidinocyclohexyl)amino)-purin-9-yl)-propionic acid

The synthesis takes place analogously to example 1 d from 3-(6-(N-(4-aminocyclohexyl)amino)-purin-9-yl)-2R-benzyloxycarbonylamino-propionic acid (example 21c). Yield: 80%.

Example 22

2R-Benzyloxycarbonylamino-3-(6-(N-(3-guanidinomethylbenzyl)amino)-purin-9-yl)-propionic acid

22a) 2R-benzyloxycarbonylamino-3-(6-(N-(3-tert-butyloxycarbonylaminomethyl-benzyl)amino)-purin-9-yl)-propionic acid tert-butyl ester

The synthesis takes place analogously to example 1b from 3-aminomethyl-1-(tert-butyloxycarbonyl-aminomethyl)-benzoyl and N9-(3-(2R-(benzyloxycarbonylamino)-tert-butyl-propionate)-6-chloropurine (Example 21a). : 51%.

22b) 3-(6-(N-(3-aminomethylbenzyl)amino)-purin-9-yl)-2R-benzyloxycarbonylamino-propionic acid

The synthesis takes place analogously to example 1c from 2R-benzyloxycarbonylamino-3-(6-(N-(3-tert-butyloxycarbonylarmnomethylbenzyl)amino)-purin-9-yl)-propionic acid tert-butyl ester (example 22a). Yield: 100%.

22c) 2R-benzyloxycarbonylamino-3-(6-(N-(3-guanidinomethylbenzyl)amino)-puri 9-yl)-propionic acid

The synthesis takes place analogously to example 1d from 3-(6-(N-(3-aminomethylbenzyl)amino)-purin-9-yl)-2R-benzyloxycarbonylamino-propionic acid (example 22b). Yield: 30%.

Example 23

3-(6-((4-(benzimidazol-2-ylamino)-butyl)-amino)-purin-9-yl)-2S-benzyloxycarbonyl-amino-propionic acid

23a) 1-(4-Tetr-butyloxycarbonylamino-butyl)-3-(2-nitrophenyl)-thiourea

To 0.97 g (5.15 mmol) of 4-(tert-butyloxycarbonylaminobutyl)-1-amine in 25 ml of absol. DMF was added dropwise at 0°C 0.928 g (5.15 mmol) of 2-nitrophenyl isotocyanate in 5 ml absol. DMF. It was then stirred for 1 hour at 0°C. The solvent was distilled off and the residue chromatographed over silica gel (EE:n-heptane 1:2 to 1:1). Yield: 1.8 g (95%).

23b) 3-(2-aminophenyl)-1-(4-tert-butyloxycarbonylamino-butyl)-thiourea

1.78 g (4.8 mmol) of 1-(4-tert-butyloxycarbonylamino-butyl)-3-(2-nitrophenyl)-thiourea (Example 23a) was dissolved in 120 ml of methanol and hydrated at RT for 3 h over 1 g Pd/C (1 bar). The catalyst was filtered off, the filtrate evaporated and chromatographed over silica gel (EE:n-heptane 1:1). Yield: 1.4 g.

23c) 4-(benzimidazol-2-ylamino)-1-(tert-butyloxycarbonylamino)-butane

1.79 g (8.28 mmol) of yellow mercuric oxide and 27 mg of flower of sulfur and the reaction mixture heated for 3 hours to 50-55°C. It was suctioned off and washed with ethanol. The filtrate was evaporated and the product chromatographed over silica gel (DCM:methanol 9:5, then 9:1). Untraded: 43%.

23d) 4-(benzimidazol-2-ylamino)-1-aminobutane

198 mg (0.65 mmol) of 4-(benzimidazol-2-ylamino)-1-(tert-butyloxycarbonylamino)-butane (Example 23c) was dissolved at 0°C in 20 ml of 95% trifluoroacetic acid and stirred for 2 hours at 0 °C, then evaporated at RT during 30 min. The residue was co-evaporated three times with toluene, then stirred with ether and washed with pentane and dried in vacuo. Yield: 100%.

23e) 3-(6-((-(benzimidazol-2-ylamino)-butyl)-amino)-purin-9-yl)-2S-benzyloxy-carbonylamino-propionic acid tert-butyl ester

The synthesis proceeds analogously to example 1b from 4-(benzimidazol-2-ylamino)-1-aminobutane (example 23d) and N<9->(3-(2S-(benzyloxycarbonylamino)-tert-butylropionate))-6-chloropurine (example let). Yield: 32%.

23f) 3-(6-((4-(benzimidazol-2-ylamino)-butyl)-amino)-purin-9-yl)-2S-benzyloxy-carbonylamino-propionic acid

The synthesis takes place analogously to example 1c from 3-(6-((4-(benzimidazol-2-ylamino)-butyl)-amino)-purin-9-yl)-2S-benzyloxycarbonylamino-propionic acid tert-butyl ester (Example 23e). Yield: 100%.

Example 24

2S-Benzyloxycarbonylamino-3-(6-(4-((4,5-dihydro-1H-imidazol-2-ylamino)-methyl)-piperidin-1-yl)-purin-9-yl)-propionic acid

24a) 3-(6-(4-(aminomethyl)-piperidin-1-yl)-purin-9-yl)-2S^ propionic acid tert-butyl ester

The synthesis takes place analogously to example 1b from 4-(aminomethyl)-piperidine and N<9->(3-(2S-(benzyloxycarbonylamino)-tert-butylpropionate))-6-chloropurine (example 1 a).

Yield: 96.4%.

24b) 3-(6-(4-(aminomethyl)-piperidin-1-yl)-purin-9-yl)-2S-benzyloxycarbonylamino-propionic acid

The synthesis takes place analogously to example 1c from 3-(6-(4-(aminomethyl)-piperidin-1-yl)-purin-9-yl)-2S-benzyloxycarbonylamino-propionic acid tert-butyl ester (example 24a)

Yield: 100%.

24c) 2S-Benzyloxycarbonylamino-3-(6-(4-((4,5-dihydro-1H-imidazol-2-ylamino)-methyl)-piperidin-1-yl)-purin-9-yl)-propionic acid

The synthesis takes place analogously to example 4 from 3-(6-(4-(aminomethyl)-piperidin-1-yl)-purin-9-yl)-2S-benzyloxycarbonylamino-propionic acid (example 24 b). Yield: 95%.

Example 25

2R-Benzyloxycarbonylamino-3-(6-(4-((4,5-dihydro-1H-imidazol-2-ylamino)-methyl)-piperidin-1-y])-purin-9-yl)-propionic acid

The synthesis takes place analogously to example 24 starting from N<9->(3-(2R-(benzyloxycarbonyl-amino)-tert-butylpropionate))-6-chloropurine (example 21a).

Example 26

2S-Benzyloxycarbonylamino-3-(6-(4-(guanidinomethyl)-piperidin-1-yl)-purin-9-yl) propionic acid

The synthesis takes place analogously to example 1d from 3-(6-(4-(aminomethyl)-piperidin-1-yl)-purin-9-yl)-2S-benzyloxycarbonylamino-propionic acid (example 24b). Yield: 74%.

Example 27 2S-Benzyloxycarbonylamino-3-(6-(3-(3-benzylureido)-phenylsulfanyl)-purin-9-yl)-propionic acid 27a) 3-(6-(3-(amino-phenylsulfanyl)-purine-9 -yl)-2S-benzyloxycarbonylamino-propionic acid tert-butyl ester 0.602 mmol of 3-mercaptoaniline was stirred with 0.602 mmol of N<9->(3-(2S-(benzyloxycarbonylamino)-tert-butyl-propionate)-6-chloropurine (Example 1a) in DMF and DIPEA during 12 h. The reaction solution was evaporated, the residue was partitioned between EE and saturated NaHCO3 solution, the phases were separated, the organic phases were washed with half-saturated NaHCO3 solution and NaCl solution, dried, evaporated and the product chromatographed over silica gel (EE:heptane 1:1) Yield: 190 mg.

27b) 2S-Benzyloxycarbonylamino-3-(6-(3-(3-benzylureido)-phenylsulfanyl)-purin-9-yl)-propionic acid tert-butyl ester

To 180 mg of (3-(6-(3-amino-phenylsulfanyl)-purin-9-yl)-2S-benzyloxycarbonylamino-propionic acid tert-butyl ester (Example 27a) in 30 ml of absolute acetonitrile was added 46.1 mg benzyl isocyanate in 1 ml of acetonitrile by syringe.The mixture was stirred for 48 h at RT, evaporated and the residue chromatographed over silica gel (DCM:EE 7:3 to 1.1).Yield: 205 mg.

27c) 2S-Benzyloxycarbonylamino-3-(6-(3-(3-benzylureido)-phenylsulfanyl)-puryl)-propionic acid

The synthesis takes place analogously to example 1c from 2S-benzyloxycarbonylamino-3-(6-(3-(3-benzylureido)-phenylsulfanyl)-purin-9-yl)-propionic acid tert-butyl ester (example 27b). Yield: 100%.

Example 28 2S-neopentyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-piperidin-1-yl)-purin-9-yl)-propionic acid 28a) 2S-amino -3-(6-(4-carboxy-piperidin-1-yl)-purin-9-yl)-propionic acid tert-butyl ester 1.7 g 2S-benzyloxycarbonylamino-3-(6-(4-carboxypiperidin-1- yl)-purin-9-yl)-propionic acid tert-butyl ester (Example 10a) was dissolved in 200 ml AcOH and filtered off over Pd/C at 1 atm H 2 pressure. The catalyst was filtered off, the solvent filtered off and the residue lyophilized. Yield 100%.

28b) 2S-neopentyloxycarbonylamino-3-(6-(4-carboxy-piperidin-1-yl)-purin-9-yl)-propionic acid tert-butyl ester

390 mg (1 mmol) of 2S-amino-3-(6-(4-carboxy-piperidin-1-yl)-purin-9-yl)-propionic acid tert-butyl ester (Example 20a) in 4 ml of DMF was reacted at 0°C with 230 mg (1 mmol) N-(neopentyloxycarbonyloxy)-succinimide and 0.17 ml DIPEA and after slow heating stirred for 12 h at RT. The reaction mixture was evaporated and the residue chromatographed (Lobar-C, DCM:MeOH:AcOH:H 2 O 90:10:1:1).

Yield: 540 mg.

28c) 2S-neopentyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimylcarbamoyl)-piperidin-1-yl)-purin-9-yl)-propionic acid tert-butyl ester 505 mg (1 mmol) 2S-neopentyloxycarbonylamino-3-(6-(4-carboxypiperidin-1-yl)-purin-9-yl)-propionic acid tert-butyl ester (Example 20b) was dissolved in 10 ml of acetonitrile, reacted with 250 mg of DCCI and 184 g of pentafluorophenol and then stirred for 30 minutes at RT. This was filtered, evaporated in mother liquor, taken up in 5 ml of DMF, reacted with 200 mg of 2-amino-1,4,5,6-tetrahydropyrimidine and stirred for 12 hours at RT. The solvent was distilled off in vacuo and the residue chromatographed (Lobar-C, DCM:MeOH:AcOH:H2 = 98:8:0.8:0.8). Yield: 270 mg.

28d) 2S-neopentyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-piperidin-1-yl)-purin-9-yl)-propionic acid

The synthesis proceeds analogously to example 19c from 2S-neopentyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-piperidin-1 -yl)-purin-9-yl)-propionic acid- tert-butyl ester (Example 28c). Yield: 94%.

Example 29

2S-(1-adamantylmethyloxycarbonylamino)-3-(-6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-piperidin-1-yl)-purin-9-yl)-propionic acid

29a) 2S-(1-adamantylmethyloxycarbonylamino)-3-(6-(4-carboxy-piperidin-1-yl)-purin-9-yl)-propionic acid tert-butyl ester

The synthesis takes place analogously to example 28b from N-(1-adamantylmethyloxycarbonyloxy)-succinimide and 2S-amino-3-(6-(4-carboxypiperidin-1-yl)-purin-9-yl)-propionic acid tert-butyl ester (example 28a ). Yield: 85%.

29b) 2S-(1-adamantylmethyloxycarbonylamino)-3-(6-(4-(1,4,5,6-tetrahydropyrrinidin-2-<yl>lcarbamoyl)-piperidin-1-yl)-purin-9-yl) -propionic acid tert-butyl ester

The synthesis takes place analogously to example 28c from 2S-(1-adamantylmethyloxycarbonylamino)-3-(6-(4-carboxy-piperidin-1-yl)-purin-9-yl)-propionic acid tert-butyl ester (example 29a). Yield: 75%.

29c) 2S-(1-adamantylmethyloxycarbonylamino)-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbaoyl)-piperidin-1-yl)-purin-9-yl)-propionic acid

The synthesis proceeds analogously to example 19c from 2S-(1-adamantylmethyloxycarbonylamino)-3-(6-(4-(1,4,5,6-terphahydropyrimidin-2-ylcarbamoyl)-piperidin-1-yl)-purin-9-yl )-propionic acid tert-butyl ester (Example 29b). Yield: 100%.

Pharmacological investigation

As a test method, the antagonistic effect of the inventive compounds on the vitronectin receptor ccvP3 is determined and below the inhibition of the binding of kistrin on the human vitronectin receptor (VnR) is described (avp3-ELISA test; the test method is abbreviated "K/VnR" when listing the test results) .

Cleaning of the chest

Kistrin is purified as described in the method of Dennis et al, as described in Proe. Nati. Acad. Pollock. USA 1989, 87,2471-2475 und PROTEINS; Structure, Functions and Genetics 1993,15,312-321.

Purification of human vitronectin receptor (avp3)

Human vitronectin receptor is isolated from human placenta according to the method of Pytela et al, Methods Enzymol. 1987,144,475. Human vitronectin receptor avp3 can also be isolated from certain cell lines (for example from 293 cells, from a human embryonic kidney cell line), which have been cotransfected with DNA sequences for both subunits ccv and p3 of the vitronectin receptor. The subunits were extracted with octyl glycoside and finally chromatographed over concanavalin A, heparin-sepharose and S-300.

Monoclonal antibodies

Murine monoclonal antibodies, specific for the P3 subunit of the vitronectin receptor, are prepared according to the method of Newman et al, Blood, 1985, 227-232, or according to similar methods. Rabbit Fab 2 anti-mouse Fc conjugate to horseradish peroxidase (anti-mouse Fc HRP) was obtained from Pel Freeze (Catalog no. 715 305-1).

ELISA test

The ability of compounds to inhibit the binding of kistrin to the vitronectin receptor can be determined by the ELISA test. For this purpose, Nunc 96-well microtiter plates are coated with a solution of kistrin (0.002 mg/ml) according to the method of Dennis et al, as described in PROTEINS: Structure, Function and Genetics 1993,15, 312, 321. The dishes are then washed twice with PBS/0.05% Tween-20 and blocked by incubation (60 min) with bovine serum albumin (BSA, 0.5%, RIA grade or better) in Tris-HCl (50 mM), NaCl (100 mM ), MgCl2 (1 mm) CaCli (1 mm), MnCl2 (1 mm),

pH 7. Solutions of known inhibitors and test compounds are set up in concentrations from 2 x 10"12 to 2 x 10"6 mol/l in analysis buffer (BSA (0.5%, RIA quality or better) in Tris-HCl (50 mm), NaCl, (100 mm), MgCl2 (1 mm), CaCl2 (1 mm), MnCl2 (1 mm), pH 7). Blocked dishes are emptied and each of 0.025 ml of this solution containing a defined concentration (2 x 10"12 to 2 x 10"<6> mol/l) of either a known inhibitor or a test compound is added to each well. 0.025 ml of a solution of the vitronectin receptor in test buffer (0.03 mg/ml) was pipetted into each well of the dish and the dish is incubated in a stirrer for 60-180 min at room temperature. Meanwhile, a solution (6 ml/dish) of a murine monoclonal antibody specific for the P3 impurity of the vitronectin receptor is prepared in assay buffer (0.0015 mg/ml). To a solution is added a second rabbit antibody (0.001 ml of stock solution/6 ml of murine monoclonal anti-p3 antibody solution, which constitutes an anti-mouse Fc HRP antibody, and this mixture of murine anti-p3 antibody and rabbit anti- mouse Fc HRP antibody-conjugate is incubated during the receptor-inhibitor incubation time.The test dish is washed four times with PBS solution containing 0.05% Tween-20, and 0.05 ml/well of the antibody mixture is pipetted into each well in the dish and incubate for 60-180 min. The dish is washed four times with PBS/0.05% Tween-20 and finally with 0.05 ml/well of a PBS solution containing 0.67 mg/ml o -phenylenediamine and

0.012% H2O2. Alternatively, o-phenylenediamine can be used in a buffer (pH 5) containing Na3PO4 and citric acid. Color development is stopped with 1 N H2SO4 (0.05 ml/well). Absorbance is measured in each well at 492-405 nm and the data is evaluated according to standard methods.

The following test results were obtained:

Claims (12)

1. Compounds, characterized in that they have the formula I where: G means a residue of formula II W means a residue of formula III A means-CH2-or where X is phenyl or adamantyl; R<4> means NHR<3> where R<3> means siler dihydroimidazolyl; or CO2R<2> where R2 means H or C1-C6-alkyl B means -S-, -NH-, a direct bond or a piperidyl or imidazolyl group; D means -A-, -C3-C7-cycloalkylene-, -phenylene-, -CONH-, -CO2-, -CO-NH-(CH2)n-NH-, -NHCO- or -Ph-NH-CO- NH-; E means hydrogen, Q-Ce-alkyl, phenyl-Ci-C6-alkyl, dihydroimidazolyl, benzimidazolyl or tetrahydropyrimidyl; n means 0, 1, 2, 3, 4 or 5; m means 0, 1, 2, 3, 4 or 5; and their physiologically tolerable salts. 2. Compounds, characterized in that they have the formula I according to claim 1, wherein G means a residue of formula II W means a residue of formula H1 A means-CH2-or where X means phenyl or adamethyl R<4> means CO2R2, where R2 means H or C1-C6 alkyl, B means -S-, -NH-, a direct bond or a piperidyl or imidazolyl group; D means -A-, -C3-C7-cycloalkylene-, -phenylene-, -CONH-, -NH-, -CO2-, -CO-NH-(CH2)n-NH-, -NHCO- or -Ph- NH-CO-NH-; E means hydrogen or a residue from the series n means 0, 1, 2, 3 or 4; m means 0 or 1; and physiologically tolerable salts. 3. Compounds of formula I according to claim 1 or 2, characterized in that: G means a residue of formula II W means a residue of formula III A means -CH2- or where X is phenyl or adamantyl; R<4> means CChR^ where R<2> means H or C 1 -C 6 alkyl, B means -S-, -NH-, a direct bond or a piperidyl or imidazolyl group; D means a -NH-, -C(O)-NH- or -NH-C(O)-; E means hydrogen or a residue from the series n means 1,2,3 or 4; m means 0 or 1; and physiologically tolerable salts thereof. 4. Compounds of formula I according to claim 1 and/or 2, characterized in that G means a residue of formula II W means a residue of formula IA A means -CHr; R<4> means CO2R<2>, where R<2> means H or d -C4-alkyl, B means 1,4-piperidinyl to which the nitrogen atom of the piperidine is attached the purine lattice; D means -NH-, -C(O)-NH- or -NH-C(O)-; E means hydrogen or a residue from the series n means 1,2,3 or 4; m means 0 or 1; and physiologically tolerable salts thereof. 5. Compounds of formula I according to one or more of claims 1 to 4, characterized in that G means a residue of formula II W means a residue of formula HI A means -CH2-; R<4> means CO2R<2>, where R<2> means H or C1-C4 alkyl, B means 1,4-piperidinyl, the nitrogen atom of the piperidine being attached to the purine lattice; D means -NH-, -C(0)-NH-, the group -C(0)-NH- being the nitrogen atom bound to group E; E means a remainder from the sequence n means 0 or 1; m means 0; and physiologically tolerable salts thereof. 6. Compounds, characterized in that they have formula Bi where R<3> -NH-C(0)-0-CH2X where X means phenyl or adamantyl, Rh means the carboxylic acid group COOH or means a carboxylic acid derivative; in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts as well as their prodrugs thereof. 7. Connection, characterized by. that it is 2S-benzyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-yl-carbamoyl)-piperidin-1-yl)-purin-9-yl)-propionic acid and their physiologically tolerable salts as well as prodrugs thereof. 8. Process for producing a compound of the formula I according to one or more of claims 1-7, characterized in that two or more fragments which can be retrosynthetically derived from the formula I are connected. 9. Process according to claim 8, characterized in that for the preparation of a compound of formula I, a compound of formula rv is reacted where LI means a leaving group, stepwise with a compound of formula V, and with a compound of formula VII to a compound of formula VIII since in the formulas V, VU and VHl can L2 means a leaving group; the residue Rn means -(CH2)n-A-(CH2)m-R<10> the residue R<15> means-B-(CH2)„-D-(CH2)m-R<13> R<10> has the meanings given in claims 1 to 7 to the group R<4>, as the groups standing for R<4> can also be present in protected form; R<13> has the meanings of the groups D-E specified in claims 1 to 7, since D-E containing groups can also be present in protected form, or R<13> means a group, which can be converted into the group D-E; A, n and m have the meanings given in claims 1 to 7; and then optionally the groups R<10> and R13 are transferred to the groups R<4> and E. 10. Compounds with the formula I according to one or more of claims 1-7 and/or physiologically tolerable salts for use as medicine. 11. Compounds with the formula I according to one or more of claims 1-7 and/or physiologically tolerable salts thereof for use as inhibitors of bone resorption or osteoclasts, as inhibitors of tumor growth or tumor metastasis, as anti-inflammatory agents, for therapy or prophylaxis of cardiovascular diseases, for therapy or prophylaxis of nephropathies or retinopathies, or as vitronectin receptor antagonists for the therapy or prophylaxis of diseases, which depend on the interaction between vitronectin receptors and their ligands by cell-cell or cell-matrix interaction processes. 12. Pharmaceutical preparation, characterized in that it contains at least one compound of formula I according to one or more of claims 1 to 7 and/or a physiologically tolerable salt thereof in addition to pharmaceutically tolerable carriers and/or additives.