AU728865B2 - Substituted purine derivatives, processes for their preparation, their use, and compositions comprising them - Google Patents

Description

'Iu/Ul 2/5/91 Regulation 3.2(2)

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: *8 4* Invention Title: SUBSTITUTED PURINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION, THEIR USE, AND COMPOSITIONS COMPRISING

THEM

The following statement is a full description of this invention, including the best method of performing it known to us 1 4 HOECHST AKTIENGESELLSCHAFT HOE 96/F 354 Dr.EK/sch Description Substituted purine derivatives, processes for their preparation, their use, and compositions comprising them The present invention relates to compounds of the formulae I and la W Wa N N N

N

N N x I x G Ga (la) oo in which X, Y, W, Wa, G and Ga have the meanings indicated below, and to their physiologically tolerable salts and their prodrugs, their preparation, their use and pharmaceutical preparations comprising them.

The compounds of the formula I are valuable pharmaceutical active compounds. In particular, they are vitronectin receptor antagonists and are suitable for the therapy and prophylaxis of illnesses which are based on the interaction between vitronectin 0' receptors and their ligands in cell-cell or cell-matrix interaction processes or which can be prevented, alleviated or cured by influencing this interaction. The invention relates, inter alia, to the use of compounds of the formula I and of their physiologically tolerable salts and of pharmaceutical preparations which contain such compounds, as therapeutics for the prevention, alleviation or cure of illnesses which are caused at least partially by an undesired extent of bone resorption, angiogenesis or proliferation of cells of the vascular smooth musculature, or for whose therapy or prophylaxis an influencing of these processes is intended. In particular, the compounds of the formula I are suitable, for example, as inhibitors of bone resorption, as inhibitors of tumor growth and tumor metastasis, as antiinflammatories, for the treatment or prophylaxis of cardiovascular disorders, 2 such as, for example, arteriosclerosis or restenosis, or for the treatment or prophylaxis of nephropathies and retinopathies, such as, for example, diabetic retinopathy.

The compounds of the formulae I and la according to the invention inhibit bone resorption by osteoclasts. Bone diseases against which the compounds of the formula I can be employed are especially osteoporosis, hypercalcemia, osteopenia, for example caused by metastases, dental disorders, hyperparathyroidism, periarticular erosions in rheumatoid arthritis and Paget's disease. The compounds of the formula I can furthermore be employed for the alleviation, avoidance or therapy of bone disorders which are caused by glucocorticoid, steroid or corticosteroid therapy or by a lack of sex hormone(s). All these disorders are characterized by bone loss which is based on the inequilibrium between bone formation and bone destruction.

Human bones are subject to a constant dynamic renovation process comprising bone resorption and bone formation. These processes are controlled by types of cell specialized for these purposes. Bone formation is based on the deposition of bone matrix by osteoblasts, and bone resorption is based on the destruction of bone 20 matrix by osteoclasts. The majority of bone disorders are based on a disturbed equilibrium between bone formation and bone resorption. Osteoporosis is characterized by a loss of bone matrix. Activated osteoclasts are polynuclear cells having a diameter of up to 400 pm, which 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 region between their cell membrane and the bone matrix. The acidic environment and the proteases cause the destruction of the bone.

Studies have shown that the attachment of osteoclasts to the bones is controlled by integrin receptors on the cell surface of osteoclasts. Integrins are a superfamily of receptors which include, inter alia, the fibrinogen receptor allbB 3 on the blood platelets and the vitronectin receptor av 3 The vitronectin receptor aB33 is a membrane glycoprotein which is expressed on the cell surface of a number of cells I) 3 such as endothelial cells, cells of the vascular smooth musculature, osteoclasts and tumor cells. The vitronectin receptor av13, which is expressed on the osteoclast membrane, controls the process of attachment to the bone and bone resorption and thus contributes to osteoporosis. av13 in this case binds to bone matrix proteins such as osteopontin, bone sialoprotein and thrombospontin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).

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

Wayne et al. Clin. Invest. 1997, 99, 2284) were able to demonstrate in the rat the in vivo efficacy of the inhibition of bone resorption by a vitronectin receptor antagonist.

The vitronectin receptor avB 3 on human cells of the vascular smooth musculature of 20 the aorta stimulates the migration of these cells into the neointima, which finally 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) and Mitjans et al., J. Cell Science 1995, 108, 2825) showed that antibodies against av1 3 or avB 3 antagonists can cause a shrinkage of tumors by inducing the apoptosis of blood vessel cells during angiogenesis. Cheresh et al. (Science 1995, 270, 1500) describe anti-av 3 antibodies or ava 3 antagonists which inhibit the bFGF-induced angiogenesis process in the rat eye, a property which can be used therapeutically in the treatment of retinopathies.

EP-A-0 528 586 and EP-A-0 528 587 disclose aminoalkyl- or heterocyclylsubstituted phenylalanine derivatives, and WO 95/32710 discloses aryl derivatives I 4 as inhibitors of bone resorption by osteoclasts. WO 95/28426 describes RGD peptides as inhibitors of bone resorption, angiogenesis and restenosis. WO 96/00574 and WO 96/26190 describe benzodiazepines, inter alia, as vitronectin receptor antagonists or integrin receptor antagonists. WO 96/00730 describes fibrinogen receptor antagonist templates, in particular benzodiazepines, which are linked to a nitrogen-bearing 5-membered ring, as vitronectin receptor antagonists.

EP-A-0 531 883 describes fused 5-membered heterocycles which inhibit fibrinogen binding to platelets.

The present invention relates to compounds of the formulae I and la 4 1

W

N N N N

N

N

I

G (I) Wa N N N N x I Ga 4 in which: X is hydrogen, NR 6

R

6 fluorine, chlorine, bromine, OR 6

SR

6 hydroxy-(Cl-C 6 alkyl-NH, (hydroxy-(C 1

-C

6 )-alkyl) 2 N, amino-(C 1

-C

6 )-alkyl-NH, (amino-(C-C 6 alkyl) 2 N, hydroxy-(C 1

-C

6 )-alkyl-0, hydroxy-(C 1

-C

6 )-alkyl-S or NH-CO-R 6 Y is R 6 fluorine, chlorine, bromine, cyano, NR 6

R

6

OR

6

SR

6 or hydroxy-(C 1

C

6 )-alkyl-NH; G is a radical of the formula II

-(CR

1

R

2

)-A(CR

1

R

2 )m-(CR 1

R

3 )i-(CR R 2 )q-R 4 W is a radical of the formula III -B-(CR R 2 )r-A'(CR 1

R

2 )r_(CR 1

R

3 )k-(CR 1

R

2 )t-D-E (Ill); Ga is a radical of the formula Ila

-(R

1 2 CR R 2

R

3

R

2 )t-D-E (IlIa); Wa is a radical of the formula lIla

-B-(CR

1

R

2

R

2 )m-(CR 1

R

3 )i-(CR R 2 )q-R 4 (lila); A, A' independently of one another are a direct bond, -C(O)NR 5

-NR

5

-NR

5 -S2- (C 5

-C

1 4)-arylene, where in the aryl .:..*radical one to five carbon atoms can be replaced by one to five heteroatoms,

(C

2 -C4)-alkynylene, (C 2

-C

4 )-alkenylene, or a divalent radical of a 3- to 7membered saturated or unsaturated ring which can contain one or two heteroatoms, such as, for example, nitrogen, sulfur or oxygen, and which can be monosubstituted or disubstituted by radicals from the group consisting of =S and R 3

R

1

R

2 independently of one another are hydrogen, fluorine, chlorine, cyano, nitro,

(C

1

-C

1 0 )-alkyl, (C 3

-C

14 )-cycloalkyl, (C 3

-C

1 4 )-cycloalkyl-(C 1

-C

8 )-alkyl, (C 5

C

1 4-aryl, (C 5

-C

1 4 )-aryl-(C 1

-C

8 )-alkyl, R 6

-O-R

7

R

6

_S(O)P-R

7 or R 6

R

6

'N-R

7

R

3 independently of one another is hydrogen, fluorine, chlorine, cyano, nitro,

(C

1

-C

1 8 )-alkyl, (C 3

-C

1 4 )-cycloalkyl, (C 3

-C

1 4 )-cycloalkyl-(C 1

-C

8 )-alkyl, (C 5

C

1 4-aryl, (C 5

-C

1 4-aryl-(C 1

-C

8 )-alkyl, R 6

-O-R

7

R

6

R

6 4

N-R

7

R

6 C(O)-O-R

R

6

C(O)R

7

R

6

OC(O)R

7

R

6

N(R

6

R

6

S(O)PN(R

5

R

6

OC(O)N(R

5

)R

7

R

6

C(O)N(R

5

*)R

7

R

6

N(R

6

')C(O)N(R

5

)R

7 R6N(R 6

')S(O)PN(R

5

)R

7

R

6

S(O)PR

7

R

6

SC(O)N(R

5

)R

7

R

6

N(R

6

')C(O)R

7 or

R

6

N(R

6 ')S(O)PR where alkyl can be monounsaturated or polyunsaturated and where furthermore alkyl and aryl can be monosubstituted or polysubstituted by fluorine, chlorine, bromine, cyano, R 6

R

6

'NR

7 nitro,

R

6

OC(O)R

7

R

6

C(O)R

7

R

6

N(R

6

')C(O)R

7

R

6

N(R)S)R

7 k 6 or-O-R; 6 R 4 is C(O)R 8 C(S)R 8 S(O)pR 8

P(O)R

8 R 8 or a radical of a four- to eightmembered saturated or unsaturated heterocycle which contains 1, 2, 3 or 4 heteroatoms from the group consisting of N, 0, S, such as, for example, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiadiazolyl; R 5 independently of one another is hydrogen, (CI-Cl 0 )-alkyl, (C 3

-C

14 )-cycloalkyl,

(C

3

-C

1 4 )-cycloalkyl-(C 1

-C

8 )-alkyl, (C 5 -C 4)-aryl or (C 5

-C

1 4 )-aryl-(C 1 -C,)-alkyl; R 6 R 6 independently of one another are hydrogen, (C 1

-C,

8 )-alkyl, (C 3

-C

1 4)cycloalkyl, (C 3

-C

14 )-cycloalkyl-(C 1

-C

8 )-alkyl, (C 5

-C

14 )-aryl, in which 1 to carbon atoms can be replaced by heteroatoms such as N, 0, S, or CC4) aryl-(Cl-C 8 )-alkyl, in which, in the aryl moiety, 1 to 5 carbon atoms can be :.replaced by heteroatoms such as N, 0, S, or R 6 and R 6 together with the atoms connecting them, form a ring system, in particular a 4- to 8-membered ring system which can optionally also contain additional, in particular one, two or three additional, heteroatoms from the group consisting of N, 0, S and which can be saturated or unsaturated, in particular saturated, such as, for example, morpholine, thiomorpholine, piperazine, piperidine, pyrrolidine; R 7 independently of one another is (C 1 -C4)-alkylene or a direct bond; R 8

R

8 independently of one another are hydroxyl, (Cl-C 8 )-alkoxy, (C 5

-C

1 4)-aryl-

(C

1

-C

8 )-alkoxy, (C 5 -C 4)-aryloxy, (C 1

-C

8 )-alkylcarbonyloxy-(C 1

-C

4 )-alkoxy,

(C

5 -C 4)-aryl-(C 1

-C

8 )-alkylcarbonyloxy-(C 1

-C

8 )-alkoxy, NR 6 R 6 (di((C 1

-C

8 alkyl)amino)carbonylmethyloxy, (di((C 5

-C

1 4 )-aryl-(C 1

-C

8 )-alkyl)amino)carbonylmethyloxy, (C 5

-C

1 4)-arylamino, the radical of an amino acid,

N-((C

1

-C

4 )-alkyl)piperidin-4-yloxy, 2-methylsulfonylethoxy, 1, 3-thiazol-2ylmethyloxy, 3-pyridylmethyloxy, 2-(di((Cl-C4)-alkyl)amino)ethoxy or the radical Q- (CH 3 3

N+-CH

2

-CH

2 in which Q- is a physiologically tolerable anion; B is -NR 5 -NR 5 -C(0)-NR 5 a direct bond or a divalent radical of a 3- to 7-membered saturated or unsaturated ring which can 6 7 contain one or two heteroatoms, such as, for example, nitrogen, suifur or oxygen, and which can be monosubstituted or disubstituted by radicals from the group consisting of =S and R 3 D is a direct bond, -NR 6 -C(0)-NR 6

-NR

6 -S(0)u-NR 6 -NR6-C(O)-NR 6

-NR

6

-C(S)-NR

6

-NR

6 -S(O)u-NR 6

-NR

6 -NR6-N=CR6-, -NR6-S(O)u-, -(C5-Ci4)-aryl-CO-, -(C5-C14)-aryl-S(O)u-,

-N=CR

6

-R

6 C=N- or -R 6

C=N-NR

6 where the divalent radicals representing D are bonded to the group E via the free bond on the right side; E is hydrogen, R6C(=NR 6

)-NR

6

R

6 R6'N-C(=NR 6

R

6

R

6

'N-C(=NR

6

)-NR

6 or a radical of a 4- to 11-membered, monocyclic or polycyclic, aromatic or nonaromatic ring system which can optionally contain 1, 2, 3 or 4 heteroatoms from the group consisting of N, O and S and can optionally be monosubstituted, disubstituted or trisubstituted by radicals from the group consisting of R 3

R

5 =S and R 6

R

6

'N-C(=NR

6 such as, for example, the following radicals: a a a a.

a. a.

a.

R

5

R

3

N

S /'3

N

R

3

N

R3 S

^CN

R

N

NN

N"N

s

N,

N

Cii

I

9tl r r r r

N

N

9I Ul '<0C

S..

S

S.

S.

\N<N N N A(

\I:

N NI7 t 9H

N

N

H

HN yNH

INH

N N N 0,N-NN

N

R 0 R NH 2 N N H N N NH HN N I 02 provided that E is different from hydrogen if one or both of the groups B and D are a direct bond, and provided that the radical of a ring system representing E is not a phenyl radical or a furyl radical; n is zero, one, two three, four or five; m is zero, one, two, three, four or five; 20 s is zero; one, two, three, four or five; t is zero; one, two, three, four or five; k is zero or one; u is one or two; v is zero, one, two or three; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs; where, instead of the purine structure shown in the formulae I and la, a 3deazapurine structure, a 7-deazapurine structure or a 7-deaza-8-azapurine structure can also be present.

All radicals and indices which can occur several times in the compounds of the formulae I and la, for example the radicals R 1

R

2 and R 3 occurring in the radicals G and W and the radicals R 5

R

6

R

6

R

7 and indices occurring therein, but also all other radicals and indices to which this applies, can each independently of one another have the meanings indicated. They can be identical or different. Likewise, heteroatoms in heterocycles or substituents in radicals which can be present several times independently of one another can have the meanings indicated and can be identical or different.

The alkyl radicals occurring in the substituents can be straight-chain or branched, saturated or mono- or polyunsaturated. This also applies if they carry substituents or occur as substituents of other radicals, for example in alkoxy radicals, alkoxycarbonyl radicals or aralkyl radicals. The same applies to the divalent alkylene radicals.

Examples of suitable (Cl-C 18 )-alkyl radicals are: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, undecyl, dodecyl, tridecyl, hexadecyl, octadecyl, the n-isomers of these radicals, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, 2,3,4-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl. Preferred alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and terto butyl.

Unsaturated alkyl radicals are, for example, alkenyl radicals such as vinyl, 1propenyl, allyl, butenyl, 3-methyl-2-butenyl or alkynyl radicals such as ethynyl, 1propynyl or propargyl. Alkenylene and alkynylene radicals can be straight-chain or branched. Examples of alkenylene radicals are vinylene or propenylene, examples of alkynylene radicals are ethynylene or propynylene.

Cycloalkyl radicals can be monocyclic, bicyclic or tricyclic. Monocyclic cycloalkyl radicals are, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, furthermore, for example, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl or cyclotetradecyl, which, however, can also all be substituted by, for example, (Cl-C 4 )-alkyl. Examples of substituted cycloalkyl 11 radicals which may be mentioned are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.

Bicyclic and tricyclic cycloalkyl radicals can be unsubstituted or can be substituted in any desired suitable positions by one or more oxo groups and/or one or more identical or different (C 1

-C

4 )-alkyl groups, for example methyl groups or isopropyl groups, preferably methyl groups. The free bond of the bicyclic or tricyclic radical can be located in any desired position of the molecule; the radical can thus be bonded via a bridgehead atom or via an atom in a bridge. The free bond can also be located in any desired stereochemical position, for example in an exo-position or an endo-position.

Examples of parent structures of bicyclic ring systems are norbornane bicyclo[2.2.1 ]heptane), bicyclo[2.2.2]octane and bicyclo[3.2.1]octane. An example of a system substituted by an oxo group is camphor 1,7,7-trimethyl-2-oxobicyclo[2.2.1]heptane).

Examples of parent structures of tricyclic systems are twistane tricyclo[4.4.0.0 3 8 ]decane, adamantane tricyclo[3.3.1.1 3 7 ]decane), noradamantane tricyclo[3.3.1.03, 7 ]nonane), tricyclo[2.2.1 .0 2 6 ]heptane, tricyclo[5.3.2.0 4 9 ]dodecane, tricyclo[5.4.0.0 2 9 ]undecane or tricyclo[5.5.1.0 3 ,11]tridecane.

(C

5

-C

14 )-aryl includes heterocyclic (C 5

-C

1 4)-aryl radicals in which ring carbon atoms are replaced by heteroatoms such as nitrogen, oxygen or sulfur, and carbocyclic

(C

6

-C

1 4)-aryl radicals. Examples of carbocyclic aryl radicals are phenyl, naphthyl, biphenylyl, anthryl or fluorenyl, where 1-naphthyl, 2-naphthyl and in particular phenyl are preferred. Aryl radicals, in particular phenyl radicals, can be monosubstituted or polysubstituted, preferably monosubstituted, disubstituted or trisubstituted, by identical or different radicals from the group consisting of (C 1

-C

8 alkyl, in particular (C 1

-C

4 )-alkyl, (C 1

-C

8 )-alkoxy, in particular (C 1

-C

4 )-alkoxy, halogen, such as fluorine, chlorine and bromine, nitro, amino, trifluoromethyl, hydroxyl, methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C 1

-C

4 12 alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, (R 9 0) 2

(R

9 0) 2 or tetrazolyl, where R 9 is hydrogen, (Ci-Clo)-alkyl, (C 6

-C

1 4)-aryl or (C 6

-C

1 4)-aryl-

(C

1

-C

8 )-alkyl. The same applies to the corresponding arylene radicals.

In monosubstituted phenyl radicals, the substituent can be located in the 2-position, the 3-position or the 4-position, the 3- and the 4-position being preferred. If phenyl is disubstituted, the substituents can be in the 1,3- or 1,4-position relative to one another. With respect to the linkage site, the substituents can be located in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or Preferably, in disubstituted phenyl radicals the two substituents are arranged in the 3-position and the 4-position, relative to the linkage site.

Aryl groups or arylene groups can also be monocyclic or polycyclic aromatic ring systems in which 1, 2, 3, 4 or 5 ring carbon atoms are replaced by heteroatoms, such as, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, Squinoxalinyl, quinazolinyl, cinnolinyl, B-carbolinyl, or a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of these radicals. These heterocycles can 20 be substituted by the same substituents as the abovementioned carbocyclic aryl systems.

In the series of these aryl groups or of the corresponding arylene groups, monocyclic or bicyclic aromatic ring systems having 1, 2 or 3 heteroatoms from the group consisting of N, O, S, which can be unsubstituted or substituted by 1, 2 or 3 substituents from the group consisting of (C 1

-C

6 )-alkyl, (Cl-C 6 )-alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxyl, (C -C 4 )-alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl, are preferred.

Particularly preferred here are monocyclic or bicyclic aromatic 5- to ring systems having 1 to 3 heteroatoms from the group consisting of N, O, S, which can be substituted by 1 to 2 substituents from the group consisting of (C 1

-C

4 )-alkyl,

(C

1

-C

4 )-alkoxy, phenyl, phenoxy, benzyl and benzyloxy.

13 Examples of saturated and unsaturated rings, in particular of 3- to 7-membered saturated or unsaturated rings which can contain one or two heteroatoms such as, for example, nitrogen, sulfur or oxygen and can optionally be monosubstituted or disubstituted by =S or R 3 are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, tetrahydropyran, 1,4-dioxacyclohexane, morpholine, thiomorpholine, piperazine, piperidine, pyrrolidine, dihydroisoxazole, tetrahydroisoxazole, 1,3-dioxolane, 1,2-dithiolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, 2,3-dihydrothiophene, 2,5-dihydrothiophene, 2-imidazoline, 3-imidazoline, 4-imidazoline, 2-oxazoline, 3-oxazoline, 4-oxazoline, 2-thiazoline, 3-thiazoline, 4-thiazoline, thiazolidine, a-thiapyran, a-pyran, y-pyran.

8 8.

The radical of an amino acid representing R andlor R is, as usual in peptide chemistry, formally obtained by removing a hydrogen atom from the amino group of 015 the amino acid. By means of the free bond on the amino group formally obtained hereby, the radical of the amino acid is then bonded, for example, to the CO group in the group CO-R 8 Amino acids can be natural or unnatural amino acids, a-Amino acids are preferred. Amino acids can exist in different stereochemical forms, for example as D- or L-amino acids, and in stereochemically homogeneous form or in the form of mixtures of stereoisomers. Amino acids which may be mentioned, for example, are (cf. Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Volume XV/1 and 2, Georg Thieme Verlag, Stuttgart, 1974): Aad, Abu, yAbu, ABz, 2ABz, sAca, Ach, Acp, Adpd, Ahb, Aib, 3Aib, Ala, BAla, AAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys) 2 Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, GIn, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hile, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, lie, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, BLys, ALys, Met, Mim, Min, nArg, NIe, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, APro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, BThi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, tert-butylglycine (Tbg), neopentylglycine (Npg), cyclohexylglycine (Chg), cyclohexylalanine (Cha), 2-thienylalanine (Thia), 14 2,2-diphenylaminoacetic acid, 2-(p-tolyl)-2-phenylaminoacetic acid, 2-(pchlorophenyl)aminoacetic acid; furthermore: pyrrolidine-2-carboxylic acid; piperidine-2-carboxylic acid; I ,2,3,4tetrahydroisoquinoline-3-carboxylic acid; decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylic acid; decahydroquinol ine-2-carboxyl ic acid; octahydrocyclopenta[b]pyrrole-2-carboxyl ic acid; 2-azabicyclo[2 2]octane-3carboxylic acid; 2-azabicyclo[2.2.1I]heptane-3-carboxylic acid; 2azabicyclo[3. 1. 0]hexane-3-carboxylic acid; 2-azaspiro[4. 4]nonane-3-carboxyl ic acid; 2-azaspiro[4. 5]decane-3-carboxylic acid; spiro(bicyclo[2.2. 1 ]heptane)-2, 3acid; spiro(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid; 2-azatricyclo[4.3.0.1 6 9 ]decane-3-.carboxylic acid; decahydrocyclohepta[b]pyrrole-2-carboxyl ic acid; decahydrocycloocta[c]pyrrole-2carboxylic acid; octahydrocyclopenta[c]pyrrole-2-carboxylic acid; octahydroisoindole-1 -carboxylic acid; 2,3, 3a,4,6a-hexahydrocyclopenta[b]pyrrole-2carboxylic acid; 2,3,3a,4, 5,7a-hexahydroindole-2-carboxylic acid; tetrahydrothiazole- -carboxylic acid; isoxazolidine-3-carboxylic acid; pyrazolidine-3-carboxylic acid, hydroxypyrrolidine-2-carboxylic acid; all of which can be optionally substituted (see '.20 following formulae): N Ca- N CO- .1

CO-;

-CO-.

N N

S

S

**SS

S.

S

S.

S

.co-.

'S '0 S. S S. .0 *55*55 (q

SIS

S S ,S Sq a S..

CO-;

N

N

R~Ca-

N

co-.

C0; N C0 N C-

N

16

HO

CO-

N

The heterocycles on which the abovementioned radicals are based are disclosed, for example, in US-A-4,344,949; US-A 4,374,847; US-A 4,350,704; EP-A 29,488; EP-A 31,741; EP-A 46,953; EP-A 49,605; EP-A 49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870; EP-A 79,022; EP-A 84,164; EP-A 89,637; EP-A 90,341; EP-A 90,362; EP-A 105,102; EP-A 109,020; EP-A 111,873; EP-A 271,865 and EP-A 344,682.

Furthermore, the amino acids can also be present as esters or amides, such as, for example, as the methyl ester, ethyl ester, isopropyl ester, isobutyl ester, tert-butyl ester, benzyl ester, unsubstituted amide, methylamide, ethylamide, semicarbazide or w-amino-(C 2

-C

8 )-alkylamide.

Functional groups of the amino acids can be protected. Suitable protective groups such as, for example, urethane protective groups, carboxyl protective groups and 15 side-chain protective groups are described in Hubbuch, Kontakte (Merck) 1979, No.

3, pages 14 to 23 and in Bullesbach, Kontakte (Merck) 1980, No. 1, pages 23 to The following may be mentioned in particular: Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(N0 2 Z(Haln), Bobz, Iboc, Adpoc, Mboc, Acm, terto* Butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.

The compounds of the formulae I and la according to the invention may be present as E/Z isomers. The invention relates to pure E isomers and pure Z isomers as well as to E/Z isomer mixtures in all ratios. The compounds of the formulae I and la can contain optically active carbon atoms which independently of one another may have the R- or S-configuration. They can be present 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. The invention relates to both pure enantiomers and enantiomer mixtures in all ratios and diastereomers and 17 diastereomer mixtures in all ratios. Diastereomers, including E/Z isomers, can be separated into the individual isomers, for example, by chromatography. Racemates can be separated into the two enantiomers, for example, by chromatography on chiral phases or by resolution. If mobile hydrogen atoms are present, the present invention also includes all tautomeric forms of the compounds of the formulae I and la.

Physiologically tolerable salts of the compounds of the formulae I and la are, in particular, pharmaceutically utilizable or nontoxic, physiologically utilizable salts.

Such salts of compounds of the formulae I and la which contain acidic groups, for example carboxyl, are, for example, alkali metal salts or alkaline earth metal salts, such as, for example, sodium salts, potassium salts, magnesium salts and calcium salts, and also salts with physiologically tolerable quaternary ammonium ions and "15 acid addition salts with ammonia and physiologically tolerable organic amines, such as, for example, triethylamine, ethanolamine or tris(2-hydroxyethyl)amine.

Compounds of the formulae I and la, which contain basic groups, for example one or more amino groups, amidino groups or guanidino groups, form acid addition salts, .20 for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid.

A physiologically tolerable anion which is contained in the compounds of the formulae I and la when R 8 and/or R 8 is the 2-trimethylammonio-ethoxy radical, is, in particular, a monovalent anion or an equivalent of a polyvalent anion of a nontoxic, physiologically utilizable, in particular also pharmaceutically utilizable, inorganic or organic acid, for example the anion or an anion equivalent of one of the abovementioned acids suitable for the formation of acid addition salts. Q- can thus be, for example, one of the anions (or an anion equivalent) from the group consisting of chloride, sulfate, phosphate, acetate, citrate, benzoate, maleate, fumarate, tartrate, methanesulfonate and p-toluenesulfonate.

18 Salts can be obtained from the compounds of the formulae I and la by customary methods known to those skilled in the art, for example by combining the compounds of the formulae I and la with an inorganic or organic acid or base in a solvent or dispersant, or also from other salts by cation exchange or anion exchange. The present invention also includes all salts of the compounds of the formulae I and la which, because of low physiological tolerability, are not directly suitable for use in pharmaceuticals, but are suitable, for example, as intermediates for carrying out other chemical modifications of the compounds of the formulae I and la or as starting materials for the preparation of physiologically tolerable salts.

The present invention moreover includes all solvates of compounds of the formulae I and la, for example hydrates or adducts with alcohols, and also derivatives of the compounds of the formulae I and la, for example esters, prodrugs and metabolites, which act like the compounds of the formulae I and la. The invention relates in particular to prodrugs of the compounds of the formulae I and la, which can be converted into compounds of the formulae I and la under physiological conditions.

Suitable prodrugs for the compounds of the formulae I and la, i.e. chemically modified derivatives of the compounds of the formulae I and la having properties *I'.o0 which are improved in a desired manner, are known to those skilled in the art. More detailed information relating to prodrugs is found, for example, in Fleisher et al., SAdvanced Drug Delivery Reviews 19 (1996) 115-130; Design of Prodrugs, H.

Bundgaard, Ed., Elsevier, 1985; H. Bundgaard, Drugs of the Future 16 (1991) 443; Saulnier et al., Bioorg. Med. Chem. Lett. 4 (1994) 1985; Safadi et al., Pharmaceutical Res. 10 (1993) 1350. Suitable prodrugs for the compounds of the formulae I and la are especially ester prodrugs of acid groups, for example of carboxylic acid groups, in particular of a COOH group representing R 4 and also acyl prodrugs and carbamate prodrugs of acylatable nitrogen-containing groups such as amino groups, amidino groups or guanidino groups, in particular of the groups R 6

-C(=NR

6

)-NR

6

R

6

R

6

'N-C(=NR

6

R

6

R

6

'N-C(=NR

6

)-NR

6 and the 4- to 11-membered, monocyclic or polycyclic, aromatic or nonaromatic ring system representing the group E. In the acyl prodrugs or carbamate prodrugs, a hydrogen atom located on a nitrogen atom is replaced one or more times, for example twice, 19 in these groups by an acyl group or carbamate group. Suitable acyl groups and carbamate groups for the acyl prodrugs and carbamate prodrugs are, for example, the groups R 6 -CO and R 6 0-CO, in which R 6 has the meanings indicated above, i.e.

hydrogen, (Ci-C 18 )-alkyl, (C 3

-C

1 4)-cycloalkyl, (C 3 -Ci4)-cycloalkyl-(Ci-C 8 )-alkyl, (C 5

C

14 )-aryl, in which 1 to 5 carbon atoms can be replaced by heteroatoms such as N, O, S, or (C 5

-C

14 )-aryl-(C 1

-C

8 )-alkyl, in which 1 to 5 carbon atoms in the aryl moiety can be replaced by heteroatoms such as N, O, S, combinations of substituent meanings which in the individual case lead to unstable compounds, for example to unstable free carbamic acids, not being suitable. These prodrugs can be prepared by customary methods familiar to those skilled in the art for the preparation of acylamines and carbamates.

The present invention is furthermore not restricted to the compounds according to the formulae I and la having a purine parent structure, but also includes those compounds which instead of the purine parent structure shown in the formulae I and la have a 3-deazapurine structure, 7-deazapurine structure or 7-deaza-8-azapurine structure, i.e. compounds of the formulae Ib and Ic, Id and le and If and Ig.

W Wa "N

N

o. N I

X

X G (Ib) G a (Ic) W Wa -N N N N N N N x I x I n (Id) Ga (le) W Wa

NN

N N N N X X I G (If)

G

a (ig) All the above and following details relating to the compounds of the formulae I and la apply to the compounds of the formulae Ib and Ic, Id and le, If and Ig correspondingly. If compounds of the formulae I and la are being discussed, then, if not stated otherwise, the deaza analogs and deaza-aza analogs of the formulae Ib and Ic, Id and le, If and Ig are also included. Preferably, in the compounds according to the invention the purine structure actually shown in formulae I and la is present, in which the nitrogen atoms are present in the 3-position and in the 7position and a carbon atom with the group Y bonded thereto is present in the 8position.

S@OS

In the compounds of the formulae I and la, X is preferably hydrogen, NR 6

R

6 hydroxy-(C 1

-C

6 )-alkyl or NH-CO-R 6 particularly preferably hydrogen, NR6R 6 or 6 .20 NH-CO-R 6 very particularly preferably hydrogen or NH 2 Y is preferably hydrogen.

4 is preferably C(O)R 8 Preferred compounds according to the invention are also So. those of the formulae I and la in which R 3 is R 6

R

6

N-R

7 R60C(O)N(R 5

)R

7 RS(O)N(R)R 7

R

6

C(O)N(RS)R

7 or R 6

N(R

6

')C(O)N(R

5

)R

7 where p here is 1 or 2, in particular compounds in which R 3 is R60C(O)N(R 5

)R

7 or R 6 S(O)pN(R 5

)R

7 (where p 1 or particularly preferred compounds here are those in which a lipophilic radical is contained in R 3 for example compounds in which R 6 and/or R 6 for example in the group R60C(O)N(R 5

)R

7 is (C 4

-C

14 )-alkyl, (C 5

-C

1 4)-aryl-(Cl-C4)alkyl, for example benzyl, (C 5

-C

14 )-cycloalkyl or (C 5

-C

1 4 )-cycloalkyl-(C 1 -C4)-alkyl, preferred cycloalkyl radicals here in particular being the 1-adamantyl radical and the 2-adamantyl radical.

A preferred group of compounds according to the invention is formed by compounds of the formulae I and la in which: 21 X is hydrogen, NH- 2 OH or NH-CO-R 6 Y is hydrogen; G is a radical of the formula 11 (CRR R 2 n-A-(C R 1

R

2 )m_(CRR R 3 )i-(CR R 2 )q-R 4 (1I); W is a radical of the formula Ill -B(CR' R 2 )rA'(CRR R 2 )r-(CR 1 R R 3 )k-(CR 1 R R 2 )t-D-E (Ill); G a is aradical of the formula Ila 15 -(CR 1

R

2

R)-C

1 R)k-(CR'R R)t-D-E (IlIa);

W

V~a is a radical of the formula lila

*:B-(CR

1

R

2 )nA-(CRI R 2 )m_(CR 1 R 3 )i(CR 1 R 2 )q-R 4 (lHla); A, A' independently of one another are a direct bond, -C(O)NR 5

-NR

5 -NR 5 -S2- (C 5

-C

1 4)-arylene, it being possible in the aryl radical for one to five carbon atoms to be replaced by one to five heteroatoms, (C 2

-C

4 )-alkynylene, (C 2

-C

4 )-alkenylene, or a divalent radical of a 3- to 7-membered saturated or unsaturated ring, which can contain one or two heteroatoms, such as, for example, nitrogen, sulfur or oxygen and which can be monosubstituted or disubstituted by =S or R 3

R

1 R 2 independently of one another are H, fluorine, chlorine, CN, nitro, (Ci-C 10 alkyl, (C 3 -CI 4 )-cycloalkyl, (C 3 2 )-cycloalkyl-(C 1

-C

8 )-alkyl, (C 5 4 )-aryl,

(C

5

-C

14 )-aryl-(C 1

-C

8 )-alkyl, R 6 _O-R R 6 -S(O)p-R 7 or R 6 R 6 N-R 7 independently of one another is H, fluorine, chlorine, ON, nitro, (C 1

-C

14 22 alkyl, (C 3

-C

1 4 )-cycloalkyl, (C 3 -C 4)-cycloalkyl-(C 1

-C

8 )-alkyl, (C 5

-C

1 4)-aryl,

(C

5

-C

1 4)-aryl-(C 1

-C

8 )-alkyl, R 6

_O-R

7 R 6 7

R

6 R 6

N-R

7

R

6 CO2 R 7 R 6

COR

7

R

6 OC(O)R 7 R 6 N(R 5 )C(O)0R 7 R 6 S(O)pN(R 5 )R 7 R 6 0C(O)N(RI)R 7 R 6 C(O)N(R 5 )R 7

R

6 N(R 5 )C(O)N(R 5 )R 7 R 6

N(R

5 )S(O)pN(R 5 )R 7 R 6 S(O)pR 7

R

6 SC(O)N(R 5 )R 7 R 6 C(O)R 6 R 6 N(R 5 )C(O)R 7 or R 6 N(R 5 )S(O)PR 7 it being possible for alkyl to be monounsaturated or polyunsaturated and it furthermore being possible for alkyl and aryl to be monosubstituted or polysubstituted by fluorine, chlorine, bromine, CN, R 6

N(R

5 )R 7 R 6 R 6 NR 7 nitro, R 6 OC(O)R 7 R 6 C(O)R 7 R 6 N(R 5 )C(O)R 7 R 6 N(R 5 )S(O)PR 7 R 6 R 6 -0-R 7 R 4 is C(O)R 8

C(S)R

8

S(O)PR

8

POR

8

R

8 an L- or 0-amino acid or a four- to eight-membered, saturated or unsaturated heterocycle which contains 1, 2, 3 or 4 heteroatoms from the group consisting of N, 0, S, such as, for example, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiadiazolyl;

R

5 is H, (C 1 -Clo )-alkyl, (C 3

-C

1 4 )-cycloalkyl,'(C 3 -Cl 1 4)-cycloalkyl-(C 1

-C

8 )-alkyl,

(C

5

-C

1 4 )-aryl or (C 5

-C

1 4 )-aryl-(C 1

-C

8 )-alkyl; ?0 R 6 R 6 independently of one another are H, (C 1

-C

8 )-alkyl, (C 3

-C

14 )-cycloalkyl, (C 3

C

14 )-CYCloalkyl-(Cj-C 8 )-alkyl, (C 5

-C

14 )-aryl, it being possible for 1 5 carbon atoms to be replaced by heteroatoms, or (C 5

-C

14 )-aryl-(C 1

-C

8 )-alkyl, it being possible for 1 5 carbon atoms in the aryl moiety to be replaced by heteroatoms, or R 6 and R together with the atoms connecting them, form a ring system which can optionally also contain further heteroatoms from the group consisting of N, S, 0, such as, for example, morpholine, piperazine, piperidine, pyrrolidine;

R

7 independently of one another'is (Cl-C 4 )-alkylene or a direct bond;

R

8

R

8 independently of one another are OH, (C 1

-C

8 )-alkoxy, (C 5

-C

14 )-aryl-(C 1

-C

8 alkoxy, (C 5

-C

1 4 )-aryloxy, (C 1

-C

8 )-alkylcarbonyloxy-(C 1

-C

4 )-alkoxy, (C 5

-C

1 4)aryl-(C 1

-C

8 )-alkylcarbonyloxy(C 1

-C

6 )-alkoxy, NR 6

R

6

(C

1

-C

8 II I 23 dialkylaminocarbonylmethyloxy,

(C

5 -C 4 -aryl-(C -C 8 dialkylaminocarbonylmethyloxy, (C 5

-C

1 4)-arylamino or an L- or D-amino acid; a B is O, S, NR 5

-NR

5 -C(0)-NR 5 a direct bond or a divalent radical of a 3- to 7-membered saturated or unsaturated ring which can contain one or two heteroatoms, such as, for example, nitrogen, sulfur or oxygen, and which can be monosubstituted or disubstituted by =S or R 3 D is a direct bond, -NR 6 -C(0)-NR 6

-NR

6 -SO2NR 6

-NR

6

-C(O)-NR

6

-NR

6

-C(S)-NR

6

-NR

6 -S(O)u-NR 6

-NR

6

-NR

6

-N=CR

6

-NR

6

-(C

5

-C

14 )-aryl-CO-, -(C 5

-C

14 )-aryl-S(O)u-,

-N=CR

6 -RC=N- or -R6C=N-NR 6 E is hydrogen, R 6

-C(=NR

6

)NR

6

R

6

R

6

'N-C(=NR

6

R

6

R

6

'N-C(=NR

6

)-NR

6 or a 4- to 11-membered, mono- or polycyclic, aromatic or nonaromatic ring system which can optionally contain 1- 4 heteroatoms from the group consisting of N, O and S and can optionally be monosubstituted to trisubstituted by R 3

R

5 =S or R 6

R

6

'N-C(=NR

6 such as, for example, R0 the radicals indicated with their structural formulae in the above definition of

E;

n m i

P

q r s t k u v is zero, one, two, three, four or five; is zero, one, two, three, four or five; is zero or one; independently of one another is zero, one or two; independently of one another is zero, one or two; is zero, one, two, three, four, five or six; is zero, one, two, three, four or five; is zero, one, two, three, four or five; is zero or one; is one or two; in the radicals indicated in the above definition of E is the numbers zero, one, two or three; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts, where, in this group of preferred compounds, the analogs having a 3-deazapurine structure, 7-deazapurine structure or 7-deaza-8azapurine structure are not included.

A further group of preferred compounds is formed by compounds of the formulae I and la in which: X is hydrogen, NR 6

R

6 hydroxy-(C 1

-C

6 )-alkyl-NH or NH-CO-R 6 4* Y is hydrogen; G is a radical of the formula II -(CR R 2 -A(CR R 2 )m CR 1 R) (CR 1

R

2 )q-R 4

(II);

W is a radical of the formula III

R

2

R

2 )s(CR R 3 )k-(CR 1

R

2 )t-D-E (III); Ga is a radical of the formula Ila

-(CR

1

R

2 )r-A CR R 2 s

(CR

1

R

3 k

CR

1

R

2 D-E (Illa); Wa is a radical of the formula Ila

-B-(CR

1

R

2 )n-A-(CR 1

R

2 )m CR 1 R) CR 1

R

2 )q-R 4 (Ilia); A, A' independently of one another are a direct bond, -C(O)NRS-, -NR 5

-NR

5

(C

5

-C

14 )-arylene, it being possible for one to three carbon atoms in the aryl radical to be replaced by one to three heteroatoms from the group consisting of 0, N, S, (C 2

-C

4 )-alkynylene or

(C

2

-C

4 )-alkenylene; RI, R 2 independently of one another are hydrogen, fluorine, cyano, (Cl-C 4 )-alkyl,

(C

5

-C

6 )-aryl, (C 5

-C

6 )-aryI-(Cj-C4)-alkyl, R 6 -0-R 7 or R 6

R

6

'N-R

7

R

3 independently of one another is hydrogen, (C,-C 1 8 )-alkyl, (C 3

-C

1 4)-cycloalkyl,

(C

3 -C 4)-cycloalkyl-(C 1

-C

8 )-alkyl, (C 5

-C

1 4)-aryl, (C 5

-C

1 4-aryl-(C 1

-C

8 )-alkyl,

R

6

R

6

'N-R

7

R

6 C(0)R 7

R

6 S(0)PN(R 5

)R

7

R

6 OC(0)N(R 5

)R

7

R

6 C(0)N(R 5 )R

R

6

N(R

6 )C(0)N(R 5

)R

7

R

6

N(R

6 )S(0)PN(R 5

)R

7 or R 6

N(R

6 )C(0)R it being possible for alkyl to be monounsaturated or polyunsaturated and it furthermore being possible for alkyl and aryl to be monosubstituted or polysubstituted by fluorine, chlorine, bromine, cyano, R R 6

N

7 nitro, R6CO)7 R6(O4)R, R6N(R6')C(U)R7, R6N(R6)(O)PR7, R 6 or R 6 0R 7

R

4 is C(0)R 8

R

5 independently of one another is hydrogen or (Cl-C4)-alkyl; 20 R 6 RV independently of one another are hydrogen, (C 1

-C

18 )-alkyl, (C 3

-C

14 cycloalkyl, (C 3

-C

1 4 )-cycloalkyl-(C 1

-C

8 )-alkyl, (C 5

-C

1 4 )-aryl, in which one to three carbon atoms can be replaced by one to three heteroatoms from the group consisting of N, S, 0, or are (C 5

-C

14 )-aryl-(C 1

-C

8 )-alkyl, in which one to three carbon atoms in the aryl moiety can be replaced by one to three heteroatoms from the group consisting of N, S, 0, or R 6 and R 6 together with the atoms connecting them, form a ring system which can optionally also contain additional heteroatoms from the group consisting of N, S, 0, such as, for example, morpholine, piperazine, piperidine, pyrrolidine; R7 independently of one another is (Cl-C 2 )-alkylene or a direct bond; R8 independently of one another is hydroxyl, (C 1

-C

4 )-alkoxy, (C 5

-C

14 )-aryl-(C 1

C

4 )-alkoxy, (C 5 -CI 4 )-aryloxy, (C 1

-C

8 )-alkylcarbonyloxy-(C 1

-C

4 )-alkoxy, (C 5 qI 26

C

14 )-aryl-(C 1 -C4-alkylcarbonyloxy-(C 1 -C4)-alkoxy or the radical of an amino acid; B is -NR 5 a direct bond or a divalent radical of a 3- to 7-membered saturated or unsaturated ring which can contain one or two heteroatoms, such as, for example, nitrogen, sulfur or oxygen and which can be monosubstituted or disubstituted by radicals from the group consisting of Sand R 3 D is a direct bond, -NR 6 -C(0)-NR 6

-NR

6

-NR

6 -C(0)-NR 6

-NR

6

-NR

6

-N=CR

6

R

6

C=N-NR

6

-N-CR

6 or -R 6 where the divalent radicals representing 0 are bonded to the group E via the free bond on the right side; E is hydrogen, R 6

-C(=NR

6

)-NR

6

R

6

R

6

N-C(-NR

6

R

6

R

6

N-C(=NR

6

')-NR

6 or a radical from the group consisting of

A*W

4

I

R

N

R3

N

-f N

N

N

H R NN N

N

27 H N N SN

NH

H 0 which can optionally be monosubstituted to trisubstituted by radicals from the group consisting of R 3

R

5 =S and R 6

R

6

'N-C(=NR

6 n is one, two, three or four; m is zero or one; i is zero or one; q is zero or one; p independently of one another is zero, one or two; 5 r is zero, one, two, three, four or five; s is zero, one or two; t is zero, one or two; k is zero or one; v is zero, one, two or three; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.

Particularly preferred compounds of the formulae I and la are those in which: X is hydrogen, NR 6 R6' or NH-CO-R 6 Y is hydrogen; G is a radical of the formula II

-(CR

1

R

2 )-A CR'R 2 )m CR R 3 CR R 2 q -R (II); 28 W is a radical of the formula Ill -Bl-(CRR R 2 rA'-(CR'R 2 I R 3

R

2 (Ill); Ga is a radical of the formula Ila -<CR'R 2 )rA:(CRR R 2 8

-(CR

1 R R 3 )k-(CR'R R 2 )t-D-E (Ila); Wa is a radical of the formula Ilila

R

2 2 )m_(CR1 R 3 )i(CR 1 R 2 )q-R 4 (Illa); A, A' independently of one another are a direct bond, -C(O)NR 5

-NR

5 or

(C-C

6 )-arylene, it being possible for one to two carbon atoms in the aryl radical to be replaced by nitrogen atoms;

R

1 R are hydrogen; R. 3 independently of one another is hydrogen, (Cl-Cl 0 )-alkyl, (C 3 -Cl 4 10cycloalkyl, (C 3 -C 4)-cycloalkyl-(C, -C 8 )-alkyl, (C 5

-C

1 4 )-aryl, (C 5

-C

1 4 )-aryl- (Cl-C 8 )-alkyl, R 6

R

6 R 6 OC(O)N(R 5

R

6 C(O)N(R 5

)R,

R

6 N(R 6 )C(O)N(R 5 )R 7

R

6 C(O)R 7 or R 6

N(R

6 it being possible for 9 alkyl to be monounsaturated or polyunsaturated and it furthermore being possible for alkyl and aryl to be monosubstituted or polysubstituted by fluorine, chlorine, bromine, cyano, R 6 R 6 NR 7 R 6 C(O)R 7 R 6 N(R 6

)C(O)R,

R6or R 6 0OR 7 R4 is C(O)R 8 R 5 independently of one another is hydrogen or (Cl-C 4 )-alkyl; R 6 R 6 independently of one another are hydrogen, (Cl-C 8 )-alkyl, (C 3 -Cl 2 cycloalkyl, (C 3

-C

12 )-cycloalkyl-(C 1

-C

8 )-alkyl, (C 5

-C

1 4)-aryl, in which one to 29 three carbon atoms can be replaced by one to three heteroatoms from the group consisting of N, S, 0, or are (C 5

-C

1 4)-aryl-(C 1

-C

8 )-alkyl, in which one to three carbon atoms in the aryl moiety can be replaced by one to three heteroatoms from the group consisting of N, S, 0;

R

7 is a direct bond;

S.

RO independently of one another is hydroxyl, (C 1 -C4)-alkoxy, (C 5

-C

1 4)-aryl-(Cj-

C

4 )-alkoxy, (C 5

-C

1 4 )-aryloxy, (C 1

-C

8 )-alkylcarbonyloxy-(C 1

-C

4 )-alkoxy, (C 5

C

1 4)-aryl-(Cl-C 4 )-alkylcarbonyloxy-(C 1 -C4)-alkoxy or the radical of an amino acid; B is -NR 5 a direct bond or a divalent radical of a 3- to 7-membered saturated or unsaturated ring, which can contain one or two heteroatoms, such as, for example, nitrogen, sulfur or oxygen and which can be monosubstituted or disubstituted by radicals from the group consisting of =0, =S and R 3 D is a direct bond, -NR 6 -C(0)-NR 6 or -NR 6 E is hydrogen, R6-C(=NR 6

)-NR

6 R 6 R 6 N-C(=NR 6 R 6 R 6 'N-C(=NR 6 6 or a radical from the group consisting of

R

5 R3

N

N

R

N

R3(

N>

N

N

R

3 N

NN

which can optionally be monosubstituted to trisubstituted by radicals from the group consisting of R 3

R

5 =S and R 6

R

6

'N-C(=NR

6 r is zero, one, two, three, four or five; s is zero or one; t is zero or one; k is zero or one; n is one, two, three or four; m is zero or one; i is zero or one; q is zero or one; :iin all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.

Particularly preferred compounds of the formula I are furthermore those in which: X is hydrogen, NR 6

R

6 or NH-CO-R 6 0 Y is hydrogen; G is a radical of the formula II

-(CR

1

R

2 -A CR 1

R

2 m

(CR

1

R

3 i

-(CR

1

R

2 )q-R 4

(II);

W is a radical of the formula III

-B-(CR

1

R

2 )r-A CR' R 2 s (CR R 3 )k(C R R 2 )t-D-E (III); A, A' are a direct bond;

R

1

R

2 independently of one another are hydrogen, (C 1

-C

4 )-alkyl, (C 5

-C

6 )-aryl or (C 5

-C

6 )-aryl-(C1-C 4 )-alkyl; 31

R

3 independently of one another is hydrogen, (C 1

-C,

8 )-alkyl, (C 3

-C

14 )-cyCloalkyl,

(C

3 -Cl 1 4 )-cycloalkyl-(C 1

-C

8 )-alkyl, (C 5

-C

1 4 )-aryl, (C 5

-C

14 )-aryl-(C 1 -C,)-alkyl,

R

6

R

6

'N-R

7

R

6

OC(O)N(R

5

)R

7

R

6

SO

2

N(R

5

)R

7

R

6

C(O)N(R

5 )R

R

6

N(R

6

')C(O)N(R

5

R

6

C(O)R

7 or R 6

N(R

6 it being possible for alkyl to be monounsaturated or polyunsaturated and it furthermore being possible for alkyl and aryl to be monosubstituted or polysubstituted by fluorine, chlorine, bromine, cyano, R 6

R

6

'NR

7

R

6

C(O)R

7

R

6

N(R

6

R

6 or R 6 0IR 7

R

4 is C(O)R 8

R

5 independently of one another is hydrogen or (Cl-C4)-alkyl;

R

6 R independently of one another are hydrogen, (CI-C 18 )-alkyl, (C 3

-C

12 15 cycloalkyl, (C 3

-C

1 2 )-cycloalkyl-(C.,-C 8 )-alkyl, (C 5

-C,

4 )-aryl, in which 1 to 3 carbon atoms can be replaced by 1 to 3 heteroatoms from the group consisting of N, S, 0, or are (C 5

-C

1 4)-aryl-(C 1

-C

8 )-alkyl, in which 1 to 3 carbon atoms in the aryl radicals can be replaced by 1 to 3 heteroatoms :from the group consisting of N, S, 0, and it also being possible for R 6 and 6 together with the atoms connecting them, to form a ring system which can optionally also contain additional, in particular one, two or three, heteroatoms from the group consisting of N, S, 0;

R

7 is a direct bond;

R

8 independently of one another is hydroxyl, (C 1

-C

4 )-alkoxy, (C 5

-C

14 )-aryl-(C 1 C4)-alkoxy, (C 5 -C 4)-aryloxy, (C 1

-C

8 )-alkylcarbonyloxy(C 1

-C

4 )-alkoxy or (C 5

C

1 4 )-aryl-(C 1

-C

4 )-alkylcarbonyloxy(C 1

-C

4 )-alkoxy; B is I ,4-piperidinediyl or 1 ,4-piperazinediyl, where in the case of the 1,4piperidinediyl radical the nitrogen atom of the piperidine is bonded to the purine structure; 32 D is a direct bond, -NR 6 -C(0)-NR 6 or -NR 6 E is hydrogen, R 6

C(=NR

6

)NR

6

R

6

R

6

R

6

R

6 'N-C-(=NR6')-NR 6 or a radical from the group consisting of

N

N

I

N

which can optionally be monosubstituted to trisubstituted by radicals from the group consisting of R 3

R

5 =S and R 6

R

6

'N-C(=NR

6 r s k m

C

i q is zero, one or two; is zero or one; is zero or one; is zero or one; is zero, one or two; is zero or one; is zero or one; is zero or one; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.

Very particularly preferred compounds of the formula I are those in which: X is hydrogen; Y is hydrogen; G is a radical of the formula 11

-(CR

1

R

2 1

R

2 )m,(CRI R 3 1

-(CR

1

R

2 )q-R 4 W is a radical of the formula III

A

-B(CR' R 2 )rA'(CR' R 2 8

-(CR

1

R

3 )k-(CR 1

R

2 )t-D-E (Ill); A, A' are a direct bond;

R

1

R

2 independently of one another are hydrogen or (Cl-C 2 )-alkyl, in particular hydrogen;

R

3 is R 6

R

6

'N-R

7

R

6

OC(O)N(R

5

)R

7

R

6

SO

2

N(R

5

)R

7

R

6

C(O)N(R

5

)R

7 or

R

6

N(R

6

')C(O)N(R

5

)R

7 in particular R 6

OC(O)N(R

5

)R

7

R

4 is C(O)R 8

R

5 is hydrogen or (Cl-C 2 )-alkyl, in particular hydrogen; I.

S.

R 6

RV

independently of one another are hydrogen, (C 1

-C,

8 )-alkyl, (C 3

-CI

2 cycloalkyl, (C 3 -Cl 2 )-CYCloalkyl-(Cl-C 8 )-alkyl, (C 5

-C

14 )-aryl, in which 1 to 3 carbon atoms can be replaced by 1 to 3 heteroatoms from the group consisting of N, S, 0, or are (C 5

-C

14 )-aryl-(C 1

-C

8 )-alkyl, in which 1 to 3 carbon atoms in aryl radicals can be replaced by 1 to 3 heteroatoms from the group consisting of N, S, 0, and it also being possible for R 6 and R 6 together with the atoms connecting them, to form a ring system which can optionally also contain additional, in particular one, two or three, heteroatoms from the group consisting of N, S, 0; 4- 4, is a direct bond; RD is hydroxyl, (C.,-C4)-alkoxy, (C 5

-C

1 4)-aryl-(Cj-C 4 )-alkoxy, (C 5

-C

14 )-aryloxy,

(C

1

-C

8 )-alkylcarbonyloxy(C 1 -C4)-alkoxy or (C 5 -C 4)-aryl-(C 1

-C

4 alkylcarbonyloxy-(Cl-C 4 )-alkoxy, in particular hydroxyl or (Cl-C 4 )-alkoxy; B is I ,4-piperidinediyl, where the nitrogen atom of the piperidine is bonded to the purine structure; D is -NR 6 or -C(0)-NR 6 where in the group -C(0)-NR 6 the nitrogen atom is bonded to the group E; E is R 6 R 6

N-C(=NR

6 or a radical from the group consisting of 4. so

R

R

3

N

N

-B B

B.

NN

NN N which can optionally be monosubstituted to trisubstituted by radicals from the group consisting of R 3 R 5 =S and R 6

R

6

N-C(=NR

6 is zero or one; is zero; is zero; r t k is zero; n is one; m is zero; i is one; q is zero; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.

Especially preferred compounds according to the invention are the compounds of the formula Ih H

H

O N O HN (Ih) (k)

N

.N

N

N

N N Rh S COOH

R

3 0 NH 0 in which R 3 is R 6

R

6

'N-R

7

R

6 0C(0)N(R 5

)R

7

R

6

SO

2

N(R

5

)R

7

R

6 C(O)N(Rs)R 7 or

R

6

N(R

6 ')C(0)N(R 5

)R

7 in particular RO 6

C(O)N(R

5

)R

7

R

6

R

6 and R 7 being as previously defined and Rh is the carboxylic acid group COOH or a carboxylic acid derivative, for example an ester such as, for example, a (C 1

-C

4 )-alkyl ester, i.e. for example the group COO-(C,-C 4 )-alkyl; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs. In compounds of the formula Ih in which R 7 is a direct bond, the sterochemcial center in the formula Ih preferably has the Sconfiguration. Compounds of the formula Ih in which R 7 is a direct bond can be named as 2-amino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)piperidin-1yl)purin-9-yl)propionic acid and derivatives thereof, for example esters, optionally substituted on the 2-amino group. A particularly especially preferred compound is 2S-benzyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-yl-carbamoyl)piperidin-1-yl)-purin-9-yl)-propionic acid of the formula Ik and its physiologically tolerable salts and its prodrugs.

Compounds of the formulae I and la can generally be prepared, for example in the course of a convergent synthesis, by linkage of two or more fragments which can be derived retrosynthetically from the formulae I and la. In the preparation of the compounds of the formulae I and la, it can generally be advantageous or necessary :i in the course of the synthesis to introduce functional groups which could lead to undesired reactions or side reactions in the respective synthesis step, in the form of precursors which are later converted into the desired functional groups, or temporarily to block functional groups by a protective group strategy suited to the synthesis problem, what is known to those skilled in the art (Greene, Wuts, Protective Groups in Organic Synthesis,Wiley, 1991).

The present invention also relates to processes for the synthesis of the compounds of the formula I, which comprise carrying out one or more of the following steps for the synthesis of the compounds of the formula I.

al) A compound of the formula IV, 1 N 1

N

Y

(IV)

N

N

H

in which L1 is a customary leaving group known to those skilled in the art, for example chlorine, bromine, iodine, OTos or OMes, preferably chlorine or bromine, and 37 X and Y are as defined above, but functional groups can optionally also be present in the form of precursors or can temporarily be protected by a protective group, is reacted with a compound of the formula V L2-(CR 1

R

2 )n-A-(CR 1

R

2 )m-(CR'R 3

R

1

R

2 )q-R 0

(V)

in which

R

1

R

2

R

3 A, n, m, i and q are as defined above,

R

10 is defined as R above, but is optionally protected by a protective group, for example for R 4 COOH by a tert-butyl or a methyl or ethyl protective group, L2 is hydroxyl or a leaving group known to those skilled in the art, for example chlorine, bromine, iodine, OTos, OMes or OTf, to give a compound of the formula VI 0 :20 1 Ill

R

1 is -(CR 1

R

2

R

2 )m(CR'R 3 )i-(CR R 2 )q-R 10 and for which otherwise the above meanings apply, the reaction being carried out according to methods known to those skilled in the art (see source literature in J. March, Advanced Organic Chemistry, Fourth Edition, Wiley, 1992). Preferably, the reaction is carried out in a suitable organic solvent or diluent, for example DCM, CHCI 3 THF, diethyl ether, n-heptane, n-hexane, n- 38 pentane, cyclohexane, diisopropyl ether, methyl tert-butyl ether, acetonitrile, DMF, DMSO, dioxane, toluene, benzene, ethyl acetate or a mixture of these solvents, if appropriate with addition of a base such as, for example, butyllithium, lithium diisopropylamide (LDA), sodium hydride, sodium amide, potassium tert-butoxide, CaCO 3 Cs 2

CO

3 triethylamine, diisopropylethylamine or complex bases (sodium amide/R 12 0Na, where R 12 is (C 2

-C

6 )-alkyl or CH 3

CH

2 0CHCH 2 For L2 OH, the reaction can be carried out, for example, by 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 the formula VI is reacted with a compound of the formula

VII

S•H-B-(CR

1

R

2 )r-A'-(CR'R 2 s

(CR

1

R

3 )k-(CR'R 2 )t-R 1 3

(VII)

V0" in which R 13 is -D-E or a group R 14 which can be converted into D-E and which is S: optionally provided with suitable protective groups, and for which otherwise the above meanings apply. R 1 4 is, for example, an optionally protected amino group 6

-NHR

6 it being possible to employ, for example, the Boc protective group as a protective group, a protected carboxylic acid ester, an aldehyde a keto group -C(O)R 6 or a protected mercapto group.

In this reaction, a compound of the formula VIII

R

5 i N- N y-Y

(VIII)

N

N

R

is obtained, in which

R

15 is -B-(CR 1

R

2 )r-A'-(CRR 2 )s-(CR 1 R)k-(CR 1

R

2 )t-R 13 and for which otherwise the above meanings apply.

11 39 The reaction is carried out according to methods known to those skilled in the art (see source literature in J. March, Advanced Organic Chemistry, Fourth Edition, Wiley, 1992), preferably in a suitable organic solvent or diluent, for example DCM,

CHCI

3 THF, diethyl ether, n-heptane, n-hexane, n-pentane, cyclohexane, diisopropyl ether, methyl tert-butyl ether, acetonitrile, DMF, DMSO, dioxane, toluene, benzene, ethyl acetate or mixtures of these solvents, if appropriate with addition of a base such as, for example, butyllithium, lithium diisopropylamide (LDA), sodium hydride, sodium amide, potassium tert-butoxide, CaCO 3 Cs 2

CO

3 triethylamine, diisopropylethylamine or complex bases (sodium amide/R 12 0Na, where R 12 is (C 2

-C

6 )-alkyl or CH 3

CH

2 0CH 2

CH

2 where for B NR 6 an excess of VII can also serve as a base.

a3) If appropriate, the protective groups in the compound of the formula VIII on S R 13 and/or R 10 are removed by known methods (Greene, Wuts, Protective Groups in Organic Synthesis,Wiley, 1991). If, for example, R 13 is a Boc-protected amino group, the Boc group can be removed, for example, by reaction with trifluoroacetic acid.

a4) If appropriate, R 13 in the compound of the formula VIII is then reacted according to known processes to give the group D-E, for example by one of the following processes.

a4.1) By reaction of compounds where R 13

NHR

6 with 1 H-pyrazole-1 -carboxamidine or cyanamide a guanidine is obtained (see Bernatowicz et al., J. Org. Chem. 57 (1992) 2497).

a4.2) By reaction of compounds where R 13

NHR

6 with a monocyclic system or polycyclic system of the type

N

R

in which L3 is a nucleophilically substitutable leaving group such as, for example, halogen or SH, SCH 3

SOCH

3

SO

2

CH

3 or HN-NO 2 compounds with the end group

N

N N

N

R

6

R

6 are obtained (for the process see, for example, A.F. McKay et al., J. Med. Chem. 6 (1963) 587; M.N. Buchman et al., J. Am. Chem. Soc. 71 (1949) 766; F. Jung et al., J. Med. Chem. 34 (1991) 1110; or G. Sorba et al., Eur. J. Med. Chem. 21 (1986), 391) a4.3) By reaction of compounds where R 13

NHR

6 with compounds of the type R6 R6 N| N L3

R

6 in which L3 is a nucleophilically substitutable leaving group such as, for example, halogen or SH, SCH 3

SOCH

3 S02CH 3 or HN-NO 2 compounds with the end group

R

6

SN

R6 R6 R6 41 are obtained (for the process see, for example, Miller, Synthesis 1986, 777; or Brimble, J. Chem. Soc., Perkin Trans. 1 (1990) 311).

a4.4) By reaction of compounds where R 13

NHR

6 with a monocyclic or polycyclic system of the type

N

N L3

R

6 in which L3 is a nucleophilically substitutable leaving group such as, for example, S SCH3, compounds with the end group

N

N N N N

R

6

R

6 are obtained (for the process see, for example, T. Hiroki et al., Synthesis (1984) 703; or M. Purkayastha et al., Indian J. Chem. Sect. B 30 (1991) 646).

a 4.5) Compounds in which -D-E is the radical of an aminoguanidinylimine of the type

R

6

\N

or of a cyclic aminoguanidinylimine of the type NN N CR6 N N R6

R

6 can be prepared, for example, by condensation of compounds of the formula

R

6 N N R6 NH 2 or 6 6 *6 with ketones or aldehydes of the type O=C(R 6 or corresponding acetals or ketals according to customary literature processes, for example analogously to N. Desideri et al., Arch. Pharm. 325 (1992) 773-777 or A. Alves et al., Eur. J. Med. Chem. Chim.

Ther. 21 (1986) 297-304, where the above aminoguanidinylimines may be obtained as E/Z isomer mixtures which can be separated by customary chromatographic methods.

a4.6) Compounds in which -D-E is R 6

-C(=NR

6

)-NR

6

-N=C(R

6 or a radical containing a monocyclic system or a polycyclic system, of the type R R6 N can be obtained analogously to a4.7) Compounds in which is -S(0) 2

NR

6 can be prepared, for example, by oxidizing compounds with R 13 SH to sulfonic acids (R 13

SO

3 H) by methods known from the literature (cf. Houben-Weyl, Methoden der Organischen Chemie, Bd. E12/2, Georg Thieme Verlag, Stuttgart 1985, p. 1058ff), from which the i, 11 11 43 compounds with -S(0) 2

NR

6 are then prepared, for example, directly or via corresponding sulfonyl halides by linkage of an amide bond, where oxidationsensitive groups in the molecule, such as, for example, amino groups, amidino groups or guanidino groups, are protected by suitable protective groups if necessary before carrying out the oxidation.

a4.8) Compounds in which is -S(O)NR 6 can be prepared, for example, by converting compounds with R 13 SH into the corresponding sulfide and then oxidizing with meta-chloroperbenzoic acid to the sulfinic acids (R 1 3

SO

2 H) (cf.

Houben-Weyl, Methoden der Organischen Chemie, Vol. El11/1, Georg Thieme Verlag, Stuttgart 1985, p. 618f), from which the corresponding sulfinamides can be prepared according to methods known from the literature. Generally, other methods known from the literature can also be used for the preparation of compounds of the formulae I and la with -S(O)uNR 6 (u 1, 2) (cf. Houben-Weyl, Methoden der Organischen Chemie, Vol. E11/1, Georg Thieme Verlag, Stuttgart 1985, p. 618ff or Vol. E11/2, Stuttgart 1985, p. 1055ff).

a4.9) Compounds in which -D-E is R 6

R

6

'N-C(=NR

6

)-NR

6 or the radical of a S cyclic acylguanidine of the type

N

N

R

6 16

R

can be prepared, for example, by reacting a compound, in which R 13 is -C(O)-L4 and L4 is an easily nucleophilically substitutable leaving group, with the appropriate guanidine (derivative) of the type

R

6

N

N

NH

R

6 R6 or the cyclic guanidine (derivative) of the type

N

I 6 SR6 R The activated acid derivatives with the group L4(O)C- indicated above, in which L4 .can be, for example, an alkoxy group, preferably a methoxy group, a phenoxy group, S from the carboxylic acid chlorides on which they are based (L4 CI), which for their part can in turn be prepared in a manner known per se from the carboxylic acids on which they are based, for example using thionyl chloride. In addition to the carboxylic acid chlorides (L4 CI) further activated acid derivatives with the group of the type L4(O)C- can also be prepared in a known manner directly from the carboxylic acids on which they are based (L4 OH), such as, for example, the methyl esters (L4 OCH 3 by treating with gaseous HCI in methanol, the imidazolides (L4 1-imidazolyl) by treating with carbonyldiimidazole (cf. Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)) or the mixed anhydrides (L4

C

2

H

5 OC(O)O or TosO) with Cl-COOC 2

H

5 or tosyl chloride in the presence of triethylamine in an inert solvent. The activation of the carboxylic acids can also be carried out using carbodiimides like dicyclohexylcarbodiimide (DCCI) or using O- ((cyano(ethoxycarbonyl)methylene)amino)-1, 1,3,3-tetramethyluronium tetrafluoroborate ("TOTU") (Konig et al., Proc. 21st Europ. Peptide Symp. 1990, (Eds. Giralt, Andreu), Escom, Leiden, 1991, p. 143) and other activating reagents customary in peptide chemistry (a number of suitable methods for the preparation of activated carboxylic acid derivatives are given with source literature in J. March, Advanced Organic Chemistry, Third Edition (John Wiley Sons, 1985), p. 350). The reaction of an activated carboxylic acid derivative having the group of the type L4(O)C- with the respective guanidine (derivative) is preferably carried out in a manner known per se in a protic or aprotic polar, inert organic solvent, the reaction of the methyl esters (L4 OMe) with the respective guanidines advantageously being carried out in methanol, isopropanol or THF at temperatures from 20°C up to the boiling temperature of these solvents. Most reactions of compounds having the group L4(O)C- with salt-free guanidines are advantageously carried out in aprotic inert solvents such as THF, dimethoxyethane or dioxane, it also being possible, however, to use water as a solvent when using a base such as, for example, NaOH in the reaction of compounds having the group L4(O)C- with guanidines. If L4 CI, the reaction is advantageously carried out with the addition of an acid scavenger, for example in the form of excess guanidine (derivative), for the binding of the V hydrohalic acid.

a a4.10) Compounds in which -D-E is R 6

-C(=NR

6

)-NR

6 or a radical comprising S a monocyclic system or polycyclic system, of the type

R

can be obtained analogously to a4.9).

a4.11) Compounds in which -D-E is the radical of a sulfonylguanidine or sulfoxylguanidine of the type R 6 R6'N-C(=NR 6

)-NR

6 (u 1, 2) or

I

46 C N (u 1, 2) I 1

R

6

R

6 can be prepared by methods known from the literature by reaction of compounds of the formulae R 6

R

6

'N-C(=NR

6

)-NHR

6 and

N

NH

6

R

6

R

6 with compounds in which R 13 is S(O)u-L5 (u 1, 2) and L5 is, for example, Cl or

NH

2 for example analogously to S. Birtwell et al., J. Chem. Soc. (1946) 491 or Houben Weyl, Methoden der Organischen Chemie, Vol. E4, Georg Thieme Verlag, Stuttgart 1983; p. 620 ff.

a4.12) Compounds in which -D-E is R 6 -C(=NR6)NR 6 (u 1, 2) or the radical S comprising a monocyclic system or polycyclic system, of the type 0 1

R

6 1, can be obtained analogously to a4.11).

a4.13) Compounds in which is -NR 6 can be prepared, for example, by first reacting a compound with R 13

-NHR

6 with a suitable carbonic acid derivative, preferably phosgene, diphosgene (trichloromethyl chloroformate), triphosgene (bistrichloromethyl carbonate), ethyl chloroformate, i-butyl chloroformate, bis(1-hydroxy- 1H-benzotriazolyl) carbonate or N,N'-carbonyldiimidazole, in a solvent which is inert to the reagents used, preferably DMF, THF or toluene, at temperatures between 47 0 C and the boiling point of the solvent, preferably between 0°C and 60 0 C, to give a compound in which R 13 is L6

NR

6 where L6, depending on the carbonic acid derivative used, is, for example, a hydroxyl group, halogen such as, for example, chlorine, ethoxy, isobutoxy, benzotriazol-1-oxy or 1 -imidazolyl. The subsequent reaction of these derivatives with R 6

R

6

'N-C(=NR

6 )-NR6'H or R 6

-C(=NR

6

)-NHR

6 or with the compound comprising a monocyclic system or polycyclic system, of the type 9* N

N

NH or

HN

R 6 is then carried out as described above for the preparation of acylguanidines (or their derivatives) in a4.9).

a4.14) Compounds of the formula I in which -D-E is a bis-aminotriazole radical or a bis-aminooxadiazole radical can be prepared, for example, according to P.J. Garrett et al., Tetrahedron 49 (1993) 165 or R. Lee Webb et al., J. Heterocyclic Chem. 24 (1987)275.

a4.15) Compounds of the formula I in which -D-E is a urea group or a thiourea group can be synthesized according to known methods, such as are summarized, for example, in C. Ferri, Reaktionen der organischen Synthese, Georg Thieme Verlag, Stuttgart 1978, for example by reaction of the corresponding amines with isocyanates or isothiocyanates.

If appropriate, after the reaction of R 13 in the compound of the formula VIII to 48 give the group D-E, further protective groups still to be removed are removed by known methods (see Greene, Wuts, see above).

a6) If appropriate, the compounds of the formula I obtained are converted into their salts, in particular into pharmaceutically utilizable or nontoxic, physiologically tolerable salts, and/or are converted into prodrugs.

The present invention furthermore also relates to processes for the synthesis of the compounds of the formula la, which comprise carrying out one or more of the 10 following steps for the synthesis of the compounds of the formula la.

bl) A compound of the formula IV is reacted with a compound of the formula IX, .L2-(CR'R 2 )r-A'(CR'R 2 3 )k-(CR R 2 )t-R 1 3

(IX);

in which R 1

R

2

R

3 r, s, k, t, R 13 and L2 are as defined above, S. to give a compound of the formula X 1

N

II Y (X) X N N

X(X

SR

1 6

R

in which R 1 6 is -(CR'R2)r-A'-(CR'R2)s-(CR1R3)k-(CR'R2)t-R13 L1, X and Y are as defined above and the meanings indicated above otherwise apply. The reaction is carried out by methods known to those skilled in the art (see source literature in J.

March, Advanced Organic Chemistry, Fourth Edition, Wiley, 1992), preferably in a suitable organic solvent or diluent, for example DCM, CHCI 3 THF, diethyl ether, n-heptane, n-hexane, n-pentane, cyclohexane, diisopropyl ether, methyl tert-butyl ether, acetonitrile, DMF, DMSO, dioxane, toluene, benzene, ethyl acetate or mixtures of these solvents, if appropriate with addition of a base such as, for 1 49 example, butyllithium, lithium diisopropylamide (LDA), sodium hydride, sodium amide, potassium tert-butoxide, CaC03, Cs 2

CO

3 triethylamine, diisopropylethylamine or complex bases (sodium amide/R 12 0Na, where R 12 is (C 2

C

6 )-alkyl or CH 3

CH

2

OCHCH

2 For L2 OH, the reaction can be carried out, for example, by the conditions described for the Mitsunobu reaction (Hughes, Organic Reactions 42 (1992) 335-656), for example by reaction with triphenylphosphine and DEAD in THF.

b2) The compound of the formula X is reacted with a compound of the formula 10 XI S H-B-(CRR2)-A-(CRR2)-(CRR3-(CRR2)-R10

(XI);

.N

X

S

in which R 1

R

2

R

3

R

10 A, B, n, m, i and q are as defined above, V6009 to give a compound of the formula XII

R

17 0

N

(CRR3i-(C 2)q-Rand the meanings indicated above otherwise apply.

formula I.(XII) S1 16 (CR' R 3 )i-(CR R 2 )qR 10 and the meanings indicated above otherwise apply.

In the process for the synthesis of the compounds of the formula I, step a2) can also be carried out before al). In the process for the synthesis of the compounds of the formula la, step b2) can also be carried out before bl).

The introduction of carbon substituents in the 6-position of the purine structure can be carried out, for example, by Stille coupling, such as described, for example, in Langli et al., Tetrahedron 52 (1996) 5625; Gundersen, Tetrahedron Lett. 35 (1994) 3153, or by Heck coupling, such as described, for example, in Koyama et al., Nucleic Acids Res., Symp. Ser. 11 (1982) 41.

A substituent X in position 2 of the purine structure can also be introduced by known methods at the end of the synthesis of the compounds of the formulae I and la, such as described, for example, in D. A. Nugiel, J. Org. Chem. 62 (1997) 201-203; N. S.

Gray, Tetrahedron Lett. 38 (1997) 1161 and the references cited there.

A substituent representing Y in the 8-position can be introduced by known methods, such as described, for example, 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 the formulae I and la according to the invention and their physiologically tolerable salts can be administered to animals, preferably to S mammals, and in particular to humans as pharmaceuticals per se, in mixtures with one another or in the form of pharmaceutical preparations which permit enteral or parenteral use and which, as active constituent, contain an efficacious dose of at least one compound of the formula I or of the formula la or of a salt thereof or of a prodrug thereof in addition to customary pharmaceutically innocuous vehicles and/or additives. The pharmaceutical preparations normally contain approximately 0.5 to 90% by weight of the therapeutically active compounds.

The pharmaceuticals 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. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions or infusion solutions, microcapsules or rods, percutaneously, for example in the form of ointments or tinctures, or nasally, for example in the form of nasal sprays.

51 The pharmaceutical preparations are prepared in a manner known per se, pharmaceutically inert inorganic or organic vehicles being used. For the production of pills, tablets, coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc.

Vehicles for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable vehicles for the production of solutions and syrups are, for example, water, sucrose, invert sugar, glucose, polyols, etc. Suitable vehicles for the production of injection solutions are water, alcohols, glycerol, polyols, vegetable oils, etc. Suitable vehicles for 10 microcapsules, implants or rods are copolymers of glycolic acid and lactic acid.

*e In addition to the active compounds and vehicles, the pharmaceutical preparations can additionally contain additives, such as, for example, fillers, extenders, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings or aromatizers, thickeners, diluents, o oee buffer substances, and also solvents or solubilizers or agents for achieving a depot effect, and also salts for altering the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula I or la and/or their physiologically tolerable salts, and also, in addition to at least one compound of the formula I or la or of a salt thereof, additionally one or more other therapeutically active substances.

The dose can vary within wide limits and is to be suited to the individual conditions in each individual case. In the case of oral administration, the daily dose is in general approximately 0.01 to 100 mg/kg, preferably 0.1 to 5 mg/kg, in particular 0.3 to 0.5 mg/kg, of body weight to achieve effective results. Also in the case of intravenous administration the daily dose is in general approximately 0.01 to 100 mg/kg, preferably 0.05 to 10 mg/kg, of body weight. The daily dose can be divided, in particular in the case of the administration of relatively large amounts, into several, for example 2, 3 or 4, part administrations. If appropriate, depending on the individual behavior, it may be necessary to deviate upwards or downwards from the daily dose indicated.

52 Apart from use as pharmaceutical active compounds, the compounds of the formulae I and la can also be employed for diagnostic purposes, for example in in vitro diagnoses, and as tools in biochemical investigations in which inhibition of the vitronectin receptor or influencing of cell-cell or cell-matrix interactions is intended.

Furthermore, they can be used as intermediates for the preparation of other compounds, in particular of other pharmaceutical active compounds, which are obtainable from the compounds of the formulae I and la, for example, by modification or introduction of residues or groups.

Abbreviations used: AcOH acetic acid Boc tert-butoxycarbonyl DCCI dicyclohexylcarbodiimide DCM dichloromethane DEAD diethyl azodicarboxylate **oo DIPEA diisopropylethylamine DMF dimethylformamide DMSO dimethyl sulfoxide EA ethyl acetate HOOBt 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine MeOH methanol Mes methylsulfonyl :26. RT room temperature Tf trifluoromethylsulfonyl THF tetrahydrofuran Tos p-toluenesulfonyl Z benzyloxycarbonyl The terms "comprise", "comprises", "comprised" and "comprising" when used in this specification are taken to specify the presence of stated features, integers, steps or components, but does not preclude the presence or addition of one or more other 4tires, integers, steps, components or groups thereof.

:I

(r

I

53 Examples Compounds of the formulae I and la which in the 6-position of the purine structure contain an amino group which is not a constituent of a ring can also be regarded as derivatives of adenine 6-aminopurine) and can be designated as such in the nomenclature of the compounds. Substituents which are bonded to the nitrogen atom of the amino group in the 6-position of adenine are provided in this notation with the addendum N 6 Substituents which are bonded to the ring nitrogen atom in the 9-position are provided with the addendum N 9 In the name of the substituent it is indicated at the beginning via which position in the substituent the substituent is bonded to the nitrogen atom N 6 or N 9 in the chosen notation. The same applies to compounds which are designated as N 9 -substituted derivatives of purine.

:.NH 6 6 N1 N 7 1jN N 8 Puri ne 8 Adenine 2 Pu 2. N 4 S: N 4 9 3 3 Example 1

N

6 -(1-(5-Guanidinopentyl))-N 9 -(3-(2S-(benzyloxycarbonylamino)propionic acid))adenine 1 a) N 9 -(3-(tert-Butyl 2S-(benzyloxycarbonylamino)propionate))-6-chloropurine 2.63 g (17 mmol) of 6-chloropurine and 4.46 g (16.5 mmol) of triphenylphosphine were suspended in 50 ml of absol. THF under argon. 2.56 ml (16.3 mmol) of DEAD were added at RT and the mixture was stirred at RT for 15 minutes, a clear solution being formed. 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 of absol. THF, were added to this solution during the 54 course of 1.5 h. The mixture was then stirred at RT for a further 2 h. The solvent was evaporated, and the residue was triturated with ether and chromatographed through silica gel (toluene:EA 98:2 to 2.85 g (51 of pure product being obtained.

'H-NMR (200 MHz, DMS0): 5 1.30 9H, C(CH 3 3 4.48-4.73 (in, 3H, N 9

-CH

2 CH(NHZ)); 4.98 2H, CH 2 -aryl); 7.19-7.40 (in, 5H, aryl-H); 7.87 1IH, NH); 8.61 8.77 (2 s, 2H, C 6 -H C 8 MS (FAB): mWe =432.1 (100%; 376.0 1 b) N 6 -(5-(tert-Butyloxycarbonylamino)pentyl))-N 9 -(3-(tert-buty 2S-(benzyloxycarbonylamino)propionate))-adenine 0. 170 ml (1 mmol) of DIPEA and 5 mg of potassium iodide were added to a solution of 431 mg (1 mmol) of N 9 -(3-(tert-butyl 2S-(benzyloxycarbonylamino)propionate))-6chloropurine (Example 1 a) and 404 mg (2 inmol) of 1 -pentylamine in 5 ml of absol. DMVF and the mixture was stirred at 40 0 C for 72 h.

The solvent was evaporated and the residue was chromatographed through silica gel (toluene:EA 7:3 to 190 mg of pure product being obtained.

MS (FAB): m/e 598.3 (100%; 1 c) N 6 -(5-Aminopentyl))-N 9 -(3-(2-(benzyloxycarbonylamino)propionic acid))adenine 190 mng (0.32 minol) of N 6 -(5-(tert-butyloxycarbonylamino)pentyl))-N 9 -(3-(tertbutyl 2S-(benzyloxycarbonylamino)propionate))-adenine (Example 1 b) were dissolved in 2 ml of 90% strength trifluoroacetic acid and the solution was stirred at IRT for 2 h. It was evaporated to dryness and the residue was coevaporated twice with acetic acid. The residue was then dissolved in water and freeze-dried. Yield: 134 mg MS mWe 442.3 308.2 Id) N 6 -(5-Guanidinopentyl))-N 9 -(3-(2S-(benzyloxycarbonylamino)propionic acid))-adenine 34 mg (0.077 mmol) of N 6 _(1-(5-aminopentyl))-N 9 (benzyloxycarbonylamino)propionic acid))-adenine (Example 1Ic) were dissolved in ml of water and 0.5 ml of DMF and the solution was treated with 0.033 ml (0.193 mmol) of DIPEA and 13.5 mg (0.092 mmol) of 1IH-pyrazole-1 -carboxamidine hydrochloride and stirred at RT for 40 h. The solvent was then evaporated, the residue was taken up in water and the solution was freeze-dried. For further purification, it was chromatographed through silica gel (DCM: methanol: acetic acid:water 15:5: 1: Yield: MS (FAB): m/e 484.2 (100%; Example 2

N

6 -(4-Guanidinobutyl))-N 9 -(3-(2S-(benzyloxycarbonylamino)propionic acid))adenine 2a) N 6 -(4-(tert-Butyloxycarbonylamino)butyl 9 -(3-(tert-butyI 2S- (benzyloxycarbonylamino)propionate))-adenine Synthesis analogously to l b from 431 mg (1 mmol) of N 9 -(3-(tert-butyl 2S- (benzyloxycarbonylamino)propionate))-.6-chloropurine (Example I a) and 376 mg (2 mmol) of 4-(tert-butyloxycarbonylamino)-1-butylamine. Yield: 214 mg 1 H-NMR (200 MHz, DMSO): 5 1.30 9H, C(CH 3 3 1.38 9H, C(CH 3 3 1.41 (in, 2H, CH 2 I1.57(m, 2H, CH 2 3.46 (in, 2H, CH 2 -NH-Boc); 2.92 2H, C 2

-NH-

CH

2 4.31-4.58 (mn, 3H, N 1

-CH

2 -CH(NHZ)); 5.01 2H, CH 2 -aryl); 6.99 1IH, C 2 NH); 7.10-7.38 (in, 5H, aryl-H); 7.75 (in, 1 H, NH-Boc); 7.91 1 H, NH-Z); 8.02 8.20 (2 s, 2H, C 6 -H C 8 MS Wne 584.3 (100%; 2b) N 6 _(1I -(4-Aininobutyl))-N 9 -(3-(2S-(benzyloxycarbonylainino)propionic acid))adenine Synthesis analogously to Example 1Ic from N 6 -(4-tertbutyloxycarbonylanino)butyl)-N 9 -(3-(tert-butyI 2S- (benzyloxycarbonylamino)propionate)-adenine (Example 2a). Yield: 96%.

MS m/e 428.2 (100%; 294.1 2c) N 6 I-(4-Guan id inobutyl))-N 9 -(3-(2S-(benzyloxycarbonylam ino)-prop ionic acid))adenine Synthesis analogously to Example 1Id from N 6 -(4-aminobutyl))-N 9 (benzyloxycarbonylamino)propionic acid))-adenine (Example 2b). Yield: 76%.

MS mWe 470.1 Example 3 N 6 _(1-(3-Guanidinopropyl))-N 9 -(3-(2S-(benzyloxycarbonylamino)propionic acid))adenin e 3a) N 6 I-(3-(tert-Butyloxycarbonylamino)propyl))-N 9 -(3-(tert-butyI 2S- (benzyloxycarbonylam ino) prop ionate))-aden ine Synthesis analogously to l b from 60 mg 14 mmol) of N 9 -(3-(tert-butyl 2Sam ino) prop ionate))-6..ch loropuri ne (Example 1Ia) and 30 mg (0.17 mmol) of 3-(tert-butyloxycarbonylamino)-1-propylamine. Yield: 30 mg 1H-NMR (200 MHz, DMSO): 8 1.28 9H, C(CH 3 3 1.36 9H, C(CH 3 3 1.68 (in, 2H, CH 2

-CH

2

-CH

2 1.41 (in, 2H, CH 2 2.98 2H, C 2

-NH-CH

2 3.46 2H,

CH

2 -NH-Boc); 4.29-4.59 (in, 3H, N 1

-CH

2 -CH(NHZ)); 5.00 2H, CH 2 -aryl); 6.82 (t, 1IH, C 2 7.21-7.40 (in, 5H, aryl-H); 7.72 (in, I H, NH-Boc); 7.91 1IH, NH-Z); 8.03 8.20 (2 s, 2H, C 6 -H C 8 MS m/e 570.3 (100%; 3b) N 6 -(lI-(3-Aminopropyl))-N 9 -(3-(2S-(benzyloxycarbonylamino)propionic acid))adenine Synthesis analogously to Example 1ic from N 6 -(3-(tertbutyloxycarbonylainino)propyl))-N 9 -(3-(tert-butyI 2S- 57 (benzyloxycarbonylamino)propionate))-adenine (Example 3a). Yield: 100%.

MVS m/e 414.2 (100%; 280.1 3c) N 6 -(3-Guanidinopropyl) )-N 9 -(3-(2S-(benzyloxycarbonylamino)propionic acid))-adenine Synthesis analogously to Example 1Id from N 6 -(3-aminopropyl))-N 9 (benzyloxycarbonylamino)propionic acid))-adenine (Example 3b). Yield: 66%.

MVS m/e 456.3 130.1 (100).

Example 4

N

6 -(4-(4,5-Dihydro-1 H-imidazol-2-ylamino)butyl))-N 9 (benzyloxycarbonylamino)propionic acid))-adenine 153 mg (0.36 mmol) of N 6 -(4-aminobutyl))-N 9 (benzyloxycarbonylamino)propionic acid))-adenine (Example 2b) and 88 mg (0.36 :mmol) of 2-(methylmercapto)-2-imidazoline hydroiodide were dissolved in 2 ml of water and the solution was adjusted to pH 9.0 using I N NaOH. It was stirred at 50 0 C for 100 h. The solution was then brought to pH 1.5 using I N HCI, the solvent was evaporated and the residue was chromatographed several times through silica gel (DCM:MeOH 9:1 to 1:2, in each case using 0.1 AcOH, 0. 1% H 2 then DCM:MeOH:H 2 0:AcOH 8:2:0.4:0.4. Yield: 7 mg MVS (FAB): m/e 496.2 100%); 518.2 Example N 6(1I -(3-Guanidinopropyl))-N 9 -(4-(2S-(benzyloxycarbonylamino)butyric acid))adenine

N

9 -(4-(tert-Butyl 2S-(benzyloxycarbonylamino)butyrate))-6-chloropurine Synthesis analogously to Example I a from 6-chloropurine and N-benzyl-

I.

58 oxycarbonyl-L-homoserine tert-butyl ester. Yield: 24%.

1 H-NMR (200 MHz, DM50): 8 1.34 9H, C(CH 3 3 2.08-2.43 (in, 2H, N-CH 2

CH

2 3.81-3.93(m, 1H, CH-NHZ); 4.39 2H, N 9

-CH

2 5.02 2H, CH 2 -aryl); 7.26-7.42 (in, 5H, aryl-H); 7.87 1IH, NH); 8.63 8.75 (2 s, 2H, C 6 -H C 8 MS (FAB): mle 446.1 (100%; 390.1

N

6 1-(3-(tert-B utyloxycarbonyl amino) propyl 9 -(4-(tert-butyl 2S- (benzyloxycarbonylamino)butyrate))-adenine Synthesis analogously to 1 b from 50 mg 11 mmol) of N 9 -(4-(tert-butyl 2S- (benzyloxycarbonylamino)butyrate))-6-chloropurine (Example 5a) and 38 mg (0.22 mmol) of 3-(tert-butyloxycarbonylamino)-1 -propylamine. Yield: 26 mg (41 MS m/e 584.3 (100%; 5c) N 6 -(3-Aminopropyl))-Ng-(4-(2-(benzyloxycarbonylamino)butyric acid))adenine Synthesis analogously to Example I c from N 6 -(3-(tertbutyloxycarbonylam ino)propyl))-N 9 -(4-(tert-buty 2S-(benzyloxycarbonylamino)butyrate))-adenine (Example Sb). Yield: 94%.

MS (FAB): m/e 428.3 (100%;

N

6 -(3-Guanidinopropyl))-N 9 -(4-(2S-(benzyloxycarbonylamino)butyric acid))adenine Synthesis analogously to Example 1Id from N 6 -(3-aminopropyl))-N 9 (benzyloxycarbonylamino)butyric acid))-adenine (Example Sc). Yield: 71 MS (FAB): m/e 470.3 Se) N-Benzyloxycarbonyl-L-hoinoserine 6 g (S0.4 minol) of L-homoserine were largely dissolved in S0 ml of DMF and treated at 0 0 C in portions with 12.S6 g (S0.4 mmol) of N-(benzyloxycarbonyloxy)succiniinide.

The mixture was stirred at 0 0 C for 1 h, then at RT for 48 h. The solvent was distilled 1 59 off and the residue was partitioned between EA and a saturated NaCI solution. The organic phase was washed with saturated NaCI solution, with 5% strength citric acid and again with saturated NaCI solution, dried, filtered and concentrated. The crystalline residue was stirred in ether, filtered off with suction, and washed with ether and pentane. Yield: 9.55 g 1 H-NMR (200 MHz, DMSO): 6 1.61-1.95 2H, CH 2

-CH

2 3.42 2H, CH 2 OH); 4.08 1H, CH-NH-Z); 4.57 broad, 1H, OH); 5.02 2H, CH 2 7.32 5H, aryl-H), 7.49 1H, NH-Z).

MS m/e 236.1 (M+H*-H 2 0, 192.1 91.0 (100).

5f) 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-2pyrrolidone and treated successively with 53.9 g (390 mmol) of K 2 C0 3 and 98.7 g (720 mmol) of tert-butyl bromide. The solution was stirred at 55 0 C for 22 h. The reaction mixture was poured into 1.5 I of ice water, extracted twice with toluene, and the organic phase was washed twice with saturated NaCI solution, dried, filtered and concentrated. The product was chromatographed through silica gel for further purification (n-heptane EA 7:3 to Yield: 2.0 g 1H-NMR (200 MHz, CDCI 3 5 1.45 9H, tBu); 1.51-1.74 2.03-2.26 2H, o**o CH 2

-CH

2 3.01 broad, 1H, OH); 3.70 2H, CH 2 4.41 1H, CH-NH- 5.12 2H, CH 2 5.60 1H, NH-Z); 7.36 5H, aryl-H),.

MS m/e 310.3 254.2 (100).

Example 6

N

6 -(1-(4-Guanidinobutyl))-N 9 -(4-(2S-(benzyloxycarbonylamino)butyric acid))adenine 6a) N 6 -(1-(4-(tert-Butyloxycarbonylamino)butyl)-N 9 -(4-(tert-butyl 2S- (benzyloxycarbonylamino)butyrate))-adenine Synthesis analogously to 1 b from 50 mg 11 mmol) of N 9 -(4-(tert-Butyl (benzyloxycarbonylamino)butyrate))-6-chloropurine (Example 5a) and 41 mg (0.22 mmol) of 4-(tert-butyloxycarbonylamino)-1 -butylamine. Yield: 38 mg MIS mle 598.3 (100%; 6b) N 6 -(lI-(4-Aminobutyl))-N 9 -(4-(2-(benzyloxycarbonylamino)butyric acid))-adenine Synthesis analogously to Example 1 c from N 6 -(4-(tertbutyloxycarbonylamino)butyl 9 -(4-(tert-butyl 2S-(benzyloxycarbonylamino)butyrate))-adenine (Example 6a). Yield: 100%.

NMS (FAB): m/e 442.3 (100%; 6c) N 6 -(l1-(4-Guanidinobutyl))-N 9 -(4-(2S-(benzyloxycarbonylamino)butyric acid))adenine Synthesis analogously to Example 1Id from N 6 -(-(4-aminobutyl))-N 9 (benzyloxycarbonylamino)butyric acid))-adenine (Example 6b). Yield: MS W/e 484.3 350.2 333.2 130. 0 (100).

Example 7 0 0.0 N 6 I-(3-Guanidinopropyl))-N 9 -(3-propionic acid)-adenine 7a) N 9 -(tert-butyl 3-propionate)-6-chloropurine 15.45 g 1 mol) of 6-chloropurine, 43.5 ml 3 mol) of tert-butyl acrylate and 1. 34 ml (7 mmol) of 5.22 N sodium methoxide (in MeOH) were dissolved in 400 ml of absol. MeOH and boiled under reflux for 4.5 h with repeated addition of 2.6 ml (14 mmol) of 5.22 N sodium methoxide (in MeOH). For working-up, the solid was filtered off with suction, the solvent was evaporated and the residue was chromatographed (toluene:EA 3:1) through silica gel H 2 Yield: 1.35 g 1 H-NMR (200 MHz, DMSO): 5 1.29 9H, C(CH 3 3 2.95 2H, CH 2 4.50 2H, N-CH 2 8.70 8.79 (2 s, 2H, C 6 -H C 8 61 MS m/e 283.1 227.0 (100).

7b) N 6 -(lI-(3-(tert-Butyloxycarbonylamino)propyl 9 -(tert-butyl 3-propionate)adenine Synthesis analogously to l b from 282 mg (1.0 mmol) of N 9 -(tert-butyl 3-propionate)- 6-chioropurine (Example 7a) and 209 mg (1.2 mmol) of 3-(tertbutyloxycarbonylamino)-1 -propylamine. Yield: 160 mg MS m/e 421.2 (100%; 365.2 321.2 265.1 7c) N 6 -(3-Aminopropyl))-N 9 -(3-propionic acid)-adenine *Synthesis analogously to Example 1Ic from N 6 _(1-(3-(tertbutyloxycarbonylamino)propyl 9 -(tert-butyl 3-propionate)-adenine (Example 7b).

Yield: 100%.

H-NMR (200 MHz, DMSO): 6 1.88 2H, CH 2

-C

2

-CH

2 H H

CH

2

CH

2 3.56 (in, 2H, CH 2

-NH

2 4.38 2H, N 9

-CH

2 7.72 broad, 2H,

NH

2 7.95 1IH, NH); 8.15 8.23 (2 s, 2H, C 6 -H C 8 MS m/e 265.1 (100%; 248.1 176.0 7d) N 6 I -(3-Guanidinopropyl))-N 9 -(3-propionic acid)-adenine Synthesis analogously to Example 1Id from N 6 -(3-aminopropyl))-N 9 -(3-propionic acid)-adenine (Example 7c). Yield: 41 1 H-NMR (200 MHz, 020): 5 1.95 2H, CH 2

-CH

2

-CH

2 2.71 2H, CH 2 3.24 2H, Gua-CH 2 3.65 (in, 2H, CH 2

-NH

2 4.40 2H, N 9

-CH

2 8.00 8.15 (2 s, 2H, C 6 -H C 8 MS m/e 307.1 (100%; 290.1 Example 8

N

6 I -(4-Guan id inobutyl))-N 9 -(3-prop ionic acid)-adenine 8a) N 6 -(lI-(4-(tert-Butyloxycarbonylam ino)butyl 9 -(tert-butyl 3-propionate)adenine Synthesis analogously to l b from 141 mg (0.5 mmol) of N 9 -(tert-butyl 3-propionate)- 6-chloropurine (Example 7a) and 104 mg (0.55 mmol) of 4-(tertbutyloxycarbonylamino)-l -butylamine. Yield: 130 mg 1 H-NMR (200 MHz, DM50): 8 1.32 9H, C(CH 3 3 1.35 9H, C(CH 3 3 1.40 2H, CH 2 1.57 2H, CH 2 2.84 2H, -CH 2 2.95 2H, C 2

-NH-CH

2 3.45 (in, 2H, CH 2 -NH-Boc); 4.34 2H, N 9

-CH

2 6.78 1IH, C 2 -N 7.70 (in, 1IH, NH-Boc); 8.08 8.19 (2 s, 2H, C 6 -H C 8 MS m/e 435.2 (100%; 379.2 335.2 279.1 8b) N 6 -(4-Aminobutyl))-N 9 -(3-propionic acid)-adenine Synthesis analogously to Example 1Ic from N 6 -(4-(tertbutyloxycarbonylamino)butyl

)-N

9 -(tert-butyl 3-propionate)-adenine (Example 8a).

Yield: 100%.

1 H-NMR (200 MHz, DMSO): 5 1.50-1.70 (in, 4H,-CH 2

-CH

2 2.74-2.91 (in, 4H,

NHC

2

+H

2 3.50 (in, 2H, CH 2

-NH

2 4.36 2H, N 9

-CH

2 764 (,bod 2H, NH 2 7.90 1IH, NH); 8.11 8.21 (2 s, 2H, C 6 -H C 8 MS (FAB): W/e 279.2 (100%; 8c) N 6 _(1I -(4-Guanid inobutyl))-N 9 -(3-prop ionic acid)-adenine Synthesis analogously to Example 1Id from N 6 -(4-aminobutyl))-N 9 -(3-propionic acid)-adenine (Example 8b). Yield: MS W/e 321.1 (100%; Example 9 N 6 -(5-Guanidinopentyl))-N 9 -(3-propionic acid)-adenine 63 9a) N 6 I -(5-(tert-Butyloxycarbonylamino)butyl 9 -(tert-butyl 3-propionate)adenine Synthesis analogously to l b from 282 mg (1.0 mmol) of N 9 -(tert-butyl 3-propionate)- 6-chloropurine (Example 7a) and 243 mg (1.2 mmol) of butyloxycarbonylamino)-l -pentylamine. Yield: 219 mg (41 MS m/e 449.3 (100%; 9b) N 6 _(lI-(5-Aminopentyl))-N 9 -(3-propionic acid)-adenine Synthesis analogously to Example I c from N 6 butyloxycarbonylamino)pentyl))-N 9 -(tert-buty 3-propionate)-adenine (Example 9a).

Yield: 100%.

'H-NMR (200 MHz, DMSO): 5 1.39 (in, 2H, CH) 1.016 i,4,2xC 2 2.79 (dt, 2H, NH-CH 2 2.89 (mn, 2H, CH 2 3.48 (in, 2H, CH 2

-NH

2 4.37 2H, N 9 CHO); 7.67 broad, 2H, NH 2 8.04 1IH, NH); 8. 13 8.25 (2 s, 2H, C 6 -H C 8 MS m/e 293.1 (100%; 9c) -(5-Guanidinopentyl))-N 9 -(3-propionic acid)-adenine Synthesis analogously to Example 1Id from N 6 -(5-aminopentyl))-N 9 -(3-propionic acid)-adenine (Example 9b). Yield: 37%.

1 H-.NMR (200 MHz, DMSO): 8 1.38-1.79 (mn, 6H, 3 x CH 2 2.80 2H, NH-CH 2 3.12 (in, 2H, CH 2 3.58 (in, 2H, CH 2 -Gua); 4.43 2H, N 9

-CH

2 8.07 8.21 (2 s, 2H, C 6 -H C 8 MS (FAB): m/e 335.2 (100%; Example

N

6 -(2-Acetic acid)-N 9 -(lI-(5-aininopentyl ))-adenine

N

6 -(tert-Butyl 2-acetate)-adenime 64 155 mg (1 mmol) of 6-chloropurine and 420 mg (2 mmol) of glycine tert-butyl ester hydrochloride (80% strength) were dissolved in 5 ml of absol. DMF and treated with 0.17 ml of DIPEA and a spatula tipful of potassium iodide and the mixture was stirred at 50 0 C for 6 h. The solvent was evaporated and the residue was chromatographed through silica gel (toluene:EA 1:1 to Yield: 76 mg (31%) MS 250.0 193.9 163.9 (100).

N

6 -(2-Acetic acid)-N 9 75 mg (0.3 mmol) of N 6 -(tert-butyl 2-acetate)-adenine (Example 10a), 214 mg (0.6 mmol) of 5-(tert-butyloxycarbonylamino)pentyl 4-toluene-sulfonate) and 42 mg (0.3 mmol) of K 2 C0 3 were dissolved in 6 ml of absol. DMF and the solution was stirred at

O**

RT for 5 days. The solvent was evaporated and the residue was chromatographed through silica gel (toluene:EA 7:3 to Yield: 92 mg MS 435.3 349.3 (100).

*eo 10c) N 6 -(2-Acetic acid)-N 9 S Synthesis analogously to Example 1c from N 6 -(2-acetic acid)-N 9 butyloxycarbonylamino)pentyl))-adenine (Example 10b). Yield: 93%.

MS m/e 279.2 (M+H) 249.1 (100).

Example 11

N

6 -(2-(N-(2-Aminoethyl)acetamide))-N 9 -(2-acetic acid)-adenine 11a) N 9 -(tert-butyl 2-acetate)-adenine 6.76 g (0.05 mol) of -adenine were suspended in 300 ml of absol. DMF under N 2 then 2.4 g (0.06 mol) of NaH dispersion were added and the mixture was stirred at RT for 2 h. 14.7 ml (0.1 mol) of tert-butyl bromoacetate were added dropwise in the course of 30 min, a clear solution being formed. It was stirred at RT for a further 5 h.

The solvent was evaporated, the residue was stirred with 500 ml of water, and the solid was filtered off with suction and crystallized from ethanol. Yield: 5.1 g (41%) 'H-NMR (200 MHz, DMSO): 5 1.42 9H, tBu); 4.95 2H, N 9

-CH

2 7.22 (s, broad, 2H, W 6 HO; 8.10 8.15 (2 s, 2H, C 6 -H C 8 MS m/e =250.1 65 194. 0 (100).

11 b) N 6 -(ethyl 2-acetate)-N 9 -(tert-butyl 2-acetate)-adenine 978 mg (3 mmol) of NaH and 250 mg (1 mmol) of N 9 -(tert-butyl 2-acetate)-adenine (Example 11 a) were suspended in 10 ml of absol. DMF and 0. 12 ml of ethyl 41 ,10 chloroacetate was added dropwise during the course of 10 min. The mixture was then stirred at 50 0 C for 6 h, then the same amount of CSCO 3 was added again and 00 4 the mixture was stirred at 50 0 C for 6 h. The solvent was evaporated and the residue *was partitioned between water and EA. The organic phase was dried and 6% a 004. concentrated. Yield: 16%.

1 H-NMR (200 MHz, DM50): 5 1.20 3H, CH 2

-CH

3 1.41 9H, tBu); 4.00-4.28 (in, 4H, CH 2

-CH

3 N -CH 2 4.98 2H, N 9

-CH

2 8.09 broad, 1 H, N 6 H;81 8.21 (2 s, 2H, C 6 -H C 8 MS m/e 336.3 100%); 280.3 11 c) N 6 -(2-Acetic acid)-N 9 -(tert-butyl 2-acetate)-adenine 249 mg (0.74 mmol) of N 6 -(ethyl 2-acetate)-N 9 -(tert-butyl 2-acetate)-adenine (Example 11 b) were dissolved in 6 ml of dioxane:water:triethylamine and stirred at RT for 4 days. The solvent was evaporated and the residue was chromatographed through silica gel (DCM:MeOH 95:5 to 90:10). Yield: 36%.

MS W/e 308.3 100%).

li d) N 6 -(2-(N-(2-tert-Butyloxycarbonylaminoethyl)acetamide))-N9-(tert-butyI 2acetate)-adenine mng (0.26 minol) of N 6 -(2-acetic acid)-N 9 -(tert-butyl 2-acetate)-adenine (Example 1 Ic), 42 mg (0.26 inmol) of 2-tert-butyloxycarbonylaminoethylamine were dissolved 66 in 5 ml of absol. DMF under argon and the mixture was treated at 0 0 C with 85 mg (0.26 mmol) of TOTU and 0.13 ml (0.78 mmol) of DIPEA and stirred at 0 0 C for min and at RT for 2.5 h. It was diluted to 100 ml using EA, then washed with saturated potassium hydrogencarbonate solution, dried and concentrated. It was chromatographed through silica gel (DCM:MeOH 98:2 to 90:10). Yield: MS m/e 450.3 (M+H 100%).

11 e) N 6 -(2-(N-(2-Aminoethyl)acetamide))-N 9 -(2-acetic acid)-adenine Synthesis analogously to Example Ic from N 6 -(2-(N-(2-tertbutyloxycarbonylaminoethyl)acetamide))-N 9 -(tert-butyl 2-acetate)-adenine (Example 11d).

Yield: m/e 293.1 (100%; Example 12

N

6 -(4-(2S-(Benzyloxycarbonylamino)butyric acid))-N 9 -(I-(3-guanidinylpropyl))adenine 12a) N 9 -(3-(tert-Butyloxycarbonylamino)propyl))-6-chloropurine 154.6 mg (1 mmol) of 6-chloropurine were dissolved in 2.5 ml of absol. DMF and treated with stirring with 331.7 mg (2.4 mmol) of K 2 C0 3 and 285.8 mg (1.2 mmol) of tert-butyl N-(3-bromopropyl)carbamate. The mixture was stirred at RT for 11 h, the solvent was evaporated, the residue was taken up in EA and the solution was washed twice with saturated NaHC03 solution, then with NaCI solution, dried, filtered and concentrated. The residue was chromatographed through silica gel (EA:n-heptane Yield: 267 mg 'H-NMR (200 MHz, DMSO): 6 1.37 9H, tBu); 2.00 (tt, 2H,

CH

2

-CH

2

-CH

2 2.95 (dt, 2H, CH 2 4.30 2H, N 9

-CH

2 6.91 broad, 1H, NH); 8.70 8.78 (2 s, 2H, C 6 -H C 8 MS m/e 312.2 (100%; 256.1 67 1 2b) N 6 -(4-(2S-(Benzyloxycarbonylamino)butyric acid))-N 9 -(1I-(3-(tert-butyloxycarbonylamino)propyl))-adenine 370 mg 19 mmcl) of N 9 -(3-(tert-butyloxycarbonylamino)propyl))-6-chloropurine (Example 12a) were dissolved in 10 ml of absol. DMF and 5 ml of DIPEA. 449 mg (1.8 mmol) of 2S-benzyloxycarbonylamino-4-aminobutyric acid were added at RT and the mixture was stirred at 65 0 C for 50 h. The solvent was evaporated and the residue was partitioned between EA and saturated NaCI solution (20% KHSO4). The organic phase was washed with water, dried, filtered and concentrated. The residue was chromatographed through silica gel (EA:MeOH Yield: 331 mg 1 H-NMR (200 MHz, DMSO): 8 1.39 9H, tBu); 1.73-2.21 (in, 2H, CH 2

-CH(NH-

1.90 (in, 2H, CH -CH -CH 2 2.2(t H-NHBoc); 3.15 (dt, 2H, N 6

H-CH

2 3.88-4.10 (mn, 1IH, CH-NHZ); 4.14 2H, N 9

-CH

2 5.03 2H, CH 2 6.91 (t, broad, 1IH, NH-Boc); 7.37 5H, Ar-H); 7.55-7.81 (in, 2H, NH-Z N H-CH 2 8.13 '00:1015 8.19 (2 s, 2H, C 6 -H C 8 MS m/e 528.2 (100%; 1 2c) N 6 -(4-(2S-(Benzyloxycarbonylamino)butyric acid))-N 9 -(1I-(3-aminopropyl))adenine mng (0.06 mmcl) of N 6 -(3-(2S-(benzyloxycarbonylam ino)prop ionic acid))-N 9 (tert-butyloxycarbonylainino)propyl))-adenine (Example 12b) were dissolved in 2 ml of 90% strength trifluoroacetic acid, the solution was stirred at RT for 70 min and concentrated, and the residue was stirred several times with ether. The residue was then dissolved in water, and the solution was freeze-dried. Yield: 100%.

MS m/e 428.2 (100%; 294.1 1 2d) N 6 -(4-(2S-(Benzyloxycarbonylamino)butyric acid))-N 9 -(lI-(3-guanidinylpropyl))adenine Synthesis analogously to Example 1 d from N 6 (benzyl oxycarbonylam ino)prop ionic acid))-N 9 -(3-aminopropyl))-adenine (Example 12c). Yield: 77%.

68 MS mie 470.3 336.2 (100).

Example 13 N 6 -(4-(2S-(Benzyloxycarbonylamino)butyric acid))-N 9 -(3-(4,5-dihydro-1 Himidazol-2-ylamino)propyl))-adenine Synthesis analogously to Example 4 from N 6 (benzyloxycarbonylamino)propionic acid))-Ng-(lI-(3-aminopropyl))-adenine (Example 12c). Yield: 63%.

MS m/e 496.3 (100%; Example 14

N

6 -(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N 9 adenine 1 4a) N 9 -(lI-(5-(tert-Butyloxycarbonylamino)pentyl ))-6-chloropurine 20 Synthesis analogously to Example 12a from 6-chioropurine and tert-butyl tosyloxypentyl)carbamate. Yield: 66%.

'H-NMR (200 MHz, DMSO): 8 1.11-1.48 (in, 4H, 2 x CH 2 1.35 9H, tBu); 1.87 (tt, 2H, CH 2 2.97 (dt, 2H, CH 2 -NHBoc); 4.28 21-, N 9

-CH

2 6.72 broad, 1 H, NH); 8.71 8.78 (2 s, 2H, C 6 -H C 8 MS mle 340.2 (100%; 284.1 1 4b) N 6 -(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N 9 butyloxycarbonylamino)pentyl))-adenine Synthesis analogously to Example 12b from N 9 butyloxycarbonylamino)pentyl))-6-chloropurine and 2S-benzyloxycarbonylamino- 3-aminopropionic acid. Yield: 23%.

p 69 1 H-NMR (200 MHz, DM50): 5 1. 10-1.49 (in, 41-, 2 x CH 2 1.36 9H, tBu); 1.62- 1.88 (in, 2H, CH 2 2.87 (dt(2H, CH 2 -NHBoc); 3.68-4.98 (in, 5H, N 9

-CH

2

CH

2

-CH-

NHZ); 5.00 2H, CH 2 6.75 broad, 1 H, NH); 8.02 8.20 (2 s, 2H, C 6 -H

C

8 MS (FAB): mle =542.3 (100%; 1 4c) N 6 -(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N 9 1-(5-amino-pentyl adenine Synthesis analogously to Example 1 2c from N 6 (benzyloxycarbonylamino)propionic acid))-N 9 pentyl))-adenine (Example 14b). Yield: 100%.

'H-NMR (200 MHz, DMSO): 5 1. 18-1.40 1.44-1.65 1.71-1.93 (2 mn, 6H, 3 x

:.CH

2 2.77 (dt(2H, CH 2 -NHBoc); 3.64-4.35 (mn, 51-, N 9

-CH

2

CH

2 CH-NHZ); 5.00 (s, 152H, CH 2 7.66 (in, 3H, NH 3 8.20 8.24 (2 s, 2H, C 6 -H C 8 MS Wne 442.3 308.2 (100).

1 4d) N 6 -(3-(2S-(Benzyloxycarbonylainino)propionic acid))-N 9 guanidinylpentyl))-adenine Synthesis analogously to Example 1 d from N 6-(3-(2S- (benzyloxycarbonylainino)propionic acid))-N 9 -(lI-(5-aminopentyl))-adenine (Example 14c). Yield: MS Wne 484.3 350.2 Example N 6 S-(Benzyloxycarbonyl aiino)prop ionic acid))-N 9 5-dihydro-1 Himidazol-2-ylamino)pentyl))-adenine Synthesis analogously to Example 4 from N 6 (benzyloxycarbonylainino)propionic acid)-N 9 -(lI-(5-aminopentyl))-adenine (Example 14c). Yield: MS mle 510.3 376.2 (100).

Example 16 N 6 -(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N 9 -(lI-(3-guanidinylpropyl))adenine 1 6a) N 6 Benzyloxycarbonylam ino)prop ionic acid))-N 9 I-(3-(tertbutyloxycarbonylamino)propyl))-adenine Synthesis analogously to Example 12b from N 9 -(I-(3-(tertbutyl oxycarbonylamino)propyl))-6-chloropurine (Example 12a) and 2Sbenzyloxycarbonylamino-3-aminopropionic acid. Yield: 27%.

1 H-NMR (200 MHz, DMSO): 5 1.37 9H, tBu); 1.90 (in, 2H, CH 2

-CH

2

-CH

2 2.92 (dt, 2H, CH 2 -NHBoc); 3.86 (in, broad, 2H, CH 2 4.13 2H, N 9

-CH

2 4.40 (in, 1IH, CH-NHZ); 5.01 2H, CH 2 6.92 broad, 1IH, NH-Boc); 7.33 (s, Ar-H); 7.55-7.75 (mn, 2H, NH-Z N 6

H-CH

2 8.16 8.22 (2 s, 2H, C 6 -H C 8 MS Wne 514.3 (100%; 1 6b) N 6 -(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N 9 -(lI-(3-amino-propyl))adenine Synthesis analogously to Example 1 2c from N 6 (benzyloxycarbonylamino)propionic acid))-N 9 -(lI-(3-(tert-butyloxycarbonylamino)propyl))-adenine (Example 1 6a). Yield: 100%.

MS Wne 414.2 (100%; 280.2 1 6c) N 6 -(3-(2S-(Benzyloxycarbonylainino)propionic acid))-N 9 guanidinylpropyl))-adenine Synthesis analogously to Example 1 d from N 6 (benzyloxycarbonylainino)propionic acid))-N 9 -(lI-(3-aminopropyl))-adenine (Example 71 16b). Yield: 98%.

MS mWe 456.3 322.2 (100).

Example 17

N

6 -(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N 9 -(lI-(4-guanidinyl-butyl))adenine 1 7a) N 9 -(lI-(4-tert-Butyloxycarbonylamino)butyl ))-6-chloropurine Synthesis analogously to Example 12a from 6-chloropurine and tert-butyl N-(4tosyloxybutyl)carbamate. Yield: 66%.

1H-NMR (200 MHz, DMSO): 5 1.30 (in, 2H, CH 2 1.35 9H, tBu); 1.86 (tt, 2H,

CH

2 2.93 (dt, 2H, CH 2 -NHBoc); 4.31 2H, N -CH 2 6.79 broad, 1 H, NH); 8.72 8.78 (2 s, 2H, C 6 -H C 8 MS m/e 326.2 270.1 (100).

1 7b) N 6 -(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N 9 -(1I-(4-(tert-butyloxycarbonylamino)butyl))-adenine Synthesis analogously to Example 12b from Ng-(1-(4-tertbutyloxycarbonylamino)butyl))-6-chloropurine (Example 1 7a) and 2Sbenzyloxycarbonylamino-3-aminopropionic acid. Yield: 33%.

1 H-NMR (200 MHz, DMSO): 5 1.30 (in, 2H, CH 2 1.35 9H, tBu); 1.75 (mn, 2H,

CH

2 2.91 (dt(2H, CH 2 -NHBoc); 3.71-4.34 (in,5H, CH 2 -CH(NH-Z) N 9

-CH

2 5.01 2H, CH 2 6.89 broad, 1IH, NH-Boc); 7.35 5H, Ar-H); 7.46-7.73 (in, 2H, NH-Z N 6

H-CH

2 8.10 (broad) 8.20 (2 s, 2H, C 6 -H C 8 MS (FAB): ine 528.4 (100%; 1 7c) N 6 S-(Benzyl oxycarbonyl am ino) prop ion ic acid))-N 9 1-(4-aminobutyl))adenine

(S

72 Synthesis analogously to Example 1 2c from N 6 (benzyloxycarbonylam ino) prop ionic acid))-N 9 -(4-tert-butyloxycarbonylaminobutyl))--adenine (Example 1 7b). Yield: 100%.

'H-NMR (200 MHz, DM50): 6 1.48 (in, 2H, CH 2 1.87 (in, 2H, CH 2 2.80 (dt, 2H,

CH

2

-NH

2 3.694.02 (in, 2H, CH 2 4.20 2H-, N 9

-CH

2 4.36 (m,I1H, CH(NH-Z)); 5.01 2H, CH 2 7.33 5H, Ar-H); 7.64 broad, 4H, NH3

N

6

H-CH

2 8. 10 (broad) 8.20 (2 s, 2H, C 6 -H C 8 MS W/e 428.3 294.2 (100).

1 7d) N6-(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N 9 guanidinylbutyl))-adenine Synthesis analogously to Example 1 d from N 6 (benzyloxycarbonylamino)propionic acid))-N 9 -(l1-(4-aminobutyl))-adenine (Example IT 17c). Yield: 78%.

MS m/e 470.2 336.2 (100).

Example 18 -t N0 N 6 -(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N 9 5-dihydro-1 Himidazol-2-yl)amino)butyl))-adenine Synthesis analogously to Example 4 from N 6 (benzyloxycarbonylamino)propionic acid))-N 9 -(l1-(4-aminobutyl))-adenine (Example 17c). Yield: 41 MS m/e 496.3 362.2 (100).

Example 19 2S-Benzyloxycarbonylamino-3-(6-(4-(1 ,4,5,6-tetrahydropyrimidin-2-yIcarbamoyl)piperidin-1 -yl)purin-9-yl)propionic acid 1 9a) tert-Butyl 2S-benzyloxycarbonylamino-3-(6-(4-carboxypiperidin-1 -yl )purin-9-yI propionate 73 260 mg (0.6 mmol) of tert-butyl 2S-benzyloxycarbonylamino-3-(6-chloropurin-9-yl)propionate (Example la), 116.3 mg (0.9 mmol) of piperidine-4-carboxylic acid and 310 mg (2.4 mmol) of DIPEA in 4 ml of absol. DMF were stirred at 60 0 C for 16 h. A further 310 mg of DIPEA were then added and the mixture was again stirred at 600C for 24 h. The solvent was evaporated and the residue was partitioned between EA and water. The organic phase was washed again with KHSO 4

/K

2

SO

4 solution, then with NaCI solution, dried, filtered and concentrated. The residue was chromatographed through silica gel Yield: 219 mg MS m/e 525.3 (100%; 19b) tert-Butyl 2S-benzyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2ylcarbamoyl)piperidin-1 -yl)purin-9-yl)propionate 126 mg (0.24 mmol) of tert-butyl 2S-benzyloxycarbonylamino-3-(6-(4-carboxy- :i15 piperidin-1-yl)purin-9-yl)propionate (Example 19a), 39.3 mg (0.29 mmol) of 2-amino- 1,4,5,6-tetrahydropyrimidine hydrochloride, 86.6 mg (0.264 mmol) of TOTU (O- ((ethoxycarbonyl)cyanomethylen-amino)-N, N'-tetramethyluronium tetrafluoroborate K6nig et al., Proceedings of the 21st 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 absol. DMF. The solution was stirred at RT for 3 h, then a further 28 mg of DIPEA were added and the solution was A stirred at RT for 12 h. The reaction mixture was adjusted to pH 6 using glacial acetic acid/toluene the reaction solution was concentrated, the residue was partitioned between EA and saturated NaHC03 solution, and the organic phase was washed with NaCI, dried and concentrated. The residue was chromatographed through silica gel (EA:MeOH:TEA 85:15:1.5). Yield: 70 mg.

MS m/e 606.4 416.3 275.7 (100).

19c) 2S-Benzyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)piperidin-1-yl)purin-9-yl)propionic acid mg of tert-butyl 2S-benzyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin- 2-ylcarbamoyl)piperidin-1 -yl)purin-9-yl)propionate (Example 19b) were dissolved in 74 16 ml of precooled 95% strength trifluoroacetic acid and stirred first at 0 0 C for min, then at RT for 30 min. The trifluoroacetic acid was removed in a rotary evaporator, and the residue was coevaporated three times with toluene, stirred in ethanol/ether washed with ether and dried in vacuo. Yield: 59 mg.

MS m/e 550.3 416.3 (100).

Example 2S-Benzyloxycarbonylamino-3-(lI-(9-(2-guanidinoethyl)-9H-purin-6-y)-1 H-imidazol- 4-yl)propionic acid 0, 20a) N 9 -(lI-(2-(tert-Butyloxycarbonylamino)ethyl))-6-chloropurine The synthesis was carried out analogously to Example 12a from 6-chioropurine and ~*tert-butyl N-(2-tosyloxyethyl)carbamate. Yield: 36%.

'H-NMR (200 MHz, DM50): 5 1.24 9H, tBu); 3.40 d, 2H, CH -NHBoc); 4.35 (t, 2H, N 9

-CH

2 6.91 broad, I H, NH); 8.60 8.78 (2 s, 2H, C6-H C8-H).

MS (FAB): m/e 298.2 (100%; 20b) 2S-Benzyloxycarbonylamino-3-(lI-(9-(2-(tert-butyloxycarbonylamino)ethyl )-9H- 0 purin-6-yl)-1 H-imidazol-4-yl)propionic acid The synthesis was carried out analogously to Example 12b from N 9 -(1-(2-(tertbutyloxycarbonylamino)ethyl))-6-chloropurine (Example 21 a) and Nc-Z-L-histidine.

Yield: 33%.

MS m/e 551.3 (100%; 3-(lI-(9-(2-Aminoethyl)-9H-purin-6-yl)-1 H-imidazol-4-yl)-2S-benzyloxycarbonylaminopropionic acid The synthesis was carried out analogously to Example 12c from 2Sbenzyloxycarbonylamino-3-(1 -(9-(2-(tert-butyloxycarbonylamino)ethyl)-9H-purin.6yl)-1 H-imidazol-4-yl)propionic acid (Example 20b). Yield: 100%.

MS m/e 451.3 'H-NMR (200 MHz, DM50): 5 2.87-3.15 (in, 2H, lm-CH 2 3.38-3.51 (in, 2H, CH 2

NH

2 4.36 (m,I1H, CH-NHZ); 4.60 2H, N 9

-CH

2 5.00 2H, CH 2 7.28 aryl-H); 7.62 1 H, NH-Z); 8.23 9.05 (2 s, 2H-, lmH); 8.71 8.88 (2 s, 2H, C6-H C8-H).

2S-Benzyloxycarbonylamino-3-(l1-(9-(2-guan idinoethyl)-9H-purin-6-yI Himidazol-4-yI)propionic acid The synthesis was carried out analogously to Example I d from aminoethyl)-9H-purin-6-yl)-1 H-imidazol-4-yl)-2S-benzyloxycarbonylamino-propionic acid (Example 20c). Yield: 38%.

MS We 493.3 Example 21 :15 2R-Benzyloxycarbonylamino-3-(6-(N-(4-guanidinocyclohexyl)amino)purin-9yl)propionic acid 21 a) N 9 -(3-(tert-butyl 2R-(Benzyloxycarbonylamino)propionate))-6-chloropurine The synthesis was carried out analogously to Example I a from 6-chioropurine and N-benzyloxycarbonyl-D-serine tert-butyl ester.

MS (FAB): m/e 432.2 (100%; 376.1 21 b) tert-Butyl 2 R-benzyloxycarbonylamino-3-(6-( N-(4-(tertbutyloxycarbonylamino)cyclohexyl)amino)purin-9-yl)propionate The synthesis was carried out analogously to Example I b from 4-amino-I -(tertbutyloxycarbonylamino)cyclohexane and N 9 -(3-(tert-butyl 2R-(benzyloxycarbonylamino)propionate))-6-chloropurine (Example 21 Yield: MS (FAB): m/e 610.3 (100%; 21 c) 3-(6-(N-(4-Aminocyclohexyl)amino)purin-9-yl )-2Rbenzyloxycarbonylaminopropionic acid The synthesis was carried out analogously to Example 1 c from tert-butyl 2Rbenzyloxycarbonylamino-3-(6-(N-(4-(tert-butyloxycarbonylamino)cyclohexyl)amino)purin-9-yI)propionate (Example 21 Yield: 100%.

MS m/e 454.2 21 d) 2R-Benzyloxycarbonylamino-3-(6-(N-(4-guanidinocyclohexyl)amino)-purin-9yl)propionic acid The synthesis was carried out analogously to Example 1 d from aminocyclohexyl)amino)purin-9-yl)-2R-benzyloxycarbonylaminopropionic acid (Example 21 Yield: MS W/e 496.3 Example 22 2R-Benzyloxycarbonylamino-3-(6-(N-(3-guanidinomethylbenzyl )amino)-purin-9yl)propionic acid '20 22a) tert-Butyl 2R-benzyloxycarbonylamino-3-(6-(N-(3-tertbutyloxycarbonylaminomethylbenzyl )amino)purin-9-yl)propionate The synthesis was carried out analogously to Example 1 b from 3-aminomethyl-1 (tert-butyloxycarbonylami nomethyl )benzene and N 9 -(3-(tert-butyl 2R- (benzyloxycarbonylam ino) prop ionate)-6-ch loropuri ne (Example 21 Yield: 51 MS mWe 632.3 (100%; 22b) 3-(6-(N-(3-Aminomethylbenzyl)amino)purin-9-yl)-2Rbenzyloxycarbonylaminopropionic acid The synthesis was carried out analogously to Example 1 c from tert-butyl 2Rbenzyloxycarbonylam ino-3-(6-( N-(3-tert-butyloxycarbonylaminomethylbenzyl)amino)purin-9-yl)propionate (Example 22a). Yield: 100%.

77 MS mie 476.2 342.2 22c) 2R-Benzyloxycarbonylam ino-3-(6-( N-(3-guan idinomethyl benzyl )amino)purin-9yl)propionic acid The synthesis was carried out analogously to Example 1 d from aminomethylbenzyl)amino)purin-9-yl )-2R-benzyloxycarbonylamino-propionic acid (Example 22b). Yield: MS m/e 518.3 .:2Example 23 3-(6-((4-(Benzimidazol-2-ylamino)butyl )amino)purin-9-yl )-2S-benzyloxycarbonylaminopropionic acid 23a) I -(4-tert-Butyloxycarbonylaminobutyl)-3-(2-n itrophenyl)thiourea 0.928 g (5.15 mmol) of 2-nitrophenyl isothiocyanate in 5 ml of absol. DMF was added dropwise at 0 0 C to 0.97 g (5.15 mmol) of 4-(tert-butyloxycarbonylaminobutyl)- 1-amine in 25 ml of absol. DMF. The solvent was distilled off and the residue was chromatographed through silica gel (EA:n-heptane 1:2 to Yield: 1.8 g MS m/e 369.2 100%).

23b) 3-(2-Aminophenyl)-1 -(4-tert-butyloxycarbonylaminobutyl)thiourea 1.78 g (4.8 mmol) of I -(4-tert-butyloxycarbonylaminobutyl)-3-(2-nitrophenyl)thiourea (Example 23a) were dissolved in 120 ml of methanol and hydrogenated (1 bar) over 1 g of Pd/C at RT for 3 h. The catalyst was filtered off, the filtrate was concentrated and the residue was chromatographed through silica gel (EA:n-heptane Yield: 1.4 g.

23c) 4-(Benzimidazol-2-ylamino)-1 -(tert-butyloxyc-arbonylamino)butane 1.79 g (8.28 mmol) of yellow mercuric oxide and 27 mg of flowers of sulfur were 78 added to 1.4 g (4.14 mmol) of 3-(2-aminophenyl)-1 -(4-tertbutyloxycarbonylaminobutyl)thiourea (Example 23b) in 30 ml of ethanol and the reaction mixture was heated at 50-55 0 C for 3 h. The solid was filtered off with suction and washed with ethanol. The filtrate was concentrated and the product was chromatographed through silica gel (DCM:methanol 9:5, then Yield: 43%.

MS m/e 305.2 100%).

23d) 4-(Benzimidazol-2-ylamino)-1 -aminobutane 198 mg (0.65 mmol) of 4-(benzimidazol-2-ylamino)-1 -(tertbutyloxycarbonylamino)butane (Example 23c) were dissolved in 20 ml of strength trifluoroacetic acid at 0 0 C and stirred at 0 0 C for 2 h, then concentrated at RT during the course of 30 min. The residue was coevaporated three times with toluene, then stirred with ether and washed with pentane and dried in vacuo. Yield: 100%.

MS m/e 205.2 100%).

23e) tert-Butyl 3-(6-((4-(benzimidazol-2-ylamino)butyl)amino)purin-9-yl)- The synthesis was carried out analogously to Example 1 b from 4-(benzimidazol-2ylamino)-1 -aminobutane (Example 23d) and N 9 -(3-(tert-butyl 2Soxycarbonylam ino) prop ionate))-6-ch loropu ri ne (Example 1 Yield: 32%.

MS m/e 600.3 (100%; 23f) 3-(6-((4-(Benzimidazol-2-ylamino)butyl)amino)purin-9-yl)-2Sbenzyloxycarbonylaminopropionic acid The synthesis was carried out analogously to Example 1 c from tert-butyl (benzimidazol-2-ylamino)butyl)amino)purin-9-yl)-2S-benzyloxy.

carbonylaminopropionate (Example 23e). Yield: 100%.

MS m/e 544.2 Example 24 2S-Benzyloxycarbonylamino-3-(6-(4-((4,5-dihydro-1 H-imidazol-2-ylamino)methyl)piperidin-1 -yl)purin-9-yl)propionic acid 24a) tert-Butyl 3-(6-(4-(Aminomethyl)piperidin-1 -yl)purin-9-yl)-2Sbenzyloxycarbonylaminopropionate The synthesis was carried out analogously to Example l b from 4- (aminomethyl)piperidine and N 9 -(3-(tert-butyl 2S-(benzyloxycarbonylamino)- JO0 propionate))-6-chloropurine (Example 1Ia). Yield: 96.4%.

MS mle 510.3 (100%; 24b) 3-(6-(4-(Aminomethyl)piperidin-l -yl)purin-9-yl)-2Sbenzyloxycarbonylaminopropionic acid The synthesis was carried out analogously to Example 1Ic from tert-butyl (aminomethyl )piperidin-1 -yl )purin-9-yl)-2S-benzyloxycarbonylamino-propionate :(Example 24a). Yield: 100%.

MS m/e 454.3 24c) 2S-Benzyloxycarbonylamino-3-(6-(4-((4, 5-dihydro-l H-imidazol-2-yl- 5 amino)methyl)piperidin-1 -yl)purin-9-yl)propionic acid The synthesis was carried out analogously to Example 4 from (aminomethyl)piperidin-1 -yl)puri n-9-yl)-2 S-benzyloxycarbonylam ino-prop ionic acid (Example 24b). Yield: MS m/e 522.3 Example 2R-Benzyloxycarbonylamino-3-(6-(4-((4, 5-dihydro-1 H-imidazol-2-ylamino)methyl)piperidin-1 -yl)purin-9-yl)propionic acid The synthesis was carried out analogously to Example 24 from N 9 -(3-(tert-butyl 2R- (benzyloxycarbonylamino)propionate))-6-chloropurine (Example 21 a).

MS m/e 522.3 Example 26 2S-Benzyloxycarbonylamino-3-(6-(4-(guanidinomethyl)piperidin-1 -yl)purin-9yl)propionic acid The synthesis was carried out analogously to Example I d from (aminomethyl)piperidin-1 -yl)puri n-9-yl)-2S-benzyloxycarbonylam ino-prop ion ic acid JO1 (Example 24b). Yield: 74%.

MS W/e 496.3 Example 27 2S-Benzyloxycarbonylamino-3-(6-(3-(3-benzylureido)phenylsulfanyl)purin-9yl)propionic acid 27a) tert-Butyl 3-(6-(3-aminophenylsulfanyl )puri n-9-yl )-2Sbenzyloxycarbonylaminopropionate 0.602 mmol of 3-mercaptoaniline were stirred in DMF and DIPEA for 12 h together with 0.602 mmol of N 9 -(3-(tert-butyl 2S-(benzyloxycarbonylamino)propionate))-6chioropurine (Example I The reaction solution was concentrated, the residue was partitioned between EA and saturated NaHCO 3 solution, the phases were separated, the organic phase was washed with half-saturated NaHCO 3 solution and NaCI solution, dried and concentrated, and the product was chromatographed through silica gel (EA:heptane Yield: 190 mg.

MS m/e 521.3 100%).

27b) tert-Butyl 2S-benzyloxycarbonylamino-3-(6-(3-(3-benzylureido)phenylsulfanyl)purin-9-yl)propionate 46.1 mg of benzyl isocyanate in 1 ml of acetonitrile were added by means of a syringe to 180 mg of tert-butyl 3-(6-(3-aminophenylsulfanyl)purin-9-yl)-2S- 81 benzyloxycarbonylaminopropionate (Example 27a) in 3 ml of absol. acetonitrile. The mixture was stirred at RT for 48 h and concentrated, and the residue was chromatographed through silica gel (DCM:EA 7:3 to Yield: 205 mg.

MS m/e 654.4 100%).

27c) 2S-Benzyloxycarbonylam ino-3-(6-(3-(3-benzylureido)-phenylsulfanyl )puri n-9yl)propionic acid The synthesis was carried out analogously to Example 1 c from tert-butyl 2S- 10 benzyloxycarbonylamino-3-(6-(3-(3-benzylureido)phenysulfanyl )purin-9yl)propionate (Example 27b). Yield: 100%.

MS mWe 598.4 100%).

Example 28 2 S-Neopentyl oxycarbonyl am 1,4, 5,6-tetrahydropyri mid in-2-ylcarbamoyl)piperidin-1 -yl)purin-9-yl)propionic acid 28a) tert-Butyl 2S-amino-3-(6-(4-carboxypiperidin-1 -yl)purin-9-yl)-propionate 1.7 g of tert-butyl 2S-benzyloxycarbonylamino-3-(6-(4-carboxypiperidin-1 -yl)purin-9yl)propionate (Example 19a) were dissolved in 200 ml of AcOH and hydrogenated over Pd/C at an H 2 pressure of 1 atm. The catalyst was filtered off, the solvent was distilled off and the residue was lyophilized. Yield: 100%.

MS mWe 391.3 100%).

28b) tert-Butyl 2S-neopentyloxycarbonylam ino-3-(6-(4-carboxypiperidin-1 -yl )purin-9yl)propionate 390 mg (1 mmol) of tert-butyl 2S-amino-3-(6-(4-carboxypiperidin-1 -yl)purin-9yl)propionate (Example 20a) in 4 ml of OME were treated at 0 0 C with 230 mg (1 mmol) of N-(neopentyloxycarbonyloxy)succinimide and 0.17 ml of DIPEA and, after slowly warming, stirred at RT for 12 h. The reaction mixture was concentrated and the residue was chromatographed (Lobar-C, 0CM: MeOH:AcOH: H 2 0 90:10:1:1).

82 Yield: 540 mg.

MS mle 505.4 100%).

28c) tert-Butyl 2S-neopentyloxycarbonylamino-3-(6-(4-( 1,4, 5,6-tetrahydropyrim idin- 2-ylcarbamoyl)piperidin-1 -yl)purin-9-yI)propionate 505 mg (1 mmol) of tert-butyl 2S-neopentyloxycarbonylamino-3-(6-(4carboxypiperidin-1 -yl)purin-9-yl)propionate (Example 20b) were dissolved in 10 ml of acetonitrile, treated with 250 mg of DCCI and 184 mg of pentafluorophenol and then stirred at RT for 30 minutes. The mixture was filtered, the mother liquor was concentrated, the residue was taken up in 5 ml of DMF, and the solution was treated with 200 mg of 2-amino-I ,4,5,6-tetrahydropyrimidine and stirred at RT for 12 h. The solvent was distilled off in vacuo and the residue was chromatographed (Lobar-C, DCM:M :cO:2 98:8:0.8:0.8). Yield: 270 mg.

MS m/e 586.5 100%).

28d) 2S-Neopentyloxycarbonylamino-3-(6-(4-( 1,4, 5,6-tetrahydropyrimidin-2ylcarbamoyl)piperidin-1 -yl)purin-9-yl)propionic acid The synthesis was carried out analogously to Example I19c from tert-butyl 2Sneopentyloxycarbonylami 1,4, 5,6-tetrahydropyri mid in-2-ylcarbamoyl piperidin-1-yl)purin-9-yl)propionate (Example 28c). Yield: 94%.

MS m/e 530.4 Example 29 2S-( I -Adamantylmethyloxycarbonylamino)-3-(6-(4-(1 5,6-tetrahydropyrimidin-2ylcarbamoyl)piperidin-1 -yl)purin-9-yl)propionic acid 29a) tert-Butyl 2S-(lI-adamantylmethyloxycarbonylam ino)-3-(6-(4-carboxy-pi peridin- 1 -yl)purin-9-yl)propionate The synthesis was carried out analogously to Example 28b from N-(1 adamantylmethyl-oxycarbonyloxy)succinimide and tert-butyl 2S-amino-3-(6-(4- 83 carboxypiperidin-1 -yI)purin-9-yl)propionate (Example 28a). Yield: MS mle 583.4 100%).

29b) tert-Butyl 2S-( I -adamantylmethyloxycarbonylamino)-3-(6-(4-( I ,5,6tetrahydropyrimidin-2-ylcarbamoyl)piperidin-1 -yI)purin-9-yl )propionate The synthesis was carried out analogously to Example 28c from tert-butyl 2S-(1 adamantylmethyloxycarbonylamino)-3-(6-(4-carboxypiperidin-1 -yl)purin-9-yl propionate (Example 29a). Yield: JO MS m/e 664.5 29c) 2S-( I -Adamantylmethyloxycarbonylamino)-3-(6-(4-( 1,4, 5,6-tetrahydropyrimidin- 2-ylcarbamoyl)piperidin-1 -yl)purin-9-yl)propionic acid The synthesis was carried out analogously to Example 1 9c from tert-butyl 2S-(1 adamantylmethyloxycarbonylamino)-3-(6-(4-( 1,4,53 6-tetrahydropyrimidin-2-ylcarbamoyl)piperidin-1 -yI)purin-9-yl)propionate (Example 29b). Yield: 100%.

MS m/e 608.4 0 0.

OV* Pharmacological testing The inhibition of binding of kistrin to human vitronectin receptor (VnR) is described below as a test method by which, for example, the antagonistic action of the compounds according to the invention on the vitronectin receptor ct..

4 3 can be determined (avIl 3 ELISA Test; the test method is abbreviated to "KIVnR" in the listing of the test results).

Purification of kistrin Kistrin is purified according to the methods of Dennis et al., as described in Proc.

I

I1 84 Natl. Acad. Sci. USA 1989, 87, 2471-2475 and PROTEINS: Structure, Function and Genetics 1993, 15, 312-321.

Purification of human vitronectin receptor (c 1 3 Human vitronectin receptor is obtained from the human placenta according to the method of Pytela et al., Methods Enzymol. 1987,144, 475. Human vitronectin receptor ol 3 can also be obtained from some cell lines (for example from 293 cells, a human embryonic kidney cell line), which are co-transfected with DNA sequences .:10 for both subunits cv and 133 of the vitronectin receptor. The subunits were extracted with octyl glycoside and then chromatographed through concanavalin A, heparin- Sepharose and S-300.

Monoclonal antibodies S. Murine monoclonal antibodies, specific for the B 3 subunits of the vitronectin receptor, are prepared according to the method of Newman et al., Blood, 1985, 227- 232, or by a similar process. The rabbit Fab 2 anti-mouse Fc conjugate to horseradish peroxidase (anti-mouse Fc HRP) was obtained from Pel Freeze S.20 (Catalog No. 715 305-1).

o ELISA test The ability of substances to inhibit the binding of kistrin to the vitronectin receptor can be determined using an 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, 312-321. The plates are then washed twice with PBS/0.05% Tween-20 and blocked by incubating (60 min) with bovine serum albumin (BSA, RIA grade or better) in Tris-HCI (50 mM), NaCI (100 mM), MgC 2 (1 mM), CaCI 2 (1 mM), MnCI 2 (1 mM), pH 7. Solutions of known inhibitors and of the test substances are prepared in concentrations from 2 x 10-1 2 to 2 x 10 6 mol/l in assay buffer (BSA RIA grade or better) in Tris-HCI (50 mM), NaCI (100 mM), MgCl 2 (1 mM), CaC12 (1 mM), MnCI 2 (1 mM), pH The blocked plates are emptied, and in each case 0.025 ml of this solution, which contains a defined concentration (2 x 10- 12 to 2 x 10 6 mol/I) either of a known inhibitor or of a test substance, are added to each well. 0.025 ml of a solution of the vitronectin receptor in the test buffer (0.03 mg/ml) is pipetted into each well of the plate and the plate is incubated at room temperature for 60-180 min on a shaker. In the meantime, a solution (6 ml/plate) of a murine monoclonal antibody specific for the 13 subunit of the vitronectin receptor is prepared in the assay buffer (0.0015 mg/ml). A second rabbit antibody (0.001 ml of stock solution/6 .10 ml of the murine monoclonal anti-B 3 antibody solution) which is an anti-mouse Fc HRP antibody conjugate is added to this solution, and this mixture of murine anti-B 3 antibody and rabbit anti-mouse Fc HRP antibody conjugate is incubated during the time of the receptor-inhibitor incubation. The test plates are washed four times with PBS solution which contains 0.05% Tween-20, and in each case 0.05 ml/well of the antibody mixture is pipetted into each well of the plate and incubated for 60-180 min.

The plate is washed four times with PBS/0.05% Tween-20 and then developed with 0.05 ml/well of a PBS solution which contains 0.67 mg/ml of o-phenylenediamine and 0.012% of H 2 0 2 Alternatively to this, o-phenylenediamine can be employed in a buffer (pH 5) which contains Na 3

PO

4 and citric acid. The color development is stopped using 1 N H 2

SO

4 (0.05 ml/well). The absorption for each well is measured at 492-405 nm and the data are evaluated by standard methods.

The following test results were obtained: Compound KNnR KNVnR of Example Inhibition at 10 pM (in

IC

50 (pM) 1 75 1.1 2 80 0.7 3 77 2.2 4 93 0.15 12 86 0.58 Compound of Example K/VnR Inhibition at 10 pM (in K/VnR

IC

50

(PM)

.ao 6 6 6 6S*.* *666 a a 6*S6 a a a 4* C, a. 66 66666w *e a 46 a 13 14 1 4c 16 1 6b 17 18 19 23 24 25 26 0.19 0.65 0.21 0.54 0.17 0.075 0.004 0.16 0.052 0.345 0.36

Claims (8)

1. A compound of the formula I or la, NNN N :NN x Ix (IG 8 in which: *X is hydrogen, NR 6 R 6 fluorine, chlorine, bromine, OR 6 SR 6 hydroxy-(Cl-C 6 alkyl-NH, (hydroxy-(C 1 -C 6 )-alkyl) 2 N, amino-(C 1 -C 6 )-alkyl-NH, (amino-(C 1 C 6 )-alkyl)AN hydroxy-(C 1 -C 6 )-alkyl-O, hydroxy-(Cl~-C 6 )-alkyl-S or :NH-CO-R 6 Y is R 6 fluorine, chlorine, bromine, cyano, NR 6 Rr, OR 6 SR 6 or hydroxy-(C- C 6 )-alkyl-NH; G is a radical of the formula 11 -(CRR R 2 ,A-(CR 1 R 2 )m(CR 1 R 3 )i.(CR 1 R 2 )q-R 4 (I) W is a radical of the formula Ill Ga is a radical of the formula Ila -(CR 1 R 2 )r-A'-(CR 1 R 2 1 R 3 )k(CR 1 R 2 )tDE (l) (Ila); J, f p 88 Wa is a radical of the formula Ilila A, A' independently of one another are a direct bond, -C(0)NR 5 -NR 5 -NR 5 -S02-, (C 5 -CU4-arylene, where in the aryl radical one to five carbon atoms can be replaced by one to five heteroatoms, (C 2 -C 4 )-alkynylene, (C 2 -C 4 )-alkenylene, or a divalent radical of a 3- to 7- membered saturated or unsaturated ring which can contain one or two 10 heteroatoms and which can be monosubstituted or disubstituted by radicals 0. 3 from the group consisting of =S andR *R 1 R 2 independently of one another are hydrogen, fluorine, chlorine, cyano, nitro, (C 1 -C 1 0 )-alkyl, (C 3 -C 1 4 )-cycloalkyl, (C 3 -C 4)-cycloalkyl-(C 1 -C8)-alkyl, (C 5 C 1 4 )-aryl, (C 5 -C 1

4-aryl-(C 1 -C 8 )-alkyl, R 6 -0-R 7 R 6 _S(0)P-R 7 or R 6 R 6 'N-R 7 *R 3 independently of one another is hydrogen, fluorine, chlorine, cyano, nitro, (C 1 -C 1 8 )-alkyl, (C 3 -C 1 4)-cycloalkyl, (C 3 -C 4)-cycloalkyl-(Cl 1 -C 8 )-alkyl, (C 5 C 1 4-aryl, (C 5 -C 1 4-aryl-(C 1 -C 8 )-alkyl, R 6 -0-R 7 R 6 R 6 'N-R 7 R 6 C(0)-0-R 7 R 6 C(0)R 7 R 6 OC(0)R 7 R 6 N(R 6 ')C(0)0R 7 R 6 S(0)PN(R 5 )R ~.R 6 0C(0)N(R 5 )R 7 R 6 C(0)N(R 5 )R 7 R 6 N(R 6 ')C(0)N(R 5 )R 7 R 6 N( 6 )S0)~NR) 7 R 6 S(0)pR 7 R 6 SC(0)N(R 5 )R 7 6 N(R 6 ')C(0)R 7 or R 6 N(R 6 ')S(0)PR where alkyl can be monounsaturated or polyunsaturated and where furthermore alkyl and aryl can be monosubstituted or polysubstituted by fluorine, chlorine, bromine, cyano, R 6 R 6 'NR 7 nitro, R 6 OC(0)R 7 R 6 C(0)R 7 R 6 N(R 6 ')C(0)R 7 R 6 N(R 6 )S(0)PR 7 R 6 or R 6 -0-R 7 R4 is C(0)R 8 S(0)PR 8 P(O)R 8 R 8 or a radical of a four- to eight- membered saturated or unsaturated heterocycle which contains 1, 2, 3 or 4 heteroatoms from the group consisting of N, 0, S; R 5 independently of one another is hydrogen, (Cl-Cl 0 )-alkyl, (C 3 -C 14 cycloalkyl, (C 3 -C 1 4 )-cycloalkyl-(C 1 -C 8 )-alkyl, (C 5 -C 1 4 )-aryl or (C 5 -C 1 4 )-aryl- (C 1 -C 8 )-alkyl; R 6 R 6 independently of one another are hydrogen, (C 1 -C 18 )-alkyl, (C 3 -C 1 4)-CYCloalkyl, (C 3 -C 4)-cycloalkyl-(C 1 -C 8 )-alkyl, (C 5 -C 4)-aryl, in which I to 5 carbon atoms can be replaced by heteroatoms such as N, 0, S, or (C 5 -C 1 4)-aryl-(C 1 -C 8 )-alkyl, in which, in the aryl moiety, 1 to 5 carbon atoms can be replaced by heteroatoms such as N, 0, S, or R 6 and together with the atoms connecting them, form a ring system, in particular a 4- to

8-membered ring system which can optionally also contain additional heteroatoms from the group consisting of N, 0, S and which can be saturated or unsaturated; R 7 independently of one another is (C 1 -C4)-alkylene or a direct bond; R8R8 VO 20 independently of one another are hydroxyl, (Cl-C 8 )-alkoxy, (C 5 -C,4)-aryl- (C 1 -C 8 )-alkoxy, (C 5 -C 1 4 )-aryloxy, (C 1 -C 8 )-alkylcarbonyloxy-(C 1 -C4)-alkoxy, (C 5 -C 4)-aryl-(C 1 -C 8 )-alkylcarbonyloxy-(C 1 -C 8 )-alkoxy, NR 6 R 6 (di((C 1 -C 8 alkyl)amino)carbonylmethyloxy, (di((C 5 -C 1 4 )-aryl-(Cl -C 8 )-alkyl)- amino)carbonylmethyloxy, (C 5 -C 1 4)-arylamino, the radical of an amino acid, N-((C 1 -C 4 )-alkyl)piperidin-4-yloxy, 2-methylsulfonylethoxy, I ,3-thiazol-2- ylmethyloxy, 3-pyridylmethyloxy, 2-(di((Cl-C4)-alkyl)amino)ethoxy or the radical Q- (CH 3 3 N+-CH 2 -CH 2 in which Q- is a physiologically tolerable anion; B is -NR 5 -NR 5 -C(0)-NR 5 a direct bond or a divalent radical of a 3- to 7-membered saturated or unsaturated ring which can contain one or two heteroatoms and which can be monosubstituted or disubstituted by radicals from the group consisting of =S and R 3 D is a direct bond, -NR 6 -C(0)-NR 6 -NR 6 -S(0)u-NR 6 -NR 6 -C(0)-NR 6 -NR 6 -C(S)-NR 6 -NR 6 -S(0)u-NR 6 -NR 6 -N=CR 6 -R 6 C=N- or -R 6 C=N-NR 8 where the divalent radicals Representing D are bonded to the group E via the free bond on the right side; E is hydrogen, R 6 -C(=NR 6 )-NR 6 R 6 R6'N-C(=NR 6 R 6 R6'N-C(=NR 6 )-NR 6 -or a radical of 4- to 11-membered, monocyclic or polycyclic, aromatic or nonaromatic ring system which can optionally contain 1, 2, 3 or 4 heteroatoms from the group consisting of N, 0 and S and can optionally be monosubstituted, distributed or trisubstituted by radicals from the group consisting of R 3 R 5 =S and R 6 R 6 'N-C(=NR 6 provided that E is different from hydrogen if one or both of the groups B and D are a direct bond, and provided that the radical of a ring system representing E is not a phenyl radical or a furyl radical; n is zero, one, two, three, four or five; m is zero, one, two, three, four or five; i is zero or one; p independently of one another is zero, one or two; q is zero, one or two; r is zero, one, two, three, four, five or six; s is zero, one, two, three, four or five; t is zero, one, two, three, four or five; k is zero or one; u is one or two; v is zero, one, two or three; in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts and its prodrugs; where, instead of the purine structure shown in the formulae I and la, a 3- deazapurine structure, a 7-deazapurine structure or a 7-deaza-8-azapurine structure can also be present. 2. A compound of the formula I or la as claimed in claim 1, in which: X is hydrogen, NR 6 R6, hydroxy-(C 1 -C 6 )-alkyl-NH or NH-CO-R 6 91 Y is hydrogen; G is a radical of the formula 11 R 2 R 2 R 3 )i-(CRI R 2 )q-R 4 (I) W is a radical of the formula Ill R 2 R 2 8 -(CR 1 R 3 R 2 )tD-E (Ill); a Ga is a radical of the formula Ila (CR'R R)rA'(CR'R R) 8 -(CR 1 R 3 )k-(CR'R R)t-D-E (IlIa); Wa is a radical of the formula Ilila .o -B3-(CR' R2) nA-(CR 1 R2)m-(CR' R'3)(CR' R2 )qR (Ilia); A, A' independently of one another are a direct bond, -C(O)NR 5 -NR 5 -NR 5 -S02-, (C 5 -C1 4 )-arylene, it being possible one to three carbon atoms in the aryl radical to be replaced by one to 0 0 0 0three heteroatoms from the group consisting of 0, N, S, (C 2 -C4)-alkynylene or (C 2 -C 4 )-alkenylene; R 2 independently of one another are hydrogen, fluorine, cyano, (Cl-C4)-alkyl, (C 5 -C 6 -aryl, (C 5 -C 6 )-aryl-(C 1 -C 4 )-akyl, R 6 -O-R 7 or R 6 R 6 'N-R 7 R 3 independently of one another is hydrogen, (Cl-C1 8 )-alkyl, (C 3 -C, 4 cycloalkyl, (C 3 -C 4)-cycloalkyl-(Cl -C 8 )-alkyl, (C 5 -C, 4 )-aryl, (C-C,4)-aryl- (C 1 -C 8 -alkyl, R 6 R 6 'N-R 7 R 6 C(O)R 7 R 6 S(O)PN(R 5 )R R 6 0C(O)N(R )R 7 R 6 C(O)N(R 5 )R7, R 6 N(R 6 ')C(O)N(R 5 )R 7 R6N(R 6 ')S(O)PN(R 5 )R 7 or R 6 N(R 6 )C it being possible for alkyl to be monounsaturated or polyunsaturated and it furthermore being possible for alkyl and aryl to be 92 monosubstituted or polysubstituted by fluorine, chlorine, bromine, cyano, R 6 R6'NR 7 nitro, R60C(O)R 7 R 6 C(O)R 7 R 6 N(R6')C(O)R R 6 N(R 6 7 R 6 or R 6 0R 7 R is C(O)R 8 R 5 independently of one another is hydrogen or (C 1 -C4)-alkyl; R 6 R 6 independently of one another are hydrogen, (C 1 -C, 8 )-alkyl, (C 3 -C 1 4)- cycloalkyl, (C 3 -C 1 4)-cycloalkyl-(C -C 8 )-alkyl, (C 5 -C 14 )-aryl, in which one to three carbon atoms can be replaced by one to three heteroatoms from the group consisting of N, S, O, or are (Cs-C 1 4)-aryl-(C 1 -C 8 )-alkyl, in which one S* to three carbon atoms in the aryl moiety can be replaced by one to three i heteroatoms from the group consisting of N, S, 0, or R 6 and R 6 together with the atoms connecting them, form a ring system which can optionally also contain additional heteroatoms from the group consisting of N, S, O; 7 independently of one another is (C 1 -C 2 )-alkylene or a direct bond; R 8 independently of one another is hydroxyl, (C 1 -C 4 )-alkoxy, (C 5 -C, 4 )-aryl-(C 1 C4)-alkoxy, (C 5 -C 1 4)-aryloxy, (C 1 -C 8 )-alkylcarbonyloxy-(C -C4)-alkoxy, (C 5 C 1 4)-aryl-(C 1 -C4)-alkylcarbonyloxy-(C 1 -C 4 )-alkoxy or the radical of an amino acid; B is -NR 5 a direct bond or a divalent radical of a 3- to 7-membered saturated or unsaturated ring which can contain one or two heteroatoms and which can be monosubstituted or disubstituted by radicals from the group consisting of =S and R 3 D is a direct bond, -NR 6 -C(0)-NR 6 -NR -NR 6 -C(0)-NR 6 -NR 6 -NR 6 -N=CR 6 -R 6 C=N-NR 6 -N=CR 6 or -R 6 where the divalent radicals representing D are bonded to the group E via the free bond on the right side; 93 E is hydrogen, R 6 -C(=NR 6 )-NR 6 R 6 R6'N-C(=NR 6 R 6 R 6 'N-C(=NR6')-NR 6 or a radical from the group consisting of R R 3 N N R 3 N N f N O VY t H CN N H R 5 H NH R H R5 N R R N N which can optionally be monosubstituted to trisubstituted by radicals from the group consisting of R 3 R 5 =S and R 6 R 6 'N-C(=NR 6 n m q p r s t k is one, two, three or four; is zero or one; is zero or one; is zero or one; independently of one another is zero, one or two; is zero, one, two, three, four or five; is zero, one or two; is zero, one or two; is zero or one; 94 Y is zero, one, two or three; in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts and its prodrugs. 3. A compound of the formula I or la as claimed in claim 1 and/or 2, in which: X is hydrogen, NR 6 R 6 or NH-CO-R 6 10 Y is hydrogen; 9% 0 G is a radical of the formula 11 -(CR'R R 2 )-A(CR1 R 2 )m_(CR 1 R 3 )i(CR'R R 2 4 (I W is a radical of the formula Ill R 2 )rA'{CR' R 2 R 3 )k-(CRIR R 2 )tDE (l) G a is a radical of the formula Ila -(CR 1 R 2 )rA(CR' R 2 8 R 1 R 3 R 2 )t-D-E (Ila); Wa is a radical of the formula lila -B(CR 1 R 2 )-A(CR'R 2 )m-(CR'R R 3 R 1 R 2 )q-R 4 (11 la); A, A' independently of one another are a direct bond, -C(O)NR 5 -NR 5 or (C 5 -C 6 -arylene, it being possible for one to two carbon atoms in the aryl radical to be replaced by nitrogen atoms; R 1 R 2 are hydrogen; R 3 independently of one another is hydrogen, (C 1 -C 10 )-alkyl, (C 3 -Cl4)- cycloalkyl, (C 3 -C 1 4 )-cycloalky-(CI-C 8 )-alkyl, (C 5 -C 1 4 )-aryl, (C 5 -C 1 4-aryl- (C 1 -C 8 -alkyl, R 6 R 6 'N-R 7 R 6 OC(O)N(R 5 )RI, R 6 C(O)N(R 5 )R, R 6 N(R 6 )C(O)N(R 5 )R 7 R 6C(O)R 7 or R 6 N(R 6 )C(O)R it being possible for alkyl to be monounsaturated or polyunsaturated and it furthermore being possible for alkyl and aryl to be monosubstituted or polysubstituted by fluorine, chlorine, bromine, cyano, R 6 R6NR 7 R 6 C(O)R 7 R 6 N(R 6 )C(O)R, R6or R 6 OR T R4 is C(O)R 8 independently of one another is hydrogen or (C 1 -C 4 )-alkyl; RR' independently of one another are hydrogen, (CI-C 8 )-alkyl, (C 3 -C 12 cycloalkyl, (C 3 -C 12 )-CYCloalkyl-(C 1 -C 8 )-alkyl, (C 5 -C1 4 )-aryl, in which one to V three carbon atoms can be replaced by one to three heteroatoms from the group consisting of N, S, 0, or are (C 5 -C 14 )-aryl-(Cj-C 8 )-alkyl, in which one to three carbon atoms in the aryl moiety can be replaced by one to three heteroatoms from the group consisting of N, S, 0; R7 is adirect bond; R8 independently of one another is hydroxyl, (Cl-C4)-alkoxy, (C 5 -C 14 )-aryl-(Cl- C 4 )-alkoxy, (C 5 -C 1 4 )-aryloxy, (C 1 -C 8 )-alkylcarbonyloxy-(C 1 -C 4 )-alkoxy, (C 5 C 1 4)-aryl-(Cl-C4)-alkylcarbonyloxy-(Cl-C 4 )-alkoxy or the radical of an amino acid; B is -NR 5 a direct bond or a divalent radical of a 3- to 7-membered saturated or unsaturated ring, which can contain one or two heteroatoms and which can be monosubstituted or disubstituted by radicals from the group consisting of =S and R 3 D is a direct bond, -NR 6 -C(O)-NR 6 or -NR 6 E is hydrogen, R-C(=NR 6 )-NR 6 R 6 R 6 'N-C(=NR 6 RR 6 'N-C(=NR 6 ')-NR 6 or a radical from the group consisting of R 5 N N R 5 R 3 N N R R 3 N ^vN i. S S .5S *5 i S. S S. N R3 CCI_ NS N /N which can optionally be monosubstituted to trisubstituted by radicals from the group consisting of R 3 R 5 =S and R 6 R 6 'N-C(=NR 6 is zero, one, two, three, four or five; is zero or one; is zero or one; is zero or one; is one, two, three or four; is zero or one; is zero or one; is zero or one; m i q in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts and its prodrugs. 4. A compound of the formula I as claimed in claim 1 and/or 2, in which: X is hydrogen, NR6R 6 or NH-CO-R 6 Y is hydrogen; G is a radical of the formula 11 R 2 R 2 )m(CRI R 3 1 R 2 )q-R 4 (I) W is a radical of the formula Ill -B-(CR R 2 )rA'-(CR 1 R 2 8 R 3 R 2 )t-D-E (Ill); A, A' are adirect bond; *R 1 R 2 independently of one another are hydrogen, (C 1 -C 4 )-alkyl, (C 5 -C 6 )-aryl or (C 5 -C 6 )-aryl-(C, -C 4 )-alkyl; R 3 independently of one another is hydrogen, (C,-Cls)-alkyl, (C 3 -Cl4)- cycloalkyl, (C 3 -C 4)-CyCloalkyl-(C 1 -C 8 )-alkyl, (C 5 -C 1 4 )-aryl, (C 5 -C 4)-aryl- (C 1 -C 8 )-alkyl, R 6 R 6 N-R 7 R 6 QC(O)N(R 5 )R 7 R 6 SO 2 N(R 5 )R 7 6C 59,6) 7 ,i R 6 (O)N(R )R 7 R 6 N(R R 6 C(O)R 7 or R6N(R 61 )C(O)R 7 ,i being possible for alkyl to be monounsaturated or polyunsaturated and it *9furthermore being possible for alkyl and aryl to be monosubstituted or polysubstituted by fluorine, chlorine, bromine, cyano, R R 6 NR 7 R 6 C(O)R, R 6 N(R 6 7 R 6 or R 6 0OR 7 R 4 is C(O)R 8 independently of one another is hydrogen or (C,-C4)-alkyl; R 6 R 6 independently of one another are hydrogen, (C 1 -C, 8 )-alkyl, (C 3 -C, 2 cycloalkyl, (C 3 -Cl 2 )-cycloalkyl-(Cl-C 8 )-alkyl, (C 5 -C1 4 )-aryl, in which 1 to 3 carbon atoms can be replaced by 1 to 3 heteroatoms from the group consisting of N, S, 0, or are (C 5 -C 14 )-aryl-(C 1 -C 8 )-alky, in which 1 to 3 carbon atoms in the aryl radicals can be replaced by 1 to 3 heteroatoms 98 from the group consisting of N, S, 0, and it also being possible for R 6 and R, together with the atoms connecting them, to form a ring system which can optionally also contain additional, in particular one, two or three, heteroatoms from the group consisting of N, S, 0; R 7 is a direct bond; R8 independently of one another is hydroxyl, (C 1 -C4)-alkoxy, (C 5 -C 1 4)-aryl-(C 1 C 4 )-alkoxy, (C 5 -C 14 )-aryloxy, (C 1 -C 8 )-alkylcarbonyloxy(C 1 -C4)-alkoxy or (C 5 C 1 4 )-aryl-(C 1 -C 4 )-alkylcarbonyloxy(C 1 -C4)-alkoxy; B is I ,4-piperidinediyl or I ,4-piperazinediyl, where in the case of the 1,4- .**piperidinediyl radical the nitrogen atom of the piperidine is bonded to the nimrine structure; D is a direct bond, -NR 6 C0-R-o N 6 C0- E is hydrogen, R 6 -C(=NR 6 )NR 6 R 6 R 6 'N-C(-NR 6 R 6 R 6 'N-C-(=NR 6 ')-NR 6 or a radical from the group consisting of R 5 R 5 R3f N R3_ NR N N N N N N\ which can optionally be monosubstituted to trisubstituted by radicals from the group consisting of R 3 R 5 =S and R 6 R 6 'N-C(=NR 6 99 r is zero, one or two; s is zero or one; t is zero or one; k is zero or one; n is zero, one or two; m is zero or one; i is zero or one; q is zero or one; in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts and its prodrugs. 5. A compound of the formula I as claimed in one or more of claims 1 to 4, in which: X is hydrogen; Y is hydrogen; G is a radical of the formula II .i R 2 )n-A-(CR R 2 )m (CR' R 3 CR 1 R 2 )q-R 4 (II); W is a radical of the formula III -B-(CR 1 R 2 r A' C R 1 R 2 s CR 1 R 3 k C R 1 R 2 t -D-E (III); A, A' are a direct bond; R 1 R 2 independently of one another are hydrogen or (C 1 -C 2 )-alkyl; R 3 is R 6 R 6 'N-R 7 R60C(O)N(R')R 7 R 6 SO 2 N(R)R 7 R 6 C(O)N(R 5 )R 7 or R 6 N(R 6 )C(O)N(R)R 7 100 R4 is C(O)R 8 is hydrogen or (Cl-C 2 )-alkyl, in particular hydrogen; R 6 R 6 10 es S. 0 0 0@@e S@ S S independently of one another are hydrogen, (C 1 -C, 8 )-alkyl, (C 3 -C 12 cycloalkyl, (C 3 -C 1 2 )-cycloalkyl-(C 1 -C 8 )-alkyl, (C 5 -C 4)-aryl, in which I to 3 carbon atoms can be replaced by I to 3 heteroatoms from the group consisting of N, S, 0, or are (C 5 -C 1 4)-aryl-(C 1 -C 8 )-alkyl, in which 1 to 3 carbon atoms in aryl radicals can be replaced by 1 to 3 heteroatoms from the group consisting of N, S, 0, and it also being possible for R 6 and R 6 together with the atoms connecting them, to form a ring system which can optionally also contain additional heteroatoms from the group consisting of N,S, 0; is a direct bond; is hydroxyl, (C 1 -C4)-alkoxy, (C 5 -C 1 4 )-aryl-(C 1 -C4)-alkoxy, (C 5 -C 4)-aryloxy, (C 1 -C 8 )-alkylcarbonyloxy(C 1 -C 4 )-alkoxy or (C 5 -C 1 4 )-aryl-(C 1 -C 4 alkylcarbonyloxy-(C 1 -C4)-alkoxy; 64@ B is I ,4-piperidinediyl, where the nitrogen atom of the piperidine is bonded to the purine structure; D is -NR 6 or -C(0)-NR 6 where in the group -C(0)-NR 6 the nitrogen atom is bonded to the group E; E is R 6 R 6 N-C(=NR 6 or a radical from the group consisting of 2I 101 R 5 R 5 N N N N R 3 R3 NN N R5 R :.which can optionally be monosubstituted to trisubstituted by radicals from the group consisting of R 3 R 5 =S and R 6 R 6 'N-C(=NR 6 :15 r is zero or one; s is zero; t is zero; k is zero; .n is one; m is zero; i is one; q is zero; in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts and its prodrugs. 6. A compound of the formula Ih 102 H HN O N N (Ih) in which R 3 is RNR 6 'N-R 7 R 6 0C(O)N(Rs)R 7 R 6 SO 2 N(R 5 )R 7 R 6 C(O)N(R 5 )R 7 or R 6 N(R 6 R 6 R 6 and R 7 are defined as in claims 1 to 5 and Rh is the carboxylic acid group COOH or a carboxylic acid derivative; in all its stereoisomeric forms and mixtures thereof in all ratios and its physiologically tolerable salts and its prodrugs. *N 7. 2S-Benzyloxycarbonylamino-3-(6-(4-(1, 4, 5, 6-tetrahydropyrimidin-2-yl- carbamoyl)piperidin-1-yl)purin-9-yl)propionic acid and its physiologically tolerable 2 salts and its prodrugs. 8. A process for the preparation of a compound of the formula I or la as claimed in one or more of claims 1 to 7, which comprises linking two or more fragments which can be derived retrosynthetically from the formula I or la.

9. The process as claimed in claim 8, wherein for the preparation of a compound of the formula I, a compound of the formula IV N""N N (IV) N N "i a 103 in which L1 is a leaving group and X and Y are as defined in claims 1 to 7, but functional groups can also be present in the form of precursors or in protected form, is reacted stepwise with a compound of the formula V L2-(CR 1 R 2 )n-A- CR 1 R 2 m CRR 3 )i-(CR'R 2 )q-R 10 (V) and with a compound of the formula VII H-B-(CR 1 R 2 )r-A'-(CR 1 R 2 )-(CR 1 R 3 )k(CR 1 R 2 )-R 3 (VII) to give a compound of the formula VIII R N r N N N Iil R where in the formulae V, VII and VIII 2..:20 L2 is a leaving group; the radical R 11 is -(CR'R 2 )n-A CR'R 2 )m(CR 1 R 3 )i CR 1 R 2 )q-R 1 0 the radical R 15 is -B-(CR 1 R 2 )r-A'-(CR1R 2 )s-(CR'R 3 )k-(CR1R 2 )-R 13 R 10 has the meanings of R 4 given in claims 1 to 7, where the groups representing R 4 can also be present in protected form; R 13 has the meanings of the group D-E given in claims 1 to 7, where groups contained in D-E can also be present in protected form, or R 13 is a group which can be converted into the group -D-E; R 1 R 2 R 3 A, B, X, Y, n, m, i, q, r, s, k and t have the meanings indicated in claims 1 to 7; and then, if desired, the groups R 10 and R 13 are converted into the groups R 4 and D-E; 104 or, for the preparation of a compound of the formula la, a compound of the formula IV is reacted stepwise with a compound of the formula IX L2-(CR 1 R 2 )r-A'-(CR 1 R 2 )s-(CR 1 R 3 )k-(CR'R 2 )t-R 13 (IX) and with a compound of the formula XI H-B-(CR 1 R 2 )n-A-(CR R 2 R 3 RR 2 )q-R 1 0 (XI) to give a compound of the formula XII N N N N (XII) 0*s* 00.. *00* R 16 R where in the formulae IX, XI and XII the radical R 16 is -(CRR 2 )r-A' CR'R 2 s -(CR R 3 )k-(CR'R 2 )t-R 13 the radical R 17 is -B-(CR 1 R 2 )n-A-(CR'R 2 )m-(CR 1 R 3 i -(CR'R 2 )-R 10 R 1 R 2 R 3 R 10 R 13 A, B, X, Y, L2, n, m, i, q, r, s, k and t are defined as indicated for the formulae V, VII and VIII; and then, if desired, the groups R 10 and R 13 are converted into the groups R 4 and D-E. A compound of the formula I or la as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts and/or its prodrugs for use as a pharmaceutical.

11. Use of a compound of the formula I or la as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts and/or its prodrugs as an inhibitor of bone resorption by osteoclasts, as an inhibitor of tumor growth or tumor mestasis, as an 7) r z'- 105 antiinflammatory, for the therapy or prophylaxis of cardiovascular disorders, for the therapy or prophylaxis of nephropathies or retinopathies, or as a vitronectin receptor antagonist for the therapy or prophylaxis of illnesses which are based on the interaction between vitronectin receptors and their ligands in cell-cell or cell-matrix interaction processes.

12. A method for the treatment of inflammation, the treatment or prophylaxis of cardiovascular disorders, the treatment or prophylaxis of nephropathies or retinopathies, the treatment of tumors, which includes administering to a subject in need of such treatment, an effective amount of a compound of the formula I or la as claimed in one or more of claims 1 to 7.

13. A method for the treatment or prophylaxis of illnesses which are based on the interaction between vitronectin receptors and their ligands in cell-cell or cell-matrix interaction processes which includes administering to a subject in need of such treatment, an effective amount of a compound of the formula I or la as claimed in one or more of claims 1 to 7. S14. A method for the treatment of bone disorders which are based on bone resorption by osteoclasts, which includes administering to a subject in need of such treatment, an effective amount of a compound of the formula I or la as claimed in one or more of claims 1 to 7.

15. A pharmaceutical preparation comprising at least one compound of the formula I or la as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts and/or its prodrugs in addition to pharmaceutically innocuous excipients and/or additives. a a DATED this 2 5 th day of January, 2000 HOECHST AKTIENGESELLSCHAFT and GENENTECH, INC. WATERMARK PATENT AND TRADE MARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA P8456AU00 KJS/ALJ/SXH