Substituted purine derivatives, processes for their preparation and pharmaceutical drug

 

(57) Abstract:

The invention relates to new compounds of formula I and Ia in all their stereoisomeric forms or their mixtures in all ratios, and their pharmaceutically acceptable salts, which has antagonistic activity against vitronectin receptor. The compounds may be used as inhibitors of bone resorption by osteoclasts, tumor growth or metastasis of a tumor, and so on, the Invention also relates to methods of preparing compounds of formulas I and Ia and to pharmaceutical compositions based on them. In the compounds of formulas I and Ia denote: X is hydrogen, NR6R6', fluorine, chlorine, bromine, OR6, SR6, hydroxy-(C1-C6)-alkyl-NH, (hydroxy-(C1-C6)alkyl)2N, amino-(C1-C6)alkyl-NH, (amino-(C1-C6)alkyl)2N, hydroxy-(C1-C6)alkyl-O, hydroxy-(C1-C6)alkyl-S or NH-CO-R6; Y is hydrogen, G is a residue of formula II

-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R4 (II);

W is a residue of formula III

-B-(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R>-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-D-E(IIa);

Wa- the remainder of the formula IIIa

-B-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CRaR2)q-R4 (IIIa);

A, a’ - independently of one another a direct bond, -C(O)NH - or-NH-, RI, R2- independently from each other hydrogen, fluorine, chlorine, cyano, nitro, (C1-C10)alkyl, (C3-C14)cycloalkyl, (C3-C14)cycloalkyl-(C1-C8)alkyl, (C5-C14)aryl, (C1-C8)aryl-(C1-C8)alkyl, R6-O-R7, R6-S(O)p-R7or R6R6’N-R7, R3- independently from each other hydrogen, fluorine, chlorine, cyano, nitro, (C1-C18)alkyl, (C3-C14)cycloalkyl, (C3-C14)cycloalkyl-(C1-C8)alkyl, (C5-C14)aryl, (C5-C14)aryl-(C1-C8)-alkyl, R6-O-R7, R6R6’N-R7, R6C(O)-O-R7, R6C(O)R7, R6OC(O)R7, R6N(R6’)C(O)OR7, R6S-(O)pN(R5R7, R6(O)C(O)N(R5R7, R6C(O)N(R5R7, R6N(R6’)C(O)N(R5)RN(R6’)C(O)R7or R6N(R6’)S(O)pR7and the alkyl may be single or multiple unsaturated and alkyl or aryl can be substituted one or more times by fluorine, chlorine, bromine, cyano, R6R6’N-R7, nitro, R6OC(O)R7, R6C(O)R7, R6N(R6’)C(O)-R7, R6N(R6’)S(O)pR7, R6or R6-O-R7; R4means C(O)R8; R6, R6’, R5independently from each other hydrogen, (C1-C10)alkyl, (C3-C14)cycloalkyl, (C3-C14)cycloalkyl-(C1-C8)alkyl, (C5-C14)aryl, (C5-C14)aryl-(C1-C8)alkyl, R7independently from each other -(C1-C4) alkylene or a direct bond; R8hydroxy, (C1-C8)alkoxy, (C5-C14)aryl-(C1-C8)alkoxy, (C5-C14)aryloxy, (C1-C8)alkylcarboxylic-(C1-C4)alkoxy, (C5-C14)aryl-(C1-C8)alkylcarboxylic-(C1-C8)alkoxy, NR6R6’, (di-((C1-C8)alkyl)amino)carbonyloxy, (di((C5-C14)aryl-(C1-C8)alkyl)amino)carbonylmethyl the>C(O)-, -S(O)u-NR6-, -NR6C(O)-NR6-, -NR6-C(S)NR6-, -NR6-S(O)u-NR6-, -NR6-C(O)O, -NR6-N=CR6-, -NR6-S(O)u-(C5-C14)aryl-CO-, -(C5-C14)-aryl-S(O)u, -N=CR6or R6C=N-, or-R6C=N-NR6- and denoting D divalent residues through free link on the right side are associated with the group E, and E denotes hydrogen, -NH-CH(=NH), -C(=NH)-NH2or 5,6-membered aromatic or non-aromatic residue, optionally containing 1 or 2 nitrogen atom, possibly substituted by exography, the remainder R5or R3or maybe condensed with the phenyl group in the form of benzimidazole residue, n is zero, one, two, three, four or five; m is zero, one, two, three, four or five; i is zero or one; p is independently from each other, zero, one, or two; q is zero, one or two; r is zero, one, two, three, four, five or six; and s is zero, one, two, three, four or five; t is zero, one, two, three, four or five; k is zero or one; and u is one or two; in all their stereoisomeric forms or their mixtures in all ratios, and their pharmaceutically acceptable salts. 6 C. and 6 C.p. f-crystals, 1 PL.

The object of the present invention are compounds formularies acceptable salts and proletarienne means, receive them, their use and containing pharmaceuticals.

The compounds of formula I are valuable active substances of medicines. In particular, they are antagonists vitronektinove receptor and are used for treatment and prophylaxis of diseases which are based on the interaction between vitronectin receptors and their ligands in cell-cell and cell-matrix interaction processes or which may interfere with this interaction, to ease or eliminate. The invention relates, among other things, to the use of compounds of the formula I, and their physiologically acceptable salts and pharmaceutical preparations containing such compounds as drugs for the prevention, mitigation or treatment of diseases which are at least partially due to undesirable level of bone resorption, angiogenesis or cell proliferation of smooth muscles of vessels, or for the treatment and prevention seek to influence these processes. In particular, the compounds of formula I are used as inhibitors of bone resorption, inhibitors of tumor growth and metastasis of the tumor, inhibitors of inflammation, for the treatment or direct and prevention of nephropathy and retinopathy, as, for example, diabetic retinopathy.

Compounds according to the invention of the formulae I and Ia inhibit bone resorption by osteoclasts. Bone diseases, against which it is possible to apply the compounds of formula I, are primarily osteoporosis, hypercalcemia, osteopenia, for example, caused by metastatic disease, dental disease, hyperparathyroidism, periarticular erosion in rheumatoid arthritis and Paget's disease. Further, the compounds of formula I can be applied to mitigate, prevent or treat bone disease that is caused by treatment with glucocorticoids, steroids, or corticosteroids or lack of sex hormones. All these diseases are bone loss, which is caused by imbalance between the building bone and destruction of bone tissue.

Human bones are subjected to continuous dynamic process of restructuring, which includes bone resorption and building bone. These processes are managed by specialized cell types. Building bone caused by the deposition of bone matrix by osteoclasts, bone resorption is caused by destruction of bone by osteoclasts. Most of the bone based on the imbalance between the way the are multinucleated cells with a diameter of 400 μm, which break down bone matrix. Activated osteoclasts Deposit on the surface of the bone matrix and release of proteolytic enzymes and acids in the so-called "the seal", the area between the cell membrane and the bone matrix. Acidic environment and protease lead to destruction of the bone.

Studies have shown that the deposition of osteoclasts on the bone control integranova receptors on the cell surface of osteoclasts. Integrins are a superfamily of receptors to which they belong, by the way, fibrinogenesis receptorIIb3on the platelets and the vitronectin receptor v3. The vitronectin receptorv3is a glycoprotein with a constant membrane, which exprimarea on the surface of some cells, such as endothelial cells, smooth muscle cells of blood vessels, osteoclasts and tumor cells. The vitronectin receptorv3that exprimarea on the membrane of osteoclasts, manages the process deposits on the bones and bone resorption, hence contributes to osteoporosis. When thisv3binds to proteins of the bone matrix, as osteopontin, bone sialoprotein and thrombospondin that contain the motif is (S), which inhibit the destruction of the tooth by osteoclasts and the migration of osteoclasts (Horton et al., Exp. Cell Res., 1991, 195, 368). Sato and others describe in J. Cell Biol., 1990, 111, 1713, echistatin, RCD-peptide from snake venom as a potential inhibitor of bone resorption in tissue culture and as an inhibitor of attachment of osteoclasts to bone. Fischer et al. (Endocrinology, 1993, 132, 1411) were able to show on a rat that echistatin resorption of bone also in vivo. Wayne et al. (J. Clin. Invest., 1997, 99, 2284) were able to show at the rat in vivo inhibition of bone resorption antagonists vitronektinove receptor.

Vitronektinove receptorv3human smooth muscle cells of the aorta stimulates migration of these cells in neointima, which leads, finally, 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 againstv3or v3-antagonists can cause the reduction of tumors, and they induce apoptosis in cells of blood vessels during angiogenesis. Cheresh et al. (Science, 1995, 270, 1500) describe anti-v3the antibody orv3-antagonists, which inhibit bFGF-induzirovanny

From EP-A-O 528586 and EP-A-O 528587 known aminoalkyl or substituted heterocyclic derivatives of phenylalanine, from WO 95/32710 known aryl derivatives as inhibitors of bone resorption by osteoclasts. In WO 95/28426 described RGD-peptides as inhibitors of bone resorption, angiogenesis and restenosis. In WO 96/00574 and WO 96/26190 describe, among other things, the benzodiazepines as antagonists vitronektinove receptor or antagonists integranova receptor. In WO 96/00730 described matrix antagonists fibrinogenesis receptor, especially benzodiazepines, which are associated with nitrogen-containing 5-membered ring, as antagonists vitronektinove receptor. In EP-A-O 531883 described condensed 5-membered heterocycles, which inhibit the binding of fibrinogen with platelets.

The object of the present invention are compounds of formulas I and Ia

where X is hydrogen, NR6R6’, fluorine, chlorine, bromine, OR6, SR6, hydroxy-(C1-C6)alkyl-NH, (hydroxy-(C1-C6)alkyl)2N (amino-(C1-C6)alkyl-NH, (amino-(C1-C6)alkyl)2N, hydroxy-(C1-C6)-alkyl-O, hydroxy-(C1-C6)alkyl-S or NH-CO-R6;

Y - R6, fluorine, chlorine, bromine, qi the crystals II

-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R4(II)

W is a residue of formula III

- (CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-D-E (III)

Ga- the remainder of the formula IIA

-(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-D-E (IIa)

Wa- the remainder of the formula IIIa

-B-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R4(IIIa)

A, A’ independently of one another represent a direct bond, -C(O)NR5-, -NR5C(O)-, -C(O)-, -NR5-, -O-, -S-, -SO-, -SO2-, (C5-C14)-Allen, and aryl residue from 1 to 5 carbon atoms can be substituted by from 1 to 5 heteroatoms, (C2-C4)akinyan, (C2-C4)albaniles or the divalent residue of 3 - to 7-membered saturated or unsaturated ring which may contain one or two heteroatoms, such as nitrogen, sulfur or oxygen, and which may be substituted once or twice remnants of a number of =O, =S or R3;

R3-C14-cycloalkyl, (C3-C14)cycloalkyl-(C1-C8)alkyl, (C5-C14)aryl, (C5-C14)aryl-(C1-C8)-alkyl, R6-O-R7, R6-S(O)p-R7or R6R6’N-R7;

R3independently from each other hydrogen, fluorine, chlorine, cyano, nitro, (C1-C18)alkyl, (C3-C14)cycloalkyl, (C3-C14)cycloalkyl-(C1-C8)alkyl, (C5-C14)aryl, (C5-C14)aryl-(C1-C8)alkyl, R6-O-R7, R6R6’N-R7, R6C(O)-O-R7, R6C(O)R7, R6OC(O)R7, R6N(R6’)C(O)OR7, R6S-(O)pN(R5R7, R6OC(O)N(R5R7, R6C(O)N(R5R7, R6N(R6’)C(O)N(R5R7, R6N(R6’)S(O)pN(R5R7, R6S(O)pR7, R6SC(O)N(R5R7, R6N(R6’)C(O)R7or R6N(R6’)S(O)pR7and the alkyl may be single or multiple unsaturated and alkyl or aryl can be substituted one or more times by fluorine, chlorine, bromine, cyano, R6R6’NR7, nitro, R6OC(O)R7, R6C(O)R7

R4denotes C(O)R8C(S)R8, S(O)pR8, P(O)R8R8’or the remainder of the 4 - to 8-membered saturated or unsaturated heterocycle, which contains 1,2,3 or 4 heteroatoms from the series N, O, S, as, for example, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiadiazolyl;

R5- independently from each other hydrogen, (C1-C10)alkyl, (C3-C14-cycloalkyl, (C3-C14-cycloalkyl(C1-C8)-alkyl, (C5-C14)aryl or (C5-C14)aryl-(C1-C8)alkyl;

R6, R6’- independently from each other hydrogen, (C1-C18)alkyl, (C3-C14-cycloalkyl, (C3-C14-cycloalkyl-(C1-C8)alkyl, (C5-C14)-aryl, where from 1 to 5 carbon atoms may be replaced by heteroatoms like N, O, S, or (C5-C14)aryl-(C1-C8)alkyl, where the aryl part and from 1 to 5 carbon atoms can be substituted gateroad ohms, as N, O, S, or R6and R6’form together with the atoms connecting them cyclic system, preferably, from 4 - to 8-membered cyclic system which, if necessary, may also contain additional heteroatoms, preferably one, d is equipment intensive, as, for example, morpholine, thiomorpholine, piperazine, piperidine, pyrrolidine;

R7- independently from each other (C1-C4)alkylene or a direct link;

R8, R8’- independently from each other hydroxy, (C1-C8)alkoxy, (C5-C14)aryl-(C1-C8)alkoxy, (C5-C14)aryloxy, (C1-C8)alkylcarboxylic- (C1-C4)alkoxy, (C5-C14)aryl-(C1-C8)alkylcarboxylic-(C1-C8)alkoxy, NR6R6’, (di-((C1-C8)alkyl)amino)carbonyloxy, (di((C5-C14)aryl(C1-C8)alkyl)amino)carbonyloxy, (C5-C14)arylamino, the balance of amino acids, N-((C1-C4)alkyl)piperidine-4-yloxy, 2-methylsulfonylmethane, 1,3-thiazol-2-ylmethylene, 3 pyridylmethylene, 2-(di((C1-C4)alkyl)amino)ethoxy or the remainder of Q-(CH3)3N+-CH2-CH2O-, where Q-denotes a physiologically acceptable anion;

IN IS-O-, -S-, -NR5-, -NR5-C(O)-, -C(O)-NR5-, a direct bond or a divalent residue of 3 - to 7-membered saturated or unsaturated ring which may contain one or two heteroatoms, such as nitrogen, sulfur or Ki is oznachaet direct link, -NR6-, -C(O)-NR6-, -NR6-C(O)-, -S(O)u-NR6-, -NR6-C(O)-NR6-, -NR6-C(S)-NR6-, -NR6-S(O)u-NR6-, -NR6-C(O)O-, -NR6-N=CR6-, -NR6-S(O)u-, -(C5-C14)aryl-CO-, -(C5-C14)aryl-S(O)u-, -N=CR6-, -R6C=N or R6C=N-NR6- while denoting D divalent residues through free link on the right side are associated with the group E;

E is hydrogen, R6-C(=NR6)-NR6-, R6R6’N-C(=NR6)-, R6R6’N-C(=N-R6)-NR6or the remainder of the 4 - to 11-membered, monocyclic or polycyclic, aromatic or non-aromatic cyclic system, which, if necessary, may contain 1,2,3 or 4 heteroatoms from the series N, O and S and may be, if necessary, once, twice or three times substituted by residues from a number R3, R5, =O, =S, and R6R6’N-C(=NR6)- as, for example, the following residues:

, , , ,

, , , ,

, , ,

,,

, ,

,,

, , ,

, , , ,

, , , ,

, ;

n is zero, one, two, three, four or five;

m is zero, one, two, three, four or five;

iS="ptx2">

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 their stereoisomeric forms and mixtures in all respects and their physiologically acceptable salts, and their proletarienne form

and instead shown in formulas I and Ia of the rest of purine may also take place the remainder of the 3-deaza-purine residue 7-deaza-purine or a residue of 7-deaza-8-Aza-purine.

All residues and indices that can be repeatedly meet in the compounds of formulas I and Ia, for example, appear in the residuals of G and W the radicals R1, R2and R3and found in them the radicals R5, R6, R6’, R7and indexes, as well as all other residues and indices, for which it really is, can be respectively independently of each specified values. They may be the same or different. The heteroatoms can also be in the heterocycles or deputies in the residuals, which can repeatedly take place, independently of one another have the specified values and may be the same or different.

Examples of suitable residues (C1-C18)alkyl are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, undecyl, dodecyl, tridecyl, hexadecyl, octadecyl, n-isomers of these residues, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, 2,3,4-trimethylpentyl, sec-butyl, tert-butyl, tert-pentyl. Preferred alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

Unsaturated alkyl residues are, for example, alkeline remains as vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl, or alkyline remains as ethinyl, 1-PROPYNYL or propargyl. Alkenylamine residues and akinleye residues may be linear or branched. Examples alkenylamine residues are vinile or propylen, for the remainder of alkylarene - ethynylene or propylen.

The remains of cycloalkyl can be monocyclics cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, further, for example, cycloneii, cyclodecyl, cyclodecyl, cyclododecyl or collateralized, which, however, can also be substituted, for example, (C1-C4)alkyl. As examples of substituted cycloalkyl residue should be called 4-methylcyclohexyl and 2,3-dimethylcyclobutyl.

Bicyclic and tricyclic cycloalkyl residues may not be substituted or may be substituted at any suitable positions of one or more exography and/or one or more identical or different groups (C1-C4)alkyl, for example, a methyl group or an isopropyl group, preferably a methyl group. Free link bicyclic or tricyclic residue may be in any position of the molecule, therefore, the balance can be connected through the head atom of the bridge or through the atom in the bridge. Free link can be in any stereochemical position, for example, in the Exo-position or in the endo-position.

Examples of the main part of bicyclic systems are norbornane (=bicyclo[2.2.1]heptane), bicyclo[2.2.2]octane and bicyclo[3.2.1]octane. Example samisen the Asti tricyclic systems are twisted (=tricyclo[4.4.0.03,8]decane), adamantane (=tricyclo[3.3.1.13,7]decane), noradsanta (=tricyclo[3.3.1.03,7]nonan), tricyclo[2.2.1.02,6]heptane, tricyclo[5.3.2.04,9]dodecan, tricyclo[5.4.0.02,9]undecane or tricyclo[5.5.1.03,11]tridecan.

(C5-C14)aryl covers heterocyclic residues (C5-C14)aryl, in which the carbon atoms in the ring are replaced by heteroatoms as nitrogen, oxygen or sulfur, and carbocyclic residues (C6-C14)aryl. Examples of carbocyclic residue of aryl are phenyl, naphthyl, biphenylyl, antrel or fluorenyl, with a preference for 1-naphthyl, 2-naphthyl and especially phenyl. The remains of aryl, especially the remains of the phenyl may be substituted one or more times, preferably once, twice or three identical or different residues from the series (C1-C8)alkyl, especially (C1-C4)alkyl, (C1-C8)-alkoxy, especially (C1-C4)alkoxy, halogen like fluorine, chlorine and bromine, nitro, amino, trifluoromethyl, hydroxy, methylenedioxy, cyan, hydroxycarbonyl, aminocarbonyl, (C1-C4)alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, (R9O)2P(O)-, (R9O)2-P(O)-O - or tetrazolyl, and R98)alkyl. It's really for the corresponding residues of arylene.

In monosubstituted phenyl residues Deputy may be in the 2-position, 3-position or 4-position, and prefer the 3-position and 4-position. If phenyl substituted twice, the substituents can be in the 1,2-, 1,3 - or 1,4-position to each other. As for the binding sites, the substituents can be in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. Preferably, the twice substituted by residues of both phenyl substituent located at the 3-position and 4-position relative to the binding sites.

Aryl or allenbyi groups can be monocyclic or polycyclic aromatic system, where 1,2,3,4 or 5 carbon atoms in the ring are replaced by heteroatoms, such as, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazoles, phthalazine, hinely, ethanolic, honokalani, hintline, cinnoline-carbonyl or benzo-annulirovano, cyclopent-, cyclohexa or cyclohepta-annulirovano derived the mini-aryl system.

Among these aryl groups and relevant arenovich groups preferred monocyclic or bicyclic aromatic systems with 1, 2 or 3 heteroatoms from the series N, O, S, which is not substituted or may be substituted by 1, 2 or 3 substituents from the series (C1-C6)alkyl, (C1-C6)alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxy, (C1-C4)alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl.

It is particularly preferred monocyclic or bicyclic aromatic 5 - to 10-cycle system with 1 to 3 heteroatoms from the series N, O, S, which can be substituted by 1-2 substituents from the series (C1-C4)alkyl, (C1-C4)alkoxy, phenyl, phenoxy, benzyl and benzyloxy.

Examples of saturated and unsaturated rings, preferably 3 - to 7-membered saturated or unsaturated ring which may contain one or two heteroatoms, such as nitrogen, sulfur or oxygen, and can be substituted, if necessary, once or twice through =O, =S or R3represent cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclopentene, cyclohexene, cycloheptene, tetrahydropyran, 1,4-dioxocyclohexa, morpholine, tn, 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-thiazolin, thiazolidin, -thiopyran, Piran, Piran.

The specified R8and/or R8’the remainder of the amino acids get in the usual way for the chemistry of peptides, removing from the amino group of the amino hydrogen atom. Thus obtained via the free bond on the amino group of the amino acid residue linked then, for example, with group CO-R8. Amino acids may be natural or unnatural. Prefer-amino acids. Amino acids can exist in various stereochemical forms, such as D - or L-amino acids, and a single stereochemical form or in the form of mixtures of stereoisomers. As amino acids should be called, for example, (compare Houben-Weyl, Methods of organic chemistry, volume XV/1 and 2, edition, Georg Thieme, Stuttgart, 1974):

Aad, Abu, Abu, ABz, 2ABz, Aca, Ach, Acp, Adpd, Ahb, Aib, Aib, Ala, Ala, Ala, 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, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hIle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, nor, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, Lys, Lys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen,neopentylglycol (Npg), cyclohexylglycine (Chg), cyclohexylamine (Cha), 2-titillans (Thia), 2,2-diphenylsiloxane acid, 2-(p-tolyl)-2-Veniaminovna acid, 2-(p-chlorophenyl)aminouksusnoy acid;

next:

pyrrolidin-2-carboxylic acid; piperidine-2-carboxylic acid; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; decahydroquinoline-3-carboxylic acid; octahedron-2-carboxylic acid; decahydroquinoline-2-carboxylic acid; octahydrocyclopenta[b]pyrrole-2-carboxylic acid; 2-azabicyclo[2.2.2]octane-3-carboxylic acid; 2-azabicyclo[2.2.1]heptane-3-carboxylic acid; 2-azabicyclo[3.1.0]hexane-3-carboxylic acid; 2-azaspiro[4.4]nonan-3-carboxylic acid; 2-azaspiro[4.5]decane-3-carboxylic acid; Spiro(bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid; Spiro(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid; 2-azatricyclo[4.3.0.16,9]decane-3-carboxylic acid; decahydrated[b]pyrrole-2-carboxylic acid; damageresistant[C]pyrrole-2-carboxylic acid; octahydrocyclopenta[C]pyrrole-2-carboxylic acid; octahydrocyclopenta-1-carboxylic acid; and 2,3,3,4,6 and hexahydrotriazine[b]pyrrole-2-carboxylic acid; and 2,3,3,4,5,7 and-hexahedronal-2-carboxylic acid; tetrahydrocarbazol-4-carboxylic what I acid; all, if necessary, can be substituted (see the following formula):

; ; ; ;

; ; ;

; ; ;

; ; ;

; ; ;

; ; ; ;

; ; ; ;

.

Underlying the above-mentioned residues heterocycles are known, for example, from patent US-A-4 344 949; US-a-4-374 847; US-a-4 350 704; EP-29 488; EP-A 31 741; EP-A 46 953; EP-49 605; EP-49 658; UR-50 800; EP-51 020; ER-AND 52 870; UR-79 022; EP-84 164; EP-89 637; UR-90 341; UR-90 362; EP-A 105 102; ER-AND 109 020; ER-AND 111 873; EP-A 271 865 and EP-344 682.

Further, the amino acids can be represented in the form of esters or amides, such as methyl ester, ethyl ester, isopropyl ester, isobutyl ester, tert-butyl ester, benzyl ester, unsubstituted amide, methylamide, ethylamide, the formation of or-amino(C2-C8)alkylamide.

Functional groups of amino acids can be protected. Suitable protective groups are the groups, as, for example, urethane protective group, a carboxyl protective group, and the protective groups of the side chains, described by Hubbuch, Kontakte (Merk), 1979, No. 3, s. 14-23, and Bullesbach, Kontakte (Merk), 1980, No. 1, s. 23-35. Especially it should be called Aloe, Pyoc, Fmoc, Tcboc, Z, BOC, Ddz, Rooted, Adoc, Msc, Moc, Z(NO2), Z(Haln), Bobz, Iboc, Adpoc, Mboc, Acm, tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt is s E-pure isomers and Z-isomers, and a mixture of E/Z-isomers in all respects are the subject of the present invention. Compounds of formulas I and Ia can contain optically active carbon atoms that are independently from each other may have the R - or S-configuration. They can exist in the form of pure enantiomers or pure diastereomers or in the form of mixtures of enantiomers, for example, in the form of racemates or mixtures of diastereoisomers. As pure enantiomers and mixtures of enantiomers in all respects, and the diastereomers and mixtures of diastereomers in all respects are the subject of the present invention. The diastereomers, E/Z-isomers, can be divided, for example, by chromatography to separate the isomers. The racemates can, for example, by chromatography to separate on a chiral phase or by splitting of the racemate for both enantiomers. In the presence of mobile hydrogen atoms present invention also includes the tautomeric forms of the compounds of formulas I and Ia.

Physiologically tolerated salts of compounds of formulas I and Ia are preferably pharmaceutically applicable or non-toxic, physiologically salt used.

Of the compounds of formulas I and Ia, which contain acidic groups, for example carboxy, receive such solimine and calcium salts, and also salts with physiologically acceptable Quaternary ammonium ions and acid additive salts with ammonia and physiologically acceptable organic amines, such as triethylamine, ethanolamine or Tris-(2-hydroxyethyl)amine.

Compounds of formulas I and Ia, which contain basic groups, for example, one or more amino groups, Aydinoglu or guanidinium form the acid salt additive, for example, with inorganic acids as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids, as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonate or p-toluensulfonate.

Physiologically acceptable anion Q-that is contained in the compounds of formulas I and Ia, where R8and/or R8’denotes the residue of 2-ammonium-ethoxy is preferably a monovalent anion or an equivalent of a polyvalent anion of a non-toxic, physiologically used, in particular also used pharmaceutically, of inorganic or organic acids, for example, anion or an equivalent of an anion of one of the above acids, primarynav (or equivalent anion) from a number of chloride, sulfate, phosphate, acetate, citrate, benzoate, maleate, fumarate, tartrate, methanesulfonate and p-toluensulfonate.

Salt, you can get a regular, well-known expert in the ways of compounds of formulas I and Ia, for example, by reaction of compounds of formula I and Ia with an inorganic or organic acid or base in a solvent or dispersant, or by cautionable or aminoalkenes from other salts. The present invention also includes all salts of the compounds of formulas I and Ia, which due to limited physiological tolerability unsuitable for use in medicines, but used, for example, as intermediate products for the enjoyment of other chemical modifications of the compounds of formulas I and Ia as the starting material for obtaining physiologically acceptable salts.

The present invention includes, in addition, all of the solvate of the compounds of formulas I and Ia, for example hydrates or adducts with alcohols, and also derivatives of the compounds of formulas I and Ia, for example, ethers, proletarienne forms and metabolites, which act as compounds of formulas I and Ia. The subject invention are particularly proletarienne forms of the compounds of formulas I and Ia, which at physiological at the, as well as chemically modified derivatives of the compounds of formulas I and Ia, preferably with improved properties, specialist known. More detailed information about the prodrugs are, for example, in Fleisher et al., Advanced 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); Safadi et al., Pharmaceutical Res., 10 (1993), 1350. As prodrugs of compounds of formulas I and Ia specifically take into account the essential proletarienne form of acid groups such as carboxylic acid, preferably R4denoting COOH group, and allowee proletarienne forms and urethane proletarienne form alleluiah nitrogen-containing groups, amino groups, amidinopropane or guanidinium, especially denoting E groups R6-C(=NR6)-NR6-, R6R6’N-C(=NR6)-, R6R6’N-C(=NR6)-NR6and from 4 - to 11-membered, monocyclic or polycyclic, aromatic or non-aromatic cyclic system. In atilovykh proletarienne forms or urethane proletarienne forms one or more times, for example twice, in these groups on the nitrogen atom the hydrogen atom is substituted by an acyl or urethane Grundig forms take into account, for example, the group R6-CO and R6O-CO -, in which R6have the above values, hence, hydrogen, (C1-C18)alkyl, (C3-C14)cycloalkyl, (C3-C14)cycloalkyl-(C1-C8)alkyl, (C5-C14)aryl, where 1-5 carbon atoms may be replaced by heteroatoms like N, O, S, or (C5-C14)aryl-(C1-C8)alkyl, where the aryl part 1-5 carbon atoms may be replaced by heteroatoms like N, O, S, and combinations of values of the substituents, in which case lead to unstable compounds, for example, to unstable free carbamino acids, are not taken into account. These proletarienne forms you can make a regular, well-known specialist, methods for making acylamino and carbamates.

Further, the present invention is not limited to the compounds according to formulas I and Ia with the principal balance of purine, and also includes such compounds, which are instead shown in formulas I and Ia of the principal balance of purine have the remainder of the 3-deaza-purine residue 7-deaza-purine or a residue of 7-deaza-8-Aza-purine, therefore, the compounds of formulas Ib and Ic, Id and Ie, and If and Ig.

Ib and IC, Id and Ie, If and Ig, respectively. If we are talking about the compounds of formulas I and Ia include, because there are no other indications of deaza analogs and deaza-Aza-analogs of formulas Ib and Ic, Id and Ie, If and Ig. Preferably in the compounds according to the invention there is really shown in formulas I and Ia purine residue, in which the 3-position and 7-position are nitrogen atoms and 8-position carbon atom with its related group Y.

In the compounds of formulas I and Ia, X preferably denotes hydrogen, NR6R6’, hydroxy-(C1-C6)alkyl or NH-CO-R6especially preferably hydrogen, NR6R6’or NH-CO-R6, more preferably hydrogen or NH2. Y preferably denotes hydrogen, R4means is preferably C(O)R8. Preferred compounds according to the invention of the formulae I and Ia in which R3means R6R6’N-R7, R6OC(O)N(R5R7, R6S(O)pN(R5R7, R6C(O)N(R5R7or R6N(R6’)C(O)N(R5R7and p is 1 or 2, are preferred compounds in which R3means R6OC(O)N(R5R7or R6S(O)pN(R5R7(with p=1 or 2), with the which R6and/or R6’for example, in the group R6OC(O)N(R5R7means (C4-C14)alkyl, (C5-C14)aryl-(C1-C4)alkyl, e.g. benzyl, (C5-C14)cycloalkyl or (C5-C14)cycloalkyl-(C1-C4)alkyl, preferably residues cycloalkyl are here particularly preferably 1-substituted and 2-substituted.

A preferred group of compounds according to the invention comprise the compounds of formula I and Ia, where

X is hydrogen, NH2HE or NH-CO-R6;

Y is hydrogen;

G is a residue of formula II

-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R4(II);

W is a residue of formula III

B-(CRlR2)r-A’-(CRlR2)s-(CRlR3)k-(CRlR2)t-D-E- (III);

Ga- the remainder of the formula IIA

-(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-D-E- (IIA);

Wa- the remainder of the formula IIIa

-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)5
-, -O-, -S-, -SO-, -SO2-, (C5-C14)Allen, and in the rest of the aryl 1-5 carbon atoms may be substituted by 1 to 5 heteroatoms, (C2-C4)akinyan, (C2-C4)albaniles or the divalent residue of 3 - to 7-membered saturated or unsaturated ring which may contain one or two heteroatoms, such as nitrogen, sulfur or oxygen, and which may be substituted once or twice =O, =S or R3;

R1, R2- independently from each other H, fluorine, chlorine, CN, nitro, (C1-C10)alkyl, (C3-C14)cycloalkyl, (C3-C12)cycloalkyl-(C3-C8)alkyl, (C5-C14)aryl, (C5-C14)aryl-(C1-C8)alkyl, R6-O-R7, R6-S(O)p-R7or R6R6’N-R7;

R3- independently from each other H, fluorine, chlorine, CN, nitro, (C1-C14)alkyl, (C3-C14)cycloalkyl, (C3-C14)cycloalkyl-(C1-C8)alkyl, (C5-C14)aryl, (C5-C14)aryl-(C1-C8)alkyl, R6-O-R7, R6-S(O)n-R7, R6R6’N-R7, R6CO2R7, R6COR7, R6OC(O)R7, R6N(R5)C(O)OR7>(R5)C(O)N(R5R7, R6N(R5)S(O)pN(R5R7, R6S(O)pR7, R6SC(O)N(R5R7, R6C(O)R6, R6N(R5)-C(O)R7or R6N(R5)S(O)pR7and the alkyl may be singly or multiply unsaturated, and where the alkyl or aryl may be substituted one or more times by fluorine, chlorine, bromine, CN, R6N(R5R7, R6R6’NR7, nitro, R6OC(O)R7, R6C(O)R7, R6N(R5)C(O)R7, R6N(R5)S(O)pR7, R6, R6-O-R7;

R4- C(O)R8C(S)R8, S(O)pR8, POR8R8’, L - or D-amino acid or 4 - to 8-membered, saturated or unsaturated heterocycle, which contains 1,2,3 or 4 heteroatoms from the series N, O, S, as, for example, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiadiazolyl;

R5- N, (C1-C10)alkyl, (C3-C14)cycloalkyl, (C3-C14)cycloalkyl-(C1-C8)alkyl, (C5-C14)aryl or (C5-C14)aryl-(C1-C8)alkyl;

R6, R6’- independently from each other H, (C1-C8)alkyl, (C3-C14)cycloalkyl,t can be replaced by heteroatoms, or (C5-C14)aryl-(C1-C8)alkyl, and in part aryl 1-5 carbon atoms may be replaced by heteroatoms, or R6and R6’form together with the atoms connecting them cyclic system, which, if necessary, may also contain other heteroatoms from the series N, S, O, as, for example, morpholine, piperazine, piperidine, pyrrolidine;

R7denotes independently from each other (C1-C14)alkylene or a direct link;

R8, R8’- independently from each other, (C1-C8)alkoxy, (C5-C14)aryl-(C1-C8)alkoxy, (C5-C14)aryloxy, (C1-C8)alkylcarboxylic-(C1-C4)alkoxy, (C5-C14)aryl-(C1-C8)alkylcarboxylic-(C1-C6)alkoxy, NR6R6’, (C1-C8)dialkylaminomethylcalix, (C5-C14)aryl-(C1-C8)dialkylaminomethylcalix, (C5-C14)-arylamino or L - or D-amino acid;

In denotes O, S, -NR5-C(O)-, -C(O)-NR5, a direct link or a divalent residue of 3 - to 7-membered saturated or unsaturated ring which may contain one or two heteroatoms, such as, for example, will assnchat direct link, -NR6-, -C(O)-NR6-, -NR6-C(O)-SO2NR6-, -NR6-C(O)-NR6, -NR6-C(S)-NR6-, -NR6-S(O)u-NR6-, -NR6-C(O)O-, -NR6-N=CR6-, -NR6-S(O)u-, -(C5-C14)aryl-CO-, -(C5-C14)-aryl-S(O)u-, -N=CR6-, -R6C=N or R6C=N-NR6;

E is hydrogen, R6-C(=NR6)NR6-, R6R6’N-C(=NR6)-, R6R6’N-C(=NR6)-NR6- or 4 - to 11-membered, mono - or polycyclic, aromatic or non-aromatic system, which, if necessary, may contain 1-4 heteroatoms from the series N, O and S, and, if necessary, can be substituted once to three-fold R3, R5, =O, =S or R6R6’N-C(=NR6)- as, for example, residues that are specified in the aforementioned definition of E with their structural formulas;

n is zero, one, two, three, four or five;

m is zero, one, two, three, four or five;

i is zero or one;

p is independently from each other, zero, one, or two;

q is independently from each other, 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, even the Oh number zero, one, two, or three;

in all their stereoisomeric forms and mixtures in all respects, and their physiologically tolerated salts, and in this preferred group of compounds are not included analogues with 3-deaza-purine residue, 7-deaza-purine residue or 7-deaza-8-Aza-purine residue.

Another group of preferred compounds comprise compounds of formulas I and Ia, where

X is hydrogen, NR6R6’, hydroxy(C1-C6)alkyl-NH or NH-CO-R6;

Y is hydrogen;

G is a residue of formula II

-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R4(II);

W is a residue of formula III

B-(CRlR2)r-A’-(CRlR2)s-(CRlR3)k-(CRlR2)t-D-E- (III);

Ga- the remainder of the formula IIA

-(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-D-E- (IIA);

Wa- the remainder of the formula IIIa

-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R4(IIIa);

A, a’ denote independently Drinian, (C2-C4)albaniles or (C5-C14)Allen, and in the rest of the aryl 1-3 carbon atom can be substituted one to three heteroatoms from the series O, N, S;

R1, R2- independently from each other hydrogen, fluorine, cyano, (C1-C4)alkyl, (C5-C6)aryl, (C5-C6)aryl-(C1-C4)alkyl, R6-O-R7or R6R6’N-R7;

R3- independently from each other hydrogen, (C1-C18)alkyl, (C3-C14)cycloalkyl, (C3-C14)cycloalkyl-(C1-C8)alkyl, (C5-C14)aryl, (C5-C14)aryl-(C1-C8)alkyl, R6R6’N-R7, R6C(O)R7, R6S(O)pN(R5R7, R6OC(O)N(R5R7, R6C(O)N(R5R7, R6N(R6’)C(O)N(R5R7, R6N(R6’)S(O)pN(R5R7or R6N(R6’)C(O)R7and the alkyl may be singly or multiply unsaturated, and where the alkyl or aryl may be substituted one or more times by fluorine, chlorine, bromine, cyano, R6R6’NR7, nitro, R6OC(O)R7, R6C(O)R7, R6N(R6’)C(O)R7, R6N(R6’)S(O)pR7 is A. hydrogen or (C1-C4)alkyl;

R6, R6’- independently from each other hydrogen, (C1-C18)alkyl, (C3-C14)cycloalkyl, (C3-C14)cycloalkyl-(C1-C8)alkyl, (C5-C14)-aryl, where 1-3 carbon atom can be substituted by 1 to 3 heteroatoms from the series N, S, O, or (C5-C14)aryl-(C1-C8)alkyl, and aryl part 1-3 carbon atom can be substituted by 1 to 3 heteroatoms from the series N, S, O, or R6and R6’form together with the atoms connecting them cyclic system, which, if necessary, may also contain further heteroatoms from the series N, S, O, as, for example, morpholine, piperazine, piperidine, pyrrolidine;

R7- independently from each other (C1-C2)alkylene or a direct link;

R8- independently from each other hydroxy, (C1-C4)alkoxy, (C5-C14)aryl-(C1-C4)alkoxy, (C5-C14)aryloxy, (C1-C8)alkylcarboxylic- (C1-C4)alkoxy, (C5-C14)aryl-(C1-C4)alkylcarboxylic-(C1-C4)alkoxy or amino acid residue;

In denotes-O-, -S-, -NR5- a direct link or a divalent residue from example nitrogen, sulfur or oxygen, and which may be substituted once or twice remnants of a number of =O, =S or R3;

D denotes a direct bond, -NR6-, -C(O)-NR6-, -NR6-C(O)-NR6-C(O)-NR6-, -NR6-C(O)O-, -NR6-N=CR6-, -R6C=N-NR6-, -N=CR6or R6C=N, and denoting D divalent residues through free link on the right side are associated with the group E;

E is hydrogen, R6-C(=NR6)NR6’-, R6R6’N-C(=NR6’)-, R6R6’N-C(=N-R6’)-NR6or the remainder of a number

, , , ,

, , ,

, ,

which, if necessary, can be substituted once to three times the remains of a number R3, R5, =O, =S, and R6R6’N-C(=NR6)-;

n is one, two, three, or four;

m is zero or one;

i is zero or one;

q is zero or one;

p is independently from each other, zero, one, or two;

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 in all respects, their fisiologa I and Ia, where

X is hydrogen, NR6R6’or NH-CO-R6;

Y is hydrogen;

G is a residue of formula II

-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R4(II);

W is a residue of formula III

B-(CRlR2)r-A’-(CRlR2)s-(CRlR3)k-(CRlR2)t-D-E- (III);

Ga- the remainder of the formula IIA

-(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-D-E- (IIA);

Wa- the remainder of the formula IIIa

-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R4(IIIa);

A, A’ - independently of one another a direct bond, -C(O)NR5-, -NR5C(O) -, or (C5-C6)Allen, and in the aryl part 1-2 carbon atoms may be replaced by nitrogen atoms;

R1, R2is hydrogen;

R3- independently from each other hydrogen, (C1-C10)alkyl, (C3-C14)cycloalkyl, (C3-C14)cycloalkyl-(C1-C8)alkyl, (C5-C14)aryl, (C5-C14)aryl-(C1-CR6’)C(O)N(R5R7, R6C(O)R7or R6N(R6’)C(O)R7and the alkyl may be singly or multiply unsaturated, and where the alkyl or aryl may be substituted one or more times by fluorine, chlorine, bromine, cyano, R6R6’NR7, R6C(O)R7, R6N(R6’)C(O)R7, R6or R6OR7;

R4- C(O)R8;

R5- independently from each other hydrogen or (C1-C4)alkyl;

R6, R6’- independently from each other hydrogen, (C1-C8)alkyl, (C3-C12)cycloalkyl, (C3-C12)cycloalkyl-(C1-C8)alkyl, (C5-C14)-aryl, where one to three carbon atoms may be substituted by 1 to 3 heteroatoms from the series N, S, O, or (C5-C14)aryl-(C1-C8)alkyl, where the aryl part 1-3 carbon atom can be substituted by 1 to 3 heteroatoms from the series N, S, O;

R7indicates a direct link;

R8- independently from each other hydroxy, (C1-C4)alkoxy, (C5-C14)aryl-(C1-C4)alkoxy, (C5-C14)aryloxy, (C1-C8)alkylcarboxylic- (C1-C4)alkoxy, (C5-C14)aryl-(C1-C-NR5-, a direct bond or a divalent residue of 3 - to 7-membered saturated or unsaturated ring which may contain one or two heteroatoms, such as nitrogen, sulfur or oxygen, and which may be substituted once or twice remnants of a number of =O, =S or R3;

D denotes a direct bond, -NR6-, -C(O)-NR6- or-NR6-C(O)-;

E is hydrogen, R6-C(=NR6)-NR6’-, R6R6’N-C(=NR6’)-, R6R6’N-C(=NR6’)-NR6or the remainder of a number

, , ,

, ,

which, if necessary, can be substituted once to three times the remains of a number R3, R5, =O, =S, and R6R6’N-C(=NR6);

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 one or two;

in all their stereoisomeric forms and mixtures in all respects, their physiologically tolerated salts and their proletarienne form.

Further, especially preferred compounds of formula I, where

X is hydrogen, NR6R6’A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R4(II);

W is a residue of formula III

B-(CRlR2)r-A’-(CRlR2)s-(CRlR3)k-(CRlR2)t-D-E- (III);

A, a’ - a direct link;

R1, R2- independently from each other hydrogen, (C1-C4)alkyl, (C5-C6)aryl or (C5-C6)aryl-(C1-C4)alkyl;

R3- independently from each other hydrogen, (C1-C18)alkyl, (C3-C14)cycloalkyl, (C3-C14)cycloalkyl-(C1-C8)alkyl, (C5-C14)aryl, (C5-C14)aryl-(C1-C8)alkyl, R6R6’N-R7, R6OC(O)N(R5R7, R6SO2N(R5R7, R6C(O)N(R5R7, R6N(R6’)C(O)N(R5R7, R6C(O)R7or R6N(R6’)C(O)R7and the alkyl may be singly or multiply unsaturated, and where the alkyl or aryl may be substituted one or more times by fluorine, chlorine, bromine, cyano, R6R6’NR7, R6C(O)R7, R6N(R6’)C(O)R7, R6or R6OR7;

R4- C(O)R, 6’- independently from each other hydrogen, (C1-C18)alkyl, (C3-C12)cycloalkyl, (C3-C12)cycloalkyl-(C1-C8)alkyl, (C5-C14)-aryl, where 1-3 carbon atom can be substituted by 1 to 3 heteroatoms from the series N, S, O, or (C5-C14)aryl-(C1-C8)alkyl, where aryl residues 1-3 carbon atom can be substituted by 1 to 3 heteroatoms from the series N, S, O and6and R6’may form together with the atoms connecting them cyclic system, which, if necessary, may also contain additional, especially one, two or three heteroatoms from the series N, S, O;

R7- direct link;

R8independently from each other hydroxy, (C1-C4)alkoxy, (C5-C14)aryl-(C1-C4)alkoxy, (C5-C14)aryloxy, (C1-C8)alkylcarboxylic- (C1-C4)alkoxy or (C5-C14)aryl-(C1-C4)alkylcarboxylic-(C1-C4)alkoxy;

In - 1,4-piperidinyl or 1,4-piperazinyl, and in the case of 1,4-piperidinyl-balance the nitrogen atom of the piperidine is connected with purine residue;

D is a direct bond, -NR6-, -C(O)-NR6- or-NR6-C(O)-;

, , ,

, ,

which, if necessary, can be substituted once to three times the remains of a number R3, R5, =O, =S, and R6R6’N-C(=NR6)-;

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 their stereoisomeric forms and mixtures in all respects, their physiologically tolerated salts and their proletarienne form.

Especially preferred compounds of formula I, where

X is hydrogen;

Y is hydrogen;

G is a residue of formula II

-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R4(II);

W is a residue of formula III

B-(CRlR2)r-A’-(CRlR2)s-(CRlR3)k-(CRlR2)t-D-E- (III);

A, a’ - a direct link;

R1, R2- independently from each other hydrogen or (C1-C2)alkyl, especially hydrogen;

R3- R6R6’N-RN(R6’)C(O)N(R5R7especially preferably, R6OC(O)N(R5R7;

R4- C(O)R8;

R5is hydrogen or (C1-C2)alkyl, particularly preferably hydrogen;

R6, R6’- independently from each other hydrogen, (C1-C18)alkyl, (C3-C12)cycloalkyl, (C3-C12)cycloalkyl-(C1-C8)alkyl, (C5-C14)-aryl, where 1-3 carbon atom can be substituted by 1 to 3 heteroatoms from the series N, S, O, or (C5-C14)aryl-(C1-C8)alkyl, where aryl residues 1-3 carbon atom can be substituted by 1 to 3 heteroatoms from the series N, S, O and6and R6’may form together with the atoms connecting them cyclic system, which, if necessary, may also contain additional, especially one, two or three heteroatoms from the series N, S, O;

R7- direct link;

R8hydroxy, (C1-C4)alkoxy, (C5-C14)aryl-(C1-C4)alkoxy, (C5-C14)aryloxy, (C1-C8)alkylcarboxylic-(C1-C4)alkoxy or (C5-C14)aryl-(C1-C4)alkylcarboxylic-(C1-C4)alkoxy, person who piperidine associated with purine residue;

D IS-NR6- or-C(O)-NR6- and the group-C(O)-NR6the nitrogen atom linked to the group E;

E - R6R6’N-C(=NR6) or the remainder of a number

, , ,

, ,

which, if necessary, can be substituted once to three times the remains of a number R3, R5, =O, =S, and R6R6’N-C(=NR6)-;

r is zero or one;

s - zero;

t - zero;

k - zero;

n is one;

m is zero;

i - one;

q is zero;

in all their stereoisomeric forms and mixtures in all respects, their physiologically tolerated salts and their proletarienne form.

Especially preferred compounds according to the invention are compounds of the formula I

where R3means R6R6’N-R7, R6OC(O)N(R5R7, R6SO2N(R5R7, R6C(O)N(R5R7or R6N(R6’)C(O)N(R5R7especially preferably, R6OC(O)N(R5R7and Rhdenotes a carboxylic acid group COOH or carboxylic acid derivative, e.g. an ether, such as, for example, (C1-C4)alkilany ether, therefore, for example, g is their physiologically tolerated salts and their proletarienne form. In the compounds of formula Ih, in which7represents a direct link, the stereochemical center (h) in the formula Ih is in S-configuration. The compounds of formula Ih, in which R7indicates a direct relationship can be viewed as substituted, if necessary, 2-amino group of 2-amino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-yl-carbarnoyl)piperidine-1-yl)purine-9-yl)propionic acid and its derivatives, such as esters. Especially preferred 2S-benzyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-yl-carbarnoyl)piperidine-1-yl)purine-9-yl)propionic acid of the formula Ik, its physiologically tolerated salts and its proletarienne form.

The compounds of formula I and Ia can usually be obtained, for example, in the course of a convergent synthesis, by linking two or more fragments which can be used to form retrosynthesis of formulas I and Ia. Upon receipt of the compounds of formulas I and Ia usually during synthesis can be advantageous or necessary to use functional groups that are at an appropriate stage of the synthesis could lead to undesired reactions or side reactions in the preliminary stages, which later translated into the desired functional groups, or to temporarily block functional GRU Wiley, 1991).

The object of the present invention are methods of synthesis of compounds of formula I, which are distinguished by the fact that carry out one or more of the following stages of the synthesis of compounds of formula I.

a1). The compound of formula IV

where L1 denotes the usual, well-known specialist of the group that you want, for example, chlorine, bromine, iodine, OTos or OMes, preferably chlorine or bromine, and

X and Y are defined as above, however, functional groups, if necessary, can also exist in the form of the preliminary stages or can be temporarily protected by a protective group,

subjected to interaction with the compound of the formula V

L2-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R10(V)

where R1, R2, R3, A, n, m, i, and q are defined as above,

R10as described above, refers to the group R4however , if necessary, protected by a protective group, for example, R4=COOH with tert-butyl, methyl - or etilgexanol group

L2 - hydroxy or well-known specialist of the group to delete,

to obtain the compounds of formula VI

moreover, the interaction by prominent specialist methods (see literature in J. March, Advanced Organic Chemistry, Fourth Edition, Wiley, 1992). Preferably operate in a suitable organic solvent or diluent, for example: DCM, l3, THF, diethyl ether, n-heptane, n-hexane, n-pentane, cyclohexane, diisopropyl ether, methyl tert-butyl ether, acetonitrile, DMF, DMSO, dioxane, toluene, benzene, ethyl ether, acetic acid or a mixture of these solvents, if necessary, adding such grounds, as, for example, utility, sitedisability (LDA), sodium hydride, sodium amide, tert-butyl potassium, caso3, Cs2CO3, triethylamine, diisopropylethylamine or complex bases (sodium amide/R12ONa, and R12means (C2-C6)alkyl, or CH3CH2OCH2CH2). For L2=OH can be interaction, for example, described for the reaction Mitsunobu conditions (Hughes, Organic Reactions 42 (1992) 335-656), for example, the interaction with triphenylphosphine and DEAD in THF.

A2). The compound of formula VI is subjected to interaction with the compound of the formula VII)t-R13(VII)

where R13represents-D-E or group, R14that can turn into a D-E and which, if necessary, provided with suitable protective groups for which valid values above. R14means, for example, is protected, if necessary, the amino group-other6moreover , as the protective group can be applied, for example, the BOC-protective group, a protected ester of carboxylic acid, aldehyde-C(O)H, ketogroup-C(O)R6or a protected mercaptopropyl.

You get a connection formula VIII

where R15means- (CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-R13and , in addition, the actual above mentioned values.

Interaction by prominent specialist methods (see J. March, Advanced Organic Chemistry, Fourth Edition, Wiley, 1992), preferably in a suitable organic solvent or diluent, for example: DCM, l3, THF, diethyl ether, n-heptane, n-hexane, n-pentane, cyclohexane, diisopropyl ether, methyl tert-butyl ether, acetonitrile, DMF, DMSO, dioxane, toluene, benzene, ethyl ether, acetic acid or mixture is d lithium (LDA), sodium hydride, sodium amide, tert-butyl potassium, caso3, Cs2CO3, triethylamine, diisopropylethylamine or complex bases (sodium amide/R12ONa, and R12means (C2-C6)alkyl, or CH3CH2OCH2CH2), and for B=NR6as can be excess VII.

a3). If necessary, the protective group in the compound of formula VIII replace known methods (Green, Wuts, Protective Groups in Organic Synthesis, Wiley, 1991, R13and/or R10. If, for example, R13indicates a protected Vos the amino group, the BOC group can, for example, to remove the interaction with triperoxonane acid.

A4). After that, if necessary, R13in the compound of formula VIII make known methods in group D-E, for example, one of the following methods.

A4.1). The interaction of compounds with R13=OTHER6with 1H-pyrazole-1-carboxamidine or cyanamide get guanidine (see Bernatowicz et al., J. Org. Chem., 57 (1992), 2497).

A4.2). The interaction of compounds with R13=OTHER6with monocycle or political type

in which L3 represents nucleophile replaced the deleted group, such as halogen is Ruppel

(regarding methods, 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). The interaction of compounds with R13=OTHER6with compounds of the type

in which L3 represents nucleophile replaced the deleted group, such as halogen or SH, S3, S3, SO2CH3or HN-NO2,

get a connection to the destination group

(regarding methods, see, for example, Miller, Synthesis, 1986, 777, or Brimble, J. Chem. Soc., Perkin Trans., 1 (1990), 311).

A4.4). The interaction of compounds with R13=OTHER6with monocycle or political type

in which L3 represents nucleophile replaced the deleted group, as, for example, S3,

get a connection to the destination group

(regarding methods, see, for example, T. Hiroki et al., Synthesis (1984), 703, or M Purkayastha et al., Indian J. Chem. Sect., B30 (1991), 646).

a4.5). Compounds in which-D-E represents the residue aminoguanidine type

or cyclic aminoguanidine type

can be obtained, for example, by condensation of compounds is Alemi or ketals of the standard literature methods, for example, similar to N. Desideri et al., Arch. Pharm., 325 (1992), 773-777, or A. Alves et al., Eur. Chem. Chim. Ther., 21 (1986), 297-304, and above aminoguanidinium, if necessary, can be obtained as a mixture of E/Z-isomers, which can be divided into the customary chromatography methods.

A4.6). Compounds in which-D-E denotes R6-C(=NR6)-NR6-N=C(R6) or containing a monocycle or politics, the balance of type

you can get similar A4.5).

A4.7). Compounds in which D represents-S(O)2NR6can be obtained, for example, by oxidation of compounds with R13=SH are known from the literature (see Houben-Weyl, Methods of organic chemistry, vol E12/2, edition, Georg Thieme, Stuttgart, 1985, page 1058 and on the following pages) to obtain sulfonic acids (R13=SO3N), from which then, for example, directly or through the corresponding halides, sulfonic acids obtained by linking amide bond connection with D = -S(O)2-NR6- and oxidation-sensitive groups in the molecule, for example, an amino group, amidinopropane or guanidinium, if necessary, before carrying out the oxidation protects suitable protective groups.

A4.8). Compounds in which hid and then oxidation using meta-chloroperbenzoic acid to Sultanovich acids (R13=SO2H) (compare Houben-Weyl, Methods of organic chemistry, vol E11/1, Georg Thieme edition, Stuttgart, 1985, pp. 618 and next page), which are known from the literature methods can be used to obtain the corresponding amides sulfinol acid. Usually you can use also other well-known from the literature methods for producing compounds of formulas I and Ia-D- = S(O)uNR6- (u=1, 2) (compare Houben-Weyl, Methods of organic chemistry, vol E11/1 edition, Georg Thieme, Stuttgart, 1985, pp. 618 and the following pages, or volume 11/2, Stuttgart, 1985, pp. 1055 and following pages).

A4.9). Compounds in which-D-E - denotes R6R6’N-C(=NR6)-NR6-C(O) -, or the residue of a cyclic arylguanidines type

can be obtained, for example, by the interaction of the compounds in which R13denotes-C(O)-L4, and L4 denotes easily nucleophile replaced the deleted group with guanidine (derivative) of the type

or with a cyclic guanidine (derivative) of the type

The above activated acid derivative with a group L4(O) -, where L4 may denote, for example, alkoxygroup, preferably a methoxy group, fenoxaprop, phenylthiourea, methylthiourea, 2-pyridylthio or eSTEAMATiON carboxylic acid (L4=Cl), which, in turn, can be obtained again in a known manner from the source of carboxylic acids, for example, chloride tiomila. Along with anhydrides of carboxylic acids (L4=Cl) can be obtained also other activated derivatives of the acid group-type L4(O)C - known manner directly from the original carboxylic acid (L4=HE), as, for example, methyl esters (L4=co3), treatment using gaseous Hcl in methanol, imidazoline (L4=1-imidazolyl) processing using carbonyldiimidazole (cf. Staab, Angew. Chem., Int. Ed. Engl., 1, 351-367, (1962)), or mixed anhydrides (L4=C2H5OC(O)O or s) with CL-SOOS2H5or chloride tosilos in the presence of triethylamine in an inert solvent. Activation of carboxylic acids can also be performed with carbodiimide as dicyclohexylcarbodiimide (DCCI), or O-((cyano(etoxycarbonyl)methylene)amino)-1,1,3,3-tetramethyluronium-tetrafluoroborate ("TAUTOU") (Konig et al., Proc. 21st Europ. Peptide Symp., 1990 (Eds. Giralt, Andreu), Escom, Leiden, 1991, page 143) and other customary in the chemistry of peptides activating reagents (a number of suitable methods to obtain the activated derivatives of the carboxylic acids mentioned in the literature in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), page 350). Vzaimodopolnit) occurs preferably, in a known manner in proton or aprotic polar, inert organic solvent, and the interaction of the methyl ester (L4=OMe) with the corresponding guanidine mainly carried out in methanol, isopropanol or THF at temperatures from 20 C to the boiling temperature of these solvents. In the interaction of compounds with group L4(O)C - with demineralized guanidine are preferably in aprotic inert solvents, such as THF, dimethoxyethane, dioxane, and you can also use water when using a base, such as NaOH, in a solvent in the interaction of compounds with group L4(O)C - guanidine. If L4=Cl, are usually adding catchers acid, for example, in the form of excess guanidine (derivative) to bind halomonadaceae acid.

A4.10). Compounds in which-D-E denotes R6-C(=NR6)-NR6-C(O)-, or containing a monocycle or political balance type

you can get similar A4.9).

A4.11). Compounds in which-D-E represents the residue sulfanilamidna or sulfanilamides type R6R6’N-C(=N-R6)-NR6-S(O)u- (u=1, 2).

HR6or

with compounds in which R13represents S(O)u-L5 (u=1, 2) and L5 denotes, for example, CL or NH2for example, similar to S. Birtwell et al., J. Chem. Soc., (1946), 491, or Houben Weyl, Methods of organic chemistry, volume E4, ed. Georg Thieme, Stuttgart 1983, pages 620 and on the following pages.

A4.12). Compounds in which-D-E denotes R6-C(=NR6)NR6-S(O)u- (u=1, 2) or containing a monocycle or political balance type

you can get similar A4.11).

A4.13). Compounds in which D represents-NR6-C(O)-, can be obtained, for example, by the interaction of the compounds with R13= -OTHER6with a suitable derivative of carbonic acid, preferably phosgene, diphosgene (trichlorosilyl ether of Harborview acid), triphosgene (bis-trichlorosilyl ester of carbonic acid), ethyl ether of Harborview acid, isobutyl ester Harborview acid, bis(1-hydroxy-1-N-benzotriazolyl)carbonate or N,N’-carbonyl diimidazol, in an inert relative to the reagents, the solvent, preferably DMF, THF or toluene, at temperatures between -20 ° C and the boiling point of the solvent, preferably between 0 and 60, first to join, in the cat the second acid, means, for example, the hydroxy-group, halogen, such as chlorine, ethoxy, isobutoxy, benzotriazol-1-oxy or 1-imidazolyl. The subsequent interaction of these derivatives with R6R6’N-C(=NR6)-NR6’H, or R6-C(=NR6)-OTHER6or containing monocycle or political connection type

or

is then, as described above, to obtain arylguanidines (derived in A4.9).

A. 4.14). The compounds of formula I, in which D-E is a residue of bis-aminotriazole or the remainder of bis-aminoimidazole, can be obtained, for example, by P. J. Garett et al., trahedron, 49 (1993), 165, or R. Lee Webb et al., J. Heterocyclic Chem., 24 (1987), 275.

A4.15). The compounds of formula I, in which-D-E represents a group of the urea or thiourea group, can be synthesized by known methods described, for example, in C. Ferri, Reactions of organic synthesis, ed. Georg Thieme, Stuttgart 1978, for example, the interaction of the corresponding anions with isocyanates or isothioscyanates.

A. 5). After transformation R13in the compound of formula VIII to the group D-E, if necessary, otscheplaut other removable protective group by known methods (see Green, Wuts, see above).

A. 6). If necessary, palusinski tolerated salts and/or proletarienne form.

Further, the object of the present invention are methods of synthesis of compounds of formula Ia, which are distinguished by the fact that carry out one or more of the following stages of the synthesis of compounds of formula Ia.

b1). The compound of formula IV is subjected to interaction with the compound of the formula IX

L2-(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-R13(IX)

where R1, R2, R3, A’, r, s, k, t, R13and L2 are defined above, to obtain compounds of formula X

where R16means -(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-R13,

L1, X, and Y are defined above, and the rest of the valid values specified.

Interaction by prominent specialist methods (see literature in J. March, Advanced Organic Chemistry, Fourth Edition, Wiley, 1992), preferably in a suitable organic solvent or diluent, for example: DCM, l3, THF, diethyl ether, n-heptane, n-hexane, n-pentane, cyclohexane, diisopropyl ether, methyl tert-butyl ether, acetonitrile, DMF, DMSO, dioxane, toluene, benzene, ethyl ether tillite, sitedisability (LDA), sodium hydride, sodium amide, tert-butyl potassium, caso3, s3, triethylamine, diisopropylethylamine, or complex bases (sodium amide/-R12ONa, and R12means (C2-C6)alkyl, or CH3CH2OCH2CH2). For L2=OH interaction can be realized, for example, described for the reaction Mitsunobu conditions (Hughes, Organic Reactions, 42 (1992), 335-656), for example, the interaction with triphenylphosphine and DEAD in THF.

b2). The compound of formula X is subjected to interaction with the compound of the formula XI

N-V-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R10(XI)

in which R1, R2, R3, R10A , b, n, m, i and q are defined above, to obtain compounds of formula XII

where R16X and Y are defined above,

R17means-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R10in the rest of the valid values specified.

b3). For further synthesis of compounds of formula Ia are similar to the stages of A3-A6) in the synthesis of compounds of formula I.

In the second formula Ia can be accomplished stage b2) before b1).

The introduction of a Vice-carbon in 6-polozhenie purine residue can be accomplished, for example, a combination of Style, as described in Langli et al., Tetrahedron, 52 (1996), 5625; Gundersen, Tetrahedron Lett., 35 (1994), 3153, or a combination of Hecke, as described in Koyama et al., Nucleic Acid Res., Symp. Ser., 11 (1982), 41.

Deputy X in position 2 of the purine residue can be administered at the end of the synthesis of compounds of formulas I and Ia known methods, such as described in D. A. Nugiel, J. Org. Chem., 62 (1997), 201-203; N. S. Gray, Tetrahedron Lett., 38 (1997), 1161, and in the cited literature there.

Denoting Y the Deputy can be entered in the 8-position by known methods, such as described in E. J. Reist, etc., 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.

Compounds according to the invention of the formulae I and Ia and their physiologically acceptable salts can be assigned to an animal, preferably a mammal, especially a human, in the quality of medicines per se, in mixtures with one another or in the form of pharmaceutical preparations which allow enteral and parenteral use and which as active components contain an effective dose of at least one compound of formula I or formula Ia or salt sludge is a recreational substances. Pharmaceutical preparations usually contain about 0.5 to 90 wt.% therapeutically effective compounds.

Medicines you can assign orally, for example in the form of pills, tablets, pills in the shell, coated tablets, granules, hard and soft gelatine capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. But the appointment may be rectally, e.g. in the form of suppositories, or parenterally, for example in the form of injectable solutions or solutions for intravenous, microcapsules or rods, through the skin, for example, in the form of ointments or tinctures, or through the nose, for example, in the form of a fluid nose.

Obtaining pharmaceutical preparations carried out in a known manner, and is used pharmaceutically inert inorganic or organic substances-media. For more pills, tablets, coated tablets and hard gelatin capsules can be applied, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts etc. of the Substance carriers for soft gelatin capsules and candles represent, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc., In as matter-nosite the haunted spirits, etc. As matter-carriers to obtain solutions for injection is also used water, alcohols, glycerol, polyols, vegetable oils, etc. As substance carriers for microcapsules, implants or rods are used mixed polymerizate of glycolic acid and lactic acid.

Pharmaceutical drugs along with the active substances and substances-carriers can also contain additional substances, such as fillers, thinners, spray substances, binders, softeners, wetting, stabilizers, emulsifiers, preservatives, sweet substances, colorants, flavoring or aromatic substances, thickeners, solvents, buffering agents, then diluents or agents dissolved or means for receiving depot effect, and also salts for modifying the osmotic pressure, means for coating or antioxidants. They can also contain two or more compounds of the formulae I or Ia and/or their physiologically acceptable salts, hereinafter referred to, along at least one compound of formula I or Ia or one of its salt, they may contain one or more other therapeutically effective agents.

The dose may be changed in Shia dose, in General, about 0.01 to 100 mg/kg, preferably from 0.1 to 5 mg/kg, particularly preferably from 0.3 to 0.5 mg/kg of body weight to achieve effective results. With intravenous administration, the daily dose is in General about 0.01 to 100 mg/kg, preferably from 0.05 to 10 mg/kg of body weight. Daily dose, especially when using larger quantities can be separated, for example, several, 2, 3, or 4 individual assignments. If necessary, depending on individual circumstances may require a deviation from the specified daily dose up or down.

In addition, as active substances for medicinal products of the compounds of formulas I and Ia can also be used for diagnostic purposes, for example, in vitro diagnostics, and as an aid in biochemical research, where achieve inhibition vitronektinove receptor or influence on cell-cell or cell-matrix interaction. Further, they are intermediates for other compounds, especially other active substances for medicinal products, which are obtained from compounds of formulas I and Ia, for example, the change or the introduction of residues or grupal

DCCI - dicyclohexylcarbodiimide

DCM - dichloromethane

DEAD - diethylazodicarboxylate

DIPEA - diisopropylethylamine

DMF - dimethylformamide

DMSO - dimethyl sulfoxide

HER - ethyl acetate

HOOBt - 3-hydroxy-4-hydroxy-3,4-dihydro-1,2,3-benzotriazin

Meon - methanol

s - methylsulphonyl

RT - room temperature

Tf - trifloromethyl

THF - tetrahydrofuran

s - p-toluensulfonyl

Z - benzyloxycarbonyl

Examples

Compounds of formulas I and Ia, which in the 6-position of purine residue containing an amino group, which is not part of a ring, can be considered as derivatives of adenine (=6-aminopurin) and name the connection as such. Deputies

connected to the nitrogen atom of the amino group in the 6-position of adenine, the principle of the names considered with the addition of N6. Substituents that are bound to the nitrogen atom of the ring at the 9-position and has the addition of N9. In the name of the substituent in the beginning indicated, through what position Deputy Deputy at the chosen principle of the names linked to the nitrogen atom N6or N9 purine.

Example 1. N6-(1-(5-Guanidinopentanoic))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))adenine.

1A) N9-(3-(2S-Benzyloxycarbonylamino)-tert-butylphosphonate))-6-globulin.

2,63 g (17 mmol) of 6-chloropurine and of 4.46 g (16.5 mmol) of triphenylphosphine are suspended in the atmosphere of argon in 50 ml of absolute THF. To this mixture is added at RT of 2.56 ml (16.3 mmol) of DEAD and stirred for 15 minutes at RT, you get a clear solution. To this solution add of 3.78 g (12.8 mmol) of N-benzyloxycarbonyl-L-serine tert-butyl ester (obtained by M. Schultz, H. Kunz, Tetrahedron: Asymmetry 4 (1993), 1205-1220), dissolved in 50 ml of absolute F, for 1.5 hours. Then stirred for further 2 hours at RT. The solvent is evaporated, the residue triturated with ether and chromatographic on silica gel (toluene:ITS from 98:2 to 7:3), thus obtain 2.85 g (51%) of pure product.

1H-NMR (200 MHz, DMSO): =of 1.30 (s, 9H, C(CH3)3); 4,48-to 4.73 (m, 3H, N9-CH2CH(NHZ)); to 4.98 (s, 2H, CH2-aryl); 7,19-7,40 (m, 5H, aryl-H); 7,87 (d, 1H, NH); 8,61+8,77 (2s, 2H, WITH6H+WITH8-N).

MS (FAB): m/e=432,1 (100%; (M+H)+; 376,0 (60).

1b) N6-(1-(5-tert-Butyloxycarbonyl)pentyl))-N9-(3-(2S-(benzyloxycarbonylamino)-tert-butylphosphonate))adenine.

To the solution is b) 5-(tert-butyloxycarbonyl)-1-pentylamine in 5 ml of absolute DMF add 0,170 ml (1 mmol) DIPEA and 5 mg of potassium iodide and stirred the mixture for 72 hours at 40 C. The solvent is evaporated and the residue chromatographic on silica gel (toluene:ITS from 7:3 to 1:2), thus obtain 190 mg (32%) of pure product.

MS (FAB): m/e=598,3 (100%; (M+N)+).

1C) N6-(1-(5-aminopentyl))-N9-(3-(2-(benzyloxycarbonylamino)propionic acid))adenine.

190 mg (0.32 mmol) N6-(1-(5-(tert-butyloxycarbonyl)pentyl-N9-(3-(2S-(benzyloxycarbonylamino)-tert-butylphosphonate))adenine (example 1b) are dissolved in 2 ml of 90% triperoxonane acid and stirred for 2 hours at RT. Is evaporated to dryness and the residue evaporated 2 times with acetic acid. After that dissolve in water and dried by freezing. Yield 134 mg (95%).

MS (ES+): m/e=442,3 (20%; (M+N)+), 308,2 (35).

1d) N6-(1-(5-Guanidinopentanoic))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))adenine.

34 mg (0,077 mmol) of N6-(1-(5-aminopentyl))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))adenine (example 1C) is dissolved in 1.5 ml water and 0.5 ml of DMF and mixed with 0,033 ml (0,193 mmol) DIPEA and 13.5 mg (0,092 mmol) of 1H-pyrazole-1-carboxamide-hydrochloride and stirred for 40 hours at RT. After that, the solvent is evaporated, the residue is absorbed in water and dried by freezing. For further purification chromator ).

Example 2. N6-(1-(4-Guanidinate))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))adenine.

2A) N6-(1-(4-(tert-butyloxycarbonyl)butyl))-N9-(3-(2S-benzyloxycarbonylamino)-tert-butylphosphonate))adenine

Synthesis analogously to 1b from 431 mg (1 mmol) of N9-(3-(2S-(benzyloxycarbonylamino)-tert-butylphosphonate))-6-chloropurine (example 1A) and 376 mg (2 mmol) of 4-(tert-butyloxycarbonyl)-1-butylamine. The output 214 mg (37%).

1H-NMR (200 MHz, DMSO): =of 1.30 (s, 9H, C(CH3)3); to 1.38 (s, 9H, C(CH3)3); of 1.41 (m, 2H, CH2); of 1.57 (m, 2H, CH2); of 3.46 (m, 2H, CH2-NH-Boc); of 2.92 (t, 2H, C2-NH-CH2); or 4.31-4,58 (m, 3H, N1-CH2-CH(NHZ)); free 5.01 (s, 2H, CH2-aryl); 6,99 (t, 1H,2-NH); 7,10-7,38 (m, 5H, aryl-H); to 7.75 (m, 1H, NH-Boc); to $ 7.91 (d, 1H, NH-Z); 8,02+8,20 (2s, 2H, C6-H+C8-H).

MS (ES+): m/e=584,3 (100%; (M+N)+).

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

Synthesis analogously to example 1C from the N6-(1-(4-tert-butyloxycarbonyl)butyl)-N9-(3-(2S-(benzyloxycarbonylamino)-tert-butylphosphonate))adenine (example 2A). Yield 96%.

MS (ES+): m/e=428,8 (100%; (M+N)+), 294,1 (70).

2c) N6-(1-(4-Guanidinate))-N9-(3-(2S- (antilock))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))adenine (example 2b). Yield 76%.

MS (ES+): m/e=470,1 (20%; (M+N)+).

Example 3. N6-(1-(3-Guanidinopropionic))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))adenine.

3A) N6-(1-(3-(tert-Butyloxycarbonyl)propyl))-N9-(3-(2S-(benzyloxycarbonylamino)-tert-butylphosphonate))adenine.

Synthesis analogously to 1b of 60 mg (0.14 mmol) of N9-(3-(2S-(benzyloxycarbonylamino)-tert-butylphosphonate))-6-chloropurine (example 1A) and 30 mg (0,17 mmol) of 3-(tert-butyloxycarbonyl)-1-Propylamine. Yield 30 mg (38%).

1H-NMR (200 MHz, DMSO): =of 1.28 (s, 9H, C(CH3)3); of 1.36 (s, 9H, C(CH3)3); by 1.68 (m, 2H, CH2-CH2-CH2); of 1.41 (m, 2H, CH2); 2,98 (t, 2H, C2-NH-CH2); of 3.46 (t, 2H, CH2-NH-Boc); 4,29-4,59 (m, 3H, N1-CH2-CH(NHZ)); 5,00 (s, 2H, CH2-aryl); PC 6.82 (t, 1H, C2-NH); 7,21-7,40 (m, 5H, aryl-H); 7,72 (m, 1H, NH-Boc); to $ 7.91 (d, 1H, NHZ); 8,03+8,20 (2s, 2H, WITH6H+WITH8-N).

MS (ES+): m/e=570,3 (100%; (M+N)+).

3b) N6-(1-(3-Aminopropyl))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))adenine.

Synthesis analogously to example 1C from the N6-(1-(3-(tert-butyloxycarbonyl)propyl))-N9-(3-(2S-(benzyloxycarbonyl the/P>3c) N6-(1-(3-Guanidinopropionic))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))adenine.

Synthesis analogously to example 1d from the N6-(1-(3-aminopropyl))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))adenine (example 3b). Yield 66%.

MS (ES+): m/e=456,3 (20%; (M+N)+), to 130.1 (100).

Example 4. N6-(1-(4-(4,5-Dihydro-1H-imidazol-2-ylamino)butyl))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))adenine.

153 mg (0.36 mmol) of N6-(1-(4-aminobutyl))-N9-(3-(2S-(benzyloxycarbonylamino)propionic acid))adenine (example 2b) and 88 mg (0.36 mmol) of 2-(methylmercapto)-2-imidazolin-hydroiodide dissolved in 2 ml of water and with the help of 1H. NaOH establish a pH of 9.0. Stirred for 100 hours at 50 C. thereafter, the pH of the solution was adjusted using 1N. HCl to 1.5, the solvent is evaporated and the residue chromatographic several times on silica gel (DCM:MeOH 9:1 to 1:2, respectively, with 0.1% of the Asón, 0.1% Of N2About), then DCM:MeOH:H2About:Asón 8:2:0,4:0,4. Yield 7 mg (4%).

MS (FAB): m/e=496,2 (M+N+, 100%); 518,2 (M+Na+, 50).

Example 5. N6-(1-(3-Guanidinopropionic))-N9-(4-(2S-benzyloxycarbonylamino)butyric acid))adenine.

5A) N9-(4-(2S-(Benzyloxycarbonylamino)butyric acid-tert-buterin-tert-butyl ether. Yield 24%.

1H-NMR (200 MHz, DMSO): =of 1.34 (s, 9H, C(CH3)3); 2,08 is 2.43 (m, 2H, N-CH2-CH2-CH); 3,81-3,93 (m, 1H, CH-NHZ); 4,39 (t, 2H, N9-CH2); 5,02 (s, 2H, CH2-aryl); 7,26-7,42 (m, 5H, aryl-H); 7,87 (d, 1H, NH); 8,63+8,75 (2s, 2H, WITH6H+WITH8-N).

MS (FAB): m/e=446,1 (100%; (M+N)+); 390,1 (65).

5b) N6-(1-(3-(tert-Butyloxycarbonyl)propyl))-N9-(4-(2S-(benzyloxycarbonylamino)butyric acid tert-butyl ether)adenine.

Synthesis analogously to 1b from 50 mg (0.11 mmol) N9-(4-(2S-(benzyloxycarbonylamino)butyric acid tert-butyl ether)-6-chloropurine (example 5A) and 38 mg (0.22 mmol) of 3-(tert-butyloxycarbonyl)-1-Propylamine. Yield 26 mg (41%).

MS (ES+): m/e=584,3 (100%; (M+N)+).

5c) N6-(1-(3-Aminopropyl))-N9-(4-(2-(benzyloxycarbonylamino)butyric acid))adenine.

Synthesis analogously to example 1C from the N6-(1-(3-(tert-butyloxycarbonyl)propyl)-N9-(4-(2S-(benzyloxycarbonylamino)butyric acid tert-butyl ether)adenine (example 5b). Yield 94%.

MS (FAB): m/e=428,3 (100%; (M+N)+).

5d) N6-(1-(3-Guanidinopropionic))-N9-(4-(2S-(benzyloxycarbonylamino)butyric acid))adenine.

Synthesis analogously to example 1d from the N6-(1-(3-aminopropyl (70%; (M+N)+).

5e) N-Benzyloxycarbonyl-L-homoserine.

6 g (of 50.4 mmol) of L-homoserine oxidize substantially in 50 ml of DMF and, at 0 To mix parts with 12,56 g (of 50.4 mmol) of N-(benzyloxycarbonyloxy)succinimide. Stirred for 1 hour at 0 C, then 48 hours at RT. The solvent is distilled off and distribute the balance between IT and a saturated solution of NaCl. The organic phase is washed with saturated NaCl solution, 5% citric acid solution and again with saturated NaCl, dried, filtered and concentrated. The crystalline residue is stirred in ether, sucked off, washed with ether and pentane. The output of 9.55 g (75%).

1H-NMR (200 MHz, DMSO): =1,61-of 1.95 (m, 2H, CH2-CH2-OH); of 3.42 (m, 2H, CH2-OH); 4,08 (m, 1H, CH-NH-Z) of 4.57 (s, broad, 1H, OH); 5,02 (s, 2H, CH2-Ph); 7,32 (m, 5H, aryl-H); 7,49 (d, 1H, NH-Z).

MS (Cl+): m/e=236,1 (M+H+-H2O, 20%); 192,1 (50); 91,0 (100).

5f) N-Benzyloxycarbonyl-L-homoserine-tert-butyl ether.

3.8 g (15 mmol) of Z-L-homoserine and 3.42 g (15 mmol) of benzyltriethylammonium in argon atmosphere was dissolved in 110 ml of N-methyl-2-pyrrolidone and mixed by turns from 53.9 g (390 mmol) TO a2CO3and 98,7 g (720 mmol) of tert-butylbromide. Stirred for 22 hours at 55 C. the Reaction mixture is poured into 1.5 l of ice water, ek concentrate. Product for further purification chromatographic on silica gel (n-heptane:ITS from 7:3 to 1:1). Yield 2.0 g (43.1 per cent).

1H-NMR (200 MHz, CDCl3): =1,45 (s, 9H, tBu); 1,51-1,74+2,03-2,26 (m, 2H, CH2-CH2-OH); 3,01 (s, broad, 1H, OH); 3,70 (m, 2H, CH2-HE); to 4.41 (m, 1H, CH-NH-Z); 5,12 (s, 2H, CH2-Ph); the ceiling of 5.60 (d, 1H, NH-Z) of 7.36 (m, 5H, aryl-H).

MS (Cl+): m/e=310,3 (M+H+, 50%); 254,2 (100).

Example 6. N6-(1-(4-Guanidinate))-N9-(4-(2S-benzyloxycarbonylamino)butyric acid))adenine.

6A) N6-(1-(4-(tert-Butyloxycarbonyl)butyl)-N9-(4-(2S-(benzyloxycarbonylamino)butyric acid tert-butyl ether)adenine.

Synthesis analogously to 1b from 50 mg (0.11 mmol) N9-(4-(2S-(benzyloxycarbonylamino)butyric acid tert-butyl ether)-6-chloropurine (example 5A) and 41 mg (0.22 mmol) of 4-(tert-butyloxycarbonyl)-1-butylamine.

Yield 38 mg (58%).

MS (ES+): m/e=598,3 (100%; (M+N)+).

6b) N6-(1-(4-Aminobutyl))-N9-(4-(2-(benzyloxycarbonylamino)butyric acid))adenine.

Synthesis analogously to example 1C from the N6-(1-(4-(tert-butyloxycarbonyl)butyl)-N9-(4-(2S-(benzyloxycarbonylamino)butyric acid tert-butyl ether)adenine (example 6A). Output 100%.

MS (FAB): m/e=442,3 (100%; (M+N)+

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

MS (ES+): m/e=484,3 (5%; (M+N)+), 350,2 (10), 333,2 (5), 130,0 (100).

Example 7. N6-(1-(3-Guanidinopropionic))-N9-(3-propionic acid)adenine.

7a) N9-(3-Propionic acid tert-butyl ester)-6-globulin.

15,45 g (0.1 mol) of 6-chloropurine, to 43.5 ml (0.3 mol) of tert-butyl acrylate and 1.34 ml (7 mmol) 5,22 N. methanolate sodium (Meon) dissolved in 400 ml of absolute Meon and re-addition of 2.6 ml (14 mmol) 5,22 N. methanolate sodium (Meon) boil 4.5 hours when flavobacteria. Processing is sucked off, the solvent is evaporated and chromatographic the residue on silica gel (+10% N2O) (toluene:3:1). Yield 1.35 g (5%).

1H-NMR (200 MHz, DMSO): =of 1.29 (s, 9H, C(CH3)3); 2,95 (t, 2H, CH2C(O)); 4,50 (t, 2H, N-CH2); 8,70+8,79 (2s, 2H, WITH6H+WITH8-N).

MS (ES+): m/e=283,1 (70%; (M+N)+); 227,0 (100).

7b) N6-(1-(3-tert-Butyloxycarbonyl)propyl))-N9-(3-propionic acid tert-butyl ether)adenine.

Synthesis analogously to 1b from 282 mg (1.0 mmol) of N3-(3-propionic acid tert-butyl ester)-6-chloropurine (example 7a) and 209 mg 365,2 (60), 321,2 (50), 265,1 (30).

7c) N6-(1-(3-Aminopropyl))-N9-(3-propionic acid)adenine.

Synthesis analogously to example 1C from the N6-(1-(3-(tert-butyloxycarbonyl)propyl))-N9-(3-propionic acid tert-butyl ether)adenine (example 7b). Output 100%.

1H-NMR (200 MHz, DMSO): =a 1.88 (t, 2H, CH2-CH2-CH2-); 2,80-of 2.93 (m, 4H, NH-CH2+CH2-C(O)); to 3.56 (m, 2H, CH2-NH2); to 4.38 (t, 2H, N9-CH2); 7,72 (s, broad, 2H, NH2); to 7.95 (t, 1H, NH); 8,15+8,23 (2S, 2H, C6-H+C8-H).

MS (ES+): m/e=265,1 (100%; (M+N)+; 248,1 (40), 176,0 (30).

7d) N6-(1-(3-Guanidinopropionic)-N9-(3-propionic acid)adenine.

Synthesis analogously to example 1d from the N6-(1-(3-aminopropyl))-N9-(3-propionic acid)adenine (example 7C). Yield 41%.

1H-NMR (200 MHz, D2O): =1,95 (t, 2H, CH2-CH2-CH2-); a 2.71 (t, 2H, CH2-C(O)); 3,24 (t, 2H, Gua-CH2); the 3.65 (m, 2H, CH2-NH2); however, 4.40 (t, 2H, N9-CH2); 8,00+8,15 (2s, 2H, WITH6H+WITH8-N).

MS (ES+): m/e=to 307.1 (100%; (M+N)+), 290,1 (30).

Example 8. N6-(1-(4-Guanidinate))-N9-(3-propionic acid)adenine.

8a) N6-(1-(4-(tert-Butyloxycarbonyl)butyl))-N9-(3-propionic acid tert-butyl who Il)-6-chloropurine (example 7a) and 104 mg (0.55 mmol) of 4-(tert-butyloxycarbonyl)-1-butylamine. Yield 130 mg (60%).

1H-NMR (200 MHz, DMSO): =1,32 (s, N, (CH3)3); to 1.35 (s, 9H, C(CH3)3); 1,40 (t, 2H, CH2); 1.57 in (t, 2H, CH2); 2,84 (t, 2H, -CH2-C(O)); 2,95 (t, 2H, C2-NH-CH2); to 3.45 (m, 2H, CH2-NH-Boc); 4,34 (t, 2H, N9-CH2); is 6.78 (t, 1H, C2-NH); of 7.70 (m, 1H, NH-Boc); 8,08+8,19 (2s, 2H, C6-H+C8-H).

MS (ES+): m/e=435,2 (100%; (M+N)+), 379,2 (20), 335,2 (55), 279,1 (50).

8b) N6-(1-(4-Aminobutyl))-N9-(3-propionic acid)adenine.

Synthesis analogously to example 1C from the N6-(1-(4-(tert-butyloxycarbonyl)butyl)-N9-(3-propionic acid tert-butyl ether)adenine (example 8A). Output 100%.

1H-NMR (200 MHz, DMSO): =1,50-1,70 (m, 4H, -CH2-CH2-); to 2.74-2.91 in (m, 4H, NH-CH2+CH2-C(O)); 3,50 (m, 2H, CH2-NH2); 4,36 (t, 2H, N9-CH2); to 7.64 (s, broad, 2H, NH2); of 7.90 (t, 1H, NH); 8,11+8,21 (2s, 2H, C6-H+C8-H).

MS (FAB): m/e=279,2 (100%; (M+H)+).

8c) N6-(1-(4-Guanidinate))-N9-(3-propionic acid)adenine.

Synthesis analogously to example 1d from the N6-(1-(4-aminobutyl))-N9-(3-propionic acid)adenine (example 8b). Yield 65%.

MS (ES+): m/e=321,1 (100%; (M+N)+).

Example 9. N6-(1-(5-Guanidinopentanoic))-N9-(3-propionic acid)adenine.< ether)adenine.

Synthesis analogously to 1b from 282 mg (1.0 mmol) of N9-(3-propionic acid tert-butyl ester)-6-chloropurine (example 7a) and 243 mg (1.2 mmol) of 5-(tert-butyloxycarbonyl)-1-pentylamine. Yield 219 mg (41%).

MS (ES+): m/e=449,3 (100%; (M+N)+).

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

Synthesis analogously to example 1C from the N6-(1-(5-(tert-butyloxycarbonyl)pentyl))-N9-(3-propionic acid tert-butyl ether)adenine (example 9a). Output 100%.

1H-NMR (200 MHz, DMSO): =1,39 (m, 2H, CH2); 1,50-to 1.67 (m, 4H, 2 CH2); and 2.79 (dt, 2H, NH-CH2); 2,89 (m, 2H, CH2-C(O)); 3,48 (m, 2H, CH2-NH2); 4,37 (t, 2H, N9-CH2); to 7.67 (s, broad, 2H, NH2); 8,04 (t, 1H, NH); 8,13+8,25 (2s, 2H, C6-H+C8-H).

MS (ES+): m/e=293,1 (100%; (M+H)+).

9c) N6-(1-(5-Guanidinopentanoic))-N9-(3-propionic acid)adenine.

Synthesis analogously to example 1d from the N6-(1-(5-aminopentyl))-N9-(3-propionic acid)adenine (example 9b). Yield 37%.

1H-NMR (200 MHz, DMSO): =1,38-to 1.79 (m, 6H, 3 CH2); 2,80 (t, 2H, NH-CH2); of 3.12 (m, 2H, CH2-C(O)); to 3.58 (m, 2H, CH2-Gua); 4,43 (t, 2H, N9-CH2); 8,07+8,21 (2s, 2H, C6-H+C8-H).

MS (FAB): m/e=335,2 (100%; (M+H)+).

Example 10. N6 is th acid)adenine.

155 mg (1 mmol) 6-chloropurine and 420 mg (2 mmol) of the hydrochloride tert-butyl ester of glycine (80%) dissolved in 5 ml of absolute DMF and mixed with 0.17 ml of DIPEA and potassium iodide on the tip of a spatula and stirred for 6 hours at 50 C. the Solvent is evaporated and the residue chromatographic on silica gel (toluene:ITS from 1:1 to 1:2). Yield 76 mg (31%).

MS (ES+): 250,0 (M+N, 10%); 193,9 (95); 163,9 (100).

10b) N6-(2-Acetic acid)-N9-(1-(5-(tert-butyloxycarbonyl)pentyl))adenine.

75 mg (0.3 mmol) of N6-(2-acetic acid tert-butyl ether)adenine (example 10A), 214 mg (0.6 mmol) (5-(tert-butyl-oxycarbonyl)pentyl)ether 4-toluenesulfonic acid and 42 mg (0.3 mmol) TO a2CO3dissolved in 6 ml of absolute DMF and stirred for 5 days at RT. The solvent is evaporated and the residue chromatographic on silica gel (toluene:ITS from 7:3 to 1:2). Yield 92 mg (71%).

MS (ES+): 435,3 (M+N, 25%); 349,3 (100).

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

Synthesis analogously to example 1C from the N6-(2-Acetic acid)-N9-(1-(5-(tert-butyloxycarbonyl)pentyl))adenine (example 10b). Yield 93%.

MS (ES+): m/e=279,2 (15%; (M+N)+, 249,1 (100).

Example 11. N6-(2-(N-(2-amino-ethyl)ndimethylacetamide))-N9-(2-oxynol) of adenine are suspended in 300 ml of absolute DMF in an atmosphere of N2after that add 2.4 g (0,06 mol) of NaH dispersion and stirred for 2 hours at RT. Within 30 minutes was added dropwise 14.7 ml of 0.1 mol) of tert-butyl methyl ether bromoxynil acid, forming a clear solution. Stirred for further 5 hours at RT. The solvent is evaporated, the residue is stirred with 500 ml of water, sucked off and crystallized from ethanol. The output of 5.1 g (41%).

1H-NMR (200 MHz, DMSO): =of 1.42 (s, 9H, tBu); of 4.95 (s, 2H, N9-CH2); 7,22 (s, broad, 2H, N6H2); 8,10+8,15 (2s, 2H, WITH6H+WITH8-N).

MS (ES+): m/e=250,1 (M+H+, 65%), 194,0 (100).

11b) N6-(Ethyl ester-2-acetic acid)-N9-(tert-butyl ether-2-acetic acid)adenine.

978 mg (3 mmol) of NaH and 250 mg (1 mmol) of N9-(tert-butyl ether-2-acetic acid)adenine (example 11a) is suspended in 10 ml absolute DMF and added dropwise within 10 minutes of 0.12 ml ethyl ester of Chloroacetic acid. After stirred for 6 hours at 50 C, then add again the same number s3and stirred for 6 hours at 50 C. the Solvent is evaporated and the residue partitioned between water and ITS. The organic phase is dried and concentrated. Exit 16%.

1H-NMR (200 MHz, DMSO): =1,20 (t, 3H, CH2-CH3); 1.41 to (s, 9H, tBu); 4,00-to 4.28 (m, 4H, CH2
-H).

MS (ES+): m/e=336,3 (M+H+, 100%); 280,3 (60).

11c) N6-(2-Acetic acid)-N9-(2-acetic acid tert-butyl ether)adenine.

249 mg (0,74 mmol) of N6-(ethyl ester-2-acetic acid)-N9-(tert-butyl ether-2-acetic acid)adenine (example 11b) is dissolved in 6 ml of dioxane:water:triethylamine and stirred for 4 days at RT. The solvent is evaporated and the residue chromatographic on silica gel (DCM:MeOH 95:5 to 90:10). Yield 36%.

MS (ES+): m/e=308,3 (M+N+, 100%).

11d) N6-(2-(N-(2-tert-Butyloxycarbonyl)ndimethylacetamide))-N9-(tert-butyl ether-2-acetic acid)adenine.

80 mg (0.26 mmol) of N6-(2-acetic acid)-N9-(tert-butyl ether-2-acetic acid)adenine (example 11C), 42 mg (0.26 mmol) of 2-tert-butyloxycarbonyl dissolve in the atmosphere of argon in 5 ml of absolute DMF and, at 0 To mix with 85 mg (0.26 mmol) of THOTH and 0.13 ml (0.78 mmol) DIPEA and stirred for 10 minutes at 0 and 2.5 h at RT. Dilute with HER to 100 ml, then washed with a saturated solution of potassium bicarbonate, dried and concentrated. Chromatographic on silica gel (DCM:MeOH from 98:2 to 90:10). 5%.

MS (ES+): m/e=450,3 (M+N+, 100%).

11e) N6-(2-(N-(2-amino-ethyl)acetone is carbonylmethyl)ndimethylacetamide))-N9-(tert-butyl ether-2-acetic acid)adenine (example 11d). Yield 80%.

MS (ES+): m/e=293,1 (100%) (M+N)+).

Example 12. N6-(4-(2S-(Benzyloxycarbonylamino)butyric acid))-N9-(1-(3-guanidinopropionic))adenine.

12A) N9-(1-(3-(tert-Butyloxycarbonyl)propyl))-6-globulin.

154, 6mm mg (1 mmol) 6-chloropurine dissolved in 2.5 ml absolute DMF and mixed under stirring with 331,7 mg (2.4 mmol) TO a2CO3and 285,8 mg (1.2 mmol) of N-(3-tert-butyl ether bromopropyl)carbamide acid. Stirred for 11 hours at RT, the solvent is evaporated, absorb the remainder of HER and washed twice with a saturated solution Panso3then a solution of NaCl, dried, filtered and concentrated. The remainder chromatographic on silica gel (: n-heptane 8:2). Exit 267 mg (86%).

1H-NMR (200 MHz, DMSO): =of 1.37 (s, 9H, tBu); 2,00 (tt, 2H, CH2-CH2-CH2); 2,95 (dt, 2H, CH2-NH); 4,30 (t, 2H, N9-CH2); 6,91 (t, broad, 1H, NH); 8,70+8,78 (2s, 2H, WITH6H+WITH8-N).

MS (ES+): m/e=312,2 (100%; (M+N)+); 256,1 (20).

12b) N6-(4-(2S-(Benzyloxycarbonylamino)butyric acid))-N9-(1-(3-(tert-butyloxycarbonyl)propyl) adenine.

370 mg (1,19 mmol) of N9-(1-(3-(tert-butyloxycarbonyl)props (1.8 mmol) of 2S-benzyloxycarbonylamino-4-aminobutyric acid and stirred for 50 hours at 65 C. The solvent is evaporated and distribute the balance between IT and a saturated NaCl solution (20% KHSO4). The organic phase is washed with water, dried, filtered and concentrated. The remainder chromatographic on silica gel (HER:Meon 8:2). Exit 331 mg (53%).

1H-NMR (200 MHz, DMSO): =of 1.39 (s, 9H, tBu); 1,73-of 2.21 (m, 2H, CH2-CH(NH-Z)); 1,90 (m, 2H, CH2-CH2-CH2); 2,92 (dt, 2H, CH2-NH-Boc); a 3.15 (dt, 2H, N6-CH2); 3,88-4,10 (m, 1H, CH-NHZ); to 4.14 (t, 2H, N9-CH2); to 5.03 (s, 2H, CH2-Ph); 6,91 (t, broad, 1H, NH-Boc); 7,37 (s, 5H, Ar-H); 7,55-7,81 (m, 2H, NH-Z+N6H-CH2); 8,13+8,19 (2s, 2H, WITH6H+WITH8-N).

MS (ES+): m/e=528,2 (100%; (M+N)+).

12c) N6-(4-(2S-(Benzyloxycarbonylamino)butyric acid))-N9-(1-(3-aminopropyl))adenine.

30 mg (0.06 mmol) of N6-(3-(2S-(benzyloxycarbonylamino)propionic acid))-N9-(1-(3-(tert-butyloxycarbonyl)propyl) adenine (example 12b) is dissolved in 2 ml of 90% triperoxonane acid, stirred for 70 minutes at RT, concentrated and the residue is stirred several times with ether. The residue is dissolved in water and dried by freezing. Output 100%.

MS (ES+): m/e=428,2 (100%; (M+N)+); 294,1 (90).

12d) N6-(4-(2S-(Benzyloxycarbonylamino)butyric acid))-N9-(1-(3-guanidinopropionic))adenine.

MS (ES+): m/e=470,3 (25%; (M+N)+; 336,2 (100).

Example 13. N6-(4-(2S-(Benzyloxycarbonylamino)butyric acid))-N9-(1-(3-(4,5-dihydro-1H-imidazol-2-ylamino)propyl) adenine.

Synthesis analogously to example 4 from N6-(3-(2S-(benzyloxycarbonylamino)propionic acid))-N9-(1-(3-aminopropyl))adenine (example 12c). Yield 63%.

NS (ES+): m/e=496,3 (100%; (M+N)+).

Example 14. N6-(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N9-(1-(5-guanidinylation))adenine.

14a) N9-(1-(5-(tert-Butyloxycarbonyl)pentyl))-6-globulin.

Synthesis analogously to example 12A from 6-chloropurine and tert-butyl ether N-(5-totalexpenses)carbamide acid. Yield 66%.

1H-NMR (200 MHz, DMSO): =1,11 is 1.48 (m, 4H, 2 CH2); to 1.35 (s, 9H, tBu); 1,87 (tt, 2H, CH2); 2,97 (dt, 2H, CH2-NHBoc); to 4.28 (t, 2H, N9-CH2); 6,72 (t, broad, 1H, NH); 8,71+8,78 (2s, 2H, C6-H+C8-H).

MS (ES+): m/e=340,2 (100%; (M+H)+); 284,1 (50).

14b) N6-(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N9-(1-(5-(tert-butyloxycarbonyl)pentyl))adenine.

Synthesis analogously to example 12b of the N6-(1-(5-(tert-butyloxycarbonyl(pencil))-6-chloropurine and 2S-benzyloxycarbonyl is 2-1,88 (m, 2H, CH2); 2,87 (dt, 2H, CH2-NHBoc); 3,68-to 4.98 (m, 5H, N9-CH2+CH2-CH-NHZ); 5,00 (s, 2H, CH2-Ph); 6.75 in (t, broad, 1H, NH); 8,02+8,20 (2s, 2H, C6-H+C8-H).

MS (FAB): m/e=USD 542.3 (100%; (M+H)+).

14c) N6-(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N9-(1-(5-aminopentyl))adenine.

Synthesis analogously to example 12C of N6-(3-(2S-(benzyloxycarbonylamino)propionic acid))-N9-(1-(5-(tert-butyloxycarbonyl)pentyl))adenine (example 14b). Output 100%.

1H-NMR (200 MHz, DMSO): =1,18-1,40+1,44-1,65+1,71-1,93 (2m, 6H, 3 CH2); 2,77 (dt, 2H, CH2-NHBoc); 3,64 is 4.35 (m, 5H, N9-CH2+CH2CH-NHZ); 5,00 (s, 2H, CH2-Ph); 7,66 (m, 3H, NH+3); 8,20+8,24 (2s, 2H, C6-H+C8-H).

MS (ES+): m/e=442,3 (40%; (M+N)+); 308,2 (100).

14d) N6-(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N9-(1-(5-guanidinylation))adenine.

Synthesis analogously to example 1d from the N6-(3-(2S-(benzyloxycarbonylamino)propionic acid))-N9-(1-(5-aminopentyl))adenine (example 14c). Output 90%.

MS (ES+): m/e=484,3 (70%; (M+N)+); 350,2 (60).

Example 15. N6-(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N9-(1-(5-(4,5-dihydro-1H-imidazol-2-ylamino)pentyl))adenine.

The synthesis of the Academy of Sciences of the Nina (example 14c). A yield of 75%.

MS (ES+): m/e=510,3 (40%; (M+N)+); 376,2 (100).

Example 16. N6-(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N9-(1-(3-guanidinopropionic))adenine.

16A) N6-(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N9-(1-(3-(tert-butyloxycarbonyl)propyl) adenine.

Synthesis analogously to example 12b of the N9-(1-(3-(tert-butyloxycarbonyl))-6-chloropurine (example 12A) and 2S-benzyloxycarbonylamino-3-aminopropionic acid. The output is 27%.

1H-NMR (200 MHz, DMSO): =of 1.37 (s, 9H, tBu); 1,90 (m, 2H, CH2-CH2-CH2); 2,92 (dt, 2H, CH2-NHBoc); 3,86 (m, broad, 2H, CH2-CH(NH-Z)); 4,13 (t, 2H, N9-CH2); however, 4.40 (m, 1H, CH-NHZ); free 5.01 (s, 2H, CH2-Ph); 6,92 (t, broad, 1H, NH-Boc); 7,33 (s, 5H, Ar-H); 7,55 to 7.75 (m, 2H, NH-Z+N6H-CH2); 8,16+by 8.22 (2s, 2H, WITH6H+WITH8-N).

MS (ES+): m/e=514,3 (100%; (M+N)+).

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

Synthesis analogously to example 12C of N6-(3-(2S-(benzyloxycarbonylamino)propionic acid))-N9-(1-(3-(tert-butyloxycarbonyl)propyl) adenine (example 16A). Output 100%.

MS (ES+): m/e=level of 414.2 (100%; (M+N)+); 280,2 (70).

16c) N6-(3-(2S-(Benzyloxycarbonyl The P>6
-(3-(2S-(benzyloxycarbonylamino)propionic acid))-N9-(1-(3-aminopropyl))adenine (example 16b). Exit 98%.

MS (ES+): m/e=456,3 (40%; (M+N)+); 322,2 (100).

Example 17. N6-(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N9-(1-(4-guanidinylation))adenine.

17A) N9-(1-(4-tert-Butyloxycarbonyl)butyl))-6-globulin.

Synthesis analogously to example 12A from 6-chloropurine and tert-butyl ether N-(4-tosyloxy)carbamide acid. Yield 66%.

1H-NMR (200 MHz, DMSO): =1,30 (m, 2H, CH2); to 1.35 (s, 9H, tBu); 1,86 (tt, 2H, CH2); at 2.93 (dt, 2H, CH2-NHBoc); or 4.31 (t, 2H, N2-CH2); 6,79 (t, broad, 1H, NH); 8,72+8,78 (2s, 2H, C6-H+C8-H).

MS (ES+): m/e=326,2 (80%; (M+H)+); 270,1 (100).

17b) N6-(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N9-(1-(4-(tert-butyloxycarbonyl)butyl))adenine.

Synthesis analogously to example 12b of the N9-(1-(4-tert-butyloxycarbonyl)butyl))-6-chloropurine (example 17A) and 2S-benzyloxycarbonylamino-3-aminopropionic acid. Exit 33%.

1H-NMR (200 MHz, DMSO): =1,30 (m, 2H, CH2); to 1.35 (s, 9H, tBu); to 1.75 (m, 2H, CH2); only 2.91 (dt, 2H, CH2-NHBoc); 3,71-4,34 (m, 5H, CH2-CH(NH-Z)+N9-CH2); free 5.01 (s, 2H, CH2-Ph); 6.89 in (t, broad, 1H, NH-Boc); to 7.35 (s, N)+).

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

Synthesis analogously to example 12C of N6-(3-(2S-(benzyloxycarbonylamino)propionic acid))-N9-(1-(4-tert-butyloxycarbonyl))adenine (example 17b). Output 100%.

1H-NMR (200 MHz, DMSO): =1,48 (m, 2H, CH2); to 1.87 (m, 2H, CH2); 2,80 (dt, 2H, CH2-NH2); 3,69-was 4.02 (m, 2H, CH2-CH (NH-Z)); 4,20 (t, 2H, N9-CH2); 4,36 (m, 1H, CH(NH-Z)); free 5.01 (s, 2H, CH2-Ph); 7,33 (s, 5H, Ar-H); to 7.64 (s, broad, 4H, NH+3+N6H-CH2); 8,10 (wide)+8,20 (2s, 2H, WITH6H+WITH8-N).

MS (ES+): m/e=428,3 (50%; (M+N)+); 294,2 (100).

17d) N6-(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N9-(1-(4-guanidinylation))adenine.

Synthesis analogously to example 1d from the N6-(3-(2S-(benzyloxycarbonylamino)propionic acid))-N9-(1-(4-aminobutyl))adenine (example 17c). Yield 78%.

MS (ES+): m/e=470,2 (50%; (M+N)+); 336,2 (100).

Example 18. N6-(3-(2S-(Benzyloxycarbonylamino)propionic acid))-N9-(1-(4-(4,5-dihydro-1H-imidazol-2-yl)amino)butyl))adenine.

Synthesis analogously to example 4 from N6-(3-(2S-(benzyloxycarbonylamino)propionic acid))-N9-(1-(4-aminoacetanilide-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbonyl)piperidine-1-yl)purine-9-yl)propionic acid.

19a) tert-Butyl ether 2S-benzyloxycarbonylamino-3-(6-(4-carboxy-piperidine-1-yl)purine-9-yl)propionic acid.

260 mg (0.6 mmol) of tert-butyl methyl ether 2S-benzyloxycarbonylamino-3-(6-globulin-9-yl)propionic acid (example 1A), 116,3 mg (0.9 mmol) piperidine-4-carboxylic acid and 310 mg (2.4 mmol) DIPEA in 4 ml of absolute DMF is stirred for 16 hours at 60 C. After that add the rest of 310 mg of DIPEA and again stirred for 24 hours at 60 C. the Solvent is evaporated and the residue partitioned between IT and water. The organic phase is again washed with a solution of KHSO4/K2SO4then a solution of NaCl, dried, filtered and concentrated. The remainder chromatographic on silica gel (HER). Yield 219 mg (69%).

MS (ES+): m/e=525,3 (100% (M+N)+).

19b) tert-Butyl ether 2S-benzyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbonyl)piperidine-1-yl)purine-9-yl)propionic acid.

126 mg (0.24 mmol) of tert-butyl methyl ether 2S-benzyloxycarbonylamino-3-(6-(4-carboxypeptidase-1-yl)purine-9-yl)propionic acid (example 19a), to 39.3 mg (0.29 mmol) 2-amino-1,4,5,6-tetrahydropyrimidin-hydrochloride, 86,6 mg (0,264 mmol) TAUTOU (O-((etoxycarbonyl)cyanomethylene)-N,N,N’,N’-tetramethyluronium-tetrafluoroborate (W. et al., Proceedings of the 21st 3 hours at RT, then add the remaining 28 mg of DIPEA and stirred for 12 hours at RT. The reaction mixture was adjusted using glacial acetic acid/toluene (1:1) to pH 6, the reaction solution was concentrated, the residue partitioned between HER and a saturated solution Panso3, the organic phase is washed using NaCl, dried and concentrated. The remainder chromatographic on silica gel (HER:Meon:Thea 85:15:1,5). The output 70 mg.

MS (ES+): m/e=606,4 (60%; (M+N)+); 416,3 (40); 275,7 (100).

19s) 2S-Benzyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbonyl)-piperidine-1-yl)purine-9-yl)propionic acid.

80 mg of tert-butyl methyl ether 2S-benzyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbonyl)piperidine-1-yl)purine-9-yl)propionic acid (example 19b) is dissolved in 16 ml of pre-cooled 95% triperoxonane acid and stirred first for 30 minutes at 0 C, then for 30 minutes at RT. Triperoxonane acid centrifuged, the residue is evaporated three times with toluene, stirred in ethanol/ether (1:2), washed with ether and dried in vacuum. Exit 59 mg.

MS (ES+): m/e=550,3 (60%; (M+H)+); 416,3 (100).

Example 20. 2S-Benzyloxycarbonylamino-3-(1-(9-(2-guanidinate)-N-purine-6-yl)-1H-imidazol-4-yl)propionic acid.

20A) N

1H-NMR (200 MHz, DMSO): =1,24 (s, 9H, tBu); 3,40 (dt, 2H, CH2-NHBoc); of 4.35 (t, 2H, N9-CH2); 6,91 (t, broad, 1H, NH); at 8.60+8,78 (2s, 2H, C6-H+C8-H).

MS (FAB): m/e=298,2 (100%; (M+H)+).

20b) 2S-Benzyloxycarbonylamino-3-(1-(9-(2-(tert-butyloxycarbonyl)ethyl)-N-purine-6-yl)-1H-imidazol-4-yl)propionic acid.

Synthesis is carried out analogously to example 12b of the N9-(1-(2-tert-butyloxycarbonyl)ethyl))-6-chloropurine (example 21A) and N-Z-L-histidine. Exit 33%.

MS (ES+): m/e=of 551.3 (100%; (M+N)+).

20C) 3-(1-(9-(2-Aminoethyl)-N-purine-6-yl)-1H-imidazol-4-yl)-2S-benzyloxycarbonylamino acid.

Synthesis is carried out analogously to example 12C of the 2S-benzyloxycarbonylamino-3-(1-(9-(2-(tert-butyloxycarbonyl)ethyl)-N-purine-6-yl)-1H-imidazol-4-yl)propionic acid (example 20b). Output 100%.

MS (ES+): m/e=451,3 (70%; (M+N)+).

1H-NMR (200 MHz, DMSO): =2,87 is 3.15 (m, 2H, Im-CH2); 3,38-3,51 (m, 2H, CH2-NH2); 4,36 (m, 1H, CH-NHZ); 4,60 (t, 2H, N9-CH2); 5,00 (s, 2H, CH2-Ph); 7,28 (s, 5H, aryl-H); a 7.62 (d, 1H, NH-Z); 8,23+9,05 (2S, 2H, Im-H); 8,71+8,88 (2s, 2H, C6-H+C8-H).

20d) 2S-Benzyloxycarbonylamino-3-(1-(9-(2-guanidinate)-N-purine-6-yl)-1H-imidazol-4-yl)propionic acid.

Synthesis is carried out EN the lots (example 20C). Yield 38%.

MS (ES+): m/e=493,3 ((M+N)+).

Example 21. 2N-Benzyloxycarbonylamino-3-(6-(N-(4-guanidiniocarbonyl)amino)purine-9-yl)propionic acid.

21A) N9-(3-(2R-(Benzyloxycarbonylamino)-tert-butylphosphonate))-6-globulin.

Synthesis is carried out analogously to example 1 from 6-chloropurine and N-benzyloxycarbonyl-D-serine t-butyl ether.

MS (FAB): m/e=432,2 (100%; (M+N)+); 376,1 (30).

21b) tert-Butyl ether 2R-benzyloxycarbonylamino-3-(6-(N-(4-(tert-butyloxycarbonyl)cyclohexyl)amino)purine-9-yl)propionic acid.

Synthesis is carried out analogously to example 1b from 4-amino-1-(tert-butyloxycarbonyl)cyclohexane and N9-(3-(2R-benzyloxycarbonylamino)-tert-butylphosphonate))-6-chloropurine (example 21A). Yield 55%.

MS (FAB): m/e=610,3 (100%; (M+N)+).

S) 3-(6-(N-(4-Aminocyclohexane)amino)purine-9-yl)-2R-benzyloxycarbonylamino acid.

Synthesis is carried out analogously to example 1C from tert-butyl ether 2R-benzyloxycarbonylamino-3-(6-(N-(4-(tert-butyloxycarbonyl)cyclohexyl)aminopurin-9-yl)propionic acid (example 21b). Output 200%.

MS (ES+): m/e=454,2 (50%, (M+N)+).

21d) 2R-Benzyloxycarbonylamino-3-(6-(N-(4-guanidine-aminocyclohexane)amino)purine-9-yl)-2R-benzyloxycarbonylamino acid (example C). Yield 80%.

MS (ES+): m/e=496,3 (50%, (M+N)+).

Example 22. 2R-Benzyloxycarbonylamino-3-(6-(N-(3-guanidiniocarbonyl)amino)purine-9-yl)propionic acid.

22A) tert-Butyl ether 2R-benzyloxycarbonylamino-3-(6-N-(3-tert-butyloxycarbonyl)amino)purine-9-yl)propionic acid.

Synthesis is carried out analogously to example 1b from 3-aminomethyl-1-(tert-butyloxycarbonyl)benzene and9-(3-(2R-(benzyloxycarbonylamino)-tert-butyl-propionate)-6-chloropurine (example 21A). Yield 51%.

MS (ES+): m/e=to 632.3 (100%; (M+N)+).

22b) 3-(6-(N-(3-Aminomethylbenzoic)amino)purine-9-yl)-2R-benzyloxycarbonylamino acid.

Synthesis is carried out analogously to example 1C from tert-butyl ether 2R-benzyloxycarbonylamino-3-(6-(N-(3-tert-butyloxycarbonyl)amino)purine-9-yl)propionic acid (example 22A). Output 100%.

MS (ES+): m/e=476,2 ((M+H)+, 50%); 342,2 (70).

22p) 2R-Benzyloxycarbonylamino-3-(6-(N-(3-guanidiniocarbonyl)amino)purine-9-yl)propionic acid.

Synthesis is carried out analogously to example 1d from 3-(6-(N-(3-aminomethylbenzoic)amino)purine-9-yl)-2R-benzyloxycarbonylamino acid (example 22b). A 30% yield.

MS (ES+): m/e=518,3 (M+N)+neonova acid.

23a) 1-(4-tert-Butyloxycarbonyl)-3-(2-nitrophenyl)thiourea.

In 0.97 g (5,15 mmol) of 4-(tert-butyloxycarbonyl)-1-amine in 25 ml of absolute DMF pin at 0 With 0,928 g (5,15 mmol) 2-nitrophenylacetylene in 5 ml of absolute DMF. Then stirred for 1 hour at 0 C. the Solvent is distilled off and the residue chromatographic on silica gel (: n-heptane 1:2 to 1:1). Yield 1.8 g (95%).

MS (ES+): m/e=369,2 (M+N)+, 100%.

23b) 3-(2-AMINOPHENYL)-1-(4-tert-butyloxycarbonyl)thiourea.

1.78 g (4.8 mmol) of 1-(4-tert-butyloxycarbonyl)-3-(2-nitrophenyl)thiourea (example 23a) is dissolved in 120 ml of methanol and hydronaut at RT for 3 hours through 1 g Pd/C (1 bar). The catalyst is filtered off, the filtrate is concentrated and chromatographic on silica gel (: n-heptane 1:1). The output of 1.4 g

23C) 4-(Benzimidazole-2-ylamino)-1-(tert-butyloxycarbonyl)butane.

To 1.4 g (4.14 mmol) of 3-(2-AMINOPHENYL)-1-(4-tert-butyloxycarbonyl)thiourea (example 23b) in 30 ml ethanol add to 1.79 g (of 8.28 mmol) of yellow oxide of mercury and 27 mg gray and heated the reaction mixture for 3 hours to 50-55 C. is Sucked off and washed with ethanol. Thicken the filtrate and chromatographic product on silica gel (DCM:methanol 9:5, then 9x2">

198 mg (of 0.65 mmol) 4-(benzimidazole-2-ylamino)-1-(tert-butyloxycarbonyl)butane (example 23C) is dissolved at 0 in 20 ml of 95% triperoxonane acid and stirred for 2 hours at 0 C, then thicken at RT for 30 minutes. The residue is evaporated three times with toluene, then stirred with ether, washed with pentane and dried in vacuum. Output 100%.

MS (ES+): m/e=205,2 ((M+N)+, 100%).

23rd) tert-Butyl ether 3-(6-((4-(the benzimidazole-2-ylamino)butyl)amino)purine-9-yl)-2S-benzyloxycarbonylamino acid.

Synthesis is carried out analogously to example 1b from 4-(benzimidazole-2-ylamino)-1-aminobutane (example 23d) and (N9-(3-(2S-(benzyloxycarbonylamino)-tert-butylphosphonate))-6-chloropurine (example 1a). Yield 32%.

MS (ES+): m/e=600,3 (100%; (M+N)+).

23f) 3-(6-((4-the Benzimidazole-2-ylamino)butyl)amino)purine-9-yl)-2S-benzyloxycarbonylamino acid.

Synthesis is carried out analogously to example 1C from tert-butyl ether 3-(6-((4-(the benzimidazole-2-ylamino)butyl)amino)purine-9-yl)-2S-benzyloxycarbonylamino acid (example 23rd). Output 100%.

MS (ES+): m/e=544,2 ((M+N)+, 70%).

Example 24. 2S-Benzyloxycarbonylamino-3-(6-(4-((4,5-dihydro-1H-imidazol-2-ylamino)methyl)piperidine-1-yl)purine-9-xtermination acid.

Synthesis is carried out analogously to example 1b from 4-(aminomethyl)piperidine and N9-(3-(2S-(benzyloxycarbonylamino)-tert-butylphosphonate))-6-chloropurine (example 1a). Output 96,4%.

MS (ES+): m/e=510,3 (100%; (M+N)+).

24b) 3-(6-(4-(Aminomethyl)piperidine-1-yl)purine-9-yl)-2S-benzyloxycarbonylamino acid.

Synthesis is carried out analogously to example 1C from tert-butyl ether 3-(6-(4-(aminomethyl)piperidine-1-yl)purine-9-yl)-2S-benzyloxycarbonylamino acid (example 24). Output 100%.

MS (ES+): m/e=of 454.3 ((M+N)+, 30%).

24C) 2S-Benzyloxycarbonylamino-3-(6-(4-((4,5-dihydro-1H-imidazol-2-ylamino)methyl)piperidine-1-yl)purine-9-yl)propionic acid.

Synthesis is carried out analogously to example 4 from 3-(6-(4-aminomethyl)piperidine-1-yl)purine-9-yl)-2S-benzyloxycarbonylamino acid (example 24b). Yield 95%.

MS (ES+): m/e=522,3 ((M+N)+, 40%).

Example 25. 2R-Benzyloxycarbonylamino-3-(6-(4-((4,5-dihydro-1H-imidazol-2-ylamino)methyl)piperidine-1-yl)purine-9-yl)propionic acid.

Synthesis is carried out analogously to example 24 on the basis of N9-(3-(2R-(benzyloxycarbonylamino)-tert-butylphosphonate))-6-chloropurine (example 21A).

MS (ES+): m/e=522,3 ((M+N)+, 20%).

Example 26. 2S-Benzilic is analogously to example 1d from 3-(6-(4-(aminomethyl)piperidine-1-yl)purine-9-yl)-2S-benzyloxycarbonylamino acid (example 24b). Yield 74%.

MS (ES+): m/e=496,3 ((M+N)+, 40%).

Example 27. 2S-Benzyloxycarbonylamino-3-(6-(3-(3-benzylamino)-phenylsulfanyl)purine-9-yl)propionic acid.

27A) tert-Butyl ether 3-(6-(3-aminophenylalanine)purine-9-yl)-2S-benzyloxycarbonylamino acid.

0,602 mmol 3-mercaptoquinoline stirred for 12 hours together with 0,602 mmol N9-(3-(2S-(benzyloxycarbonylamino)-tert-butylphosphonate))-6-chloropurine (example 1A) in DMF and DIPEA. The reaction solution is concentrated, the residue partitioned between HER and a saturated solution Panso3, the phases are separated, the organic phase is washed polysystem solution Panso3and NaCl solution, dried, concentrated and chromatographic product on silica gel (HER:heptane 1:1). The output of 190 mg.

MS (ES+): m/e=521,3 ((M+N)+, 100%).

27b) tert-Butyl ether 2S-benzyloxycarbonylamino-3-(6-(3-(3-benzylurea)phenylsulfanyl)purine-9-yl)propionic acid.

To 180 mg of tert-butyl methyl ether 3-(6-(3-aminophenylalanine)purine-9-yl)-2S-benzyloxycarbonylamino acid (example 27A) in 3 ml of absolute acetonitrile is added via syringe 46,1 mg benzylisothiocyanate in 1 ml of acetonitrile. The mixture is stirred for 48 hours at RT, concentrated and the residue chromatogr is oxycarbonyl-3-(6-(3-(3-benzylurea)phenylsulfanyl)purine-9-yl)propionic acid.

Synthesis is carried out analogously to example 1C from tert-butyl ether 2S-benzyloxycarbonylamino-3-(6-(3-(3-benzylurea)phenylsulfanyl)purine-9-yl)propionic acid (example 27b). Output 100%.

MS (ES+): m/e=598,4 ((M+N)+, 100%).

Example 28. 2S-Neopentecostalism-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbonyl)piperidine-1-yl)purine-9-yl)propionic acid.

28a) tert-Butyl ether 2S-amino-3-(6-(4-carboxypeptidase-1-yl)purine-9-yl)propionic acid.

1.7 g of tert-Butyl methyl ether 2S-benzyloxycarbonylamino-3-(6-(4-carboxypeptidase-1-yl)purine-9-yl)propionic acid (example 19a) is dissolved in 200 ml of Asón and hydronaut on Pd/C at a pressure of H21 ATM. The catalyst is filtered off, the solvent is distilled off and the residue is subjected to lyophilization. Output 100%.

MS (ES+): m/e=391,3 ((M+N)+, 100%).

28b) tert-Butyl ether 2S-neopentecostalism-3-6-(4-carboxy-piperidine-1-yl)purine-9-yl)propionic acid.

390 mg (1 mmol) of tert-butyl methyl ether 2S-amino-3-(6-(4-carboxypeptidase-1-yl)purine-9-)propionic acid (example 20A) in 4 ml of DMF is mixed at 0 With 230 mg (1 mmol) N-(neopentecostalism)succinimide and 0.17 ml of DIPEA and after slow heating was stirred for 12 hours at RT. Reactio+): m/e=505,4 ((M+N)+, 100%).

28C) tert-Butyl ether 2S-neopentecostalism-3-(6- (4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbonyl)piperidine-1-yl)purine-9-yl)propionic acid.

505 mg (1 mmol) of tert-butyl methyl ether 2S-neopentecostalism-3-(6-(4-carboxypeptidase-1-yl)purine-9-yl)propionic acid (example 20b) is dissolved in 10 ml of acetonitrile, mixed with 250 mg DCCl and 184 mg of pentafluorophenol and then stirred for 30 minutes at RT. Filtered, concentrated mother solution, absorb in 5 ml of DMF, mixed with 200 mg of 2-amino-1,4,5,6-tetrahydropyrimidine and stirred for 12 hours at RT. The solvent is distilled off in vacuum and the residue chromatographic (Lobar C, DCM:MeOH:AcOH:H2O 98:8:0,8:0,8). Exit 270 mg.

MS (ES+): m/e=586,5 ((M+N)+, 100%).

28d) 2S-Neopentecostalism-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbonyl)piperidine-1-yl)purine-9-yl)propionic acid.

Synthesis is carried out analogously to example 19 (C) of tert-butyl methyl ether 2S-neopentecostalism-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbonyl)piperidine-1-yl)purine-9-yl)propionic acid (example 28C). Yield 94%.

MS (ES+): m/e=530,4 ((M+N)+, 20%).

Example 29. 2S-(1-Adamantanecarbonyl)-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbonyl)Pieper is but)-3-(6-(4-carboxypeptidase-1-yl)purine-9-yl)propionic acid.

Synthesis is carried out analogously to example 28b of N-(1-adamantanecarbonyl)succinimide and tert-butyl methyl ether 2S-amino-3-(6-(4-carboxypeptidase-1-yl)purine-9-yl)propionic acid (example 28a). Yield 85%.

MS (ES+): m/e=583/4 ((M+N)+, 100%).

29b) tert-Butyl ether (2S-(1-adamantanecarbonyl)-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbonyl)piperidine-1-yl)purine-9-yl)propionic acid.

The synthesis was performed analogously to example 28C of tert-butyl methyl ether 2S-(1-adamantanecarbonyl)-3-(6-(4-carboxypeptidase-1-yl)purine-9-yl)propionic acid (example 29A). A yield of 75%.

MS (ES+): m/e=664,5 ((M+N)+, 30%).

29s) 2S-(1-Adamantanecarbonyl)-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbonyl)piperidine-1-yl)purine-9-yl)propionic acid.

Synthesis is carried out analogously to example 19 (C) of tert-butyl methyl ether 2S-(1-adamantanecarbonyl)-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbonyl)piperidine-1-yl)purine-9-yl)propionic acid (example 29b). Output 100%.

MS (ES+): m/e=608,4 ((M+N)+, 10%).

Pharmacological research.

As a test method by which you can determine, for example, the antagonistic action of the compounds according to vitronectin receptor (VnR) man (v3-ELISA test; test method when printing the results of the test indicated by the abbreviation "K/VnR").

Cleaning kistrina.

Kistryn cleanse methods Dennis and others, as described in Proc. Natl. Acad. Sci. USA, 1989, 87, 2471-2475, and PROTEINS: Structure, Function and Genetics, 1993, 15, 312-321.

Cleaning vitronektinove receptor humanv3.

Vitronektinove receptor person receive from human placenta according to the method of Pytela et al., Methods Enzymol., 1987, 144, 475. Vitronektinove receptorv3a person can also be obtained from some cell lines (e.g., 293 cells, human embryonic kidney cell line human), which supererogate with DNA sequences for both unitsvand3vitronektinove receptor. Units extracted by octylglucoside and then chromatografic on Concanavalin And heparin-sepharose and S-300.

Monoclonal antibodies.

Mouse monoclonal antibodies specific for units3vitronektinove receptor, receive according to the method of Newman et al., Blood, 1985, 227-232, or similar method.

Got the rabbit conjugate Fab 2 antimisting Fc on the horseradish peroxidase (antimachine FC HRP) from the company Pel Freeze (catalogue No. 715 305-1).

the et can be set using ELISA test. For this purpose, 96-well microtiter tablets covered with a solution kistrina (0.002 mg/ml) by the method of Dennis et al., as described in PROTEINS: Structure, Function and Genetics, 1993, 15, 312-321. Then the tablets are washed twice using PBS/0.05% tween-20 and blocked by incubation (60 minutes) with albumin serum bovine (BSA, and 0.5%, RIA grade or better) in Tris-Hcl (50 mm), NaCl (100 mm), MgCl2(1 mm), CaCl2(1 mm), MnCl2(1 mm), pH 7. Prepare solutions of known inhibitors and known test substances in concentrations from 2 to 10-12up to 2 10-6mol/l buffer solution for analysis (BSA, and 0.5%, RIA grade or better) in Tris-Hcl (50 mm), NaCl (100 mm), MgCl2(1 mm), CaCl2(1 mm), MnCl2(1 mm), pH 7). Blocked plates are released and accordingly 0,025 ml of this solution containing a certain concentration of from 2 to 10-12up to 2 10-6mol/l) or known inhibitor or test substances are served in each well. 0,025 ml vitronektinove receptor in the buffer test solution (0.03 mg/ml) drops from a pipette into each well of the tablet and the plate incubated on the device for shaking 60-180 minutes at room temperature. At this time, prepare a solution (6 ml/tablet) mouse monoclonal antibodies specific for3
-antibodies), which represents the conjugate antimisting Fc HRP antibody, and the mixture of mouse antibodies-anti-3and rabbit conjugate antimisting Fc HRP-antibody incubated during incubation, the receptor-inhibitor. The test plates are washed four times S-a solution which contains 0.05% tween-20, and receives a pipette, respectively, 0.05 ml/well of a mixture of antibodies in each well of the tablet and incubated for 60-180 minutes. The tablet is washed four times using PBS/0.05% tween-20 and then allocate using 0.05 ml/well PBS solution, which contains of 0.67 mg/ml o-phenylenediamine and 0,012% H2O2. As an alternative it is possible to use o-phenylenediamine in a buffer solution (pH 5), which contains a PA3RHO4and citric acid. Color manifestation stop using 1H. H2SO4(0.05 ml/well). The absorbance measured for each well at 492-405 nm and the data evaluated by standard methods.

The table shows the obtained test results.

Compounds of the present invention are characterized by an average degree of toxicity.

1. Compounds of formulas I and Ia,

where X is hydrogen, NR6R6’, fluorine, chlorine, bromine, OR6, SR6, hydroxy- (C1-C6) alkyl)2N, hydroxy-(C1-C6)-alkyl-O, hydroxy-(C1-C6)alkyl-S or NH-CO-R6;

Y is hydrogen,

G is a residue of formula II

-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R4(II)

W is a residue of formula III

-B-(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-D-E (III)

Ga- the remainder of the formula IIA

-(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-D-E (IIa)

Wa- the remainder of the formula IIIa

-B-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CRaR2)q-R4(IIIa)

A and a’ independently of one another are a direct bond, -C(O)NH - or-NH-;

R1,R2independently from each other hydrogen, fluorine, chlorine, cyano, nitro, (C1-C10)-alkyl, (C3-C14-cycloalkyl, (C3-C14)cycloalkyl-(C1-C8)alkyl, (C5-C14) aryl, (C1-C8) aryl- (C1-C8) -alkyl, R6-O-R7, R6-S(O)p-R7or R6
C18)alkyl, (C3-C14-cycloalkyl, (C3-C14)cycloalkyl-(C1-C8) alkyl, (C5-C14)aryl, (C5-C14)aryl-(C1-C8)-alkyl, R6-O-R7, R6R6’N-R7, R6C(O)-O-R7, R6C(O)R7, R6OC(O)R7, R6N(R6’)C(O)OR7, R6S-(O)pN(R5R7, R6(O)C(O)N(R5R7, R6C(O)N(R5R7, R6N(R6’)C(O)N(R5R7, R6N(R6’)S(O)pN(R5R7, R6S(O)pR7, R6SC(O)N(R5R7, R6N(R6’)C(O)R7or R6N(R6’)S(O)pR7,

moreover, the alkyl may be single or multiple unsaturated and alkyl or aryl can be substituted one or more times by fluorine, chlorine, bromine, cyano, R6R6’N-R7, nitro, R6OC(O)R7, R6C(O)R7, R6N(R6’)C(O)-R7, R6N(R6’) S(O)pR7, R6or R6-O-R7;

R4means C(O)R8;

R6, R6’,R5independently from each other hydrogen, (C1-C10)alkyl, (C3-C14-cycloalkyl, (C3-C14)cycloalkyl-(C1P> independently from each other - (C1-C4) alkylene or a direct link;

R8hydroxy, (C1-C8)alkoxy, (C5-C14)aryl-(C1-C8)-alkoxy, (C5-C14)-aryloxy, (C1-C8)-alkylcarboxylic-(C1-C4)alkoxy, (C5-C14)-aryl- (C1-C8)-alkylcarboxylic-(C1-C8)-alkoxy, NR6R6’, (di-((C1-C8)-alkyl)amino)carbonyloxy, (di((C5-C14)-aryl-(C1-C8)-alkyl)amino)carbonylmethyl,

In simple means of communication, NH, CONH, piperidinyl, S or imidazole;

D is a direct bond, -NR6-, -C(O)-NR6-, -NR6-C(O)-, -S(O)u-NR6-, -NR6C(O)-NR6-, -NR6-C(S)NR6-, -NR6-S(O)u-NR6-, -NR6-C(O)O, -NR6-N=CR6-, -NR6-S(O)u-(C5-C14)aryl-CO-, -(C5-C14)-aryl-S(O)u, -N=CR6- or-R6C=N-, or-R6C=N-NR6- and denoting D divalent residues through free link on the right side are associated with group E,

E. means hydrogen, -NH-CH(=NH), -C(=NH)-NH2or 5,6-membered aromatic or non-aromatic residue, optionally containing 1 or 2 nitrogen atom may sameindividualas residue;

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

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

i = 0 or 1;

p = 0, 1, or 2, independently from each other;

q = 0, 1, or 2;

r= 0, 1, 2, 3, 4, 5 or 6;

s= 0, 1, 2, 3, 4 or 5;

t= 0, 1, 2, 3, 4 or 5;

k = 0 or 1;

u = 1 or 2;

in all their stereoisomeric forms or their mixtures in all ratios, and their pharmaceutically acceptable salts.

2. Compounds of formula I or Ia under item 1, where X is hydrogen, NR6R6’, hydroxy-(C1-C6)alkyl-NH or NH-CO-R6; Y is hydrogen; G is a residue of formula II

-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R4(II)

W the rest of the formula III

-B-(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-D-E (III)

Gathe remainder of the formula IIA

-(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-D-E (IIa)

Wathe remainder of the formula IIIa

-B-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CRaR2)q-R4(IIIa)

A, a’ are independently d/SUB>-C4)-alkyl, (C5-C6)aryl, (C5-C6)aryl-(C1-C4)-alkyl, R6-O-R7or R6R6’N-R7; R3independently from each other hydrogen, (C1-C18)alkyl, (C3-C14-cycloalkyl, (C3-14)cycloalkyl-(C1-C8)alkyl, (C5-C14)aryl, (C5-C14)aryl-(C1-C8)-alkyl, R6R6’N-R7, R6C(O)R7, R6S(O)pN(R5R7, R6OC(O)N(R5R7, R6C(O)N(R5R7, R6N(R6’)C(O)N(R5R7, R6N(R6’)S(O)pN(R5R7or R6N(R6’)C(O)R7and the alkyl may be single or multiple unsaturated and alkyl or aryl can be substituted one or more times by fluorine, chlorine, bromine, cyano, R6R6’NR7, nitro, R6OC(O)R7, R6COR7, R6N(R6’)C(O)R7, R6N(R6’)S(O)pR7, R6or R6-O-R7; R4means C(O)R8; R5means hydrogen or (C1-C4)alkyl; R6, R6’independently from each other hydrogen, (C1-C10)alkyl,(C3-C14-cycloalkyl, (C3-C14)CEC )alkylene or a direct link; R8hydroxy, (C1-C4)alkoxy, (C5-C14)aryl-(C1-C4)-alkoxy, (C5-C14)-aryloxy,(C1-C8)-alkyl-carbonyloxy-(C1-C4)-alkoxy, (C5-C14)-aryl-(C1-C4)-alkylcarboxylic-(C1-C4)-alkoxy; means In simple communication, NH, CONH, piperidinyl, S or imidazole; D is a direct bond, -NR6-, -C(O)-NR6-, -NR6-C(O)-, -NR6-C(O)-NR6-, -NR6-C(O)O-, -NR6-N=CR6, -N=CR6-, -R6C=N or R6C=N-NR6- and denoting D divalent residues through free link on the right side are associated with the group E; E means-NH-CH(=NH), -C(=NH)-NH2or the remainder of a number

n = 1, 2, 3 or 4; m = 0 or 1; i = 0 or 1; p = 0, 1, or 2,independently from each other; q = 0 or 1; r= 0, 1, 2, 3, 4 or 5; s = 0, 1, or 2; t = 0, 1, or 2; k = 0 or 1; v = 0, 1, 2 or 3, in all their stereoisomeric forms or their mixtures in all ratios, and their pharmaceutically acceptable salts.

3. Compounds of formulas I and Ia under item 1 and/or 2, where X is hydrogen, NR6R6’or NH-CO-R6; Y is hydrogen; G is a residue of formula II

-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R4(II)

>k-(CR1R2)t-D-E (III)

Ga- the remainder of the formula IIA

-(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-D-E (IIa)

Wa- the remainder of the formula IIIa

B-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CRaR2)q-R4 (IIIa) a And a’ independently of one another are a direct bond, -C(O)NH - or-NH-; R1, R2is hydrogen; R3independently from each other hydrogen, (C1-C10)alkyl, (C3-C14-cycloalkyl, (C3-14)cycloalkyl-(C1-C8)alkyl, (C5-C14)aryl, (C5-C14)aryl-(C1-C8)-alkyl, R6R6’N-R7, R6OC(O)N(R5R7, R6C(O)N(R5R7, R6N(R6’)C(O)(R5R7, R6C(O)R7or R6N(R6’)C(O)R7and the alkyl may be single or multiple unsaturated and alkyl or aryl can be substituted one or more times by fluorine, chlorine, bromine, cyano, R6R6’NR7, R6OC(O)R7, R6N(R6’)C(O)R7, R6or R6OR7; R4means C(O)R8; R1-C8)-alkyl, (C3-C12-cycloalkyl, (C3-C12)cycloalkyl-(C1-C8)-alkyl, (C5-C14)-aryl; R7is a direct bond; R8hydroxy, (C1-C4)alkoxy, (C5-C14)aryl-(C1-C4)-alkoxy, (C5-C14)-aryloxy, (C1-C6)-alkylcarboxylic-(C1-C4)alkoxy, (C5-C14)-aryl-(C1-C4)-alkylcarboxylic-(C1-C4)-alkoxy, means a direct bond, NH, CONH; D is a direct bond, -NR6-, -C(O)-NR6- or-NR6-C(O)-; E means-NH-CH(=NH), -C(=NH)-NH2or the remainder of a number

r= 0, 1, 2, 3, 4 or 5; s = 0 or 1; t = 0 or 1; k = 0 or 1; n = 0, 1, 2, 3 or 4; m = 0 or 1; i = 0 or 1; q = 0 or 1, in all their stereoisomeric forms or their mixtures in all ratios, and their pharmaceutically acceptable salts.

4. The compounds of formula I under item 1 and/or 2, where X is hydrogen, NR6R6’or NH-CO-R6; Y is hydrogen; G is a residue of formula II

-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R4(II)

W the rest of the formula III

-B-(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t 6)-aryl or (C5-C6)-aryl-(C1-C4)alkyl; R3independently from each other hydrogen, (C1-C18)alkyl, (C3-C14-cycloalkyl, (C3-14)cycloalkyl-(C1-C8)alkyl, (C5-C14)aryl, (C5-C14)aryl-(C1-C8)-alkyl; R6R6’N-R7, R6OC(O)N(R5R7, R6SO2N(R5R7, R6C(O)N(R5R7, R6N(R6’)C(O)N(R5R7, R6C(O)R7or R6N(R6’)C(O)R7and the alkyl may be single or multiple unsaturated and alkyl or aryl can be substituted one or more times by fluorine, chlorine, bromine, cyano, R6R6’NR7, R6C(O)R7, R6N(R6’)C(O)R7, R6or R6OR7; R4means C(O)R8; R5means hydrogen or (C1-C4)alkyl; R6, R6’independently from each other hydrogen, (C1-C18)-alkyl, (C3-C12-cycloalkyl, (C3-C12)cycloalkyl-(C1-C8)-alkyl, (C5-C14)-aryl, where 1-3 carbon atom can be substituted by 1 to 3 heteroatoms from the series N, S, O, or (C5-C14)aryl-(C1-C8)alkyl, where aryl is together with the atoms connecting them form a cyclic system, which may contain additional heteroatoms from the series N, S, O; R7is a direct bond; R8hydroxy, (C1-C4)alkoxy, (C5-C14)aryl-(C1-C4)-alkoxy, (C5-C14)-aryloxy, (C1-C8)-alkylcarboxylic-(C1-C4)alkoxy or (C5-C14)-aryl-(C1-C4)-alkylcarboxylic-(C1-C4)-alkoxy; means piperidinyl; D is a direct bond, -NR6-, -C(O)-NR6- or-NR6C(O)-; E is-NH-CH(=NH), -C(=NH)-NH2or the remainder of a number

r= 0, 1, 2, 3, 4 or 5; s = 0 or 1; t = 0 or 1; k = 0 or 1; n = 0, 1, 2, 3 or 4; m = 0 or 1; i = 0 or 1; q = 0 or 1, in all their stereoisomeric forms or their mixtures in all ratios, and their pharmaceutically acceptable salts.

5. The compounds of formula I according to one or more of the paragraphs.1-4, where X is hydrogen; Y is hydrogen; G is a residue of formula II

-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R4(II)

W the rest of the formula III

-B-(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-D-E (III)3- R6R6’N-R7, R6OC(O)N(R6R7, R6SO2N(R5R7R6C(O)N(R5R7or R5N(R6’)C(O)N(R5R7; R4- C(O)R8; R5is hydrogen or (C1-C2)alkyl; R6, R6’independently from each other hydrogen, (C1-C10)-alkyl, (C3-C12-cycloalkyl, (C3-C12)cycloalkyl-(C1-C8)-alkyl, (C5-C14)-aryl; R7is a direct bond; R8hydroxy, (C1-C4)alkoxy, (C5-C14)aryl-(C1-C4)-alkoxy, (C5-C14)-aryloxy, (C1-C8)-alkylcarboxylic-(C1-C4)alkoxy or (C5-C14)-aryl-(C1-C14)-alkylcarboxylic-(C1-C4)-alkoxy; means piperidinyl; D-N-R6- or-C(O)-NR6- and the group-C(O)-NR6the nitrogen atom linked to the group E; E means-NH-CH(=NH) or the remainder of a number

r = 0 or 1; s = 0; t = 0; k = 0; n = 1; m = 1; i = 1; q = 0, in all their stereoisomeric forms or their mixtures in all ratios, and their pharmaceutically acceptable salts.

6. The compounds of formula Ih

where R3means R6R6’N-R7, R6OC(O)N(R5R7, R

Rhdenotes a carboxylic acid group COOH,

in all their stereoisomeric forms or their mixtures in all ratios, and their pharmaceutically acceptable salts.

7. 2S-Benzyloxycarbonylamino-3-(6-(4-(1,4,5,6-tetrahydropyrimidin-2-ylcarbonyl)-piperidine-1-yl)-purine-9-yl)propionic acid and its physiologically acceptable salt.

8. The method of obtaining the compounds of formula I according to one or more paragraphs.1-7, characterized in that for obtaining the compounds of formula I a compound of formula IV

where L1denotes a group to delete;

X and Y have the values specified in paras.1-7, but functional groups can exist in a protected form,

sequentially subjected to interaction with the compound of the formula V

L2-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R10(V)

and with the compound of the formula VII

HB-(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-R13(VII)

to obtain the compounds of formula VIII

in formulas V, VII and VIII L2means remove the3)i-(CR1R2)q-R10;

R15denotes-B-(CR1R2)r-A’-(CR1R2)s -(CR1R3)k-(CR1R2)t-R13;

R10is specified in the PP.1-7 for R4 values, and denoting R4groups can also exist in a protected form;

R13is specified in the PP.1-7 values of the group D-E, and contained in D-E group can also exist in a protected form, or R13denotes a group which can be converted into a group-D-E;

R1, R2, R3And, A’, B, X, Y, n, m, i, q, r, s, k and t are specified in the PP.1-7 values

and then, if necessary, the group R10and R13transferred to group R4and D-E.

9. The method of obtaining the compounds of formula Ia according to one or more paragraphs.1-7, characterized in that for obtaining the compounds of formula Ia, the compound of formula IV is consistently subjected to interaction with the compound of the formula IX

L2-(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-R13(IX)

and with the compound of the formula XI

HB-(CR1XI)

to obtain the compounds of formula XII

in formula IX, XI and XII

the remainder R16means -(CR1R2)r-A’-(CR1R2)s-(CR1R3)k-(CR1R2)t-R13;

the remainder R17denotes-B-(CR1R2)n-A-(CR1R2)m-(CR1R3)i-(CR1R2)q-R10;

R1, R2, R3, R10, R13, A, A’, B, X, Y, L2, n, m, i, q, r, s, k and t are defined as described for formulae V, VII, and VIII, and then, if necessary, group10and R13transferred to the group R4and D-E.

10. Compounds of formulas I and Ia according to one or more paragraphs.1-7 and/or their physiologically acceptable salts, which has antagonistic activity against vitronectin receptor.

11. Compounds of formulas I and Ia according to one or more paragraphs.1-7 and/or their physiologically acceptable salts as inhibitors of bone resorption by osteoclasts, as inhibitors of tumor growth or metastasis of the tumor, as inhibitors of inflammation, for the treatment or prevention of cardiovascular diseases, for the treatment or prevention of nephropathy or pet is the quiet caused by the interaction between vitronectin receptors and their ligands in cell-cell or cell-matrix interaction processes.

12. Pharmaceutical drug, which has antagonistic activity against vitronectin receptor containing at least one compound of formula (I) or (Ia) according to one or more paragraphs.1-7 and/or their physiologically acceptable salts, together with pharmaceutically acceptable carriers and/or additives.

 

Same patents:

The invention relates to new derivatives of 2-aryl-8-oxopiperidine formula (I) having a selective affinity towards BZw3receptor, the method thereof, pharmaceutical composition and means containing it, and also to the intermediate compound of formula (II) to obtain the derivatives of 2-aryl-8-oxopiperidine

The invention relates to novel 2,6,9-triple-substituted purine derivative of General formula I, having the effect of selective inhibitors of kinases of the cell cycle, which can be used, for example, for the treatment of, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, diabetes type I, multiple sclerosis, and for the treatment of cancer, cardiovascular diseases such as restenosis, etc

The invention relates to new derivatives of substituted purine with immune modulating, in particular immunostimulatory activity in vivo and in vitro and does not exhibit toxicity, to pharmaceutical compositions and method of slowing tumor growth

The invention relates to an improved method for producing a purine compounds of General formula A, where X is hydrogen, hydroxy, chlorine, Ra and Rb denote hydrogen, acyl

The invention relates to new biologically active compounds, methods of treating diseases with their use and pharmaceutical compositions based on these compounds

The invention relates to medicine and organic chemistry and relates to the problem of creating new drugs, inhibiting the proliferation of lymphocytes

The invention relates to new derivatives of purine of formula I, II, III and IV, pharmaceutical compositions and method of treatment of a pathological state characterized by thrombotic activity

The invention relates to new derivatives of substituted purine with immune modulating, in particular immunostimulatory activity in vivo and in vitro and does not exhibit toxicity, to pharmaceutical compositions and method of slowing tumor growth

The invention relates to medicine and organic chemistry and relates to the problem of creating new drugs, inhibiting the proliferation of lymphocytes

The invention relates to analogues of nucleosides dimethoxyaniline

The invention relates to a method for producing analogues of nucleosides dimethoxyaniline

The invention relates to substituted acylaminoalkyl-brazilan General formula I

where n is 0 or 1; And is unsubstituted or substituted alcander; Ar is a substituted aryl or unsubstituted or substituted heterocyclyl an oxygen atom, Q is a group-O-, R1is unsubstituted or substituted alkyl, R2is unsubstituted or substituted alkyl, R3is hydrogen, R4or R5- independently of each other cyano or halogen, R6- alkylsulfonyl; the herbicide agent containing at least one substituted acylaminoalkyl-uracil and conventional fillers

The invention relates to new derivatives of di - or triftormetilfullerenov, the General formula I:

where, when R1represents a hydrogen atom or alkyl group with 1-5 carbon atoms, R2represents a hydrogen atom, and when R1is alkoxyalkyl group with 2-6 carbon atoms, R2represents a hydrogen atom or a fluorine atom, or their salts, which are effective for removing a wide variety of weeds, including difficult to suppress weeds that appear in the rice fields, and which are safe for mammals

The invention relates to new derivatives of thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione of General formula (I) or their pharmaceutically-acceptable salts, having immunosuppressive activity

The invention relates to new triazolo[4,5-d]pyrimidine compounds of General formula (I) or their pharmaceutically acceptable salts, which have the effect of P2T-antagonists, in particular, show inhibitory platelet aggregation activity

The invention relates to novel condensed to thienopyrimidine formula I and their physiologically acceptable salts, having the effect of inhibitors of phosphodiesterase V(PDE V), and which can be used for the treatment of diseases of the cardiovascular system and for the treatment and/or therapy of disorders of potency

The invention relates to new compounds of the formula (I) and their pharmaceutically acceptable salts and esters possessing inhibitory ability against endothelioma receptors, the Compounds can be used to treat diseases associated with abnormal vascular tone and endothelial dysfunction
Up!