Derivatives of beta-alanine

 

(57) Abstract:

The invention relates to a derivative of alanine General formula I:

in which Q1or Q3independently from each other represent CH or N, they cannot mean N; R1represents H, A, Ar or Hal, R2denotes H or A,

each of R4and R5independently denotes H, a or Hal, R6represents H or a, a denotes alkyl with 1-6 carbon atoms, Ar is an unsubstituted aryl, Hal denotes F, Cl, Br or I, n is 2, 3, 4, 5 or 6, m is 1, 2, 3 or 4, as well as their physiologically acceptable salt and solvate; two methods for their preparation and pharmaceutical product having the properties of inhibitor integrins. 4 N. and 3 C.p. f-crystals.

The present invention relates to a derivative-alanine formula

in which

each of Q1, Q2,

Q3or Q4independently of the other represents CH or N

R1represents H, A, Ar, Hal, HE, OA, CF3or OCF3,

R2denotes H or A,

each of R4and R5regardless SUP> denotes H, A, -(CH2)m-OH, -(CH2)m-O-C(O)Oh or -(CH2)m-Ah,

And represents alkyl with 1-6 carbon atoms,

AG denotes unsubstituted or mono-, bi - or tizamidine aryl,

Hal represents F, Cl, Br or I.

n is 2, 3, 4, 5 or 6,

m is 1, 2, 3, or 4

and physiologically acceptable salts and solvate.

To some extent, these compounds are known from the application WO 97/26250 or WO 97/24124.

The purpose of this invention was to provide new compounds that would have valuable properties, in particular, those that could be used for the manufacture of drugs.

It was found that the compounds of formula I and their salts along with good tolerability have very valuable pharmacological properties. First of all, they act as integrin inhibitors, in particular, preventing the interaction of integrin receptors v3 or v5 with ligands, such as binding with vitronectin receptor integrin v3. Integrins are membrane-bound, heterodimeric glycoproteins consisting of a subunit and small subunit . The relative affinity and specifying the most effective in the case of integrins v1, v3, v5, llb3, and v6 and v8, preferably v3 and v5. In particular, we have found a strong selective effect inhibitors of integrin v3. The integrin v3 is expressed on many cells, e.g., on endothelial cells, smooth muscle cells of blood vessels, for example, the aorta, the cells involved in the destruction of bone matrix (osteoclasts) or tumor cells.

The action of the compounds according to this invention can be, e.g., to be demonstrated by the method described in J. W. Smith and others in J. Biol. Chem. 1990, 265, 12267-12271.

The dependence of the source of angiogenesis from the interaction between integrins in vascular walls and proteins of the extracellular matrix is described in the P. C. Brooks, R. A. Clark, and D. A. Cheresh in Science 1994, 264, 569-571.

The possibility of inhibition of this interaction and, thus triggering apoptosis (programmed death) of angiogenic cells by cyclic peptide described by P. C. Brooks, A. M. Montgomery, M. Rosenfeld, R. A. Reisfeld, T. Ni, G. Klier and D. A. Cheresh in Gell 1994, 79, 1157-1164. In this work are described, e.g., antagonists or antibodies to v3, which, initiating apoptosis, promote shrinkage of tumors.

To prove experimentally the ability including the compounds of the present invention to prevent Prim tumor cells using tests for intercellular adhesion, which is similar to the method described in F. Mitjans, etc., J. Gell Science 1995, 108, 2825-2838.

The compounds of formula I are capable of inhibiting the binding metalloproteinase with integrins and thus to prevent the use of cells and the enzymatic activity of proteases. An example of this is the inhibition of binding of MMP-2(matrix-metalloproteinase-2-) with the vitronectin receptor v3 by cyclo-RGD-peptide, described in R. C. Brooks and others, Cell 1996, 85, 683-693.

The compounds of formula I, blocking the interaction of receptors integrins to ligands, e.g., fibrinogen with the fibrinogen receptor (glycoprotein IIb/IIIa), as antagonists inhibit the proliferation of tumor cells due to metastasis and, thus, can be used as anti-metastatic agents in the course of operations to remove tumors surgically or with surgical interventions effect on the tumor. This corresponds to the following observations:

Proliferation of tumor cells local tumor in the vascular system occurs due to the formation of microaggregates (microthrombi), due to the interaction of tumor cells with platelets. In microaggregate which can be fastened in the walls of blood vessels, thus facilitating the further penetration of tumor cells into the tissue. Since the formation of microthrombi, resulting from the binding of ligands to specific receptors integrins, e.g., v3 or llb3, participate activated platelets, the corresponding antagonists can be considered as inhibitors of metastasis.

The compounds of formula I can be used as active ingredients included in the composition of drugs in human medicine and veterinary medicine, in particular for the prophylaxis and/or therapy of diseases of the vascular system, thrombosis, myocardial infarction, arteriosclerosis, apoplexy, angina, malignant diseases, such as development or tumor metastases, osteolytic diseases such as osteoporosis, pathologically angiogenic diseases, such as e.g. inflammation, eye diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, neovascular glaucoma, ulcerative colitis, regional ileitis, atherosclerosis, psoriasis, restenosis after angioplasty, multiple sclerosis, viral infection, bacterial infection, fungal infection, acute renal negate antimicrobial substances during operations with the use of biomaterials, implants, catheters or pacemakers of the heart.

At the same time they act as antiseptics. Antimicrobial activity can be demonstrated using the method described in the P. Valentin-Weigund and others in Infection and Immunity, 1988, 2851-2855.

Some compounds of formula I are, in particular, selectively acting inhibitors of receptor integrins v3 and v6.

Some compounds of formula I are, in particular, selectively acting inhibitors of receptor integrins v5 and v6.

Some compounds of formula I are, in particular, selectively acting inhibitors of receptor integrins v3, v5 and v6.

The effect of such compounds on receptor integrin v5 and, thus, its activity as an inhibitor can be demonstrated, e.g., the method described in J. W. Smith and others in J. Biol. Chem. 1990, 265, 12267-12271.

The effect of these compounds on receptor integrin v5 and, thus, its activity as an inhibitor can be demonstrated, e.g., using the method described by J. W. Smith and others in J. Biol. Chem. 1990, 265, 12267-12271.

These are some connections are especially suitable for the treatment or elimination of pathological processes associated with the activities of the Kie, as psoriasis, bullous disease, dermatitis, and erythema, as well as pulmonary fibrosis, cystic fibrosis, endometriosis, cirrhosis of the liver or periodontitis. These pathologies can be affected by inhibitors v3 and/or v5. In particular, carcinoma, as well as the above-mentioned skin diseases and pulmonary fibrosis and, in addition, the pathology of epithelial cells is affected by inhibitors v6 (Literature: Healy D. L. and others, Hum. Reprod. Update 1998, 4(5), 736-40; D. Creamer, etc., Br. J. Dermatol. 1997, 137, 851-5; Norrby K., APMIS. 1997, 105, 417-37; D. Creamer, etc., Br. J. Dermatol. 1997, 136, 859-65; Polverini, P. J. Crit. Rev. Oral. Biol. Med. 1995, 6, 230-47; Brown, L. F., and others, J. Invest. Dermatol. 1995, 104, 744-9; Hoyt D. G., and others, Am. J. Physiol. 1997, 273, L612-7; Pilewski, J. M., and others, ibid 1997, 273, L256-63 or M. Goldman and others, Gene. Ther. 1996, 3, 811-8).

The preferred area of application of some of these compounds is therapy of cancer.

The methods used in cancer therapy, as a rule, aimed at addressing some of the plot segment in the area of development of solid tumors. Segments, among other things, represent the area of the tumor itself or embedded in the tumor blood vessels through which the tumor receives all necessary for its growth. Once the tumor stops receiving power, transcriptional activators, most often through giov growth. The latter activate the growth of blood vessels. For dividing endothelial cells of blood vessels necessary antipepticski signals sent by the receptors of the family of integrins on the surface of cells. In particular, these signals correspond receptors integrins v3 and v5 (literature: R. C. Brooks, Eur. J. Cancer, 1996, 32A, 2423-2429; P. C. Brooks and others, Gell. 1994, 79, 1157-1164).

Inhibition of these receptors integrins v3 and/or v5, in particular, v3, induces apoptosis of activated endothelial cells grown in the tumor of the blood vessel, while its unused tumor normal bed remains intact. The tumor is deprived of the power source, resulting in its development is suspended. By itself the tumor, i.e., transformed cancer cells, however,are not subjected to any treatment, therefore, after the cessation of therapy can again begin the growth of the tumor.

Receptors integrins on the surface of tumor cells differ from those expressed on normal tissue. For example, many carcinomas detected high expression of de-novo rare integrin v6, while v3 is a common symptom of progressive malignant drives of the working systems is Ani transformed cells, i.e. metastasis.

Combination therapy, at the same time aimed at the angiogenesis of the tumor tissue and the elimination of the latter as such, so far described only as inhibitors of integrin v3 in combination with cytotoxic agents (chemotherapy) or radiation (radiation therapy).

Unexpectedly, it was found that by applying selectively acting inhibitors of integrins v3 and v6, it is possible to make a medicine for such combination therapy. Thus, there is a synergistic effect. Due to the high selectivity of inhibition of receptor integrins v3 and v6, inhibition of other integrins, for example, 51 or IIb3, which play an important role, e.g., in normal tissue, should not be afraid.

It was further discovered that applying a selectively acting inhibitors of integrins v5 and v6, the same as if you would use a combination of selectively acting inhibitors of integrins v3,v5 and v6, you can also make the medicine for such combination therapy. In this case also may be a synergistic effect.

The compounds of formula I have MENR., D - and L-forms) and mixtures thereof (e.g., DL forms) are included in this formula.

Under item 1 of the claims to the compounds of the present invention also include so-called Proletarskiy derivatives, i.e., modified alkyl or acyl groups, sugars or oligopeptides of the compounds of formula I, quickly splitting in the body to the active compound according to this invention.

Furthermore, free amino or hydroxyl group as substituents of the compounds of formula I can be provided with appropriate protective groups.

Under the solvate of the compounds of formula I are those adducts of molecules of the inert solvent to compounds of formula I, formed by their mutual attraction. The solvate are, for example, mono - or dihydrate or additive compounds with alcohols, e.g. with methanol or ethanol.

The objects of this invention are the compounds of formula I and their salts and solvate under item 1 of the claims, as well as the method of obtaining compounds of the formula I, their salts and solvate, characterized in that the

(a) compound of formula II

in which Q1, Q2, Q3, Q4, R1and n have the meanings nature>

in which R2, R3, R4, R5and R6have the values listed in paragraph (1

claims,

and, if necessary, translate the radical R6N in the radical R6=

N, or

(b) a compound of formula IV

in which Q1, Q2, Q3, Q4, R1, R2and n have the meanings given

in paragraph 1 of the claims,

enter into reaction with the compound of the formula V

in which R3, R4, R5and R6have the values listed in paragraph (1

claims,

and, if necessary, translate the radical R6N in the radical R6=N

or

(C) in the compound of the formula I one or more radicals R1, R2, R3, R4and/or R5transferred to one or more radicals R1, R2, R3, R4and/or R5by, for example

(i) alkylation of the hydroxyl group of,

ii) hydrolysis of the ester group to a carboxyl group,

iii) esterification of carboxyl groups,

iv) alkylation of an amino group or

v) acylation of the amino group,

and/or

In the above formulas And denotes alkyl is linear or branched and has 1-6, preferably 1, 2, 3, 4, 5 or 6 carbon atoms. In the preferred embodiment, And represents methyl, then ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl or tert.-butyl and pentyl, 1-, 2 - or 3-methylbutyl, 1,1-, 1,2 - or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3 - or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3.3-dimethylbutyl, 1 - or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 - or 1,2,2-trimethylpropyl.

A particularly preferred value of a is methyl, ethyl, isopropyl, n-propyl, n-butyl or tert.-butyl.

AG denotes unsubstituted or mono-, bi - or tizamidine A, CF3HE, OA, OCF3, CN, NO2or Hal aryl represents phenyl, naphthyl, antrel or biphenylyl. In a preferred embodiment, AG denotes unsubstituted or mono-, bi - or tizamidine A, CF3HE, OA, OCF3, CN, NO2or Hal phenyl or naphthyl.

Thus, Ah preferably represents phenyl, o-, m - or p-were, o-, m - or p-ethylphenyl, o-, m - or p-propylphenyl, o-, m - or p-isopropylphenyl, o-, m - or p-tert.-butylphenyl, o-, m - or p-hydroxyphenyl, o-, m - or p-methoxyphenyl, o-, m - Lileya preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3, 5dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-differenl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-acid or 3-chloro-4-forfinal, 4-fluoro-2-hydroxyphenyl, naphthalene-1-yl, naphthalene-2-yl or 2-, 3-, 4-, 5-, 6-, 7- or 8-methylnaphthalene-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethylnaphthalene-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-chloronaphthalene-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-fornatale-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8 does not depend-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-hydroxynaphthalene-1-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-methylnaphthalene-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-ethylnaphthalene-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-chloronaphthalene-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-fornatale-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8 does not depend-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-hydroxynaphthalene-2-yl.

Most preferably AG denotes phenyl, o-, m - or p-forfinal, m - or p-chlorophenyl, p-were, R-triptoreline, 3-chloro-4-forfinal, 4-fluoro-2-hydroxyphenyl, naphthalene-1-yl or naphthalene-2-yl.

B -(CH2)mAr AG has one of the above preferred values, and the variable m can be equal to 1 or 2. Particularly preferred is -(CH2)m-Ar is benzyl.

IN -(CH2)mHE m can be runecsape or hydroxybutyl, most preferably hydroxyethyl.

IN -(CH2)m-O-C(O)And takes one of the above preferred values, and m may be equal to 1 or 2. In a particularly preferred embodiment, And denotes tert.-butyl, and m is 1.

Hal preferably represents F, Cl or bromine.

n is 2, 3, 4, 5 or 6, particularly preferably 3, 4 or 5.

in the preferred embodiment refers to 3-(triptoreline) or 4(triptoreline)phenyl.

preferably represents biphenyl-4-yl, 4’-forbiden-4-yl, 4’-forbiden-3-yl, 3’-forbiden-4-yl, 2’-forbiden-4-yl, 4’-chlorobiphenyl-4-yl, 3’-chlorobiphenyl-4-yl, 4’-methylbiphenyl-4-yl, 4’-(trifluoromethyl)biphenyl-4-yl, 3’-chloro-4’-forbiden-4-yl, 4’-fluoro-2-hydroxybiphenyl-4-yl, 4’-fluoro-2’-hydroxybiphenyl-4-yl, 4’-fluoro-2’-hydroxybiphenyl-3-yl, 4-(naphthalene-1-yl)phenyl, 4-(naphthalene-2-yl)phenyl or 4-(naphthalene-1-yl)-3-hydroxyphenyl.

in a preferred embodiment denotes the 2-, 3 - or 4-nitrophenyl, 4-methyl-3-nitrophenyl, 4-chloro-3-nitrophenyl, 3-nitro-2-hydroxyphenyl or 3-bromo-6-hydroxy-5-nitrophenyl.

Each of Q1, Q2, Q3or Q4independently of the other represents CH, CH, that is also the preferred value for Q3and Q4. Most preferably Q1, Q2, Q3and Q4represent CH.

R1denotes H, A, Ar, Hal, HE, OA, CF3or F3and As, AG or Hal takes the above preferred or particularly preferred meanings. R1preferably represents N or A. Substituted R1in the preferred embodiment is a 4 - or 6-position. Particularly preferably 4-position of the ring.

R2preferably denotes H or A, in a particularly preferred embodiment, N.

R3represents the

where R4and R5independently of one another denote H, A, Hal, HE, OA, CF3, F3, CN, NH2, NHA, NA2or NH-C(O)A, and AG takes one of the above values.

A particularly preferred value of R4is N, AND HE or Hal.

R5in a particularly preferred embodiment denotes H or HE.

A particularly preferred value of R4and R5

is N.

In a particularly preferred embodiment, R4

denotes H or HE, and AG probe preferred value of R4

is H, a or Hal, and R5in a particularly preferred embodiment denotes H or HE.

R3preferably represents 2-, 3 - or 4-trifloromethyl, 2-, 3 - or 4-nitrophenyl, biphenyl-3-yl, biphenyl-4-yl, 3-methyl-, 4-methyl, 5-methyl - or 6-methyl-2-(triptoreline)phenyl, 3-ethyl-, 4-ethyl-, 5-ethyl - 6-ethyl-2-(triptoreline)phenyl, 2-methyl-, 4-methyl-, 5-methyl - or 6-methyl-3-(triptoreline)phenyl, 2-ethyl-, 4-ethyl-, 5-ethyl - 6-ethyl-3-(triptoreline)phenyl, 2-methyl-, 3-methyl-, 5-methyl - or 6-methyl-4-(triptoreline)phenyl, 2-ethyl-, 3-ethyl-, 5-ethyl - 6-ethyl-4-(triptoreline)phenyl, 3-methyl-, 4-methyl-, 5-methyl - or 6-methyl-2-nitrophenyl, 3-ethyl-, 4-ethyl-, 5-ethyl - 6-ethyl-2-nitrophenyl, 2-methyl-, 4-methyl, 5-methyl - or 6-methyl-3-nitrophenyl, 2-ethyl-, 4-ethyl-, 5-ethyl - 6-ethyl-3-nitrophenyl, 2-methyl-, 3-methyl-, 5-methyl - or 6-methyl-4-nitrophenyl, 2-ethyl-, 3-ethyl-, 5-ethyl - 6-ethyl-4-nitrophenyl, 3-chloro-, 4-chloro-, 5-chloro - or 6-chloro-2-nitrophenyl, 2-chloro-, 4-chloro-, 5-chloro - or 6-chloro-3-nitrophenyl, 2-chloro-, 3-chloro-, 5-chloro - or 6-chloro-4-nitrophenyl, 3-nitro-2-hydroxyphenyl, 3-bromo-6-hydroxy-5-nitrophenyl, 4’-forbiden-4-yl, 4’-forbiden-3-yl, 3’-forbiden-4-yl, 2’-forbiden-4-yl, 4’-chlorobiphenyl-4-yl, 3’-chlorobiphenyl-4-yl, 4’-methylbiphenyl-4-yl, 4’-(t-4-yl, 4’-fluoro-2’-hydroxybiphenyl-3-yl, 4-(naphthalene-1-yl)phenyl, 4-(naphthalene-2-yl)phenyl or 4-(naphthalene-1-yl)-3-hydroxyphenyl.

Particularly preferred values of R3are 4-(triptoreline)phenyl, 3-(triptoreline)phenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, biphenyl-4-yl, 4-methyl-3-nitrophenyl, 4-fluoro-2-hydroxyphenyl or 4-chloro-3-nitrophenyl, 4’-forbiden-4-yl, 4’-forbiden-3-yl, 3’-forbiden-4-yl, 2’-forbiden-4-yl, 4’-chlorobiphenyl-4-yl, 3’-chlorobiphenyl-4-yl, 4’-methylbiphenyl-4-yl, 4’-(trifluoromethyl)biphenyl-4-yl, 3’-chloro-4’-forbiden-4-yl, 4’-fluoro-2-hydroxybiphenyl-4-yl, 4’-fluoro-2’-hydroxybiphenyl-4-yl, 4’-fluoro-2’-hydroxybiphenyl-3-yl, 4-(naphthalene-1-yl)phenyl, 4-(naphthalene-2-yl)phenyl or 4-(naphthalene-1-yl)-3-hydroxyphenyl or 3-bromo-6-hydroxy-5-nitrophenyl.

R6denotes H, A, -(CH2)m-OH, -(CH2)m-O-C(O)Oh or -(CH2)m-Ah, where A, -(CH2)m-OH, -(CH2)m-O-C(O) - and -(CH2)m-Ah take one of the above preferred or particularly preferred meanings.

The compounds of formula I in which R6preferably denotes A, -(CH2)m-OH, -(CH2)m-O-C(O)Oh or -(CH2)m-AG, and their solvate, predialogues active carboxyl group. However, in the body during metabolism of prodrugs accept biologically active form. The corresponding free acid, which corresponds to the compound of formula I with R6= N, and including its salts and solvate, shows activity in vitro.

Accordingly, an object of the present invention are, in particular, the compounds of formula I in which at least one of the mentioned radicals takes one of the above preferred values. Some preferred groups of compounds can be expressed by the following subformulae la-lk corresponding to the formula I (radicals, which does not provide a detailed definition have the meanings specified for formula (I), where

In 1a

B lb

B lc

In Id Q1, Q2, Q3and Q4formula I represents CH.

In le Q1denotes N, and Q2, Q3and Q4formula I represents CH.

In 1f R1denotes H or a, and

R3indicates or

In 1g R1represents H or A,

R3indicates or

Q1is Soboh>1, Q2, Q3and Q4denote SN, and

R3indicates or

In 4i R1represents H or A, and

R3indicates or

In 1k R1represents H or A, and

R3indicates or

Particularly preferred compounds of formula la are

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4 - trifloromethyl)propionic acid,

3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-trifloromethyl)propionic acid,

3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(3-trifloromethyl)propionic acid, or

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-trifloromethyl)propionic acid,

and their physiologically acceptable salt and solvate.

Particularly preferred compounds of formula 1b are

3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pen is wireline]acetylamino}propionic acid,

3-(2-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(2-nitrophenyl)propionic acid,

3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(2-nitrophenyl)propionic acid,

3-(2-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

3-(4-methyl-3-nitrophenyl)-3-{2-[4-(6-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

methyl ester of 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic

acid,

3-(4-methyl-3-nitrophenyl)-3-{2-[5-(6-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

3-(4-chloro-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyrimidine-2-ylamino)bucillamine]acetylamino}propionic acid, or

3-also their physiologically acceptable salt and solvate.

Particularly preferred compounds of formula 1C are

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-biphenylyl)propionic acid,

3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}-3-(4-biphenylyl)propionic acid,

3-{2-[5-(pyrimidine-2-ylamino)pentanediamine]acetylamino}-3-(4-biphenylyl)propionic acid,

3-{2-[4-(pyrimidine-2-ylamino)bucillamine]acetylamino}-3-(4-biphenylyl)propionic acid,

3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}-3-(4-biphenylyl)propionic acid, or

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-biphenylyl)propionic acid,

and their physiologically acceptable salt and solvate.

Particularly preferred compounds of formula 1d are

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-trifloromethyl)propionic acid,

3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-trifloromethyl)propionic acid,

3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(3-trifloromethyl)propionic acid,

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-the Ino]acetylamino}propionic acid,

3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

3-(4-methyl-3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

3-(2-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(2-nitrophenyl)propionic acid,

3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(2-nitrophenyl)propionic acid,

3-(2-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

3-(4-methyl-3-nitrophenyl)-3-{2-[4-(6-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

methyl ester of 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

3-(4-methyl-3-nitro the phenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-biphenylyl)propionic acid,

3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}-3-(4-biphenylyl)propionic acid,

3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}-3-(4-biphenylyl)propionic acid, or

3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-biphenylyl)propionic acid,

and their physiologically acceptable salt and solvate.

Preferred compounds of formula 1E are

3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyrimidine-2-ylamino)bucillamine]acetylamino}propionic acid,

3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyrimidine-2-ylamino)pentanediamine]acetylamino}propionic acid,

3-{2-[5-(pyrimidine-2-ylamino)pentanediamine]acetylamino}-3-(4-biphenylyl)propionic acid, or

3-{2-[4-(pyrimidine-2-ylamino)bucillamine]acetylamino}-3-(4-biphenylyl)propionic acid,

and their physiologically acceptable salt and solvate.

Preferred compounds of formula 1f are

3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}-3-(4-biphenylyl)propionic acid,

3-{2-[5-(4-methylpyridin-2-ylamino)peo]acetylamino}-3-(4-biphenylyl)propionic acid, or

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-biphenylyl)propionic acid,

and their physiologically acceptable salt and solvate.

In the rest of the compounds of formula I on p. 1 of the claims, as well as raw materials, receive essentially known methods described in the literature (e.g., in such standard works as Houben-Weyl, Methods der organischen Chemie, published by Georg-Thieme-Verlag, Stuttgart), namely, in a known suitable for carrying out the above-mentioned reaction conditions. In this case, you can also use known essentially the options detailed here, however, is not given.

If desired, the starting materials can be obtained in situ, not isolating them from the reaction mixture, but immediately tripping in further reactions with formation of compounds of formula I on p. 1 of the claims.

Several identical or different from each other - protected amino and/or hydroxyl groups may also be present in the molecule of the original substance. If present protective groups differ from each other, in many cases they can be selectively split (EUR.: T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Chemistry, 2-e edition, Wiley, new York 1991 or P. J is the traitors Century M Trost, I. Fleming, E. Winterfeldt), published by Pergamon, Oxford, 1991, PP 631-701).

The term "protective group for the amino group" is generally known and relates to groups which can be used for protecting (blocking) an amino group from chemical reactions. Typical groups of this type are, in particular, unsubstituted or substituted acyl, aryl, arelaxation or kalkilya group. As the protective group of amino group hatshepsuts upon completion of the desired reaction (or sequence of reactions), their nature and size are not important; however, preference is given to groups with 1-20, in particular 1-8, carbon atoms. The term "acyl group" in the context of this method is interpreted in its broadest sense. It refers to acyl groups derived from aliphaticity, alifaticheskih, aromatic or heterocyclic carboxylic acids or sulphonic acids, and, in particular, to alkoxycarbonyl, alkanolammonium, aryloxyalkyl and, above all, alcoxycarbenium groups. As examples of acyl groups of this type can lead to alkanoyl, such as acetyl, propionyl, butyryl; arkanoid, such as phenylacetyl; aroyl, such as benzoyl or toluyl; dichlorocarbene, SIDE 2-ideacarbon; alkenylbenzenes, such as allyloxycarbonyl (Aloka), Uralelectromed, such as KB (synonym 3), 4-methoxybenzeneboronic (MO), 4-nitrobenzenesulfonyl or 9-fluorenylmethoxycarbonyl (Fmoc); 2-(phenylsulfonyl)etoxycarbonyl; trimethylsilylacetamide (TEOC) or arylsulfonyl, such as 4-methoxy-2,3,6-trimethylphenylsulfonyl (ICTR). Preferred protective groups for the amino group are SIDE, Fmoc and ALok and CBZ, benzyl and acetyl.

The term "protective group of hydroxyl group" is generally known and relates to groups which can be used to protect a hydroxyl group against chemical reactions. Typical groups of this type are the abovementioned unsubstituted or substituted aryl, kalkilya, aroline or acyl groups, and alkyl groups, alkyl-, aryl - or aralkylamines group or O,O - or O,S-acetals. The nature and size of the protective groups of the hydroxyl group does not play a special role, since it is cleaved again after the implementation of the desired chemical reaction or sequence of reactions; preference is given to groups with 1-20, in particular 1-10 carbon atoms. As examples of protective groups hidematchcase, aroline group, such as benzoyl or p-nitrobenzoyl, acyl groups such as acetyl or pivaloyl, p-toluensulfonyl, alkyl groups such as methyl or tert.-butyl, and allyl, alkylsilane groups, such as trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert.-butyldimethylsilyl (TBS) or triethylsilyl, trimethylsilylmethyl, aralkylamines group, such as tert.-butyldiphenylsilyl (TRIPS), cyclic acetals, such as isopropylidene, cyclopentolate, cyclohexylidene, benzylidene-, p-methoxy - benzilidene-or o,p-dimethoxybenzaldehyde, acyclic acetals, such as tetrahydropyranyl (Tgp), methoxymethyl (MOM), methoxyethoxymethyl (MEM), benzoyloxymethyl (BPO) or methylthiomethyl (MTM). A particularly preferred protecting group of hydroxyl group is benzyl, acetyl, tert.-butyl or TBS.

The process of liberation of the compounds of formula 1 of their derivatives containing functional group, for one or another used protective groups known from the literature (e.g., T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Chemistry, 2nd edition, Wiley, new York 1991 or P. J. Kocienski, Protecting Groups, 1st edition, published by Georg Thieme Verlag, Stuttgart-new York, 1994). You can use essentially known, here sublattice is using TFU in dichloromethane or 3-5 N. HCl in dioxane at 15-30C, and Fmoc-group - using 5-50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30C. The Aloka-group can be split in mild conditions with a catalyst of a noble metal in chloroform at 20-30C. The preferred catalyst is tetrakis(triphenylphosphine)palladium(0).

The initial compounds of the formulas II to V, usually known. Even if they are new, they can get well-known on the merits of the methods.

The compounds of formula II, for example, receive in the presence of a base, connecting the corresponding 2-aminosidine heterocycle, where Q1, Q2, Q3or Q4take the values specified in paragraph 1 of the claims, with the corresponding esters of n-bromocarbons acid (Br-(CH2]n-COOSG1where SG1as described above, represents a protective group of hydroxyl group) with subsequent removal of the protective group under standard conditions.

The compounds of formula IV receive under standard conditions, combining (similar peptide bond) compounds of the formula II with a derivative of glycine H2N-CH2-COOSG2where SG2as described above, represents a protective group of hydroxyl group.

Souzalite reaction of the corresponding aldehyde R3-CHO with malonic acid and ammonium acetate in an appropriate solvent (particularly preferred alcohols, such as ethanol) get-amino acid of formula V, where R6denotes N. After the etherification of this free acid of the formula V under standard conditions, obtain the compounds of formula V, where R6denotes a or -(CH2)mAr.

To obtain the compounds of formula III-protected acid function of the amino acids of formula V (protection is carried out either using an appropriate protective group, or by R6representing A, -(CH2)m-OH, -(CH2)m-O-C(O)Oh or -(CH2)m-Ah) is combined with a derivative of glycine SG3-NH-CH2-COOH. Deputy SG3derived glycine SG3NH-CH2-COOH as described above, represents a protective group of amino group, which is then otscheplaut. Conventional methods of peptide synthesis are described, e.g., in Houben-Weyl, 1.c. volume 15/II, 1974, page 1-806.

The compounds of formula I can be obtained by subjecting the compound of formula II by reaction with a compound of formula III with subsequent removal of the protective group and the translation of the radical R6denoting A, -(CH2)m-OH, -(CH2)m-O-the I, the compound of formula IV in a reaction with a compound of formula V, followed by removal of protective groups, or transfer radical R6denoting A, -(CH2)m-OH, -(CH2)m-O-C(O)A or -(CH2)m-Ah, the radical R6=N.

In a preferred embodiment, the reaction of the joining is carried out in the presence of dehydrating means, e.g., carbodiimide, such as dicyclohexylcarbodiimide (DCC), hydrochloride N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide (HEAD) or diisopropylcarbodiimide (DICK), then, e.g., anhydride papapostolou acid (EUR. Angew. Chem. 1980, 92, 129), diphenylphosphinite or 2-ethoxy-N-etoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, e.g., in halogenosilanes hydrocarbon, such as dichloromethane, simple ether, such as tetrahydrofuran or dioxane, amide, such as DMF or dimethylacetamide, a nitrile such as acetonitrile, dimethylsulfoxide, or in the presence of these solvents at temperatures in the range of approximately-10-40C, preferably 0-30°C., depending on conditions, the reaction time can vary from several minutes to several days.

Highly desirable was the addition of the reagent attaching TBTU (tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethylurea) or hexafluorophosphate O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethylurea, the settlement of the Yeni, and, in addition, is not observed the formation of cytotoxic products.

Instead of the compounds of the formula II and/or IV can also be used derivatives of compounds of formula II and/or IV, preferably a pre-activated carboxylic acid or carboxylic acid halide, a symmetrical or mixed anhydride or activated ester. Such radicals to activate the carboxy group in the course of a typical acylation reactions described in the literature (e.g., in such standard works as Houben-Weyl, Methods der organischen Chemie, published by Georg-Thieme-Verlag, Stuttgart). With this purpose, activated esters formed in situ,e.g. by adding HoBT (1-hydroxybenzotriazole) or N-hydroxysuccinimide.

The reaction generally takes place in an inert solvent by using a carboxylic acid halide in the presence of an acid acceptor, preferably an organic base such as triethylamine, dimethylaniline, pyridine or quinoline.

Also, it may be appropriate to add the hydroxide, carbonate or bicarbonate of alkali or alkaline earth metal or any other salt of a weak acid of the alkali or alkaline earth metal, p is but to translate into the corresponding acid additive salt, for example, by reaction of equivalent amounts of base and acid in an inert solvent, such as ethanol, followed by evaporation. Acceptable for this reaction are, in particular, acids forming physiologically acceptable salt. So, can be used inorganic acids, e.g., sulfuric acid, sulfurous acid, detinova acid, nitric acid, halogenation acid, such as hydrochloric acid or Hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, e.g., formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, cekanova acid, hexadecanol acid, stearic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, sonic the carboxylic acid, p-toluensulfonate, glycolic acid, albanova acid,chlorprothixene acid, aspartic acid, glutamic acid, Proline, Glyoxylic acid, palmitic acid, parachlorophenylalanine acid, cyclohexanecarbonyl acid, glucose-1-phosphate, naphthalenamine and dissolvability or louisanna acid. Salts with physiologically unacceptable acids, e.g., the picrate can be used for isolating and/or purifying compounds of formula I.

On the other hand, using bases (e.g., hydroxide or sodium carbonate or potassium), the compounds of formula I can be converted to the corresponding metal salts, in particular, any alkali or alkaline earth metal, or into the corresponding ammonium salt.

The object of the present invention are also the compounds of formula I on p. 1 of the claims and their physiologically acceptable salt or solvate as the effective ingredients of the medication.

Further, the object of the present invention are compounds of formula I on p. 1 of the claims and their physiologically acceptable salt or solvate as inhibitors of integrins.

The object of the present invention are also sediment to eliminate diseases.

Further, an object of the present invention is the use of combinations of selectively acting inhibitors of integrins, which are selected from the group selectively acting inhibitors of integrin v3, combined with selectively acting inhibitors of integrin v6, selectively acting inhibitors of integrin v5 in combination with selectively acting inhibitors of integrin v6 or selectively active inhibitors of integrin v3, combined with selectively acting inhibitors of integrin v5 and those of integrin v6, in the manufacture of medicines for astronomicalevidence processes associated with the action of integrins v3 and/or v5 and v6.

The object of the present invention is the use of combinations of selectively acting inhibitors of integrins, which are selected from the group selectively acting inhibitors of integrin v3, combined with selectively acting inhibitors of integrin v6, selectively acting inhibitors of integrin v5 in combination with selectively acting inhibitors of integrin v6 or those of integrin v3 in combination with selectively acting inhibitors of integrin v5 and those of integrin v6, in the manufacture of medicines DL and receptor integrin v5 blocked angiogenesis is deeply rooted in the tumor blood vessels and, on the other hand, the inhibition of integrin receptor v6 suspended tumor development.

The object of this invention is the use of combinations of selectively acting inhibitors of integrin v3 and/or any of integrins v5 and v6 in the manufacture of drugs to eliminate diseases associated with cancer, such as metastatic solid tumors, angiofibromas, retrolental fibroplasia, hemangioma or gemangiosarkoma sarcoma.

Listed below are some of the compounds of formula I, which, in particular, selectively acting inhibitors of receptor integrins v3 and v6:

a) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-chloro-3-nitrophenyl)propionic acid;

b) triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid;

C) triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid;

d) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-trifloromethyl)propionic acid, or

e) triptorelin 3-(biphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanoate, in particular, selectively acting inhibitors of receptor integrins v5 and v6:

a) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-trifloromethyl)propionic acid, or

b) triptorelin 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid.

Listed below are some of the compounds of formula I, which, in particular, selectively acting inhibitors of receptor integrins v3, v5 and v6:

a) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-methyl-3-nitrophenyl)propionic acid;

b) triptorelin 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid;

C) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-trifloromethyl)propionic acid;

d) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(3-trifloromethyl)propionic acid, or

d) of the hydrochloride of 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid.

Most suitable for use in the manufacture of drugs for the por is particularly for treatment of cancer, as described above, are inhibitors of integrins:

a) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-chloro-3-nitrophenyl)propionic acid;

b) triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid;

C) triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid;

d) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-trifloromethyl)propionic acid;

e) triptorelin 3-(biphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

(e) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-trifloromethyl)propionic acid;

g) triptorelin 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid;

C) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-

methyl-3-nitrophenyl)propionic acid;

and) triptorelin 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propio">

trifloromethyl)propionic acid;

l) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(3-

trifloromethyl)propionic acid, or

m) of the hydrochloride of 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid.

Further, an object of the present invention is the use of selectively acting inhibitors of integrins, which are selected from the group including:

a) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-chloro-3-nitrophenyl)propionic acid;

b) triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid;

C) triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid;

d) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-trifloromethyl)propionic acid;

e) triptorelin 3-(biphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

(e) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-triftormetilfosfinov]acetylamino}propionic acid;

C) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-

methyl-3-nitrophenyl)propionic acid;

and) triptorelin 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid;

K) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-

trifloromethyl)propionic acid;

l) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(3-

trifloromethyl)propionic acid, or

m) of the hydrochloride of 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

in the manufacture of medicaments for treating pathological processes associated with the action of integrins v3 and/or v5 and v6.

The object of this invention is the use of selectively acting inhibitors of integrins, which are selected from the group including:

a) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-chloro-3-nitrophenyl)propionic acid;

b) triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid;

d) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-trifloromethyl)propionic acid;

e) triptorelin 3-(biphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

(e) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-trifloromethyl)propionic acid;

g) triptorelin 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid;

C) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-

methyl-3-nitrophenyl)propionic acid;

and) triptorelin 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid;

K) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-

trifloromethyl)propionic acid;

l) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(3-

trifloromethyl)propionic acid, or

m) of the hydrochloride of 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

in the manufacture of drugs for the existence of the ora v5 integrin blocked angiogenesis is deeply rooted in the tumor blood vessels and, on the other hand, the inhibition of integrin receptor v6 suspended tumor development.

The object of this invention is the use of selectively acting inhibitors of integrin v3 and/or selectively active inhibitors of integrins v5 and v6, which are selected from the group including:

a) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-chloro-3-nitrophenyl)propionic acid;

b) triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid;

C) triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid;

d) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-trifloromethyl)propionic acid;

e) triptorelin 3-(biphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

(e) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-trifloromethyl)propionic acid;

g) triptorelin 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid;

and) triptorelin 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid;

K) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-

trifloromethyl)propionic acid;

l) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(3-

trifloromethyl)propionic acid, or

m) of the hydrochloride of 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

in the manufacture of drugs to eliminate diseases associated with cancer, such as metastatic solid tumors, angiofibromas, retrolental fibroplasia, hemangioma or gemangiosarkoma sarcoma.

Most suitable for use in the manufacture of drugs for treatment of cancer, in which, on the one hand, through inhibition of receptor integrin v3 is blocked angiogenesis ingrown vauhall blood vessels and, on the other hand, the inhibition of integrin receptor v6 suspended the development of tumors are derived-alanine:

a) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(42 ylamino)pentanediamine]acetylamino}propionic acid;

C) triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid;

d) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-trifloromethyl)propionic acid, or

e) triptorelin 3-(biphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid.

Most suitable for use in the manufacture of drugs for treatment of cancer, in which, on the one hand, through inhibition of integrin receptor v5 blocked angiogenesis is deeply rooted in the tumor blood vessels and, on the other hand, the inhibition of integrin receptor v6 suspended the development of tumors are derived-alanine:

a) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-trifloromethyl)propionic acid, or

b) triptorelin 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid.

Most suitable for use in the manufacture of drugs for treatment of cancer, in which, on the one hand, through inhibition of receptor integrins v3 and v5 is blocked anggana v6 suspended tumor development, are derivative-alanine:

a) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-methyl-3-nitrophenyl)propionic acid;

b) triptorelin 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid;

C) triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-trifloromethyl)propionic acid;

d) triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(3-trifloromethyl)propionic acid, or

d) of the hydrochloride of 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid.

In addition to the application in the present invention selectively acting inhibitors of receptor integrins as an internal combination therapy using at least two inhibitors of integrins is also possible further combination with conventional therapies, such as radiation therapy, tumor vaccination, immunotherapy or chemotherapy. Such combined therapy (covering two approach - internal and external) should further improve the effectiveness of the treatment, Praz, reduce dose-related side effects.

Further, an object of the present invention are pharmaceutical preparations containing at least one compound of the formula I and/or one (one) of its physiologically acceptable salt or solvate, which receive, in particular, non-chemical way. In this regard, the compounds of formula I can accordingly be dosed in combination with at least one solid, liquid and/or semi-liquid carrier or auxiliary substance and, if appropriate, with one or more other active ingredients.

These drugs can be used as medicaments in human medicine and veterinary medicine. Acceptable carriers are organic or inorganic substances that can be used enterline (e.g., orally), parenterally or topically and do not react with the new compounds, for example water, vegetable oils,benzyl alcohols, alkalophile, glycols, createtemporary, gelatin, carbohydrates, such as lactose or starch, magnesium stearate, talc, vaseline. Pills, pills, pills, capsules, powders, granules, syrups, liquids or drops are used, in particular, oral, suppositories are for Ntati applied parenterally, and ointments, creams or powders are used for topical application. The new compounds can also be liofilizirovanny and received lyophilizate to use, e.g., in the manufacture of drugs for injection. The above-mentioned preparations can be sterilized and/or may include auxiliary agents such as lubricants, antioxidants, stabilizers and/or surfactants, emulsifiers, salts, with which you can change the osmotic pressure, buffer substances, colorants, flavorings and/or one or more additional active substances, e.g., one or more vitamins.

When using aerosols for inhalation, they should contain the active ingredient either dissolved or suspended in the propellant or mixture of propellants (e.g., CO2or polymorphonucleocytes). The active ingredient in this case is used in powdered form, and can be one or more additional physiologically tolerated solvents, e.g. the ethanol. Solutions for inhalation can be applied using conventional inhalers.

The compounds of formula I and their physiologically acceptable salt or solvate can be used in the s diseases, arteriosclerosis, tumours, osteoporosis, inflammations or infections.

The compounds of formula I on p. 1 of the claims and/or their physiologically acceptable salts are also used primatologica processes and developing as a result of angiogenesis, in particular, tumors or rheumatoid arthritis.

Some compounds of formula I and/or their solvate, as mentioned above, can be applied for treating pathological processes associated with the action of integrins v3 and/or v5 and v6, in particular for therapy of cancer, in which, on the one hand, through inhibition of receptor integrin v3 and/or receptor integrin v5 blocked angiogenesis is deeply rooted in the tumor blood vessels and, on the other hand, the inhibition of integrin receptor v6 suspended tumor development.

When this matter of the present invention, normally administered analogously to the compounds described in the application WO 97/26250 or WO 97/24124, preferably in amounts of about 0.05-500 mg, in particular 0.5 to 100 mg per dose. Daily dose is preferably about 0.01 to 2 mg/kg of body weight. However, the dose for each patient depends on a number of Fannie health, sex, diet, time and route of administration, rate of excretion, combination of drugs and the severity of the disease. The preferred parenteral use.

In addition, the compounds of formula I can be used as ligands of integrins in the manufacture of columns for affinity chromatography to obtain pure integrins.

When this ligand, i.e., the compound of formula I, through a linking group, e.g., carboxyl group, covalently bound to a polymeric carrier.

Acceptable polymeric substrates are essentially known in the chemistry of peptides polymer solid phase, in a preferred embodiment, possessing hydrophilic properties, for example, cross-linked polysaccharides, such as cellulose, sepharose or Sephadex®"acrylamide, polymers based on polyethylene glycol or polymers "Tentakelpolymere®".

Materials for affinity chromatography carried out in order to clear the integrins are known for being the conditions typical condensation of amino acids.

The compounds of formula I contain one or more chiral centers and therefore may exist in racemic or optically active form. Present doctitle version of the racemic mixture, which enter into reaction with optically active separating agent, formed diastereomers. As release agents are suitable, e.g., optically active acid, such as D - and L-forms of tartaric acid, diatsetilvinny acid, dibenzoyltartaric acid, almond acid, malic acid, lactic acid or the various optically active camphorsulfonic acid, such as camphorsulfonic acid. It is also advisable separation of enantiomers filled optically active separating agent (e.g., dinitrobenzonitrile) column; as a suitable eluent, e.g., hexane/isopropanol/acetonitrile, e.g. in the volume ratio 82:15:3.

Naturally, it is also possible to obtain optically active compounds of formula I by the methods described above using optically active starting materials.

All of the above and the following temperatures are in C. In the following examples, the expression "treatment as usual" means: if necessary, water is added; if necessary, the pH value of the mixture is stabilized in the range of from 2 to 10, depending on the composition of the final product; the mixture is extracted utilize purify by chromatography on silica gel, preparative GHWR and/or crystallization. Purified compounds, if necessary, is dried by freezing.

WU = retention time (in minutes) during GHUR in the following systems:

Column: Lichrosorb RP-18 (5 μm) 250 4 mm;

Lichrosorb RP-18 (15 μm) 250 50 mm.

As eluents used gradients of acetonitrile (B) with 0.1% TFU (triperoxonane acid) and water (A) from 0.1% TFU. The gradient is expressed in volume percent acetonitrile.

The preferred gradient: 5 min at 20% and 55 min 90% Century.

Detection at 225 nm.

The specified retention time was obtained from measurements using a gradient 5 min at 5% and 40 min to 80% Century.

Compounds purified by preparative method GHUR, was isolated in the form of triptoreline.

Mass spectrometry (MS) via BOIS (bombardment of accelerated atoms): MS-BOIS (M+N)+.

Example 1:

(1) and 10.5 g of 4-(triptoreline)benzaldehyde, 5,72 g of malonic acid, 8.5 g of ammonium acetate and 40 ml of ethanol for 8 h refluxed and stirred over night at room temperature. Then the cooled reaction mixture is sucked off, washed with ethanol and simple ether and dried niformation)propionic acid activated with thionyl chloride (1.2 equivalent) and at the boiling point under standard conditions atrificial methanol. As a result of processing conventional method receive methyl ester 3-amino-3-(4-trifloromethyl)propionic acid, MS-BOIS (M+N)+263.

(2) 0,364 g of [4-(pyridine-2-ylamino)bucillamine]acetic acid [obtained as a result of peptide bond 4-(pyridine-2-ylamino)butyric acid complex methyl ether aminouksusnoy acid in the presence of HOBT/TBTU and subsequent saponification difficult methyl ether, in each case, under standard conditions] are dissolved in 30 ml of DMF, and then added 0.3 g of complex methyl ester 3-amino-3-(4-trifloromethyl)propionic acid and cooled to 30C. Adding 0,321 g TBTU and 0,045 g HOBT, the mixture is neutralized to 0.22 ml of N-methylmorpholine (NMM). The reaction mixture is stirred for 2 days at room temperature. After removal of the solvent injected acetate, which absorbs the residue, after which the latter is washed with NaHCO3and saturated NaCl solution and spend processing a conventional method. Get methyl ester 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-trifloromethyl)propionic acid, MS-BOIS (M+H)+497.

(3) 280 mg complex methyl ester 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-tryptamine over night at room temperaturethe solvent and spend processing a conventional method. Get 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-trifloromethyl)propionic acid.

If you work with an excess of NaOH, get sodium salt 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-trifloromethyl)propionic acid.

Using preparative GHUR get triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-trifloromethyl)propionic acid, WU 24,93 min, MS-BOIS (M+N)+483.

Example 2:

(1) to 0.06 mole of 2-nitrobenzaldehyde, 5,72 g of malonic acid, 8.5 g of ammonium acetate and 40 ml of ethanol for 8 h refluxed and stirred over night at room temperature. Then the cooled reaction mixture is sucked off, washed with ethanol and simple ether and dried in air. Get 3-amino-3-(2-nitrophenyl)propionic acid, so pl. S.

In the subsequent esterification by activation with thionyl chloride and enter into reaction with methanol under standard conditions obtain methyl ester 3-amino-3-(2-nitrophenyl)propionic acid.

(2) methyl ester 3-amino-3-(2-nitrophenyl)propionic acid, analogously to Example 1 (2), enter into reaction with ucaut hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(2-nitrophenyl)propionic acid, MS-BOIS (M+N)+317.

(3) 360 mg of the hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(2-nitrophenyl)propionic acid are dissolved in 35 ml of DMF and added 190 mg of 4-(4-methylpyridin-2-ylamino)butyric acid. After cooling to 0C to the reaction mixture are added 450 mg TBTU and 63 mgget. This is followed by neutralization of 0.15 ml of N-methylmorpholine and stirring over night at room temperature. The solvent is distilled off, to the precipitate stirred into 30 ml of ethyl acetate, washed with 50% solution of bicarbonate and saturated sodium chloride solution and spend processing a conventional method. Get methyl ester 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(2-nitrophenyl)propionic acid.

(4) 280 mg complex methyl ester 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(2-nitrophenyl)propionic acid (raw material) is dissolved in 30 ml of dioxane and added to 0.61 ml of NaOH (2 mol/l).

After stirring over night at room temperature the solvent is distilled off and spend processing a conventional method. Get 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(2-nitrophenyl)propionic acid.

If you work with an excess of NaOH, get sodium somewho preparative GHUR get triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(2-nitrophenyl)propionic acid, WU 16,14 min, MS-BOIS (M+N)+444.

Example 3:

Analogously to Example 2 from 4-(4-methylpyridin-2-ylamino)butyric acid "AB" get

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(3-trifloromethyl)propionic acid

methyl ester 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-trifloromethyl)propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-methyl-3-nitrophenyl)propionic acid

methyl ester of 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(3-nitrophenyl)propionic acid

methyl ester 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid, using preparative GHUR get triptorelin difficult methyl ester 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid, WU KZT 19.09, MS-BOIS (M+N)+458 or

in the reaction with hydrochloride embedded ether 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-biphenylyl)propionic acid.

Example 4:

After saponification of methyl esters of compounds of Example 3 as in Example 2 (4) receive

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-

trifloromethyl)propionic acid;

sodium salt 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-trifloromethyl)propionic acid;

triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-

trifloromethyl)propionic acid; WU 24,40 min, MS-BOIS (M+H)+483;

3-(4-methyl-3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid;

triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid, WU MT 19: 18 min, MS-BOIS (M+H)+458;

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionic acid;

sodium salt 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionic acid;

triptorelin 3-{2-[4-(4-methylpyridin-2 and is 2">

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-

biphenylyl)propionic acid,

sodium salt 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-biphenylyl)propionic acid,

triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-

biphenylyl)propionic acid, WU 25,65 min, MS-BOIS (M+N)+475.

Example 5:

Analogously to Example 2 from 5-(4-methylpyridin-2-ylamino)pentanol acid "SU" get

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-trifloromethyl)propionic acid

methyl ester 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-trifloromethyl)propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(3-trifloromethyl)propionic acid

methyl ester 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(3-trifloromethyl)propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-methyl-3-nitrophenyl)propionic acid

ylamino)pentanediamine]acetylamino}propionic acid, WU 23,81 min, MS-BOIS (M+H)+486;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(2-nitrophenyl)propionic acid

methyl ester 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(2-nitrophenyl)propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(3-nitrophenyl)propionic acid

methyl ester 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-methyl-3-nitrophenyl)propionic acid

methyl ester of 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-naphthalene-2-ylphenyl)propionic acid

methyl ester of 3-(4-naphthalene-2-ylphenyl)-3-{2-[5-(4-methylpyridin-2-elogo methyl ester 3-(2-aminoethylamino)-3-(4-chloro-3-nitrophenyl)propionic acid

methyl ester of 3-(4-chloro-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid, or

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-biphenylyl)propionic acid

methyl ester 3-biphenyl-4-yl-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid; using preparative GHUR get triptorelin difficult methyl ester 3-biphenyl-4-yl-3-{2-[5-(4-methylpyridin-2-

ylamino)pentanediamine]acetylamino}propionic acid, WU 30,13 min, MS-BOIS (M+H)+503.

Example 6:

After saponification of methyl esters of the compounds of Example 5 analogously to Example 2 (4), get

3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-trifloromethyl)propionic acid,

sodium salt 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-trifloromethyl)propionic acid,

triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-trifloromethyl)propionic acid, WU are 24.88 min, MS-BOIS (M+H)+497;

3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino is olamine]acetylamino}-3-(3-trifloromethyl)propionic acid,

triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(3-trifloromethyl)propionic acid, WU 24,61 min, MS-BOIS (M+N)+497;

3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid, WU 22,13 min, MS-BOIS (M+H)+472;

3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(2-nitrophenyl)propionic acid,

sodium salt 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(2-nitrophenyl)propionic acid,

triptorelin 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(2-nitrophenyl)propionic acid, WU 16,98 min, MS-BOIS (M+H)+458;

3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(3-nitrophenyl)-3-{2-[5-(4-Mei the 3-(4-naphthalene-2-ylphenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(4-naphthalene-2-ylphenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(4-naphthalene-2-ylphenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid;

3-(4-chloro-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(4-chloro-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(4-chloro-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid, WU 22,34 min, MS-BOIS (M+H)+492 or

3-biphenyl-4-yl-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-biphenyl-4-yl-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-biphenyl-4-yl-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid, WU 27,09 min, MS-BOIS (M+N)+489.

Example 7:

Analogously to Example 2 from 4-(pyridine-2-ylamino)butyric acid "CD" get

in the reaction with hydrochloride difficult methyl ester 3-(2-amino is l)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(2-nitrophenyl)propionic acid

methyl ester 3-(2-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid, or

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-biphenylyl)propionic acid

methyl ester 3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}-3-(4-biphenylyl)propionic acid.

Example 8:

After saponification of methyl esters from Example 7, as in Example 2 (4), get

3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid, WU 19,12 min, MS-BOIS (M+H)+444;

3-(2-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(2-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

MS-BOIS (M+H)+430 or

3-biphenyl-4-yl-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-biphenyl-4-yl-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-biphenyl-4-yl-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid, WU 25,20 min, MS-BOIS (M+N)+461.

Example 9:

Analogously to Example 2 from 5-(pyridine-2-ylamino)pentanol acid "DE" get

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-methyl-3-nitrophenyl)propionic acid

methyl ester of 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(2-nitrophenyl)propionic acid

methyl ester 3-(2-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid, or

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-biphenylyl)propionic acid

methyl ester 3-biphenyl-4-yl-3-{2-[5-(pyridine-2-ylamino)pentanediamine the Fira

3-biphenyl-4-yl-3-{2-[5-(pyridine-2-

ylamino)pentanediamine]acetylamino}propionic acid, WU 28,88 min, MS-BOIS (M+H)+489.

Example 10:

After saponification of methyl esters of the compounds of Example 9, analogously to Example 2 (4), get

3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid, WU 19,78 min, MS-BOIS (M+N)+458;

3-(2-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(2-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(2-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid, WU 12,80 min, MS-BOIS (M+N)+444 or

3-biphenyl-4-yl-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-biphenyl-4-yl-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic kiislamu, WU 25,84 min, MS-BOIS (M+H)+475.

Example 11:

Analogously to Example 2 from 4-(6-methylpyridin-2-ylamino)butyric acid "EF" get

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-methyl-3-nitrophenyl)propionic acid

methyl ester of 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(6-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid.

Analogously to Example 2 from 5-(6-methylpyridin-2-ylamino)pentanol acid "FG" get

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-methyl-3-nitrophenyl)propionic acid

methyl ester of 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(6-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid.

Example 12:

After saponification of methyl esters of the compounds of Example 11, analogously to Example 2 (4), get

3-(4-methyl-3-nitrophenyl)-3-{2-[4-(6-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(6-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(6-m is-(6-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(6-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(6-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid.

Example 13:

Analogously to Example 2 from 4-(pyrimidine-2-ylamino)butyric acid "GH" get

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-methyl-3-nitrophenyl)propionic acid

methyl ester of 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyrimidine-2-ylamino)bucillamine]acetylamino}propionic acid, or

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-biphenylyl)propionic acid

methyl ester 3-{2-[4-(pyrimidine-2-ylamino)bucillamine]acetylamino}-3-(4-biphenylyl)propionic acid.

Analogously to Example 2 from 5-(pyrimidine-2-ylamino)pentanol acid "NC" get

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-methyl-3-nitrophenyl)propionic acid

methyl ester of 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyrimidine-2-ylamino)pentanediamine]ACE-(2-aminoethylamino)-3-(4-biphenylyl)propionic acid

methyl ester 3-{2-[5-(pyrimidine-2-ylamino)pentanediamine]acetylamino}-3-(4-biphenylyl)propionic acid.

Example 14:

After saponification of methyl esters of the compounds of Example 13, analogously to Example 2 (4), get

3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyrimidine-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyrimidine-2-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyrimidine-2-ylamino)bucillamine]acetylamino}propionic acid, WU 16,33 min, MS-BOIS (M+H)+445;

3-biphenyl-4-yl-3-{2-[4-(pyrimidine-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-biphenyl-4-yl-3-{2-[4-(pyrimidine-2-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-biphenyl-4-yl-3-{2-[4-(pyrimidine-2-ylamino)bucillamine]acetylamino}propionic acid, WU 24,45 min, MS-BOIS (M+H)+462;

3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyrimidine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyrimidine-2-ylamino)pentanediamine]acetylamino}propionic acid is a new acid, or

3-biphenyl-4-yl-3-{2-[5-(pyrimidine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-biphenyl-4-yl-3-{2-[5-(pyrimidine-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-biphenyl-4-yl-3-{2-[5-(pyrimidine-2-ylamino)pentanediamine]acetylamino}propionic acid.

Example 15:

Analogously to Example 2 from 4-(6-methylpyridin-2-ylamino)butyric acid "EF" get

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-methyl-3-nitrophenyl)propionic acid

methyl ester of 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(6-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid.

After saponification difficult methyl ester analogously to Example 2 (4) receive

3-(4-methyl-3-nitrophenyl)-3-{2-[4-(6-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(6-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid;

triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(6-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid, WU 20,10 min, MS-BOIS (M+H)+458.

Example 16:

methyl ester of 3-(4-methyl-3-nitrophenyl)-3-{2-[6-(4-methylpyridin-2-ylamino)hexanamide]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(3-nitrophenyl)propionic acid

methyl ester 3-{2-[6-(4-methylpyridin-2-ylamino)hexanamide]acetylamino}-3-(3-nitrophenyl)propionic acid, or

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-chloro-3-nitrophenyl)propionic acid

methyl ester of 3-(4-chloro-3-nitrophenyl)-3-{2-[6-(4-methylpyridin-2-ylamino)hexanamide]acetylamino}propionic acid.

After saponification of the above methyl esters as in Example 2 (4) receive

3-(4-methyl-3-nitrophenyl)-3-{2-[6-(4-methylpyridin-2-ylamino)hexanamide]acetylamino}propionic acid,

sodium salt of 3-(4-methyl-3-nitrophenyl)-3-{2-[6-(4-methylpyridin-2-ylamino)hexanamide]acetylamino}propionic acid;

triptorelin 3-(4-methyl-3-nitrophenyl)-3-{2-[6-(4-methylpyridin-2-ylamino)hexanamide]acetylamino}propionic acid, WU 22,10 min, MC-BOIS (M+H)+468;

3-{2-[6-(4-methylpyridin-2-ylamino)hexane is Ino)hexanamine]acetylamino}-3-(3-nitrophenyl)propionic acid,

triptorelin 3-{2-[6-(4-methylpyridin-2-ylamino)hexanamide]acetylamino}-3-(3-nitrophenyl)propionic acid, WU 18,27 min, MS-BOIS (M+N)+472 or

3-(4-chloro-3-nitrophenyl)-3-{2-[6-(4-methylpyridin-2-ylamino)hexanamide]acetylamino}propionic acid,

sodium salt of 3-(4-chloro-3-nitrophenyl)-3-{2-[6-(4-methylpyridin-2-ylamino)hexanamide]acetylamino}propionic acid,

triptorelin 3-(4-chloro-3-nitrophenyl)-3-{2-[6-(4-methylpyridin-2-ylamino)hexanamide]acetylamino}propionic acid, WU 23,33 min, MS-BOIS (M+H)+506.

Example 17:

Analogously to Example 2, from 7-(4-methylpyridin-2-ylamino)hexanoic acid "LM" get

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(3-nitrophenyl)propionic acid

methyl ester 3-{2-[7-(4-methylpyridin-2-ylamino)heptanoate]acetylamino}-3-(3-nitrophenyl)propionic acid.

After saponification difficult methyl ester analogously to Example 2 (4) receive

3-{2-[7-(4-methylpyridin-2-ylamino)heptanoate]acetylamino}-3-(3-nitrophenyl)propionic acid,

sodium salt 3-{2-[7-(4-methylpyridin-2-ylamino)heptanoate]acetylamino}-3-(3-nitrophenyl)trienyl)propionic acid, WU 20,98 min, MS-BOIS (M+H)+486.

Example 18:

Analogously to Example 2 from 5-(pyridine-2-ylamino)pentanol acid "DE" get

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(3-nitrophenyl)propionic acid

methyl ester 3-(3-nitro-phenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-chloro-3-nitrophenyl)propionic acid

methyl ester of 3-(4-chloro-3-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4’-forbiden-4-yl)propionic acid

methyl ester of 3-(4’-forbiden-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4’-forbiden-3-yl)propionic acid

methyl ester of 3-(4’-forbiden-3-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

in Navoi acid

methyl ester 3-(3’-forbiden-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(2’-forbiden-4-yl)propionic acid

methyl ester 3-(2’-forbiden-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4’-chlorobiphenyl-4-yl)propionic acid

methyl ester of 3-(4’-chlorobiphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(3’-chlorobiphenyl-4-yl)propionic acid

methyl ester 3-(3’-chlorobiphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4’-methylbiphenyl-4-yl)propionic acid

methyl ester of 3-(4’-methylbiphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

in re the l]propionic acid

methyl ester 3-[4’-(trifluoromethyl)biphenyl-4-yl]-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(3'-chloro-4'-forbiden-4-yl)propionic acid

methyl ester 3-(3'-chloro-4'-forbiden-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-naphthalene-1-ylphenyl)propionic acid

methyl ester of 3-(4-naphthalene-1-ylphenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-naphthalene-2-ylphenyl)propionic acid

methyl ester of 3-(4-naphthalene-2-ylphenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid, or

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4'-fluoro-2-hydroxybiphenyl-4-yl)propionic acid

methyl ester of 3-(4'-fluoro-2-hydroxybiphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acutely from Example 18, analogously to Example 2 (4), get

3-(3-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(3-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(3-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid, WU* 16,07 min, MC-BOIS (M+H)+444;

3-(4-chloro-3-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(4-chloro-3-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(4-chloro-3-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid, WU 18,67 min, MC-BOIS (M+H)+478;

3-(4'-forbiden-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(4'-forbiden-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(4'-forbiden-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid, to 24.66 WU min, MS-BOIS (M+H)+493;

3-(4'-forbiden-3-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]and is ylamino]acetylamino}propionic acid,

triptorelin 3-(4'-forbiden-3-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid, WU 25,36 min, MS-BOIS (M+N)+493;

3-(3'-forbiden-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(3'-forbiden-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(3'-forbiden-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid, MS-BOIS (M+H)+493;

3-(2'-forbiden-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(2'-forbiden-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(2'-forbiden-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid, MS-BOIS (M+H)+493;

3-(4'-chlorobiphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(4'-chlorobiphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(4'-chlorobiphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid the peony acid

sodium salt of 3-(3'-chlorobiphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(3'-chlorobiphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid, MS-BOIS (M+H)+510;

3-(4'-methylbiphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(4'-methylbiphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(4'-methylbiphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid, MS-BOIS (M+H)+489;

3-[4'-(trifluoromethyl)biphenyl-4-yl]-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-[4'-(trifluoromethyl)biphenyl-4-yl]-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-[4'-(trifluoromethyl)biphenyl-4-yl]-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid, MS-BOIS (M+H)+543;

3-(3'-chloro-4'-forbiden-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(3'-chloro-4'-forbiden-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine)pentanediamine]acetylamino}propionic acid, MS-BOIS (M+H)+527;

3-(4-naphthalene-1-ylphenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(4-naphthalene-1-ylphenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(4-naphthalene-1-ylphenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid, WU 24,91 min, MS-BOIS (M+H)+525;

3-(4-naphthalene-2-ylphenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(4-naphthalene-2-ylphenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(4-naphthalene-2-ylphenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid, or

3-(4'-fluoro-2-hydroxybiphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

sodium salt of 3-(4'-fluoro-2-hydroxybiphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

triptorelin 3-(4'-fluoro-2-hydroxybiphenyl-4-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid.

Example 20:

Analogously to Example 2 from 4-(pyridine-2-ylamino)massimilano)-3-(3-nitrophenyl)propionic acid

methyl ester 3-(3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-chloro-3-nitrophenyl)propionic acid

methyl ester of 3-(4-chloro-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4'-forbiden-4-yl)propionic acid

methyl ester of 3-(4'-forbiden-4-yl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4'-forbiden-3-yl)propionic acid

methyl ester of 3-(4'-forbiden-3-yl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-naphthalene-1-ylphenyl)propionic acid

methyl ester of 3-(4-naphthalene-1-ylphenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid;

in the reaction with chlorine is P CLASS="ptx2">

methyl ester of 3-(4-naphthalene-1-yl-2-hydroxyphenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid, or

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(2-hydroxybiphenyl-4-yl)propionic acid

methyl ester 3-(2-hydroxybiphenyl-4-yl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid.

Example 21:

After saponification of methyl esters of the compounds of Example 20, analogously to Example 2 (4), get

3-(3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-(3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid, WU* 15,50 min, MC-BOIS (M+H)+430;

3-(4-chloro-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(4-chloro-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-(4-chloro-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propion is ethylamino}propionic acid,

sodium salt of 3-(4'-forbiden-4-yl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-(4'-forbiden-4-yl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid, WU 24,53, MS-BOIS (M+N)+479;

3-(4'-forbiden-3-yl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(4'-forbiden-3-yl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-(4'-forbiden-3-yl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid, WU 25,06, MS-BOIS (M+H)+479;

3-(4-naphthalene-1-ylphenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(4-naphthalene-1-ylphenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-(4-naphthalene-1-ylphenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid, WU* 24,80, MS-BOIS (M+H)+511;

3-(4-naphthalene-1-yl-2-hydroxyphenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(4-naphthalene-1-yl-2-hydroxyphenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino} the amino]acetylamino}propionic acid, or

3-(2-hydroxybiphenyl-4-yl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(2-hydroxybiphenyl-4-yl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-(2-hydroxybiphenyl-4-yl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid.

Example 22:

Analogously to Example 2 from 4-(4-methylpyridin-2-ylamino)butyric acid "AB" get

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-nitrophenyl)propionic acid

methyl ester 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-nitrophenyl)propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(3-nitro-2-hydroxyphenyl)propionic acid

methyl ester 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitro-2-hydroxyphenyl)propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-chloro-3-nitrophenyl)propionic acid

methyl ester 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]a methyl ester 3-(2-aminoethylamino)-3-(4'-forbiden-3-yl)propionic acid

methyl ester of 3-(4'-forbiden-3-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4'-forbiden-4-yl)propionic acid

methyl ester of 3-(4'-forbiden-4-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-naphthalene-1-ylphenyl)propionic acid

methyl ester 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-naphthalene-1-ylphenyl)propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4-naphthalene-1-yl-2-hydroxyphenyl)propionic acid

methyl ester 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-naphthalene-1-yl-2-hydroxyphenyl)propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(5-bromo-2-hydroxy-3-nitrophenyl)propionic acid

methyl ester 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(5-bromo-2 is on ether 3-(2-aminoethylamino)-3-(4-naphthalene-2-ylphenyl)propionic acid

methyl ester 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-naphthalene-2-ylphenyl)propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4'-fluoro-2'-hydroxybiphenyl-4-yl)propionic acid

methyl ester of 3-(4'-fluoro-2'-hydroxybiphenyl-4-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid;

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(4'-fluoro-2'-hydroxybiphenyl-3-yl)propionic acid

methyl ester of 3-(4'-fluoro-2'-hydroxybiphenyl-3-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid, or

in the reaction with hydrochloride difficult methyl ester 3-(2-aminoethylamino)-3-(2-hydroxybiphenyl-4-yl)propionic acid

methyl ester 3-(2-hydroxybiphenyl-4-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid.

Example 23:

After saponification of methyl esters of the compounds of Example 22, analogously to Example 2 (4), get

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-nitrophenyl)impregnated who yl)propionic acid,

triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-nitrophenyl)propionic acid;

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitro-2-hydroxyphenyl)propionic acid,

sodium salt 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitro-2-hydroxyphenyl)propionic acid,

triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitro-2-hydroxyphenyl)propionic acid;

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-chloro-3-nitrophenyl)propionic acid,

sodium salt 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-chloro-3-nitrophenyl)propionic acid,

triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-chloro-3-nitrophenyl)propionic acid, WU 21,44 min, MS-BOIS (M+H)+478;

3-(4'-forbiden-3-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(4'-forbiden-3-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-(4'-forbiden-3-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}about)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(4'-forbiden-4-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-(4'-forbiden-4-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid;

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-naphthalene-1-ylphenyl)propionic acid,

sodium salt 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-naphthalene-1-ylphenyl)propionic acid,

triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-naphthalene-1-ylphenyl)propionic acid, WU* 25,44 min, MS-BOIS (M+N)+525;

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-naphthalene-1-yl-2-hydroxyphenyl)propionic acid,

sodium salt 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-naphthalene-1-yl-2-hydroxyphenyl)propionic acid,

triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-naphthalene-1-yl-2-hydroxyphenyl)propionic acid;

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(5-bromo-2-hydroxy-3-nitrophenyl)propionic acid,

sodium salt 3-{2-[4-(4-methylpyridin-2-ylamino)butir pyridin-2-ylamino)bucillamine]acetylamino}-3-(5-bromo-2-hydroxy-3-nitrophenyl)propionic acid;

3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-naphthalene-2-ylphenyl)propionic acid,

sodium salt 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-naphthalene-2-ylphenyl)propionic acid,

triptorelin 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-naphthalene-2-ylphenyl)propionic acid;

3-(4'-fluoro-2'-hydroxybiphenyl-4-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(4'-fluoro-2'-hydroxybiphenyl-4-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-(4'-fluoro-2'-hydroxybiphenyl-4-yl)-3-{2-{4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid;

3-(4'-fluoro-2'-hydroxybiphenyl-3-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

sodium salt of 3-(4'-fluoro-2'-hydroxybiphenyl-3-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-(4'-fluoro-2'-hydroxybiphenyl-3-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid, or

3-(2-hydroxybiphenyl-3-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)butyryl-ylamino)bucillamine]acetylamino}propionic acid,

triptorelin 3-(2-hydroxybiphenyl-3-yl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid.

Example 24:

1. Chlorhydrate

1 mmol of triptoreline 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid from Example 6 is dissolved in 10 ml of water and added dropwise to 0.1% solution of HCl. The solution is dried by freezing. Operation is repeated several times.

Receive hydrochloride 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid, WU 17,53 min, MS-BOIS (M+H)+458.

Similarly from

trifenatate 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionic acid from Example 4 get

hydrochloride 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionic acid, WU 15,13 min, MS-BOIS (M+H)+444.

2. Ampion

The appropriate addition of sodium hydroxide solution as in Example 2(4) promotes the precipitation of Amphion. Ampion corresponding to such a connection, as 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid, has the appropriate to such a connection, as 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionic acid, has the following analytical characteristics:

WU 17,01 min, MS-BOIS (M+N)+444, so pl. 212-213.

3. Methansulfonate

1 mmol of triptoreline 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid from Example 6 is dissolved in 10 ml of water and added dropwise methanesulfonyl acid. The solution is dried by freezing. Get methanesulfonate 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid.

Similarly from

trifenatate 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionic acid from Example 4 get

methanesulfonate 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionic acid, WU 17,07 min, MS-BOIS (M+H)+444.

Example 25:

(1) to 0.06 mole of 3-nitrobenzaldehyde, 5,72 g of malonic acid, 8.5 g of ammonium acetate and 40 ml of ethanol for 8 h refluxed and stirred over night at room temperature. Then the cooled reaction mixture is sucked off, washed with etazolate subsequent N-acylation using phenylacetylide under standard conditions produces 3-(3-nitrophenyl)-3-phenylacetylamino acid. This racemate was dissolved in 40 ml of water, after which the pH value of the solution by means of potassium hydroxide stabilized at the level of 7.5. Add the enzyme penicillinase and shaken for 3 days. After separation of the enzyme by the method of filtering and processing conventional method receive (R)-3-amino-3-(3-nitrophenyl)propionic acid and (S)-3-(3-nitrophenyl)-3-phenylacetylcarbinol acid.

(R)-3-Amino-3-(3-nitrophenyl)propionic acid analogously to Example 2, activating thionyl chloride and subjecting the reaction with methanol under standard conditions, atrificial to complex methyl ester 3-amino-3-(3-nitrophenyl)propionic acid and injected into reaction with BOC-Gly-HE, 4-(4-methylpyridin-2-ylamino)butyric acid. In the result of the cleavage of ester receive (R)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionic acid.

If you work with an excess of NaOH, get sodium salt (R)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionic acid.

Using preparative GHUR get triptorelin (R)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionic acid, WU 16,89 min, MS-BOIS (M+N)+444.

(S)-3-trienyl)propionic acid, which, similar to the R-enantiomers, is subjected to further reactions. Get

(S)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionic acid,

sodium salt of (S)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionic acid,

triptorelin (S)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionic acid, WU 16,89 min, MS-BOIS (M+H)+444.

Example 26: Prodrugs

1. As a result of esterification of 3-(4-chloro-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid by activation with thionyl chloride and reaction with ethanol under standard conditions is formed hydrochloride complex ethyl ester 3-(4-chloro-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid, WU 27,95, MS-BOIS (M+H)+520.

Similarly, in the esterification and subsequent preparative GHUR formed

in the processing of 3-(4-chloro-3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid

triptorelin complex ethyl ester 3-(4-chloro-3-nitrophenyl)-3-{2-[4-(4-methylp is abode 3-(4-chloro-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid

triptorelin complex ethyl ester 3-(4-chloro-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid, WU 15,29, MS-BOIS (M+N)+492;

in the processing of (R)-3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid

triptorelin complex ethyl ester (R)-3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid, WU 20,61, MS-BOIS (M+H)+472;

in the processing of (S)-3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid

triptorelin complex ethyl ester (S)-3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid, WU 20,61, MS-BOIS (M+H)+472;

in the processing of 3-(4-chloro-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid

hydrochloride complex ethyl ester 3-(4-chloro-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid, WU 27,95, MS-BOIS (M+N)+520 or

in the processing of 3-(4'-forbiden-3-yl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid

triptorelin complex e is 30,26, MS-BOIS (M+H)+521.

2. As a result of esterification of 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid by activation with thionyl chloride and enter into reaction with tert.-butanol under standard conditions with holding then preparative GHUR formed triptorelin complex tert.-butyl ester 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid, WU 27,20, MS-BOIS (M+H)+500.

Similarly, by esterification get

the propanol

triptorelin complex propyl ester 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid, WU22,24, MS-BOIS (M+H)+486;

the isopropanol

triptorelin complex isopropyl ester 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid, WU 22,03, MS-BOIS (M+H)+486 or

butanol

triptorelin difficult butyl ester 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid, WU 24,00, MS-BOIS (M+N)+500.

3. The introduction of 3-(3-nitrophenyl)-3-{2-[4-(4-methylpentylamino acid under standard conditions with holding then preparative GHUR formed triptorelin complex 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionylacetate ether of 2,2-dimethylpropionic acid, WU 69,68, MS-BOIS (M+H)+558.

4. The result of the reaction of 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid with diethylene glycol in standard conditions with holding then preparative GHUR is the formation of triptoreline complex glycol ether 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionic acid.

5. In the reaction of 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}propionic acid with benzyl alcohol under standard conditions with holding then preparative GHUR formed triptorelin complex benzyl ester 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(3-nitrophenyl)propionic acid.

Example 27: Test

In angiogenic blood vessels of the tumor clearly the presence of integrin v3, that can specifically identify them using the v3-specific inhibitors.

There is a possibility of using the method of analysis to identify a cell line of human tumors, in which instead of integrin v3, you can find the integrin v6, for example, Detroit 562, HT-29 or UCLA-P3, or those that include both the consistent line cells grow in the bodies of rodents with reduced immunity, e.g. nu/nu mice as subcutaneous tumors.

As described above, blocking inhibitors of receptor integrin v3 tumor growth is through what is grown in the tumor blood vessels begin to get apoptotic signals leading to their programmed death (apoptosis). (Lit.: R. C. Brooks, Eur. J. Cancer 1996, 32A, 2423-2429, P. C. Brooks and others, Cell 1994, 79, 1157-1164 or S. Stomblad etc., J. Clin. Invest 1996, 98, 426-433.)

Inhibitors of integrin v6 act directly on tumor development. Synergistic effect of combination therapy of the present invention is documented using the following series of tests similar to the test systems developed Mitjans, etc., J. Cell. Sci. 1995, 108, 2825-2838: tumor cells expressing v6, subcutaneously implanted, e.g., nu/nu mice. Similarly, as in the case of cell line M21 Mitjans and others, investigated the dependence of the growth of these tumor cells in mice from the use of certain inhibitors of integrins.

After implantation of tumor cells prepared in this way mice are isolated from the rest and are broken down into groups of 10 animals. Mice daily according to the present invention is treated by introducing intraperitoneally injection of the corresponding inhibitor Ezek of pyrogen. The tumor size was measured twice per week and in accordance with the results expected by its volume.

The following examples relate to pharmaceutical preparations:

Example: Vials for injection

Using 2 N. hydrochloric acid the pH of a solution of 100 g of active substance of the formula I and 5 g of the secondary acid sodium phosphate in 3 l of double-distilled water stabilized at the level of 6.5, sterilized by filtration, dispensed into vials for injection, lyophilizer in sterile and sterile seal. In each vial for injection contains 5 mg of active substance.

Example B: Suppositories

A mixture of 20 g of active substance of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allow to cool. Each suppository contains 20 m g of active substance.

Example: Solution

Prepare a solution of 1 g of active substance of the formula I, 9,38 g NaH2PO4·2H2O, 28,48 g Na2HPO4·12H2O and 0.1 g of benzylaniline in 940 ml of double-distilled water. The pH value of the solution stabilized at 6.8 complement to 1 l and sterilized by irradiation. This solution can primantis the ski conditions are mixed with 99.5 g of petroleum jelly.

Example D: Pill

A mixture of 1 kg of active substance of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate and pressed into tablets, each containing 10 mg of active substance.

Example E: Bean

Analogously to Example D, pressed tablets, then the usual method is covered with a shell containing sucrose, potato starch, talc, tragakant and dye.

Example G: Capsule

2 kg of active ingredient of formula I in the usual method of filling the capsules of hard gelatin, each of which contains 20 mg of active substance.

Example 3: Ampoules

A solution of 1 kg of active substance of the formula I in 60 l of double-distilled water is sterilized by filtration, dispensed into ampoules, lyophilizer in sterile and sterile seal. Each ampoule contains 10 mg of active substance.

Example: Aerosol inhalation

14 g of active substance of the formula I are dissolved in 10 l of isotonic NaCl solution, after which the resulting solution is poured into standard containers for aerosols with the pumping mechanism. The solution can be sprayed into the oral or naso the formula I I

in which Q1or Q3independently from each other represent CH or N, they cannot mean N;

R1represents H, A, AG, or Hal;

R2denotes H or A,

each of R4and R5independently denotes H, a or Hal;

R6represents H or A;

And denotes alkyl with 1-6 carbon atoms;

AG represents unsubstituted aryl;

Hal denotes F, Cl, Br or 1;

n is 2, 3, 4, 5 or 6;

m is 1, 2, 3, or 4

and their physiologically acceptable salt and solvate.

2. Connection on p. 1

(a) 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridine-2-ylamino)bucillamine]acetylamino}propionic acid,

(b) 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

(b) 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

(g) 3-(2-nitrophenyl)-3-{2-[5-(pyridine-2-ylamino)pentanediamine]acetylamino}propionic acid,

(d) 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(2-nitrophenyl)propionic to the lot,

(W) 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(4-trifloromethyl)propionic acid,

(C) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(4-trifloromethyl)propionic acid,

(and) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}-3-(3-trifloromethyl)propionic acid,

() 3-{2-[4-(4-methylpyridin-2-ylamino)bucillamine]acetylamino}-3-(biphenyl-4-yl)propionic acid,

(l) 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(6-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid,

(m) 3-(4-chloro-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanediamine]acetylamino}propionic acid, or

(h) 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyrimidine-2-ylamino)pentanediamine]acetylamino}propionic acid.

3. The method of obtaining compounds of formula I on p. 1, and their salts and solvate, by reacting the compounds of formula II

in which Q1, Q3and R1and n have the meanings specified in paragraph 1,

with the compound of the formula III

in which R2, R3and R6have the meanings given in paragraph 1

and, if necessary, the radical R6N pens is R4and/or R5transferred to one or more radicals R1, R2, R3, R4and/or R5by, for example, vi) alkylation of hydroxyl group, (vii) hydrolysis of the ester group to a carboxyl group, (viii) the esterification of the carboxyl group, (ix) the alkylation of an amino group, or x) acylation of the amino group and/or a basic or acidic compound of formula I by treatment with acid or base is transferred to one (one) from its salt or solvate.

4. The method of obtaining compounds of formula I on p. 1, and their salts and solvate by reacting the compounds of formula IV

in which Q1, Q3, R1, R2and n have the meanings specified in paragraph 1,

with the compound of the formula V

in which R3and R6have the meanings specified in paragraph 1 of the claims,

and, if necessary, translate the radical R6N in the radical R6= N, or in the compound of the formula I one or more radicals R1, R2, R3, R4and/or R5transferred to one or more radicals R1, R2, R3, R4and/or R5by, for example, vi) alkylation of hydroxyl group, (vii) hydrolysis of the ester group to carbon the group, and/or a basic or acidic compound of formula I by treatment with acid or base is transferred to one (one) from its salt or solvate.

5. The compounds of formula I on p. 1 and their physiologically acceptable salt or solvate as the effective ingredients of a pharmaceutical product having the properties of an inhibitor of integrins.

6. The compounds of formula I on p. 1 and their physiologically acceptable salt or solvate as inhibitors of integrins.

7. The pharmaceutical preparation having the properties of an inhibitor of integrins containing at least one compound of formula I under item 1 and/or one (one) of its physiologically acceptable salt or solvate.

 

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