Bicyclic aromatic amino acids

 

(57) Abstract:

The invention describes compounds of formula (I) in which X, Y, Z, R1, R2, R3, R4, R5, R7, R8, R11, m and n have the meanings specified in the description text, as well as their physiologically acceptable salts, inationary or diastereomers. The proposed compounds and their physiologically acceptable salts can be used as integrin inhibitors primarily for the prevention and treatment of diseases of the cardiovascular, thrombosis, myocardial infarction, coronary heart disease, arteriosclerosis, osteoporosis, pathological processes associated with angiogenesis or caused them, as well as for therapy of malignant diseases. The method of obtaining compounds of formula I and their salts. Describes obtaining a pharmaceutical composition inhibiting the integrin, comprising a compound of the formula I and/or one of its physiologically acceptable salts. 3 S. and 2 C.p. f-crystals, 1 PL.

The present invention relates to compounds of the formula I

< / BR>
in which R1denotes H, alkyl with 1-6 atoms or benzyl,

R2means R10, CO-R10, COOR6, COOR10, SO is l, -O-acyl, CN, NO2, OR10, SR10, R2or CONHR10,

R4denotes H, =O, =S, WITH1-C6alkyl or acyl,

R5denotes NH2H2N-C(=NH) or H2N-C(=NH)-NH, and the primary amino group can be protected by the usual aminosidine groups or one-, two - or three-fold substituted R10, CO-R10, COOR10or SO2R10or is identical to R6,

R7, R8each independently of each other either absent or denotes H, R7and R8both together form the relationship,

X, Y each independently from each other represents =N-, -N-, O, S, -CH2- or =C-, provided that at least one of them represents =N-, -N-, O or S,

W, Z are each independently from each other, is absent or represents O, S, NR1WITH(=O), CONH, NHCO, C(=S)NH, NHC(=S), C(=S), SO2NH, NHSO2or SA= SA',

R6represents a single or dual-core a heterocycle with 1 to 4 N, O and/or S atoms, which may be unsubstituted or have one, two or three times substituted by Hal, A, -CO-AND, HE, CN, COOH, COOA, CONH2, NO2, =NH or =O,

R9denotes H, Hal, OA, NHA, NAA', NH-acyl, O-acyl, CN, NO2, SA, SOA, SO2A, SO2Ar or SO3N,

R10denotes H, A, ago from each other denotes H or unsubstituted or one-, two or three times substituted by the radical R9alkyl or cycloalkyl with 1 to 15 C-atoms, where one, two or three methylene groups can be replaced by N, O and/or S,

AG represents an unsubstituted or one-, two - or three-fold substituted and/or R9single - or dual-core aromatic cyclic system with 0, 1, 2, 3 or 4 N, O and/or S atoms,

Hal denotes F, Cl, Br or I and

m, n are each independently of one another denotes 0, 1, 2, 3, or 4

and their physiologically acceptable salts.

Such compounds are known, for example, international applications WO 94/29273, WO 96/00730 and WO 96/18602.

The basis of the invention was based on the task to obtain new compounds with valuable properties, in particular such compounds, which could be used to manufacture the drugs.

It has been found that the compounds of formula I and their salts along with good compatibility possess valuable pharmacological properties. First of all, they are effective as inhibitors of integrin, inhibiting primarily the interaction of receptors v-integrin with a ligand. Particularly effective compounds exhibit in the case of internetov adhesion receptors in relation to the receptorv3-vitronectin. This action can be confirmed, for example, by the method described by J. W. Smith and others in Journ. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).

B. Felding-Habermann and D. A. Cheresh describe in Curr. Opin. Cell. Biol. 5, 864 (1993) the value of integrins as adhesion receptors for the detection of different features and patterns of a disease, in particular regarding the role of receptorv3-vitronectin.

The dependence of the occurrence of angiogenesis (development of blood vessels) from the interaction between vascular integrins and extracellular matrix proteins described by P. C. Brooks, R. A. Clark, and D. A. Cheresh in Science 264, 569-571 (1994).

The possibility of suppression of this interaction and thereby the opportunity for early apoptosis (programmed cell death) of angiogenic vascular cells under cyclic peptide described by P. C. Brooks, A. M. Montgomery, M. Rosenfeld, R. A. Reisfeld, T.-Hu, G. Klier and D. A. Cheresh in the Cell. 79, 1157-1164 (1994).

Proof that the compounds according to the invention also inhibit the fixation of living cells on the corresponding matrix proteins and thus prevent the fixation on the past and cancer cells can be confirmed experimentally using testh">

R. C. Brooks and others describe in Journ. Clin. Invest. 96, 1815-1822 (1995)v3antagonists that can be used for cancer and for the treatment caused tumor angiogenic diseases.

Proposed according to the invention the compounds of formula I can be used therefore as active substances in medicinal products primarily for the treatment of cancer, osteoporosis, osteolytic diseases, and also to suppress angiogenesis.

The compounds of formula I, having the ability to block the interaction of integrin receptors and ligands, such as the binding of fibrinogen with fibrinogen receptor (glycoprotein IIb/IIIa), prevent as IIb/IIIA-antagonists metastasis of cancer cells. This is confirmed by the following observations.

The spread of cancer cells from the local tumor in the vascular system occurs due to the formation of microaggregates (microthrombi), due to the interaction of cancer cells with platelets. Cancer cells are virtually protected microaggregate and therefore are not recognized by cells of the immune system. Microaggregate can be fastened in the walls of blood vessels, which facilitates further penetration Primogeniti receptors on activated platelets, IIb/IIIa-antagonists can be considered as effective inhibitors of metastasis.

Along with the binding of fibrinogen, fibronectin and factor von Willebrand (glycoprotein that promotes adhesion of platelets to subendothelial layer to the damaged endothelium) with fibrinogen receptor of platelet compounds of formula I also possess the ability to bind and other adhesive proteins such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. First of all, they prevent the formation of platelets and can therefore be used for the treatment of thrombosis, apoplexy, cardiac infarction, inflammation and arteriosclerosis.

The properties of the compounds according to the invention can also be confirmed using the methods described in EP-A1 0462960. To confirm their properties such as inhibition of binding of fibrinogen with fibrinogen receptor, you can use the method described in EP-A1 0381033.

The vast platelet aggregation effect of the proposed compounds can be confirmed in vitro using the method of born (Nature 4832, 927-929, 1962).

The object of the invention in accordance with the above are compounds of Faranah for use as integrin inhibitors. The object of the present invention are primarily compounds of the formula I in claim 1 and/or their physiologically acceptable salts, where R2means of camphor-10-sulfonyl, for the manufacture of medicinal products intended for combat due to pathological reasons angiogenic diseases, tumors, osteoporosis, inflammations and infections.

The compounds of formula I can be used as active substances in medicinal products intended for use in medicine and veterinary medicine for the prevention and/or treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina, neoplastic disease, osteolytic diseases such as osteoporosis due to pathological causes of angiogenic diseases, such as inflammation, eye diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, robotically glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, viral infection, bacterial infection, fungal infection, acute renal failure and when sales is as possessing antimicrobial activity of substances in operations, using biomaterials, implants, catheters or pacemakers. They are antiseptic. The effect of antimicrobial activity can be confirmed using the method described by R. Valentin-Weigund and others in Infection and Immunity 2851-2855 (1988).

The object of the invention is further a method of producing compounds of the formula I in claim 1 and their salts. The method differs,

a) the compound of formula I release from one of its functional derivatives by treatment by means of solvolysis or hydrogenolysis, or

b) the compound of formula II

< / BR>
in which R1, R3, R4, R5, R7, R8, R11, W, X, Y, Z, m and n have the meanings specified in paragraph 1 of the formula, is subjected to the interaction with the compound of the formula III

R2-L III

in which R2has the meaning specified in paragraph 1 of the formula, L denotes C1, Br, I, HE or reactionsare esterified HE group, or

q) what amyraut ester of the formula I, or

g) one of the residues R1and/or R5turn in the remainder R1and/or R5and/or

d) what basic or acidic compound of formula I by treatment with an acid or a base is transferred to one is aulani so in several stereoisomeric forms. All of these forms (for example, D - and L-forms), as well as their mixtures (for example, DL-forms) fall under the formula I.

Among the proposed invention compounds are also included so-called proletarienne derivatives, i.e. modified, for example, with alkyl or acyl groups, sugars or oligopeptides of the compounds of formula I, in which the body quickly split with the formation of the effective compounds according to the invention.

Above and beyond the reduction of mean:

AC acetyl

SIDE tert-butoxycarbonyl

BSAC or Z benzyloxycarbonyl

DCCI dicyclohexylcarbodiimide

DMF dimethylformamide

L-DOPA (3,4-dihydroxyphenyl)alanine

DPFN nitrate 3,5-dimethylpyrazol-1-formamidine

EDCI N - ethyl - N, N' - (dimethylaminopropyl) carbodiimide

Et ethyl

Fmoc 9-fluorenylmethoxycarbonyl

HOBT 1-hydroxybenzotriazole

Me methyl

Pri 4-methoxy-2,3,6-trimethylphenylsulfonyl

N-State N-hydroxysuccinimide

OBn benzyl ether

OBut tert-butyl ether

Oct octanoyl

OMe methyl ester

OEt ethyl ester

Orn ornithine

FOA phenoxyacetyl

TBTU O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium

For inventions in General, the following applies: all of the above in various embodiments, residues, as for example a and a' may be identical or different, in other words, their values do not depend on each other.

In the above, formula alkyl preferably represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore, 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-, 1,2,2-trimethylpropyl, heptyl, octyl, nonyl or decyl.

Cycloalkyl represents preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or 3-methyl. First of all cycloalkyl denotes the residue of a bicyclic terpene and most preferably of camphor-10-ilen balance.

Alkylene preferably represents methylene, ethylene, propylene, butylene, pentile, in addition, hexylen, reptile, octiles, Nonlin or deciles. Kalkeren means preferably alkalinity and preferably represents, for example, benzyl or phenethyl.

Cycloalkyl depict clohexane, and 1,2 - 1,3 - or 1,4-cycloheptene.

WITH-AND is alkanoyl or cycloalkenyl and preferably denotes formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanol, deletion, pentadecanol, hexadecanol, heptadecanol or octadecanol.

Acyl represents a C1-C7acyl and has 1, 2, 3, 4, 5, 6 or 7 C-atoms and preferably denotes, for example, formyl, acetyl, propionyl, butyryl, TRIFLUOROACETYL or benzoyl.

Preferred substituents of the alkyl, alkylene, cycloalkyl, cycloalkene, alkanoyl and cycloalkenyl are, for example, Hal, OA, NHA, NAA', CN, NO2, SA, SOA, SO2A, SO2Ar and/or SO3H, first of all, for example, F, Cl, hydroxy, methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, methylsulphonyl or phenylsulfonyl.

Preferred substituents AG and arylene are, for example, a and/or Hal, OA, NHA, NAA', CN, NO2, SA, SOA, SO2A, SO2Ar and/or SO3H, first of all, for example, F, Cl, hydroxy, methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, methylsulphonyl or phenylsulfonyl.

In the remainder of alkyl, alkylen the t can be replaced by N, O and/or s

AG-CO represents aroyl and means preferably benzoyl or naphtol.

AG represents an unsubstituted, preferably, as indicated above, one-deputizing phenyl, particularly preferably o-, m - or p-tolyl, 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-tianfeng, o-, m - or p-methoxyphenyl, o-, m - or p-ethoxyphenyl, o-, m - or p-forfinal, o-, m - or p-bromophenyl, o-, m - or p-chlorophenyl, o-, m - or p-methylthiophenyl, o-, m - or p-methylsulfinylphenyl, o-, m - or p - methylsulfinylphenyl, o-, m - or p-AMINOPHENYL, o-, m - or p-methylaminophenol, o-, m - or p-dimethylaminophenyl, o-, m - or p-nitrophenyl,< / BR>
preferred further 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-chloro-3-methyl-, 2-chloro-4-methyl, 2-chloro-5-methyl-, 2-chloro-6-methyl-, 2-methyl-3-chloro-, 2-methyl-4-chloro-, 2-methyl-5-chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl - or 3-methyl-4-chlorophenyl, 2-bromo-3-methyl-, 2-bromo-4-methyl-, 2-bromo-5-methyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-, 2-methyl-4-bromo-, 2-methyl-5-bromo-, 2-methyl-6-bromo-, 3-bromo-4-methyl-, 3-bromo-5-methyl - or 3-methyl-4-bromophenyl, 2,4 - or 2,5-dinitrophenyl, 2,5 - or 3,4-dim 3-chlorophenyl, 4-fluoro-3, 5dimethylphenyl, 2-fluoro-4-bromophenyl, 2.5-debtor-4-bromophenyl, 2,4-dichloro-5-were, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 2-methoxy-5-were, 2,4,6-triisopropylphenyl, naphthyl, 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, benzothiazol-5-yl or benzoxadiazole-5-yl.

In addition, AG is preferably denotes 2 - or 3-furyl, 2 - or 3-thienyl, 1-, 2 - or 3-pyrrolyl, 1-, 2-, 4 - or 5-imidazolyl, 1-, 3-, 4 - or 5-pyrazolyl, 2-, 4 - or 5-oxazolyl, 3-, 4 - or 5-isoxazolyl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-isothiazole, 2-, 3 - or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, and preferably 1,2,3-triazole-1-, -4 - or-5-yl, 1,2,4-triazole-1-, -3 - or-5-yl, 1 - or 5-tetrazolyl, 1,2,3-oxadiazol-4 - or-5-yl, 1,2,4-oxadiazol-3 - or-5-yl, 1,3,4-thiadiazole-2 - or-5-yl, 1,2,4-thiadiazole-3 - or-5-yl, 1,2,3-thiadiazole-4 - or-5-yl, 2-, 3-, 4-, 5- or 6-2H-dipiradol, 2-, 3 - or 4-4H-dipiradol, 3 - or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuran, 2-, 3-, 4-, 5-, 6- or 7-benzothiazyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4 - or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazole, 2-, 4-, 5-, 6-, or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazole, 4-, 5-, 6 - or 7-benzo-2,1,3-oxadiazole, 2-, 3-, 4-, 5-, 6-, 7- or 8-chinolin, 1-, 3-, 4-, 5-, 6-, 7- either 8-, is the quiet specified for AG, provided that there is another connection between aromatic system with the nearest adjacent fragment.

Heterocyclochain is preferably a 1,2-, 2,3 - or 1,3-pyrrolidinyl, 1,2-, 2,4-, 4,5 - or 1,5-imidazolidinyl, 1,2-, 2,3 - or 1,3-pyrazolidine, 2,3-, 3,4-, 4,5 - or 2.5-oxazolidinyl, 1,2-, 2,3-, 3,4 - or 1,4-isoxazolidine, 2,3-, 3,4-, 4,5 - or 2.5-diazolidinyl, 2,3-, 3,4-, 4,5 - or 2.5-isothiazolinones, 1,2-, 2,3-, 3,4 - or 1,4-piperidinyl, 1,4 - or 1,2-piperazinil, additionally, the preferred 1,2,3-tetrahydrocarbazol-1,2 - or 1,4-yl, 1,2,4-tetrahydrocarbazol-1,2 - or-3,5-yl, 1,2 - or 2,5-tetrahydrocarbazole, 1,2,3-tetrahydrooxazolo-2,3-, -3,4-, -4,5- or-1,5-yl, 1,2,4-tetrahydrooxazolo-2,3-, -3,4 - or 4,5-yl, 1,3,4-tetrahydrocarbazol-2,3-, -3,4-, -4,5- or-1,5-yl, 1,2,4-tetrahydrocarbazol-2,3-, -3,4-, -4,5- or-1,5-yl, 1,2,3-thiadiazole-2,3-, -3,4-, -4,5- or-1,5-yl, 2,3 - or 3,4-morpholinyl, 2,3-, 3,4 - or 2,4-thiomorpholine.

R6represents a single or dual-core a heterocycle, preferably 2 - or 3-furyl, 2 - or 3-thienyl, 1-, 2 - or 3-pyrrolyl, 1-, 2-, 4 - or 5-imidazolyl, 1-, 3-, 4 - or 5-pyrazolyl, 2-, 4 - or 5-oxazolyl, 3-, 4 - or 5-isoxazolyl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-isothiazole, 2-, 3 - or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, and preferred sedesol-3 - or-5-yl, 1,3,4-thiadiazole-2 - or-5-yl, 1,2,4-thiadiazole-3 - or-5-yl, 1,2,3-thiadiazole-4 - or-5-yl, 2-, 3-, 4-, 5- or 6-2H-dipiradol, 2-, 3 - or 4-4H-dipiradol, 3 - or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuran, 2-, 3-, 4-, 5-, 6- or 7-benzothiazyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4 - or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazole, 2-, 4-, 5-, 6-, or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazole, 4-, 5-, 6 - or 7-benzo-2,1,3-oxadiazole, 2-, 3-, 4-, 5-, 6-, 7- or 8-chinolin, 1-, 3-, 4-, 5-, 6-, 7- or 8-ethanolic, 3-, 4-, 5-, 6-, 7- or 8-indolinyl, 2-, 4-, 5-, 6-, 7- or 8-hintline.

Heterocyclic residues may also be partially or completely gidrirovanny.

R6therefore, can also denote, for example, 2,3-dihydro-2-, -3-, -4- or-5-furyl, 2,5-dihydro-2-, -3-, -4- or-5-furyl, tetrahydro-2 - or-3-furyl, 1,3-dioxolane-4-yl, tetrahydro-2 - or-3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or-5-pyrrolyl, 1-, 2 - or 3-pyrrolidinyl, tetrahydro-1-, -2 - or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrazolyl, tetrahydro-1-, -3 - or-4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or 4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or-6-pyridyl, 1-, 2-, 3 - or 4-piperidinyl, 2-, 3 - or 4-morpholinyl, t is Idro-1-, -2-, -4 - or-5-pyrimidinyl, 1-, 2 - or 3-piperazinil, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-chinolin, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-ethanolic.

The above heterocyclic systems can be one-, two - or three-fold substituted by Hal, A, -CO-AND, HE, CN, COOH, COOA, CONH2, NO2, -NH or =O.

The most preferred values of R6are 1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazole-2-yl, 2H-pyrazole-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidine-4-one-5-yl, 1-alkyl-1,5-dihydroimidazole-4-one-2-yl, pyrimidine-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl.

R11denotes H or alkyl with 1-6 C-atoms, preferably N.

In accordance with this object of the invention are such compounds of formula I in which at least one of these residues has one of the abovementioned preferred meanings. Some preferred groups of compounds can be represented by the following partial formulae Ia-Ig, falling under formula I and where not deciphered more residues have the meanings indicated in formula I, but there are some differences, namely:

in Ia) R1denotes H or alkyl with 1-6 C-atoms,

R2means R10>/BR>R5denotes H2N-C(=NH) or H2N-C(=NH)-NH,

W, Z are each independently from each other either missing or

denotes C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

R10denotes H, a or benzyl,

R11denotes H,

And denotes unsubstituted alkyl or cycloalkyl with 1-15 C-atoms and

m, n are each independently of one another denotes 0, 1 or 2;

in Ib), R1denotes H or alkyl with 1-6 C-atoms,

R2means R10, CO-R10, COOR10or SO2R10,

R3denotes H,

R4denotes H or a =O,

R5identical to R6,

W, Z are each independently from each other either missing or

denotes C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

R6represents a single or dual-core a heterocycle with 1 to 4 N, O and/or S atoms, which may be unsubstituted or have one, two or three times substituted by Hal, A, -CO-AND, HE, CN, COOH, cooa, CONH2, NO2, =NH or =O,

R10denotes H, a or benzyl,

R11denotes H,

And denotes unsubstituted alkyl or cycloalkyl with 1-15 C-atoms and

m, n are each an is oznachaet R10, CO-R10, COOR10or SO2R10,

R3denotes H,

R4denotes H or a =O,

R5denotes H2N-C(=NH) or H2N-C(=NH)-NH,

W, Z are each independently from each other either missing or

denotes C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

And denotes alkyl with 1-6 C-atoms,

R10denotes H, alkyl with 1-6 C-atoms, camphor-10-yl or benzyl,

R11denotes H,

m, n are each independently of one another denotes 0, 1 or 2;

in Id) R1denotes H or alkyl with 1-6 C-atoms,

R2means R10, CO-R10, COOR10or SO2R10,

R3denotes H,

R4denotes H or a =O,

R5identical to R6,

W, Z are each independently from each other either missing or

denotes C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

R6represents a single or dual-core a heterocycle with 1 to 4 N, O and/or S atoms, which may be unsubstituted or have one, two or three times substituted by Hal, A, -CO-AND, HE, CN, COOH, cooa, CONH2, NO2, =NH or = O,

R10denotes H, alkyl with 1-4 C-atoms
m, n are each independently of one another denotes 0, 1 or 2;

in Ie) R1denotes H or alkyl with 1-6 C-atoms,

R2means R10, CO-R10, COOR10or SO2R10,

R3denotes H,

R4denotes H or a =O,

R5identical to R6,

W, Z are each independently from each other either missing or

denotes C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

R6denotes a 1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazole-2-yl, 2H-pyrazole-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidine-4-one-5-yl, 1-A-1,5-dihydroimidazole-4-one-2-yl, pyrimidine-2-yl or 1,4,5,6-tetrahydropyrimidin-2-Il,

R10denotes H, alkyl with 1-4 C-atoms, camphor-10-yl or benzyl,

R11denotes H,

And denotes unsubstituted alkyl with 1-6 C-atoms and

m, n are each independently of one another denotes 0, 1 or 2;

If) R1denotes H or alkyl with 1-6 C-atoms,

R2means R10, CO-R10, COOR10or SO2R10,

R3denotes H,

R4denotes H or a =O,

R5denotes H2N-C(=NH) or H2N-C(=NH)-NH,

W, Z, each independently of each other either absent or about who appoints AG,

R11denotes H,

And denotes unsubstituted alkyl or cycloalkyl with 1-15 C-atoms and

m, n are each independently of one another denotes 0, 1 or 2;

in Ig) R1denotes H or alkyl with 1-6 C-atoms,

R2means R10, CO-R10, COOR10or SO2R10,

R3denotes H,

R4denotes H or a =O,

R5identical to R6,

W, Z, each independently of each other either absent or denotes a C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

R6represents a single or dual-core a heterocycle with 1 to 4 N, O and/or S atoms, which may be unsubstituted or have one, two or three times substituted by Hal, A, -CO-AND, HE, CN, COOH, cooa, CONH2, NO2, =NH or = O,

R10denotes Ah,

R11denotes H,

And denotes unsubstituted alkyl or cycloalkyl with 1-15 C-atoms and

m, n are each independently of one another denotes 0, 1 or 2.

The compounds of formula I, as well as source materials for their production in the rest get by known methods described in the literature (for example, in such fundamental publications, as Houben-Weyl, Methods der organischen Chemie, published by Georg-Thieme-Verlag, MD may also be known, not illustrated in this description to more options.

The source of the substance, if necessary, can also be formed in situ, eliminating their compulsory isolation from the reaction mixture and allows their subsequent direct conversion into compounds of formula I.

The compounds of formula I can be obtained preferably by their release from one of their functional derivatives by treatment by means of solvolysis or hydrogenolysis.

Preferred for the implementation of solvolysis, respectively hydrogenolysis are those of the original substances, which in principle fall under the formula I, but instead of one or more free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxyl groups, preferably such that instead of the N-atom with a N-atom, are aminosidine group, primarily such that instead of NH-groups are R'-N-rpynny, where R' denotes aminosidine group, and/or such which, instead of the N-atom in the hydroxyl group are hydroxyamino group, such that, although fall under the formula I, but instead of the group-COOH are group-CO who were also several identical or different protected amino and/or hydroxyl groups. In the presence of various protective groups in many cases can selectively by split.

The concept of "aminosidine group" is well known and relates to groups which are capable of protecting (blocking) an amino group from chemical reactions but which can be easily removed upon completion of the desired chemical reactions in other parts of the molecule. Typical representatives of such groups are unsubstituted or substituted acyl, aryl, arelaxation or kalkilya group. Because aminosidine group upon completion of the desired reaction (or the stage) is removed, the type and extent otherwise not play a significant role, preferred, however, groups with 1-20, especially with 1-8 C-atoms.

The term "acyl group" in relation to the proposed method is used in the broadest sense. It includes acyl groups derived from aliphatic, alifaticheskih, aromatic or heterocyclic carboxylic acids or sulphonic acids, and above all alkoxycarbonyl, aryloxyalkyl first and foremost alcoxycarbenium grouppanel, such as phenylacetyl; aroyl, such as benzoyl or toluyl; aryloxyalkanoic, such as the FOA; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichlorocyanuric, SIDE, 2-iodoxybenzoic; Uralelectromed, such as BSAC (carbobenzoxy"), 4-methoxybenzeneboronic, Fmoc; arylsulfonyl, such as MTP. Preferred aminosidine groups are SIDE and Inventory, as well as BSAC, Fmoc, benzyl and acetyl.

Cleavage aminosidine group can successfully carry out depending on the protective group, for example using strong acids, preferably TFU or perchloro acid, but equally with other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids such as benzene - or p-toluensulfonate. The presence of an additional inert solvent may, but is not always necessary. As the inert solvent preferably suitable organic solvents, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydro-furan or dioxane, amides, such as DMF, halogenated coal which may be used and mixtures of the mentioned solvents. TFU preferably used in excess without addition of any other solvent. Perchloro acid is used in the form of a mixture of acetic acid and 70% perchloro acid in the ratio 9: 1. The temperature required for the cleavage is preferably in the range from approximately 0 to approximately the 50oWith, it is advisable to operate in the range of from 15 to 30oC (room temperature).

Cleavage of SIDE groups, OBut and MTR can be carried out, for example, preferably using TFU in dichloromethane or using approximately 3 to 5N. HCl in dioxane at 15-30oWith, Fmoc-group can be split by using approximately 5-50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30oC.

Remove gidrodinamicheskim by a protective group (for example, BSAC or benzyl) can be chipped off, for example, by treatment with hydrogen in the presence of a catalyst (e.g. catalyst based on a noble metal, such as palladium, preferably on a medium such as coal). As solvents it is possible to use any of the above, first of all, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. GIII in the range from about 1 to 200 bar, preferably at 20-30oC and 1-10 bar. Hydrogenolysis of Bsoc group is expedient to carry out, for example, in the presence of 5-10% Pd/C in methanol or using ammonium formate (instead of hydrogen) in the presence of Pd/C in methanol/DMF at 20-30oC.

The compounds of formula I can be obtained preferably by the interaction of the compounds of the formula II with compounds of formula III. The initial compounds of formulas II and III, in principle, are new or they can be obtained by known methods.

In compounds of formula III, L preferably denotes C1, Br, I or reactionsare HE modified group such as alkylsulfonate with 1-6 C-atoms (preferably, methylsulfonylamino) or arylsulfonate with 6-10 C-atoms (preferably phenyl - or p-tolilsulfonil).

The conversion of compounds of the formula II is carried out usually in an inert solvent in the presence of an acid binding agent, preferably an organic base, such as triethylamine, dimethylaniline, pyridine or quinoline. It may be appropriate to add hydroxide, carbonate or bicarbonate of an alkaline or alkaline-earth metal or melodramatically or alkaline-zemelnaya depending on the environment ranges from a few minutes up to 14 days, the reaction temperature is in the range from -30 to 140, typically from -10 to 90 and above all, from approximately 0 to approximately 70oC.

As inert solvents are acceptable, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; a simple glycol ethers, such as onomatology ether or monotropy ether of ethylene glycol (methylglycol or ethylglycol), dimethyl ether of ethylene glycol (diglyme); ketones, such as acetone or butanone; amides, such as ndimethylacetamide, dimethylacetamide or dimethylformamide (DMF); NITRILES, such as acetonitrile; sulfoxidov, such as dimethylsulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters, such as ethyl acetate; water; or mixtures of these solvents.

In addition, the ester of formula I are under the measures using NaOH or KOH in dioxane/water at temperatures in the range from 0 to 60, preferably from 10 to 40oC.

Another possibility is that one of the residues R1and/or R5turn in the remainder R1and/or R5.

First of all, you can turn a carboxylic acid in one of its esters.

The transformation of the cyanide group in amedieval group exercise interaction, for example, with hydroxylamine, and the subsequent recovery of N-hydroxyamides using hydrogen in the presence of a catalyst, such as Pd/C.

We can further replace the conventional aminosidine group on hydrogen. This opportunity to implement due to the removal of the above-described protective groups by solvolysis or hydrogenolysis or release protected by a conventional protecting group of the amino group by solvolysis or hydrogenolysis.

The basis of the formula I can be translated using acid to the corresponding acid additive salt, for example, the interaction of equivalent amounts of base and acid in an inert solvent, such as ethanol and subsequent evaporation. For such a reaction is primarily suitable acids that form f is acid, nitric acid, halogenation acids, such as chloride-hydrogen acid or Hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, especially aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic 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, isonicotinamide acid, methane - or econsultation, ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, p-toluensulfonate, naphthalenamine and dissolvability, louisanna acid. About salts with physiologically unacceptable acids, for example of the picrate, it should be noted that they can be used for isolating and/or purifying compounds of formula I.

On the other hand, the acid of formula I to interact with base mo the salts may be treated primarily salts of sodium, potassium, magnesium, calcium and ammonium, and substituted ammonium salts, for example salts of dimethyl-, diethyl - or Diisopropylamine, salt monoethanol-, diethanol - or Diisopropylamine, salt cyclohexyl-, dicyclohexylamine, salts of dibenzylethylenediamine, in addition, for example, salts of arginine or lysine.

As mentioned above, the compounds of formula I contain one or more chiral centers and can therefore be represented in racemic or optically active form. Resulting racemates can by known methods of mechanical or chemical means to separate the enantiomers. Preferably the racemic mixture by reacting with an optically active separating agent form diastereoisomers. As separating agents can be used, for example, optically active acids, such as D - and L-forms of tartaric acid, diatsetilvinny acid, dibenzoyltartaric acid, almond acid, malic acid, lactic acid or the various optically active camphor sulphonic acids, such as camphor acid. Preferably also carry out the separation of the enantiomers using columns filled with optically active separating agent (for example, dinitrobenzoate ratio 82:15:3.

Optically active compounds of formula I can, of course, also be obtained by the above methods due to the use of starting materials which are already optically active.

Another object of the invention is the use of compounds of the formula I and/or their physiologically acceptable salts for pharmaceutical compositions, primarily non-chemical way. Thus they can be used in conjunction with at least one solid, liquid and/or semi-liquid carrier or auxiliary substance, and optionally in combination with one or more other active substances for the manufacture of appropriate dosage forms.

The object of the invention are hereinafter pharmaceutical composition containing at least one compound of the formula I and/or one of its physiologically acceptable salts. These compositions can be used as drugs in medicine and veterinary medicine. As carriers for these compositions can be considered organic or inorganic substances suitable for enteral (for example oral), parenteral, local injection or for use in the form of an inhalation spray and not reacherous and, the glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, vaseline. For oral assignments are designed primarily for tablets, pills, coated tablets, capsules, powders, granules, syrups, medicine or drops for rectal use - suppositories, for parenteral use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, for topical application suitable ointments, creams or powders. The new compounds can also be lyophilized and the resulting lyophilizate be used, for example, for the preparation of injection preparations. These compositions can be sterilized and/or they may contain auxiliary substances, such as oil, preservatives, stabilizers and/or wetting, emulsifying agents, salts for regulating the osmotic pressure, buffer substances, colorants, flavorings and/or one or more other active substances, for example one or more vitamins.

As of spray for inhalation can be used sprays, which contain the active substance in dissolved or suspended form in the same propellant or propellant and the creation in micronized form, moreover, you can add one or more additional physiologically acceptable solvents, for example ethanol. Inhalation solutions can be performed using a conventional inhalers.

The compounds of formula I and their physiologically acceptable salts can be used as integrin inhibitors primarily in the fight against diseases such as due to pathological reasons angiogenic diseases, thrombosis, myocardial infarction, ischemic heart disease, arteriosclerosis, tumors, inflammation and infection.

It is preferable to apply to combat pathological diseases associated with angiogenesis or associated with cancer, osteoporosis, inflammations and infections such compounds of the formula I in claim 1 and/or their acceptable salts, in which R2is camphor-10-Il.

Proposed according to the invention substance, as a rule, can be entered similarly to other known, commercially available peptides, but especially similar to the compounds described in US-A 4472305, preferably in dosages from about 0.05 to 500 mg, especially from 0.5 to 100 mg per uniform dose. Daily dose of prento special last dose depends on various factors, for example, the effectiveness of the applied compound, the age and body weight of the patient, General health, sex, diet, time and method of administration, rate of excretion, combination of drugs and the severity of the respective disease, which requires this treatment. Preferably parenteral application.

Above and beyond all temperatures are in degrees Celsius. Under used in the following examples, the term "normal processing" we mean the following: if necessary, water is added, depending on the structural characteristics of the final product pH is adjusted, if necessary, to values between 2 and 10, extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate, evaporated, purified by chromatography on silica gel and/or by crystallization.

Mass spectrometry (MS): EI (ionization by electron impact)+; FAB (bombardment with accelerated atoms) (M+N)+.

Example 1

A solution of 12 g of benzyl ether SIDE-by-3-nitro-L-tyrosine ("connection 1") in 200 ml THF hydronaut for 6 h at room temperature (RT) and normal pressure in the presence of 1 g Ino-b-tyrosine ("compound 2"), FAB 387.

A solution of 9.3 g of compound 2, a 2.36 g of maleic anhydride and 3.3 ml of triethylamine in 150 ml of DMF is heated to 80o, and then stirred for 12 hours Then the solvent is removed and the residue chromatographic on silica gel using as eluent a mixture of dichloromethane/methanol in a ratio of from 20: 1 to 10:1. In this way, in the form of a mixture of diastereoisomers gain of 5.1 g of benzyl ester of (2S)-2-tert-butyloxycarbonyl-3-(3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl)propionic acid ("compound 3"), FAB 485.

A solution of 1 g of compound 3 and 0.79 g of 2-chloro-1-methylpyridinium in 20 ml of DMF is mixed with 1 g of Z-guanidine and 1.75 ml of ethyldiethanolamine and stirred for 12 h at room temperature. After that the reaction mixture is subjected to conventional processing, receiving, after chromatography on silica gel (mixture of toluene/methanol in the ratio 10:1) 0.2 g of benzyl ester of (2S)-2-tert-butyloxycarbonyl-3- [3,4-dihydro-2-(2-benzyloxycarbonylamino-2-oxoethyl)-2H-1,4-benzoxazin-3-one-6-yl]propionic acid ("compound 4"), FAB 660.

A solution of 200 mg of compound 4 and 3 ml water and 3 ml of dioxane hydronaut at RT and normal pressure in the presence of 100 mg of palladium (10% on activated platok purified preparative GHUR (column RP-18 using a gradient mixture of acetonitrile/water + 0.3% of TFU from 1: 80 to 99:1 for 1 h), receiving 40 mg of (2S)-2-tert-butyloxycarbonyl-3- [3,4-dihydro-2-(2-guanidino-2-oxoethyl)-2H-1,4-benzoxazin-3-one-6-yl] propionic acid (compound 5) in the form of triptoreline, FAB 660.

Example 2

A solution of 6 g of ethyl ester of Z-L-DOPA ("compound 6") in 25 ml of ethanol and 25 ml of water are mixed in a protective gas atmosphere with 2.3 g of potassium carbonate. After that, the reaction mixture is heated to 60oadd 4.5 ml of epibromohydrin and heated to 90o. Then stirred for 2 h and subjected to conventional processing and the crude product is purified on silica gel. In this way receive the mixture ("mixture 8") the following pairs of isomeric position of diastereomers, which are not amenable to separation:

ethyl ester of (2S)-2-benzyloxycarbonylamino-3-(3-(3R, 3S)-hydroxymethyl-1,4-benzodioxan-6-yl)propionic acid (compound 7a) and

ethyl ester of (2S)-2-benzyloxycarbonylamino-3-(2-(2R, 2S)-hydroxymethyl-1,4-benzodioxan-6-yl)propionic acid (compound 7b") FAB 416.

A solution of 2 g of a mixture of 8 in 30 ml of pyridine is mixed at 0owith 0,413 ml methanesulfonanilide and after 2-hour stirring subjected to conventional processing. This way obtain 2.2 g of ethyl ester of (2S)-2-benzyloxycarbonylamino-3-(2/3-methylsulfonylmethyl-1,4-benzo is ml DMF was stirred at 75owithin 12 hours After the usual processing gain ethyl ester (2S)-2-benzyloxycarbonylamino-3-(2/3-azidomethyl-1,4-benzodioxan-6-yl)propionic acid ("compound 10"), FAB 441.

A solution of 1.25 g of compound 10 and 25 ml of methanol is mixed with 3.4 ml of 1N. sodium liquor and stirred for 12 h at room temperature. After the usual processing gain of 1.3 g of (2S)-2-benzyloxycarbonylamino-3-(2/3-azidomethyl-1,4-benzodioxan-6-yl)propionic acid ("compound 11"), FAB 413.

In a solution of 1.3 g of compound (11) in 40 ml of pyridine and 20 ml of water for 30 min at room temperature enter sulfide and leave to stand for 12 hours After removal of the solvents to obtain 1.5 g of (2S)-2-benzyloxycarbonylamino-3-(2/3-aminomethyl-1,4-benzodioxan-6-yl)propionic acid ("compound 12"), F 387.

A solution of 0.3 g of compound 12, 0,23 g DPFN and 0.22 ml of triethylamine in 10 ml of DMF is stirred for 12 h at 60o. After the usual processing 2-guanidinoacetate preparative GHUR (conditions similar to example 1 for the cleaning compound 5) is separated from the 3-guanidinopropionic. Output is 80 mg of (2S)-2-benzyloxycarbonylamino-3-(2-(2R,S)-guanidine-Teal-1,4-benzodioxan-6-yl)propionic acid (compound 13), FAB 429.

Prioi mixture of 0.7 g of compound 12 and the stirring is continued for a further 12 hours After the usual processing gain of 0.66 g of (2S)-2-benzyloxycarbonylamino-3-(2/3-tert-Butylochka-balsaminaceae-1,4 - benzodioxan - 6-yl) propionic acid ("compound 14"), FAB 544.

A solution of 0.15 g of compound 14 in 5 ml of dichloromethane is mixed with 0.5 ml triperoxonane acid and stirred for 8 hours After removal of the solvent, add 10 ml of DMF, and then 80 mg DPFN and 70 μl of triethylamine. The mixture is heated to 80o, and then stirred for 12 hours Cleaning and separation 2/3-isomers carry out preparative GHUR analogously to example 1. This way obtain 42 mg of (2S)-2-benzyloxycarbonylamino-3- (2-guanidinoacetate-1,4-benzodioxan-6-yl) propionic acid (compound 15"), FAB 486.

Example 4

Through a solution of 0.45 g of compound 14 in 10 ml of dioxane and 5 ml of water in the presence of 0.2 g of palladium (10% on charcoal) for 2 h miss hydrogen. After removal of the catalyst and conventional processing obtain 0.28 g of (2S)-2-amino-3-(2/3-tert-butyloxycarbonyl-1,4-benzodioxan-6-yl)propionic acid (compound 16"), FAB 410.

To a solution of 0.28 g of compound 16 in 5 ml of acetonitrile add 430 µl N, O-bis(trimethylsilyl)trifurcated (BSTFA) and then for 3 h cipai acid, and then stirred for 3 h at 70o. After the usual processing gain of 0.26 g of (2S)-2-(R)-camphorsulfonate-3-(2/3-tert-butyloxycarbonyl-atsetamidometil-1,4-benzodioxan-6-yl)propionic acid (compound 17"), FAB 624.

Similarly, the technology for connection 15 after removal of the BOC-group and guanylurea of 0.25 g of compound 17 obtain 58 mg of (2S)-2-(R)-camphorsulfonate-3-(2-guanidinoacetate-1,4-benzodioxan-6-yl)propionic acid ("compound 18"), FAB 566.

In a similar way interaction connection 16

with butylsulfonyl get (2S)-2-butylsulfonyl-3-(2/3-tert-butyloxycarbonyl-1,4-benzodioxan-6-yl)propionic acid,

4-tolylaldehyde get (2S)-2-(4-tolilsulfonil)-3-(2/3-tert-butyloxycarbonyl-1,4-benzodioxan-6-yl)propionic acid,

with benzalconihlorida get (2S)-2-benzylmaleimide-3-(2/3-tert-butyloxycarbonyl-1,4-benzodioxan-6-yl)propionic acid,

with phenylsulfonylacetate get (2S)-2-phenylsulfonyl-3-(2/3-tert-butyloxycarbonyl-1,4-benzodioxan-6-yl)propionic acid,

2-attilalongoria get (2S)-is the

with cyclohexylsulfamate get (2S)-2-cyclohexylsulfamic-3-(2/3-tert-butyloxycarbonyl-1,4-benzodioxan-6-yl)propionic acid.

The removal of the SIDE-groups and guanidinium of the above compounds get

(2S)-2-butylsulfonyl-3-(2-guanidinoacetate-1,4-benzodioxan-6-yl)propionic acid,

(2S)-2-(4-tolilsulfonil)-3-(2-guanidinoacetate-1,4-benzodioxan-6-yl)propionic acid,

(2S)-2-benzylmaleimide-3-(2-guanidinoacetate-1,4-benzodioxan-6-yl)propionic acid,

(2S)-2-phenylsulfonyl-3-(2-guanidinoacetate-1,4-benzodioxan-6-yl)propionic acid,

(2S)-2-(2-naphthylamide)-3-(2-guanidinoacetate-1,4-benzodioxan-6-yl)propionic acid and

(2S)-2-cyclohexylsulfamic-3-(2-guanidinoacetate-1,4-benzodioxan-6-yl)propionovogo acid.

Example 5

A solution of 0.3 g of compound 3 and 0,248 g of 2-aminobenzimidazole ("compound A") in 10 ml of DMF is mixed with 0.26 g of TBTU, 26 mg HOBT and 0.34 ml of N-methylmorpholine and stirred for 12 h at room temperature. After the usual processing gain of 0.14 g of benzyl ester of (2S)-2-tert-butyloxycarbonyl-3- {3,4-dihydro-2- [N-(2-benzimidazolyl) is 1 by hydrogenation of compound 19 receive 60 mg of (2S)-2-tert-butyloxycarbonyl-3- { 3,4-dihydro-2- [N-(2-benzimidazolyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 22"), FAB 510.

In a similar way interaction of compound 3 with 2 aminoimidazole ("compound B") receive benzyl ester of (2S)-2-tert-butyloxycarbonyl-3- { 3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 20) and subsequent cleavage of benzyl ether to obtain (2S)-2-tert-butyloxycarbonyl-3- {3,4-dihydro-2- [N-(2-imidazolyl)carbarnoyl-methyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 23"), FAB 460,

and the interaction of compound 3 with 2 aminomethylenemalonate ("connection") receive benzyl ester of (2S)-2-tert-butyloxycarbonyl-3- {3,4-dihydro-2- [N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 21) and subsequent cleavage of benzyl ether to obtain (2S)-2-tert-butyloxycarbonyl-3- {3,4-dihydro-2- [N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 24"), FAB 524.

Example 6

A solution of 2 g of compound 3 in 50 ml of dichloromethane is mixed with 5 ml of TFU and stirred for 1 h at room temperature. After removal of the solvent receive 2 g of benzyl ester of (2S)-amino-3-(3,4-dihydro-2 - carboxymethyl-2H-1,4-benzoxazin-3-one - 6-yl) poecillia in 25 ml of acetonitrile, add 1.2 ml of BSTFA, and then for 2 h refluxed. After that, when the 40oadd to 0.19 ml of pyridine and 0.55 g of acid chloride of (R)-camphor-10-sulfonic acid and stirred for 12 h at 70o. After the usual processing gain of 0.41 g of benzyl ester of (2S)-2- [(R)-camphorsulfonic] -3-(3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl)propionic acid (compound 26"), FAB 599.

In a similar way by the interaction of the compounds 25

with butylsulfonyl receive benzyl ester of (2S)-2-butylsulfonyl-3-(3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid,

4-tolylaldehyde receive benzyl ester of (2S)-2-(4-tolilsulfonil)-3-(3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid,

with benzalconihlorida receive benzyl ester of (2S)-2-benzylmaleimide-3-(3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl)propionic acid,

with phenylsulfonylacetate receive benzyl ester of (2S)-2-phenylsulfonyl-3-(3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl)propionic acid,

2-attilalongoria receive benzyl ester of (2S)-2-(2-naphthylamide)-3-(3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-he-is ifosamide - 3 - (3,4-dihydro - 2 - carboxymethyl - 2H-1,4-benzoxazin-3-one-6-yl)propionic acid.

Analogously to example 5 by the interaction of the connections 26

with the connection And get the benzyl ester of (2S)-2- [(R)-camphorsulfonic]-3-{3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl}propionic acid (compound 27"), FAB 714,

connection B receive benzyl ester of (2S)-2- [(R)-camphorsulfonic] -3- {3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -2H-1,4-benzoxazin-3-one-6-yl}propionic acid and

with the connection To get the benzyl ester of (2S)-2- [(R)-camphorsulfonic] -3- { 3,4-dihydro-2- [N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 29").

The removal of benzyl ester by hydrogenation

from the connection 27 receive (2S)-2- [(R)-camphorsulfonic] -3- {3,4-dihydro-2- [N-(2-benzimidazolyl)carbamoylmethyl]-2H-1,4-benzoxazin-3-one-6-yl}propionic acid (compound 28"), FAB 624, and

from compound 29 receive (2S)-2- [(R)-camphorsulfonic] -3- {3,4-dihydro-2- [N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 30"), FAB 638.

In a similar way interaction

benzyl ester of (2S)-2-butylalcohol benzyl ester of (2S)-2-butylsulfonyl - 3- { 3,4-dihydro-2- [N-(2-benzimidazolyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

connection B receive benzyl ester of (2S)-2-butylsulfonyl-3-{ 3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -2H-1,4 - benzoxazin-3-one-6-yl} propionic acid,

with the connection To get the benzyl ester of (2S)-2-butylsulfonyl-3-{ 3,4-dihydro-2-[N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4 - benzoxazin-3-one-6-yl} propionic acid;

benzyl ester of (2S)-2-(4-tolilsulfonil)-3-(3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one - 6-yl) propionic acid

with the connection And get the benzyl ester of (2S)-2-(4-tolilsulfonil)-3-{ 3,4-dihydro-2- [N-(2-benzimidazolyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

connection B receive benzyl ester of (2S)-2-(4-tolilsulfonil)-3- { 3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with the connection To get the benzyl ester of (2S)-2-(4-tolilsulfonil)-3-{3,4-dihydro-2-[N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid;

benzyl ester of (2S)-2-benzylmaleimide-3-(3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid

with the connection And get the benzyl ester of (2S)-2-benzylmaleimide-3-{ 3,4-dihydro-2- [N-(2-benzimidazolyl)carbama is silaifolia-3- { 3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -2H-1,4 - benzoxazin-3-one-6-yl} propionic acid,

with the connection To get the benzyl ester of (2S)-2-benzylmaleimide-3- { 3,4-dihydro-2- [N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid;

benzyl ester of (2S)-2-phenylsulfonyl-3-(3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid

with the connection And get the benzyl ester of (2S)-2-phenylsulfonyl-3- { 3,4-dihydro-2- [N-(2-benzimidazolyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl}propionic acid,

connection B receive benzyl ester of (2S)-2-phenylsulfonyl-3- { 3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with the connection To get the benzyl ester of (2S)-2-phenylsulfonyl-3- { 3,4-dihydro-2- [N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid;

benzyl ester of (2S)-2-(2-naphthylamide)-3-(3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid

with the connection And get the benzyl ester of (2S)-2-(2-naphthylamide)-3- { 3,4-dihydro-2- [N-(2-benzimidazolyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

connection B receive benzyl ester of (2S)-2-(2-naphthylamide)-3- { 3,4-dihydro-2- [N-(2-imidazolyl)carb(2 naphthylamide)-3- { 3,4-dihydro-2- [N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4 - benzoxazin-3-one-6-yl} propionic acid;

benzyl ester of (2S)-2-cyclohexylsulfamic-3-(3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid

with the connection And get the benzyl ester of (2S)-2-cyclohexylsulfamic-3- {3,4-dihydro-2- [N-(2-benzimidazolyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

connection B receive benzyl ester of (2S)-2-cyclohexylsulfamic-3- { 3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with the connection To get the benzyl ester of (2S)-2-cyclohexylsulfamic-3- {3,4-dihydro-2- [N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid.

A similar technique is the removal of the above benzyl ester by hydrogenation receive the following connections:

(2S)-2-butylsulfonyl-3- {3,4-dihydro-2- [N-(2-benzimidazolyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl}propionic acid,

(2S)-2-butylsulfonyl-3- {3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -2H-1,4-benzoxazin-3-one-6-yl}propionic acid,

(2S)-2-butylsulfonyl-3- { 3,4-dihydro-2- [N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl}propionic acid,
OIC acid,

(2S)-2-(4-tolilsulfonil)-3- {3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-(4-tolilsulfonil)-3- { 3,4-dihydro-2- [N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-benzylmaleimide-3- { 3,4-dihydro-2- [N-(2-benzimidazolyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl}propionic acid,

(2S)-2-benzylmaleimide-3- {3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-benzylmaleimide-3- { 3,4-dihydro-2-[N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-phenylsulfonyl-3- {3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-phenylsulfonyl-3- {3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl] -2H-1,4-benzoxazin-3-one-6-yl}propionic acid,

(2S)-2-phenylsulfonyl-3- { 3,4-dihydro-2-[N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-(2-naphthylamide)-3- { 3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl}propionic acid,

(2S)-2- (2-naphthylamide) -3- { 3,4-dihydro-2-[N- (2-imidazoli the-2-[N-(2-benzimidazo-limeter)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-cyclohexylsulfamic-3- { 3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionovogo acid,

(2S)-2-cyclohexylsulfamic-3- { 3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-cyclohexylsulfamic-3- { 3,4-dihydro-2- [N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid.

Example 7

Removal of the BOC-group using the TFU in dichloromethane

from the connection 19 receive benzyl ester of (2S)-2-amino-3- {3,4-dihydro-2- [N-(2-benzimidazolyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 31A"), FAB 500,

from the connection 20 receive benzyl ester of (2S)-2-amino-3- {3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 31B) and

from the connection 21 receive benzyl ester of (2S)-2-amino-3- {3,4-dihydro-2- [N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl}propionic acid (compound V").

A solution of 0.13 g of compound 31A in 15 ml of dichloromethane is mixed with 22 ml of acid chloride butylsulfonyl acid ("compound G") and 71 μl of triethylamine and stirred for 30 hours After the usual pererabotki is namido-3- {3,4-dihydro-2- [N-(2-benzimidazolyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 32A"), FAB 530.

In a similar way interaction connection G with subsequent hydrogenation

connection 31B receive (2S)-2-butylsulfonyl-3- {3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 32) and

connection V get (2S)-2-butylsulfonyl-3- {3,4-dihydro-2- [N-(2-benzimidazolinyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 32V").

Example 8

A solution of 2.1 g of compound 1, 3.7 g of ethyl ester of 2,4-dibromophenol acid, 1.4 g of potassium carbonate and 0.137 g of 18-crown-6 in 100 ml of toluene was stirred at 80owithin 2 hours After the usual processing obtain 1.8 g of benzyl ester of (2S)-2-tert-butyloxycarbonyl-3-[3-nitro-4-(1,4-bis (etoxycarbonyl)-4-bromobutyrate) phenyl] propionic acid (compound 34) as a colorless syrup, FAB 696.

A solution of 1.5 g of compound 34 and 0.7 g of sodium azide in 60 ml of DMF was stirred at 60owithin 12 hours After the usual processing gain of 1.3 g of benzyl ester of (2S)-2-tert-butyloxycarbonyl-3- [3-nitro-4-(1,4-bis(etoxycarbonyl) -4-azithromyci)phenyl] propionic acid (compound 35"), FAB 658.

1.1 g of compound 35 was dissolved in 50 ml of methanol, mixed with 5,9 3- [3-nitro-4-(1,4-Biscarrosse - 4-azithromyci)phenyl] propionic acid (compound 36"), FAB 512.

A solution of 0.5 g of compound 36 in 10 ml of dioxane and 5 ml of water hydronaut for 6 h in the presence of 0.1 g of palladium (10% on charcoal). At this pH value supported by the 1H. HCl level between 4 and 6. After removal of catalyst and solvent obtain 0.21 g of (2S)-2-tert-butyloxycarbonyl-3- [3,4-dihydro-2-(3-amino-3-carboxypropyl)-2H-1,4-benzoxazin-3-one-6-yl] propionic acid (compound 37), and FAB 456.

The crude product (0.2 g) connection 37 is dissolved in 10 ml of DMF, 2 ml of ethanol and 1 ml of water and within 24 h at 60oguanylurea using 0,354 g DPFN in the presence of 0.5 ml of triethylamine. After the usual processing gain of 0.1 g of (2S)-2-tert-butyloxycarbonyl-3-[3,4-dihydro-2-(3-guanidino-3-carboxypropyl)-2H-1,4-benzoxazin-3-one-6-yl] propionic acid (compound 38"), FAB 480.

A solution of 50 mg of compound 38 (triptoreline) in 2 ml of DMF is mixed with 32 mg of 2-chloro-1-methylpyridinium and 60 μl of ethyldiethanolamine and stirred for 12 hours After the usual processing obtain 22 mg of (2S)-2-tert-butyloxycarbonyl-3- { 3,4-dihydro-2- [3-(2-imino-4-Oxymetazoline-5-yl) propyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 39").

Example 9

A solution of benzyl ether diversified quantities tert-butyl ether bromoxynil acid and NaH. Then stirred for 2 hours and after normal processing receive benzyl ester 2-butylsulfonyl-3-(2-tert-butoxycarbonylmethyl-2,3-dihydrobenzo[1,4]dioxin-6-yl) propionic acid.

In a similar way after subsequent removal of the BOC-group using the TFU interaction with 2-aminobenzimidazole and the removal of benzyl ester by hydrogenation get the following connection:

(2S)-2-butylsulfonyl-3-{2- [(1H-imidazol-2-ylcarbonyl)methoxymethyl] -2,3-dihydrobenzo[1,4]dioxin-6-yl} propionic acid.

Similarly receive 2-(4-tolilsulfonil)-3- {2-[(1H-imidazol-2-ylcarbonyl)methoxymethyl] -2,3-dihydrobenzo[1,4]dioxin-6-yl} propionic acid.

Example 10

Interaction of compound 25 with 2,2,2-trichloro-1,1-dimethylethylamine ether Harborview acid with subsequent cleavage of benzyl ester by hydrogenation to obtain (2S)-2-{[(2,2,2-trichloro-1,1-dimethyl)ethyl]carboxamido} -3-(3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl)propionic acid (compound 40").

Analogously to example 5 by the interaction of connections 40 with the connection And obtain (2S)-2- {[(2,2,2-trichloro-1,1-dimethyl)ethyloxy]carboxamido} -3-{ 3,4-dihydro-2-[N-(2-benzimidazo is illogical get by (2S)-2-{[(neopentylene)ethyl]carboxamido] -3- [3,4-dihydro-2- [N-(2-benzimidazolyl)carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 524.

Example 11

Interaction at room temperature ethyl ester BOC-3-amino-L-tyrosine 5-benzyl ester (2S)-bromopentanoate [produced by the interaction of the benzyl ester of L-glutamic acid with NaNO2and KBr in sulfuric acid] and EDCI in dichloromethane after a 12-hour mixing and conventional processing receive benzyl ether of (4S)-4-bromo-4-[5-((2S)-2-tert-butyloxycarbonyl-2-ethoxycarbonylethyl) -2-hydroxyphenylarsonic] butyric acid, FAB 608.

In the 12-hour endurance with heating at 100owith DBU (diazabicyclo-7-Yong) in toluene after the usual processing gain ethyl ester (2S)-3-[(2R)-2-(2-benzyloxycarbonylamino)-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl] -2-tert-butoxycarbonylamino-propionic acid, FAB 527. After that, by hydrogenation in the presence of Pd/C to obtain ethyl ester (2S)-2-tert-butoxycarbonylamino-3-[(2R)-2-(2-carboxyethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4] oxazin-6-yl] propionic acid (compound 41"), FAB 437:

< / BR>
Analogously to example 5 by the interaction of the connections 41

with the connection And receive the ethyl ester of (2S)-2-tert-butyloxycarbonyl-3- { 3,4-dihydro-2- [N-(2-benzimidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propio is { 3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 43"), FAB 502.

After removal of ethyl ether compounds 42 and 43 with aqueous NaOH receive the following connections:

(2S)-2-tert-butyloxycarbonyl-3- { 3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 524, and

(2S)-2-tert-butyloxycarbonyl-3- { 3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl}propionic acid, FAB 474.

Similarly receive the following compound: (2S)-2-tert-butyloxycarbonyl-3- {3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl] -(2S)-2H-l, 4-benzoxazin-3-one-6-yl}propionic acid, FAB 474.

Example 12

Removal of the BOC-group using the TFU in dichloromethane of compounds 42 and 43 receive the following connections:

ethyl ester of (2S)-2-amino-3- { 3,4-dihydro-2- [N-(2-benzimidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 44) and

ethyl ester of (2S)-2-amino-3-{3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid (compound 45"), FAB 402.

Analogously to example 6 by the interaction of the connection 44 with 2,3,5,6-tetramethylenedisulfotetramine get ethyl ester (2S)-2-(2,3,5,6-tetramethylrhodamine)-3- {3,4-dihydro-2- [N-(2-Benz ether obtain (2S)-2-(2,3,5,6-tetramethylrhodamine)-3- { 3,4-dihydro-2-[N-(2-benzimidazolyl) carbamoylethyl] - (2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 620.

In a similar way interaction connection 45

with 3-chloro-6-methoxybenzenesulfonamide get ethyl ester (2S)-2-(3-chloro-6-methoxybenzenesulfonamide)-3- { 3,4-dihydro-2-[N-(2-imidazolyl) carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

1-attilalongoria get ethyl ester (2S)-2-(1-naphthylamide)-3- {3,4-dihydro-2-[N-(2-imidazolyl) carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with 2,3,5,6-tetramethylenedisulfotetramine get ethyl ester (2S)-2-(2,3,5,6-tetramethylrhodamine)-3-{ 3,4-dihydro-2-[N-(2-imidazolyl) carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with (R)-camphor-10-sulphonylchloride get ethyl ester (2S)-2-[(R)-camphor-10-ralfinamide)-3- {3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with butylsulfonyl get ethyl ester (2S)-2 - butylsulfonyl-3- { 3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with isopropyl ether of Harborview acid get ethyl ester (2S)-2-isopropoxycarbonyl-3- {3,4-dihydro-2- [N-(2-imidazolyl)carbody get ethyl ester (2S)-2-isobutoxyethene-3- {3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] - (2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with neopentylene ether Harborview acid get ethyl ester (2S)-2-neopentecostalism-3- {3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with benzyl ether of Harborview acid get ethyl ester (2S)-2-benzyloxycarbonylamino-3- [3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with benzalconihlorida get ethyl ester (2S)-2-benzylmaleimide-3- { 3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with benzosulphochloride get ethyl ester (2S)-2 - benzosulfimide-3- { 3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] - (2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

and then from these compounds by cleavage of the ether obtain the following derivatives of propionic acid:

(2S)-2-(3-chloro-6-methoxybenzenesulfonamide)-3- { 3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 578,

(2S)-2-(1-naphthylamide)-3- { 3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 564,

(2S)-2-(2,3,5,6-t the OIC acid, FAB 570,

(2S)-2- [(R)-camphor-10-ralfinamide)-3- {3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 588,

(2S)-2-butylsulfonyl-3- {3,4-dihydro-2- [N-(2-imidazo-Lil)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 494,

(2S)-2-isopropoxycarbonyl-3- { 3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 460,

(2S)-2-isobutoxyethene-3- { 3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -(2R) -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 474,

(2S)-2-neopentecostalism-3- { 3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 488.

(2S)-2-benzyloxycarbonylamino-3- { 3,4-dihydro-2- [N-(2-imidazolyl)carbamoylethyl] -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 508,

(2S)-2-benzylmaleimide-3- {3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl] - (2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 528,

(2S)-2-benzosulfimide-3- {3,4-dihydro-2- [N-(2-imidazolyl) carbamoylethyl] - (2R) -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 514.

Similarly receive (2S)-2-(1,1-dimethyl-2,2,2-trichloroacetamido)-3- }3,4-dihydro-2- [N-(2-imidazolyl)carbamoylation together with 37 g of potassium bromide in 300 ml of 2.5 N. sulfuric acid and, at 0omixed with 9.7 g of sodium nitrite. The reaction mixture is allowed to warm to room temperature and then stirred for 12 hours After the usual processing obtain 11 g of (2S)-2-bromo-4-benzyloxycarbonylamino acid in the form of oil, EI 330.

Subsequent interaction at room temperature with ethyl ether SIDE-by-3-amino-L-tyrosine and EDCI in dichloromethane after a 12-hour stirring, the normal processing and the subsequent interaction of the obtained product with DBU (diazabicyclo-7-Yong) in toluene at 100oget ethyl ester (2S)-3-[(2R)-2-(3-benzyloxycarbonylamino)-3-oxo-3,4-dihydro-2H-benzo[1,4] oxazin-6-yl] -2-tert-butoxycarbonylamino acid (compound 46"), FAB 556.

By hydrolysis of the ester with an aqueous solution of sodium liquor with subsequent cleavage of the Z group by hydrogenation (in the presence of Pd/C in dioxane/water to obtain (2S)-3-[(2R)-2-(3-aminopropyl)-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl] -2-tert-butoxycarbonylamino acid, FAB 394.

Analogously to example 3 from this compound by interaction with DPFN get (2S)-3- [(2R)-2-(3-guanidinopropionic)-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl] -2-tert-butoxycarbonylamino which indicate the ethyl ester of (2S)-2-amino-3-[(2R)-2-(3-benzyloxycarbonylamino)-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl] propionic acid (compound 47) in the form of triptoreline, FAB 456

< / BR>
Analogously to example 6 by the interaction of the compounds 47

with 2,3,5,6-tetramethylenedisulfotetramine get ethyl ester (2S)-2-(2,3,5,6-tetramethylrhodamine)-3- { 3,4-dihydro-2-(3-benzyloxycarbonylamino)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with 3-chloro-6-methoxybenzenesulfonamide get ethyl ester (2S)-2-(3-chloro-6-methoxybenzenesulfonamide)-3- { 3,4-dihydro-2-(3-benzyloxycarbonylamino)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

1-attilalongoria get ethyl ester (2S)-2-(1-naphthylamide)-3- {3,4-dihydro-2-(3-benzyloxycarbonylamino)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with (R)-camphor-10-sulphonylchloride get ethyl ester (2S)-2-[(R)-camphor-10-ralfinamide)-3- { 3,4-dihydro-2-(3-benzyloxycarbonylamino)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with butylsulfonyl get ethyl ester (2S)-2-butylsulfonyl - 3- {3,4-dihydro-2-(3-benzyloxycarbonylamino) -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 576,

with isopropyl ether of Harborview acid get ethyl ester (2S)-2-isopropoxycarbonyl-3- { 3,4-dihydro-2-(3 - benzyloxycarbonylamino) -(2R)-2H-1,4 - benzox is (2S)-2-isobutoxyethene-3- { 3,4-dihydro-2-(3 - benzyloxycarbonylamino) -(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with neopentylene ether Harborview acid get ethyl ester (2S)-2-neopentecostalism-3- { 3,4-dihydro-2-(3-benzyloxycarbonylamino)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 570,

with benzyl ether of Harborview acid get ethyl ester (2S)-2-benzyloxycarbonylamino-3-{ 3,4-dihydro-2-(3-benzyloxycarbonylamino)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with benzalconihlorida get ethyl ester (2S)-2-benzylmaleimide-3- { 3,4-dihydro-2-(3-benzyloxycarbonylamino)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

with benzosulphochloride get ethyl ester (2S)-2-benzosulfimide-3- { 3,4-dihydro-2-(3-benzyloxycarbonylamino)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid.

From the above Z-protected esters of propionic acid by cleavage of esters and hydrogenation receive the following connections:

(2S)-2-(2,3,5,6-tetramethylrhodamine)-3- { 3,4-dihydro-2-(3-aminopropyl)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-(3-chloro-6-methoxybenzenesulfonamide)-3- { 3,4-dihydro-2-(3-aminopropyl)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S) -2-(1-naphthylamide)-3- {3,4-dihydro-2-(3-Amin is-(3-aminopropyl)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-butylsulfonyl-3- { 3,4-dihydro-2-(3-aminopropyl)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-isopropoxycarbonyl-3- {3,4-dihydro-2-(3-aminopropyl)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-isobutoxyethene-3- { 3,4-dihydro-2-(3-aminopropyl)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-neopentecostalism-3- { 3,4-dihydro-2-(3-aminopropyl)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 408,

(2S)-2-benzyloxycarbonylamino-3- { 3,4-dihydro-2-(3-aminopropyl)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S) -2-benzylmaleimide-3- {3,4-dihydro-2- (3-aminopropyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-benzosulfimide-3- { 3,4-dihydro-2-(3-aminopropyl)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid.

Analogously to example 3 of the above propionic acid interaction with DPFN receive the following connections:

(2S)-2-(2,3,5,6-tetramethylrhodamine)-3- { 3,4-dihydro-2-(3-guanidinopropionic)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-(3-chloro-6-methoxybenzenesulfonamide)-3- { 3,4-dihydro-2-(3-guanidinopropionic)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-(1-naphthylamide)-3- { 3,4-dihyd is about)-3- { 3,4-dihydro-2-(3-guanidinopropionic)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-butylsulfonyl-3- { 3,4-dihydro-2-(3-guanidinopropionic)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-isopropoxycarbonyl-3- { 3,4-dihydro-2-(3-guanidinopropionic)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-isobutoxyethene-3- { 3,4-dihydro-2-(3-guanidinopropionic)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-neopentecostalism-3- { 3,4-dihydro-2-(3-guanidinopropionic)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 450,

(2S)-2-benzyloxycarbonylamino-3- { 3,4-dihydro-2-(3-guanidinopropionic)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

(2S)-2-benzylmaleimide-3- { 3,4-dihydro-2-(3-guanidinopropionic)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid and

(2S)-2-benzosulfimide-3- { 3,4-dihydro-2-(3-guanidinopropionic)-(2R)-2H-1,4-benzoxazin-3-one-6-yl} propionic acid.

The following are examples of pharmaceutical compositions and technology of their preparation in the appropriate dosage forms (example 14).

Example: Vials for injection solutions

A solution of 100 g of the active substance of the formula I and 5 g of disodium hydrogen phosphate in 3 l of double-distilled water using a 2H. hydrochloric acid set at pH 6.5, sterile filtered, zapolnaya substances.

Example B: Suppositories

A mixture of 20 g of the active substance of the formula I, 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to harden. Each suppository contains 20 mg of active substance.

Example: Solution

Prepare a solution of 1 g of the active substance of the formula I, 9,38 g NaH2PO42H2O, 28,48 g Na2HPO412H2O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. Then set to pH 6.8, adjusted to a volume of 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example D: Ointment

When observing aseptic conditions prepare a mixture of 500 mg of the active substance of the formula I with 99.5 g of petroleum jelly.

Example D: Tablets

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 tabletirujut by the conventional methods, receiving tablets, each containing 10 mg of active substance.

Example E: Bean

Analogously to example D is pressed tablets, which then according to standard technology is covered by a shell of sucrose, potato starch, talc, tragant and dye.

Example G: Capsules
freight, each of which contains 20 mg of active substance.

Example C: Ampoules

A solution of 1 kg of active substance of the formula I in 60 l of double-distilled water is sterile filtered, dispensed into ampoules under sterile conditions lyophilized sealed and sterile. Each ampoule contains 10 mg of active substance.

Example: Inhalation spray

14 g of the active substance of the formula I are dissolved in 10 l of isotonic NaCl solution and then the solution is poured into a conventional, commercially available cartridges, equipped with a pumping device. The solution can be applied to inhalation mouth and nose. Issued from cans for one pressing portion (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg

PHARMACOLOGICAL REPORT

The following test results prove that the claimed compounds are inhibitors of integrinsv3,v5and glycoprotein GPIIb/IIIa.

Test for binding receptors

Purified human integrins GPIIb/IIIa (identical IIb3) from platelets andv3,v5from the placenta during normal pregnancy was placed on the tablet for micrometrology and combined with biotinyl the IIb3 in the presence of increasing amounts of test compounds.

Method: 1 µg ml-1the Biotin-ligand were incubated with 1 µg ml-1coating of the receptor (receptor located on the cell surface) in the presence of serially diluted EMD peptide for 3 hours at a temperature of 30oC. and Then measured the number of bound ligands, using the method of determining antibiotic-alkaline phosphatase.

Literature: Charo I. F., L. Nannizzi, J. W. Smith and Cheresh D. A., J. Cell. Biol. 111, 2795-2800 (1990).

Presented in table 1, the results illustrate the tested compounds, the values of their IC50and the number of examples, according to which the received listed compounds.

1. Bicyclic aromatic amino acids of the formula I

< / BR>
in which R1denotes H or alkyl with 1-6 atoms;

R2means R10, COOR10or SO2R10;

R3denotes H;

R4denotes H or =O;

R5denotes NH2or H2N-C (=NH)-NH, and the primary amino group can be protected by the usual aminosidine groups or substituted once COOR10or is identical to R6,

R7, R8each independently of each other either absent or denotes N;

X, Y each independently SUP> C(=O), CONH or NHCO;

R6represents a single or dual-core a heterocycle with 1 to 4 N and/or O atoms, which may be replaced twice =NH or =O;

R9denotes Hal or SO3N;

R10denotes H, a or AG;

R11denotes H;

And denotes H or unsubstituted or two - or three-fold substituted by the radical R9alkyl, or cycloalkyl with 1-15 carbon atoms, and where one methylene group may be replaced by S;

AG is a threefold substituted and/or R9single - or dual-core aromatic cyclic system with 0, 1, 2, 3 or 4 N-, O - or S-atoms;

Hal denotes F, Cl, Br or I;

m, n are each independently of one another denotes 0, 1, 2 or 3,

and their physiologically acceptable salts.

2. The enantiomers or diastereoisomers of the compounds of formula I under item 1.

3. The compounds of formula I under item 1

a) (2S)-2-benzyloxycarbonylamino-3-(2-guanidinate-1,4-benzodioxan-6-yl) propionic acid;

b) (2S)-2-tert-butyloxycarbonyl-3-[3,4-dihydro-2-(2-guanidino-2-oxoethyl)-2H-1,4-benzoxazin-3-one-6-yl] propionic acid;

C) (2S)-2-benzyloxycarbonylamino-3-(2-guanidinoacetate-1,4-benzodioxan-6-yl) propionic acid;

g) (2S)-2 is I acid;

d) (2S)-2-tert-butyloxycarbonyl-3-{ 3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl]-2H-1,4-benzoxazin-3-one-6-yl} propionic acid;

e) (2S)-2-tert-butyloxycarbonyl-3-{ 3,4-dihydro-2-[2-(2-imino-4-Oxymetazoline-5-yl)ethyl]-2H-1,4-benzoxazin-3-one-6-yl} propionic acid;

g) (2S)-2-tert-butyloxycarbonyl-3-{ 3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl]-(2S)-2H-1,4-benzoxazin-3-one-6-yl) propionic acid;

C) (2S)-2-[(R)-camphorsulfonic] -3-{3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl]-2H-1,4-benzoxazin-3-one-6-yl} propionic acid,

and their physiologically acceptable salts.

4. The method of obtaining compounds of formula I on p. 1 and their salts, characterized in that the compound of formula II

< / BR>
in which R1, R3, R4, R5, R7, R8, R11, W, X, Y, Z, m and n have the meanings specified in paragraph 1, is subjected to the interaction with the compound of the formula III

R2-L III

in which R2has the meaning specified in paragraph 1 of the formula, L denotes CL, Br, I, HE or reactive esterified HE is the group to obtain the compounds of formula I in which R1, R3, R4, R5, R7, R8, R11, W, X, Y, Z, m and n have the meanings specified in paragraph 1, with Priroda subsequent stage of removal of the amino - and/or hydroxyamine group in the resulting compound of formula I by treatment by means of solvolysis or hydrogenolysis, or obtained saponification of ester of the formula I, or becoming one of the residues R1and/or R5in the resulting compound of formula I into another residue R1and/or R5and/or treatment of compounds of formula I obtained in the form of a base or acid, respectively, with an acid or a base to obtain one of its salts.

5. The pharmaceutical composition inhibiting the integrin, characterized in that it contains at least one compound of formula I under item 1 and/or one of its physiologically acceptable salts.

 

Same patents:

The invention relates to new derivatives of benzoxazinone General formula (I), where R1means N or carboxyethyl, R2represents hydrogen or alkyl, and R3is a different derivatively of amino acids, dipeptides and hydrazones acid groups, respectively, their conjugates with active substances, such as residues from a number of penicillin

The invention relates to compounds: N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl] -2-yl] methyl]-N,3,3-trimethylbutyramide and N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide and their pharmaceutically acceptable salts, such as lithium, sodium or potassium salt or a salt with a base, which is an organic amine

The invention relates to new derivatives of oxadiazole General formula I, in which X and Y denote oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen; Z denotes a radical of the formula II, R1means phenyl radical, which is optionally substituted directly or through alkylene bridges with the number of carbon atoms from 1 to 4 once, twice or three times by one or more substituents from the series halogen, C1-C4-alkyl, CF3, -NR5R6, NO2, -OR7

The invention relates to compounds of formula (I) R4-A-CH(R3)N(R2)B-R1where a is optionally substituted phenyl group, provided that the group-CH(R3)N(R2)B-R1and-OR4are in the 1,2-position relative to each other on the carbon atoms of the ring, and provided that the atom of the ring, in anthopology towards OR4- joined the group (and therefore in the 3-position relative to the-CHR3NR2-linking group) is unsubstituted; In - pyridyl or pyridazinyl; R1located on the ring In the 1,3 - or 1,4-position relative to the-CH(R3)N(R2)-linking group and represents carboxy, carbarnoyl or tetrazolyl, or R1represents a group of formula СОNRaRa1where Rais hydrogen or C1-6alkyl, and Ra1- C1-6alkyl, or R1represents a group of formula CONHSO2Rbwhere Rb- C1-6alkyl, trifluoromethyl, or a 5-membered heteroaryl selected from isooxazolyl and thiadiazolyl, optionally substituted C1-6the alkyl or C1-4alkanolamines; R2- C1-6alkyl; R3is hydrogen; R4- C1-4alkyl, C3-7cycloalkyl,1-3alkyl or their pharmaceutically acceptable salt or in vivo hydrolyzable esters

The invention relates to a new method of obtaining isoxazolidinone the compounds of formula (II) in which R represents an optionally substituted aromatic hydrocarbon group or its salt, by reacting the compounds of formula (1) or its salt with the compound of the formula (2) in the presence of an inorganic base in an aqueous solvent with getting aspartates the compounds of formula (3), which interacts with acetic anhydride using dimethylaminopyridine as a catalyst in the presence of base followed by heating for decarboxylation to obtain the compounds of formula (4), to which is added p-toluensulfonate acid to obtain oxazolidinedione derivative of the formula (5)which then restores the tetrahydrofuran in the presence of NaBH4and methanol to obtain oxazolidinones the compounds of formula (6) and its further interaction with methylchloride in the presence of triethylamine to obtain methanesulfonate derivative of the formula (7), which interacts with the compound of the formula (8) in the presence of potassium carbonate to obtain benzylidene derivative of the formula (9), which is further restored in an atmosphere of hydrogen for the floor is warping with obtaining the compounds of formula (11)

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts

The invention relates to derivatives of N-sulfanilimide formula I, where R1and R2denote hydrogen, halogen, C1-4alkyl, C1-4alkoxycarbonyl or phenyl which can be substituted one to three times, equal or different residues from the group comprising halogen, C1-4alkyl, trifluoromethyl; R3- halogen, cyano, trifluoromethyl; R4- 4-isoxazolyl, pyrazolyl, which may be substituted with halogen, C1-4the alkyl, amino group, cycloalkyl, as well as their acid-salt additive

The invention relates to a new method of obtaining diastereomeric mixture piperidinylmethyl-tripterocalyx cyclic ethers of the formulae Ia and Ib and their pharmaceutically acceptable salts, where R1is C1-C6the alkyl, R2is C1-C6by alkyl, halogen, C1-C6the alkyl or phenyl or substituted phenyl, R3is hydrogen or halogen; m = 0, 1 or 2, in which said mixture is enriched compound of formula Ia

The invention relates to a new crystalline (-)-3R,4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4-[2-(pyrrolidin-1-yl)ethoxy] phenyl} chromane hydrofolate, method thereof, pharmaceutical compositions on the basis and method of reducing or preventing the rarefaction of bone, including the introduction to the patient an effective amount of the specified new connection

The invention relates to a new method of producing compounds of the formula I

< / BR>
where a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl, - inhibitors of 5-lipoxygenase, are useful for the treatment or relief of inflammatory diseases, Allergy and cardiovascular diseases

The invention relates to new derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease

The invention relates to substituted chromalusion (thio)ureas of the formula (I):

< / BR>
where R (1) denotes hydrogen, alkyl with 1-4 C-atoms, alkoxy with 1-4 C-atoms, fluorine, chlorine, bromine, iodine, CF3, NH2, NH-alkyl with 1-4 C-atoms, N(alkyl)2with 1-4 C-atoms in the same or different alkyl residues, or S-alkyl with 1-4 C-atoms;

R (2a) denotes hydrogen or alkyl with 1 or 2 C-atoms;

R (2b) and R (2d), which are identical or different, denote hydrogen, alkyl with 1 or 2 C-atoms not substituted phenyl, substituted phenyl, unsubstituted benzyl or substituted phenyl residue, benzyl, and as the substituents in the phenyl residues are up to three identical or different substituents selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;

R (2c) and R (2e), which are identical or different, denote hydrogen or alkyl with 1 or 2 C-atoms;

R (3) denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms in the ring, CH2-cycloalkyl with 3, 4, 5 or 6 C-atoms in the ring, or CF3;

Q represents (CH2)n;

where n = 1 or 2;

Z denotes serousily, selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;

or

A denotes the residue of a saturated or unsaturated lactam of the formula:

< / BR>
where B denotes albaniles or alkylene with 3, 4, 5 or 6 C-atoms, which is unsubstituted or substituted by up to three identical or different alkyl groups with 1, 2, 3 or 4 C-atoms;

or

A denotes the residue of a bicyclic system of the formula:

< / BR>
< / BR>
< / BR>
< / BR>
and their physiologically acceptable salts

The invention relates to bicyclic compounds useful as drugs, the neutralizing effect of glycoprotein IIb/IIIa, to prevent thrombosis

The invention relates to the derivatives of colchicine formula (I), where R denotes methoxy or methylthiourea; R1means a linear or branched C1- C6alkyl, provided that when R is methoxy, R1cannot be methyl; and compounds of formula II, where R is methylthio; R1means a linear or branched C1- C6-alkyl
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