It is a polycyclic thiazolidin-2-radenovi amines containing their medicines and how to obtain medicines

 

(57) Abstract:

Describes polycyclic, thiazolidin-2-radenovi amines of the formula I and their physiologically acceptable salts

where mean (A) Y - a simple link, X - CH2, R1 - (C2-C6)-alkyl, in which one hydrogen may be replaced by OS(O)CH3; AND (C2-C6)-alkenyl; and (C2-C6)-quinil; O-CF3, O-CH2-CF3, O-CH2-CF2-CF3, O-CH2-CF2-CF2-CF3ABOUT-(C4-C6)-alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine; S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n = 0-1, and phenyl residue up to two times may be substituted (C1-C6)-alkyl; phenyl, O-(CH2)n-phenyl, and n = 0-1, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, and phenyl cycles can be from one to three times substituted by F, Cl, CF3, OCF3, (C1-C6)-alkyl, SO2-CH3ABOUT-(C1-C6)-alkyl; R1’ is H, R2 is H, R3 is H,

R4 - (C1-C6)-alkyl, R5 - (C1-C6)-alkyl, or Y is a simple link,

X - CH2, R1 and R1’ n the SUB>3With(ABOUT)HE, R4 - (C1-C6)-alkyl, (CH2)n-phenyl, and n = 1, R5 - (C1-C6)-alkyl, (CH2)n-phenyl, and n = 1, or (C) Y - a simple link, X - CH2, R1 and R1’ independently of each other H, Cl, phenyl, substituted CF3R2 - (C1-C6)-alkyl, (C2-C8)-alkenyl, R3 is H, F, R4 - (C1-C6)-alkyl, (CH2)n-phenyl, and n = 0 and phenyl may be substituted by Cl, O-(C1-C6)-alkyl; R5 - (C1-C6)-alkyl, (CH2)n-phenyl, and n = 0 and phenyl may be substituted by Cl, O-(C1-C6)-alkyl; or D) Y is a simple bond, -CH2- or-CH2-CH2-; X is CH(phenyl), and the phenyl residue may be substituted by Cl; O, S, SO2,

R1 and R1’ independently of each other H, Cl, NO2CN, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n = 0, R2 is H, R3 is H, R4 - (C1-C6)-alkyl, R5 - (C1-C6)-alkyl, or R4 and R5 together can mean-CH2-CH2- or-CH2- (CH3)2group or (E) Y - a simple link, X - CH2, R1 is Cl, R1’ is H, R2 is H;

R3 is H, R4 is phenyl, and the phenyl residue may be substituted up to two times F, Cl, O-(C1-C3)-alkyl, (C1-C6)-alkyl-C3)-alkyl. Compounds suitable for the treatment of obesity, for the prophylaxis or treatment of diabetes type II. Also describes the medicinal product to suppress appetite and/or weight loss and medicine for the prevention and treatment of type II diabetes, as well as the method of obtaining drugs by mixing the active substance with a pharmaceutically acceptable carrier and the mixture result in a usable form. 4 N. and 7 C.p. f-crystals, 2 tab.

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives.

The prior art known derivatives of thiazolidine with a decreasing appetite for action (Austrian patent No. 365181).

The objective of the invention is to provide compounds that have therapeutically applicable lowering appetite action. In this regard, the objective is to get the connection, lowering the appetite, which is increased in comparison with the compounds of the patent AT 365181.

This invention thus relates to polycyclic, thiazolidin-2 - ildenafil amines of the formula I

where mean

H5), SN(C3H7);

R1 is CN, COOH, COO(C1-C6)alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)alkyl]2, (C2-C6)-alkyl, (C2-C6)-alkenyl; and (C2-C6)-quinil; O-CH2CF3, O-CH2-CF2-CF3ABOUT-(C4-C6)-alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine, or one hydrogen may be replaced by HE, OC(O)CH3, O-CH2Ph, NH2or N(COOCH2Ph)2;

S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n=0-6, and the phenyl residue up to two times may be substituted by F, Cl, Br, HE, CF3, NO2CN, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl or NH2; NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, biphenyl, O-(CH2)n-phenyl, and n=0-6, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl or 2 - or 3-thienyl, and phenyl, biphenylene, raftiline, peredelnye, foronline or thienyl cycles each can be from one Kilom, NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;

1,2,3-triazole-5-yl, and triazole ring in 1-, 2 - or 3-position may be replaced by stands or benzyl;

tetrazol-5-yl, and tetrazole ring in 1 - or 2-position may be replaced by stands or benzyl;

R1’ is H, F, Cl, Br, J, CH3, CF3, O-(C1-C3)-alkyl, NO2, SO2-NH2, SO2NH-(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2or R1;

R2 is H, (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, C(O)-(CH2)n-phenyl, C(O)-(CH2)n-thienyl, C(O)-(CH2)n-pyridyl, C(O)-(CH2)n-furyl, and n=0-5, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl, C(O)-(C1-C6)-alkyl, C(O)-(C3-C6-cycloalkyl;

R3 is H, (C1-C6)-alkyl, F, CN, N3, O-(C1-C6)-alkyl, CH2-COO(C1-C6alkyl), CH2WITH THE H3)2, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, and n=0-5, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl, (C2-C6)-quinil, (C2-C6)-alkenyl, C(O)och3WITH(O)OCH2CH3WITH(ABOUT)IT, C(O)NH2WITH(O)N3WITH(O)N(CH3)2, OS(O)CH3;

R4 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, and n=0-5, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

R5 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, and n=0-5, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

or

R4 and R5 together form the group - CH2-CH2-, - CH2- (WHEN P CLASS="ptx2">In)

Y is a simple bond, -CH2- or-CH2-CH2-;

X - CH2CH(CH3), CH(C2H5), SN(C3H7);

R1 and Rl’ are independently from each other

H, F, Cl, Br, J, NO2, CN, COOH, COO(C1-C6) alkyl, CONH2, N(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl; and (C2-C6)-quinil; O-(C1-C6)-alkyl, O-CH2CF3, O-CH2-CF2-CF3ABOUT-(C4-C6)-alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine, or one hydrogen may be replaced by HE, OC(O)CH3, O-CH2Ph, NH2or N(COOCH2Ph)2;

S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n=0-6, and the phenyl residue up to two times may be substituted by F, CL, Br, HE, CF3, NO2CN, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2; SO2-NH2, SO2NH-(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, NH2, NH-(C1-C6)-alkyl, N((C1and 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl or 2 - or 3-thienyl, and phenyl, biphenylene, raftiline, peredelnye, foronline or thienyl cycles each can be from one up to 3 times substituted by F, Cl, Br, J, HE, CF3, NO2CN, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;

1,2,3-triazole-5-yl, and triazole ring in 1-, 2 - or 3-position may be replaced by stands or benzyl;

tetrazol-5-yl, and tetrazole ring in 1 - or 2-position may be replaced by stands or benzyl;

R2 is H, (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, C(O)-(CH2)n-phenyl, C(O)-(CH2)n-thienyl, C(O)-(CH2)n-pyridyl, C(O)-(CH2)n-furyl, and n=0-5, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl, C(O)-(C1-C6)-alkyl, C(O)-(C3-C6-cycloalkyl;

R3 - (C4-C68cycloalkyl), CH2-COOH, CH2-CONH2CH2THE ON3CH2-SOP(CH3)2, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, and n=0-5, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl, (C2-C6)-quinil, (C2-C6)-alkenyl, C(O)och3WITH(O)OCH2CH3WITH(O)HE, C(O)NH2WITH(O)N3WITH(O)N(CH3)2, OS(O)CH3;

R4 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, and n=0-5, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

R5 - (C1-C6) - alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, and n=0-5, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-ptx2">-CH2-CH2-CH2- or - CH2-CH2-CH2-CH2-;

or

C)

Y is a simple bond, - CH2- or - CH2-CH2-;

X - CH2CH(CH3), CH(C2H5), SN(C3H7);

R1 and R1’ independently of each other H, F, Cl, Br, J, NO2, CN, COOH, COO(C1-C6) alkyl, CONH2, N(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C2-C6)-alkyl, (C1-C6)-alkenyl; (C2-C6)-quinil; O-(C1-C6)-alkyl, O-CH2-CF3, O-CH2-CF2-CF3, O-(C4-C6)-alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine, or one hydrogen may be replaced by HE, OC(O)CH3, O-CH2-Ph, NH2or N(COOCH2Ph)2;

S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n=0-6, and the phenyl residue up to two times may be substituted by F, C1, Br, HE, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2; SO2-NH2, SO2NH-(C1-C6)-alkyl, SO, NH(C1-C7)-acyl, phenyl, biphenyl, O-(CH2)n-phenyl, and n=0-6, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl or 2 - or 3-thienyl, and phenyl, biphenylene, raftiline, peredelnye, foronline or thienyl cycles each can be from one up to 3 times substituted by F, Cl, Br, J, HE, CF3, NO2CN, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NN-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;

1,2,3-triazole-5-yl, and triazole ring in 1-, 2 - or 3-position may be replaced by stands or benzyl;

tetrazol-5-yl, and tetrazole ring in 1 - or 2-position may be replaced by stands or benzyl;

R2 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, C(O)-(CH2)n-phenyl, C(O)-(CH2)n-thienyl, C(O)-(CH2)n-pyridyl, C(O)-(CH2)n-furyl, and n=0-5, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3(With<>-cycloalkyl;

R3 is H, (C1-C6)-alkyl, F, CN, N3, O-(C1-C6)-alkyl, CH2-COO(C1-C6alkyl), CH2-COO(C3-C8cycloalkyl), CH2-COOH, CH2-CONH2CH2THE N3CH2-CON(CH3)2, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, and n=0-5, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl, (C2-C6)-quinil, (C2-C6)-alkenyl, C(O)och3WITH(O)OCH2CH3WITH(ABOUT)IT, C(O)NH2WITH(O)N3WITH(O)N(CH3)2, OS(O)CH3;

R4 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, and n=0-5, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

R5 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)nB>1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

or

R4 and R5 together form the group - CH2-CH2-, - CH2- (CH2)2, -CH2-CH2-CH2- or-CH2-CH2-CH2-CH2-;

or D)

Y is a simple bond, -CH2- or-CH2-CH2-;

X - CH(phenyl), and the phenyl residue may be substituted by F, C1, Br or J,

O, S, SO, SO2or N-R6;

R1 and R1’ independently of each

H, F, Cl, Br, J, NO2, CN, COOH, COO(C1-C6) alkyl, CONH2, CONH(C1-C6) alkyl, CON[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl; and (C2-C6)-quinil; O-(C1-C6)-alkyl, O-CH2-CF3, O-CH2-CF2-CF3ABOUT-(C4-C6)-alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine, or one hydrogen may be replaced by HE, OC(O)CH3, O-CH2-Ph, NH2or N(COOCH2Ph)2;

S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n=0-6, and the phenyl residue to DV is B>6)-alkyl, NH2; SO2-NH2, SO2NH-(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, biphenyl, O-(CH2)n-phenyl, and n=0-6, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl or 2 - or 3-thienyl, and phenyl, biphenylene, raftiline, peredelnye, foronline or thienyl cycles each can be from one up to 3 times substituted by F, Cl, Br, J, HE, CF3, NO2CN, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, COOH, COO-(C1-C6)-alkyl, CONH2;

1,2,3-triazole-5-yl, and triazole ring in 1-, 2 - or 3-position may be replaced by stands or benzyl;

tetrazol-5-yl, and tetrazole ring in 1 - or 2-position may be replaced by stands or benzyl;

R2 is H, (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, C(O)-(CH2)n-phenyl, C(O)-(CH2)n-thienyl, C(O)-(CH2)n-pyridyl, C(O)-(CH23, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl, C(O)-(C1-C6)-alkyl, C(O)-(C3-C6-cycloalkyl;

R3 is H, (C1-C6)-alkyl, F, CN, N3, O-(C1-C6)-alkyl, CH2-COO(C1-C6alkyl), CH2-COO(C3-C8cycloalkyl), CH2-COOH, CH2-CONH2CH2THE N3CH2-CON(CH3)2, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, and n=0-5, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl, (C2-C6)-quinil, (C2-C6)-alkenyl, C(O)och3WITH(O)OCH2CH3WITH(ABOUT)IT, C(O)NH2WITH(O)N3WITH(O)N(CH3)2, OS(O)CH3;

R4 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, and n=0-5, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6) - alkyl;

R5 - (C1-C6)-alkyl, (C3-WITHn-furyl, and n=0-5, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

or

R4 and R5 together form the group-CH2-CH2-, -CH2- (CH3)2,

-CH2-CH2-CH2- or-CH2-CH2-CH2-CH2-;

R6 - SO2-(C6H4-4-CH3);

or

E)

Y is a simple bond, -CH2- or-CH2-CH2-;

X - CH2CH(CH3), CH(C2H5), SN(C3H7);

R1 is H, F, Cl, Br, J, CH3, CF3, O-(C1-C3)-alkyl;

R1’ is H, F, Cl, Br, J, NO2;

R2 is H;

R3 is H, (C1-C3)-alkyl;

R4 is phenyl, and the phenyl residue may be substituted up to two times F, Cl, Br, J, (C1-C6)-alkyl, (C3-C6-cycloalkyl, O-(C1-C3)-alkyl, CF3, F3, O-CH2-phenyl, COOH, COO-(C1-C6)-alkyl, COO(C3-C6-cycloalkyl, CONH2;

R5 - phenyl, and the phenyl residue may be substituted up to two times F, Cl, Br, J, (C1-C6)-alkyl, (C3-C6-cycloalkyl, O-(C1-C3-cycloalkyl, CONH2;

and their physiologically acceptable salts and physiologically functional derivatives.

Preferred are the compounds of formula I, where

mean:

A)

Y is a simple bond, -CH2-;

X - CH2CH(CH3), CH(C2H5), SN(C3H7);

R1 is CN, COOH, COO(C1-C6)alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)alkyl]2, (C2-C6)-alkyl, (C2-C6)-alkenyl; and (C2-C6)-quinil; O-CH2CF3, O-CH2-CF2-CF3ABOUT-(C4-C6)-alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine, or one hydrogen may be replaced by HE, OC(O)CH3, O-CH2Ph, NH2or N(COOCH2Ph)2;

S-(C1-C6)-alkyl, S-(CH2)n-phenyl, and the phenyl residue up to two times may be substituted by F, Cl, Br, HE, CF3, NO2CN, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, and n=0-6, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl be from one to 3 times replaced by F, Cl, J, HE, CF3CN, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NN-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, COOH, COO-(C1-C6)-alkyl, CONH2;

1,2,3-triazole-5-yl, and triazole ring in 1-, 2 - or 3-position may be replaced by stands or benzyl;

tetrazol-5-yl, and tetrazole ring in 1 - or 2-position may be replaced by stands or benzyl;

Rl’ - H, F, Cl, Br, J, CH3, CF3, O-(C1-C3)alkyl, SO2-NH2, SO2NH-(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl)2or R1;

R2 is H, (C1-C6)-alkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, C(O)-(CH2)n-phenyl, C(O)-(CH2)n-thienyl, C(O)-(CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

R3 is H, (C1-C6)-alkyl, F, CN, O-(C1-C6)-alkyl, CH2-COO(C1-C6alkyl), CH2-COO(C3-C8cycloalkyl), CH2-COOH, CH2-CONH2CH2-CONHCH3CH2- =0-3, and where the phenyl, thienyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl, (C2-C6)-quinil, (C2-C6)-alkenyl, C(O)och3WITH(O)OCH2CH3WITH(ABOUT)IT, C(O)NH2WITH(O)N(CH3)2, OS(O)CH3;

R4 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

R5 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

or

R4 and R5 together form the group-CH2-CH2-, -CH2- (CH3)2or

-CH2-CH2-CH2-;

or

In)

Y is a simple bond, - CH2-;

X - CH2CH(CH3), CH(C2H5), SN(C3H7);

R1 and R 6) alkyl, CON[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl; (C2-C6)-quinil; O-(C1-C6)-alkyl, O-CH2-CF3, O-CH2-CF2-CF3ABOUT-(C4-C6)-alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine, or one hydrogen may be replaced by HE, OC(O)CH3, O-CH2-Ph, NH2or N(COOCH2Ph)2;

S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, and the phenyl residue up to two times may be substituted by F, CL, Br, HE, CF3, NO2CN, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; SO2-NH2, SO2NH-(C1-C6)-alkyl, SO2N[ (C1-C6)-alkyl]2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, and n=0-6, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl or 2 - or 3-thienyl, and phenyl, raftiline, peredelnye, foronline or thienyl rings may each be from one to 3 times substituted by F, Cl, J, HE, CF3CN, F3, O-(C1-C6)-alkyl, (C1-C6-alnilam, CONH2;

1,2,3-triazole-5-yl, and triazole ring in 1-, 2 - or 3-position may be replaced by stands or benzyl;

tetrazol-5-yl, and tetrazole ring in 1 - or 2-position may be replaced by stands or benzyl;

R2 is H, (C1-C6)-alkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, C(O)-(CH2)n-phenyl, C (O)-(CH2)n-thienyl, C(O)-(CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

R3 - (C4-C6)-alkyl, F, CN, N3, O-(C1-C6)-alkyl, CH2-COO(C1-C6alkyl), CH2-COO(C3-C8cycloalkyl), CH3-COOH, CH2-CONH2CH2-CONHCH2CH2-SOP(CH3)2, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl, (C2-C6)-quinil, (C2-C6)-alkenyl, C(O)och3WITH(O)OCH2CH3WITH(ABOUT)IT, C(O)NH2-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6) - alkyl;

R5 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

or

R4 and R5 together form the group - CH2-CH2-, - CH2- (CH3)2or

-CH2-CH2-CH2-;

or

C)

Y is a simple bond or - CH2-;

X - CH2CH(CH3), SN(C2H5), SN(C3H7);

R1 and R1’ independently of each

H, F, Cl, Br, J, CN, COOH, COO (C1-C6) alkyl, CONH2, CONH(C1-C6) alkyl, CON[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, O-(C1-C6) - alkyl, O-CH2-CF3, O-CH2-CF2-CF3ABOUT-(C4-C6)-alkyl, pri replaced IT, OS(O)CH3, O-CH2-Ph, NH2or N(SOON2PH)2;

S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n=0-6, and the phenyl residue up to two times may be substituted by F, Cl, Br, HE, CF3, NO2CN, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; SO2-NH2, SO2NH-(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, NH-(C1-C6)-alkyl, N((C1-C6)alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, and n=0-4, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl or 2 - or 3-thienyl, and phenyl, raftiline, peredelnye, foronline or thienyl rings may each be from one to 3 times substituted by F, Cl, J, HE, CF3CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, COOH, COO-(C1-C6)-alkyl, CONH2;

1,2,3-triazole-5-yl, and triazole ring in 1-, 2 - or 3-position may be replaced by stands or benzyl;

tetrazol-5-yl, and tetrazole ring in 1 - or 2-position may be replaced by stands or benzil n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, C(O)-(CH2)n-phenyl, C(O)-(CH2)n-thienyl, C(O)(CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

R3 is H, (C1-C6)-alkyl, F, CN, O-(C1-C6)-alkyl, CH2-COO(C1-C6alkyl), CH2-COO(C3-C8cycloalkyl), CH2-COOH, CH2-CONH2CH2THE N3CH2-SOP(CH3)2, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl may each be substituted up to two times with C1, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl, (C2-C6)-quinil, (C2-C6)-alkenyl, C(O)och3WITH(O)OCH2CH3WITH(ABOUT)IT, C(O)NH2WITH(O)N(CH3)2, OS(O)CH3;

R4 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl may each be substituted up to two times CL, F, CN, CF3, (C1-Calkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

or

R4 and R5 together form the group - CH2-CH2-, - CH2- (CH3)2or

-CH2-CH2-CH2-;

or

D)Y is a simple bond, - CH2-;

X - CH(phenyl), and the phenyl residue may be substituted by F, Cl or Br,

O, S, SO, SO2or N-R6;

R1 and Rl’ are independently from each other

H, F, Cl, Br, J, CN, COOH, COO (C1-C6) alkyl, CONH2, CONH(C1-C6) alkyl, CON[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, O-CH2-CF3, O-CH2-CF2-CF3,O-(C4-C6)-alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine, or one hydrogen may be replaced by HE, OC(O)CH3, O-CH2-Ph, NH2or N (COOCH2Ph)2;

S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2) IS F3ABOUT-(C1-C6)-alkyl, (C1-C6)-alkyl ohms; SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, and n=0-6, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl or 2 - or 3-thienyl, and phenyl, raftiline, peredelnye, foronline or thienyl rings may each be from one to 3 times substituted by F, Cl, J, HE, CF3CN, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, COOH, COO-(C1-C6)-alkyl, CONH2;

1,2,3-triazole-5-yl, and triazole ring in 1-, 2 - or 3-position may be replaced by stands or benzyl;

tetrazol-5-yl, and tetrazole ring in 1 - or 2-position may be replaced by stands or benzyl;

R2 is H, (C1-C6)-alkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, C(O)-(CH2)n-phenyl, C(O)-(CH2)n-thienyl, C(O)-(CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl, furyl, each can be up to d>-C6)-alkyl, F, CN, O-(C1-C6)-alkyl, CH2-COO(C1-C6alkyl), CH2-COO(C3-C8cycloalkyl), CH2-COOH, CH2-CONH2CH2THE N3CH2-SOP(CH3)2, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl, (C2-C6)-quinil, (C2-C6)-alkenyl, C(O)och3WITH(O)OCH2CH3WITH(ABOUT)IT, C(O)NH2WITH(O)N3WITH(O)N(CH3)2, OS(O)CH3;

R4 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

R5 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, HE -C(CH3)2- or-CH2-CH2-CH2-;

R6 - SO2-(C6H4-4-CH3);

or

E)

Y is a simple bond or - CH2-;

X - CH2CH(CH3), SN(C2H5), SN(C3H7);

R1 is H, F, Cl, Br, J, CH3, CF3,O-(C1-C3)-alkyl;

R1’ is H, F, Cl, Br, J;

R2 is H;

R3 is H, (C1-C3) - alkyl;

R4 is phenyl, and the phenyl residue may be substituted up to two times F, Cl, Br, J, (C1-C6)-alkyl, (C3-C6- cycloalkyl, O-(C1-C3)-alkyl, CF3, F3, O-CH2-phenyl,

COOH, COO-(C1-C6)-alkyl, CONH2;

R5 - phenyl, and the phenyl residue may be substituted up to two times F, Cl, Br, J, (C1-C6)-alkyl, (C3-C6-cycloalkyl, O-(C1-C3)-alkyl, CF3, F3, O-CH2-phenyl, COOH, COO-(C1-C6)-alkyl, CONH2;

and their physiologically acceptable salts and physiologically functional derivatives.

Especially preferred are the compounds of formula I, where mean

A)

Y - a simple link;

X - CH2CH(CH3), SN(C2H5),UB>2, (C2-C6)-alkyl, (C2-C6)-alkenyl; and (C2-C6)-quinil; O-CH2-CF3, O-CH2-CF2-CF3ABOUT-(C4-C6) - alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine, or one hydrogen may be replaced by HE, OC(O)CH3, O-CH2-Ph, NH2or N(SOON2PH)2;

S-(C3-C6) - alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, and the phenyl residue up to two times may be substituted by F, Cl, Br, HE, CF3, NO2CN, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C3-C7)-acyl, phenyl, O-(CH2)n-phenyl, and n=0-6, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl or 2 - or 3-thienyl, and phenyl, raftiline, peredelnye, foronline or thienyl rings may each be from one to 2 times substituted by F, C1, HE, CF3CN, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl ohms, COOH, COO-(C1-C6)-alkyl, CONH2;

1,2,3-triazole-5-yl, and triazole ring in 1-, 2 - or 3-position may be replaced by stands of gasoline or the sludge;

R1’ is H, F, C1, CH3, CF3, O-(C1-C3)alkyl, SO2NH2, SO2NH-(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2or Rl;

R2 is H, (C1-C6)-alkyl, (CH2)n-phenyl, (CH2)n-pyridyl, C(O)-(CH2)n-phenyl, C(O)-(CH2)n-pyridyl, and n=0-3, and where the phenyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, O-(C1-C6)-alkyl;

C(O)-(C1-C6)-alkyl;

R3 is H, (C1-C6)-alkyl, F, CN, O-(C1-C6)-alkyl, CH2-COO(C1-C6alkyl), CH2-COO(C3-C8cycloalkyl), CH2-COOH, CH2-CONH2CH2THE N3CH2-SOP(CH3)2, (CH2)n-phenyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, O-(C1-C6)-alkyl, (C2-C6)-quinil, C(O)och3WITH(O)OCH2CH3WITH(O)HE, C(O)NH2WITH(O)N(CH3)2, OS(O)CH3;

R4 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, PI is Kilom;

R5 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, O-(C1-C6)-alkyl;

or

R4 and R5 together form the group-CH2-CH2-, - CH2- (CH3)2or

-CH2-CH2-CH2-;

or

In)

Y is a simple bond, -CH2-;

X - CH2CH(CH3), CH(C2H5), SN(C3H7);

R1 and Rl’ are independently from each other

H, F, Cl, Br, J, CN, COOH, COO (C1-C6) alkyl, CONH2, CON[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, O-CH2-CF3,O-CH2-CF2-CF3ABOUT-(C4-C6)-alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine, or one hydrogen may be replaced by HE, OC(O)CH3, O-CH2-Ph, NH2or N(COOCH2Ph)2;

S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, and phenyl mod is)-alkyl; SO2-NH2, SO2NH-(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, and n=0-6, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl or 2 - or 3-thienyl, and phenyl, raftiline, peredelnye, foronline or thienyl rings may each be from one to 3 times substituted by F, Cl, J, HE, CF3CN, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2N((C1-C6)-alkyl)2, COOH, COO-(C1-C6)-alkyl, CONH2;

1,2,3-triazole-5-yl, and triazole ring in 1-, 2 - or 3-position may be replaced by stands or benzyl;

tetrazol-5-yl, and tetrazole ring in 1 - or 2-position may be replaced by stands or benzyl;

R2 is H, (C1-C6)-alkyl, (CH2)n-phenyl, (CH2)n-pyridyl, C(O)-(CH2)n-phenyl, C(O)-(CH2)n-pyridyl, and n=0-3, and where the phenyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl, C(O)-(C1-C6)-alkyl;

R3 - (C4-C6)-alkyl, F, CN, N3, O-(C1-C6-Ilkiv>-CONH2CH2THE N3CH2-SOP(CH3)2, (CH2)n-phenyl, (CH3)n-pyridyl, and n=0-3, and where the phenyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, O-(C1-C6)-alkyl, (C2-C6)-quinil, C(O)och3WITH(O)OCH2CH3WITH(O)HE, C(O)NH2WITH(O)N3WITH(O)N(CH3)2, OS(O)CH3;

R4 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, O-(C1-C6)-alkyl;

R5 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, O-(C1-C6)-alkyl;

or R4 and R5 together form the group - CH2-CH2-, -CH2- (CH3)2or

-CH2-CH2-CH2-;

or

C)

Y is a simple bond or-CH2-;

X - CH2CH(CH3), CH(C2H5), SN(C32, N[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, O-CH2-CF3, O-CH2-CF2-CF3ABOUT-(C4-C6) - alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine, or one hydrogen may be replaced by HE, OC(O)CH3, O-CH2-Ph, NH2or N(SOON2Ph)2;

S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n=0-6, and the phenyl residue up to two times may be substituted by F, Cl, Br, HE, CF3, NO2, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; SO2-NH2, SO2NH-(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2N((C1-C6)alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, and n=0-4, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl or 2 - or 3-thienyl, and phenyl, raftiline, peredelnye, foronline or thienyl rings may each be from one to 3 times substituted by F, Cl, J, HE, CF3CN, F3, O-(C1-C6)-alkyl, (C1-C6)-Ala)-alkyl, CONH2;

1,2,3-triazole-5-yl, and triazole ring in 1-, 2 - or 3-position may be replaced by stands or benzyl;

tetrazol-5-yl, and tetrazole ring in 1 - or 2-position may be replaced by stands or benzyl;

R2 - (C1-C6) - alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, C (O)-(CH2)n-phenyl, C(O)-(CH2)n-thienyl, C (O)-(CH2)n-pyridyl, and n=0-3, and where the phenyl, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl; C(O)-(C1-C6)-alkyl;

R3 is H, (C1-C6)-alkyl, F, CN, O-(C1-C6)-alkyl, CH2-COO(C1-C6alkyl), CH2-COO(C3-C8cycloalkyl), CH2-COOH, CH2-N2CH2THE N3CH2-SOP(CH3)2, (CH2)n-phenyl, (CH2)-pyridyl, and n=0-3, and where the phenyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, O-(C1-C6)-alkyl, (C2-C6)-quinil, C(O)och3WITH(O)OCH2CH3With(O)HE, C(alkyl, (CH2)n-phenyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, O-(C1-C6)-alkyl;

R5 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, O-(C1-C6)-alkyl;

or R4 and R5 together form the group - CH2-CH2-, - CH2- (CH3)2or

-CH2-CH2-CH2-;

or

D)

Y is a simple bond or-CH2-;

X - CH(phenyl), and the phenyl residue may be substituted

F or C1

O, S, SO2or N-R6;

R1 and R1’ independently of each

H, F, Cl, Br, J, CN, COOH, COO(C1-C6) alkyl, CONH2, CON[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, O-CH2-CF3,O-CH2-CF2-CF3ABOUT-(C4-C6)-alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine, or one of the waters is B>-C6)-alkyl, S-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n=0-6, and the phenyl residue up to two times may be substituted by F, Cl, Br, HE, CF3, NO2CN, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; SO2-NH2, SO2NH(C1-C6)-alkyl, SO2NH[(C1-C6)-alkyl]2, NH2N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, and n=0-6, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl or 2 - or 3-thienyl, and phenyl, raftiline, peredelnye, foronline or thienyl rings may each be from one to 3 times substituted by F, Cl, J, HE, CF3CN, F3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2N((C1-C6)-alkyl)2, COOH, COO-(C1-C6)-alkyl, CONH2;

1,2,3-triazole-5-yl, and triazole ring in 1-, 2 - or 3-position may be replaced by stands or benzyl;

tetrazol-5-yl, and tetrazole ring in 1 - or 2-position may be replaced by stands or benzyl;

R2 is H, (C1-C6)-alkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl,Il, thienyl, pyridyl, furyl, each can be up to two times substituted by Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

C(O)-(C1-C6)-alkyl;

R3 is H, (C1-C6)-alkyl, F, CN, O-(C1-C6)-alkyl, CH2-COO(C1-C6alkyl), CH2-COO(C3-C8cycloalkyl), CH2-COOH, CH2-CONH2CH2-CONHCH3CH2-SOP(CH3)2, (CH2)n-phenyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, pyridyl may each be substituted up to two times CL, F, CN, CF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, (C2-C6)-quinil, C(O)och3WITH(O)OCH2CH3WITH(O)HE, C(O)NH2WITH(O)N3WITH(O)N(CH3)2, OS(O)CH3;

R4 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, pyridyl may each be substituted up to two times Cl, F, CN, CF3, (C1-C3)-alkyl, O-(C1-C6)-alkyl;

R5 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-pyridyl, and n=0-3, and where the phenyl, pyridyl, each can be up to two times Sames who form the group - CH2-CH2-, - CH2-C(CH3)2or

-CH2-CH2-CH2-;

R6 - SO2-(C6H4-4-CH3);

or

E)

Y is a simple bond or - CH2-;

X - CH2CH(CH3), CH(C2H5), SN(C3H7);

R1 is H, F, Cl, Snz, CF3, O-(C1-C3)-alkyl;

R1’ is H, F, C1;

R2 is H;

R3 is H, (C1-C3)-alkyl;

R4 is phenyl, and the phenyl residue may be substituted up to two times F, Cl, (C1-C6) - alkyl, (C3-C6)cycloalkyl, O-(C1-C3)-alkyl, CF3THE CO2-phenyl, COOH, COO-(C1-C6)-alkyl, CONH2;

R5 - phenyl, and the phenyl residue may be substituted up to two times F, Cl, (C1-C6)-alkyl, (C3-C6- cycloalkyl, O-(C1-C3)-alkyl, CF3THE CO2-phenyl, COOH, COO-(C1-C6)-alkyl, CONH2;

and their physiologically acceptable salts and physiologically functional derivatives.

Especially preferred are the compounds of formula I, where mean

Y - a simple link;

X - CH2;

R1 and R1’ independently of each

(C2-C6)-quinil, and in the alkyl, alkenyl and etkinlik residues hydrogen may be replaced by HE, OC(O)CH3, O-CH2-Ph, NH2or N(COOCH2Ph)2; OCF3THE CO2CF3;- (C1-C4)-alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine, or one hydrogen may be replaced by HE, OC(O)CH3, O-CH2-Ph, NH2or N(COOCH2Ph)2;

SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n=0-3, and the phenyl residue may be substituted by F, Cl, HE, CF3, O-(C1-C4)-alkyl;

NH-(CO)-(C1-C3)-alkyl; (CH2)n-phenyl, S-(CH2)n-phenyl, O-(CH2)n-phenyl, and n=0-3, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl or 2 - or 3-thienyl, and phenyl, raftiline, peredelnye, foronline or thienyl rings every time can be substituted by F, Cl, CF3, (C1-C6) - alkyl, O-(C1-C6)-alkyl and alkyl residues hydrogen may be replaced by HE, OC(O)CH3, O-CH2-Ph, NH2or N(SOON2PH)2;

1,2,3-triazole-5-yl, and triazole ring in 1-, 2 - or 3-position may be replaced by stands or benzo is a ZIL;

R2 is H, (C1-C4)-alkyl, (C5-C6-cycloalkyl; (CH2)n-phenyl, and n=0-3, With(A)-(C1-C4)-alkyl or C(O)-phenyl;

R3 - F, (C4-C6)-alkyl, CH2-phenyl, whereby phenyl may be substituted up to two times F, Cl, CF3ABOUT-(C1-C3)-alkyl, (C1-C3)-alkyl, COOH, CO-O-(C1-C3)-alkyl or CONH2;

R4 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, and n=0-3, and the phenyl residue may be substituted up to two times F, Cl, O-(C1-C4)-alkyl or HE;

R5 - (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, and n=0-3, and the phenyl residue may be substituted up to two times F, Cl, O-(C1-C4)-alkyl or HE;

and their physiologically acceptable salts.

Especially preferred are the compounds of formula I of the following structure:

In particular, the connection:

This invention relates also to compounds of formula I in the form of their racemates, racemic mixtures and pure enantiomers, as well as to their diastereomers and their mixtures.

Pharmaceutically acceptable salts because of their high solubility in order to keep pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable additive salts of acids of the proposed compounds are salts of inorganic acids such as hydrochloric acid, Hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acid as well as organic acids, such as acetic acid, benzolsulfonat, benzoic, citric, econsultancy, fumaric, gluconic, glycolic, setinova, lactic, lactobionic, maleic, malic, methansulfonate, succinic, p-toluensulfonate, wine and triperoxonane acid. For medical purposes especially suitable salt of hydrochloric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), and salts of alkaline earth metals (such as magnesium salts and calcium).

Especially preferred are hydrobromide and hydrochloride, in particular, hydrochloride.

Salts with a pharmaceutically unacceptable anion also included within this invention as a necessary intermediate products to obtain or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic purposes, for example, when applied in vitro.

The object of the present invention are prodrugs of the proposed compounds. Such prodrugs can be metabolized in vivo into compounds according to the invention. These prodrugs may themselves be or not to be active.

The proposed connection can exist in various polymorphic forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the proposed compounds related to this invention and are a further aspect of the invention.

Hereinafter all references to "compound(I) according to the formula (I)" refers to the compound (s) of formula (I). as described above, and their salts, solvate and physiologically functional derivatives.

The number of compounds according to formula (I), which is required to achieve the desired biological effect depends on a number of factors, for example, selected specific connections, intended use, type of administration and the clinical condition of the patient. The daily dose is in INTA the dose may for example, to be in the range from 0.3 mg to 1.0 mg/kg, and may be in the form of infusion of 10 ng to 100 ng per kilogram per minute. Suitable for this purpose infusion solutions may contain from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter. Single dose can contain, for example, from 1 mg to 10 g of the active substance. Thus, ampoules for injection may contain from 1 mg to 100 mg, and intended for oral administration of single doses, as, for example, tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case of pharmaceutically acceptable salts calculated above weight data on the weight of the salt ions released thiazolidin-2 - ylidene. For the prevention or therapy of the abovementioned conditions can be applied to compounds according to formula (I) individually in the form of compounds, but preferably they are together with an acceptable carrier in the form of pharmaceutical compositions. The carrier must be pharmaceutically acceptable in the sense that it is compatible with other ingredients of the composition and is not harmful to the health of patients. The carrier may be solid or liquid or both and is preferably formed with SOEDINENIYa way there could be other pharmaceutically active substances, including other compounds according to formula (I). The proposed pharmaceutical composition can be obtained by known pharmaceutical methods, which mainly consist in the fact that the ingredients are mixed with pharmacologically acceptable carriers and/or auxiliary substances.

According to the invention pharmaceutical compositions are those suitable for oral, rectal, local, paralega (for example sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although suitable route of administration in each individual case depends on the type and severity treatable condition and the type of the used compounds according to formula (I). Index formulation and index formulations of extended actions also apply to this invention. Preferred are the preparative form, resistant to acids and gastric juice. Suitable resistant to gastric juice coating include acetated cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose and anionic polymers of methacrylic acid and methyl ester of methacrylic acid.

Pharmaceutical compositions which are intended for peroral (sublingual) administration include tablets for sucking, which contain the compound according to formula (I) with a flavoring substance, normally sucrose and gum Arabic or Trianta, and lozenges that contain this compound in an inert basis such as gelatin and glycerol or sucrose and gum Arabic.

Suitable pharmaceutical compositions for parenteral administration include, preferably, a sterile aqueous compositions of the compounds according to formula (I), which preferably is isotonic with the blood of the intended recipient. These preparative form, preferably administered intravenously, although administration can be given subcutaneously, intramuscularly or intradermally in the form of injections. These preparative forms, preferably, can be prepared by mixing the compound with water, and the resulting solution make sterile and isotonic with blood. Suitable for injection proposed composition contain mainly from 0.1 to 5 wt.% active compounds.

Suitable pharmaceutical compositions for rentalsmake the compounds of formula (I) with one or more suitable solid carriers, preferably cocoa butter, and shaping the resulting mixture.

Suitable pharmaceutical compositions for topical application to the skin presents preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil. As the carrier can be used vaseline, lanolin, polyethylene glycol, alcohol or a combination of two or more such substances. The active substance is usually represented in a concentration of from 0.1 to 15 wt.% compositions, for example, from 0, 5 up to 2%.

It is also possible transdermal administration. Suitable pharmaceutical compositions for transdermal injection may be presented in separate patches, which are designed for long-term contact with the epidermis of the patient. This patch contains the active substance, if necessary in tebufelone aqueous solution, dissolved and/or dispergirovannom in adhesive means or dispergirovannom in the polymer. A suitable concentration of the active substance is from about 1% to 35%, preferably from about 3% to 15%. As a special active substance may, as described in Pharmaceutical Research, 2(6); 318 (1986), be released by electrotransport or iontophoresis.

Before the, the

A) compounds of General formula II,

where R1, R1’, R3, and X and Y have the above meanings and Z is the residue of an active ester of an inorganic or organic acid, is subjected to the interaction with timeonline General formula III, which are in tautomeric forms IIIa and IIIb, and S,

where R4 and R5 have the above meanings and

C) if necessary, the compounds of General formula I (R2 = H) was transferred using organic or inorganic acid additive salts of the acids or the salts of compounds of General formula I (R2 = H) with organic or inorganic bases in the free basic compounds of formula I (R2 = H).

As inorganic acids take into account halogenation acid, such as hydrochloric acid and Hydrobromic acid, and sulfuric acid, phosphoric acid and amidosulfonic acid. As organic acids should be mentioned: formic acid, acetic acid, benzoic acid, p-toluensulfonate, benzosulfimide, succinic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, citric acid, L-ascorbic acid, salicylic acid, setinova acid, meta is CLASS="ptx2">The compounds of formula I may also exist in their tautomeric forms:

The proposed compounds of formula I (R2 = H), in addition, may be in their possible geometric isomeric structures.

Alkyl, alkeline and alkyline residues in the substituents Rl, R1’, R2, R3, R4 and R5 can be both linear and branched.

Along with the tautomeric form with an open circuit Ia cyclic compounds of formula I (R2 = H) at different R4 and R5 are in equilibrium with the position isomers of the compounds of formula Ib (R2 = H) and their additive salts with acids.

Which of the two cyclic isomers of I (R2 = H) or Ib (R2 = H) or additive, acid salts are preferred, depends especially on the sizes of different spatial sizes of the substituents R4 or R5 in such a way that lesser amount, the Deputy is in the 3 position TIA-solodilovoj cyclic system.

For the proposed connections the following is only one of the possible isomeric or tautomeric forms of each substance.

The above-described method of obtaining preferably carried out in such a way that the compound (II) interact with timeonline III in a molar ratio of from 1:1 to 1:1,5. Reaction,AK sulfoxide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, dioxane, tetrahydrofuran, acetonitrile, nitromethane or dimethyl ether of diethylene glycol. As a particularly preferable solvent was methyl ester of acetic acid and ethyl ester of acetic acid, short-chain alcohols, such as methanol, ethanol, propanol, isopropanol, as well as lower dialkylamide, as, for example, acetone, butane-2-one or hexane-2-it. May also be used mixtures of the above reaction media; as well as mixtures of the above solvents with solvents, which are less suitable, as, for example, mixtures of methanol with benzene, ethanol with toluene, methanol, diethyl ether or tert-butylmethylamine ether, ethanol with carbon tetrachloride, acetone, chloroform, dichloromethane or 1,2-dichloroethane, and each time the polar solvent should be used in excess. Components of the reaction can be suspended or dissolved in any reaction medium. In principle, the components of the reaction can interact without solvent, in particular, when thiourea has the lowest possible melting point. The reaction proceeds poorly Ekaterina and may be carrying the RNA interval between 20 and 40 C. The duration of the reaction depends strongly on the reaction temperature and is between 2 min and 3 days at higher or lower temperatures. In favorable temperature interval, the duration of reaction is usually from 5 minutes to 48 hours

As is often the compound I (R2 = H) are deposited in the form of their insoluble additive salts of acids, it is sensible to add the precipitator. As such apply, for example, hydrocarbons, such as benzene, toluene, cyclohexane or heptane, or carbon tetrachloride; in particular, as a particularly suitable applicable alkalemia the acetic acid esters, such as ethyl ether, acetic acid or n-butyl ester of acetic acid, or a simple dialkyl ethers, such as diethyl ether, diisopropyl ether, di-n-butyl ether or tert-butyl methyl ether. If at the end of the reaction, the reaction mixture remains in solution can be precipitated salts of compounds I (R2 = H), if necessary after concentration of the reaction solution, one of these precipitators. Optionally, the solution of the reaction mixture is filtered into a solution of one of these precipitators with stirring. Since the reaction of compounds II with timoc the net. Processing of the reaction mixture can also be carried out in such a way as to make alkaline reaction mixture by adding an organic base, such as triethylamine or diisobutylamine or ammonia, or the research or piperidine, or 1,8-diazabicyclo[5.4.0]-undec-7-ene, and after concentration to purify the reaction product is chromatographically, for example, on a column of silica gel. Suitable eluents for this was, for example, a mixture of ethyl ester of acetic acid with methanol, mixtures of dichloromethane with methanol, mixtures of toluene with methanol or ethyl ester, acetic acid or a mixture of ethyl ester of acetic acid with hydrocarbons, such as heptane. If purification of the crude product to carry out, as described, can be obtained from a clean base of the formula I (R2 = H) to obtain the product of the merger of the acid of formula I (R2 = H), which base is dissolved or suspendered in organic proton solvent such as methanol, ethanol, propanol or isopropanol, or in an organic aprotic solvent such as ethyl ether, acetic acid, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, acetone, or butane-2-it, and then about ogorodnoi acid, dissolved in an inert solvent, such as diethyl ether or ethanol, or another of the above-mentioned inorganic and organic acids. The compounds of formula I (R2 = H) can be recrystallized from a suitable inert solvent, such as acetone, butane-2-it, acetonitrile, nitromethane. But especially preferred is the deposition of the solvent, as, for example, dimethylformamide, dimethylacetamide, nitromethane, acetonitrile, preferably, methanol or ethanol.

The compounds of formula I or Ib, R2 = (C1-C6)-alkyl, (C3-C6-cycloalkyl or (CH2)n-aryl, and n=0-5, and aryl have the above values, it is possible to obtain, if

AA) additive salts of acids of formula I or Ib, R2 = H is introduced into the reaction in a solvent of the formula R2-OH, and R2 has the above meanings, at temperatures from -20 ° C to 120 C, preferably from -5 C to 50 C from 2 h to 4 days, preferably from 4 hours to 2 days or

ab) free base of formula I or Ib, R2 = H is introduced into the reaction in a solvent of the formula R2-OH, and R2 has the above meaning, with equimolar excess or catalytic amount, preferably, the catalytic amount of the inorganic ildo 120, preferably from -5 C to 50 C from 2 h to 4 days, preferably from 4 hours to 2 days

or

ac) interaction on AA) and ab) is carried out in an inert aprotic solvent such as dichloromethane, chloroform, 1,2-dichloroethane, heptane, benzene, toluene, acetonitrile, nitromethane, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, diethyl ether, diisopropyl ether, tert-butyl methyl ether, acetone, butane-2-one or dialkylamide ether acetic acid, as, for example, ethyl ester acetic acid, by adding from 1 to 5, preferably 1.5-2 equivalents of the compounds of formula R2-OH

or

ad) compounds of the formula I or Ib, R2 = H in an inert aprotic solvent, such as tetrahydrofuran, dioxane, dimethyl ether of ethylene glycol, nitromethane, acetonitrile or dimethylformamide, di-methylacetamide or N-methyl-2-pyrrolidone, using a base, such as sodium hydride, diisopropylamide lithium, KOH or potassium carbonate, transferred to their alcoholate and then by adding the alkylating means of the formula R2-X, where X denotes chlorine, bromine, iodine, O-C(O)CH3, O-C(O)-CF3, O-C(O)-C6H4-4-NO2O-SO2-CH3O-SO2-CF3O-SO2-C6H4-4-CH3is in up to 2 days preferably, from 20 minutes to 12 o'clock

The compounds of formula I or Ib R2 N, which received the above-described method from AA to ad), or deposited in the form of sparingly soluble additive salt of the acid is then sucked off, washed with a small amount of a suitable solvent and dried or remain in solution. The treatment can be carried out so that the reaction composition after the formation of a simple ester of the formula I or Ib R2 N neutralize inorganic or organic base, e.g. triethylamine, and the mixture was concentrated and then chromatographic on silica gel. Thus obtained pure basis of formulas I or Ib R2 N may, as described above for compounds of formula I or Ib, R2 = H, can be translated into an additive salt of the acid.

The compounds of formula I or Ib R2 = C(O) - (C1-C6)-alkyl, C(O)-(C3-C6-cycloalkyl or C(O)-(CH2)n-aryl, and aryl means phenyl, thienyl, pyridyl or furyl, and n are as defined above, it is possible to obtain, if

ba) as described in AA-AC), with the difference that instead of connecting R2-OH enter the compound R2-COOH, and R2 is (C1-C6)-alkyl, (C3-C6- cycloalkyl or (CH2)n-Ari,5 equivalent of the compound R2-COOH, and refuse to add is described in AA-AC) inorganic or organic acid catalysts, however, preferably, the injected acid cation-exchanger

or

bb) the compound of formula I or Ib, R2 = H (free base) is injected into the reaction with the compound of the formula R2-COOH, and R2 means (A) - (C1-C6)-alkyl, C(O)-(C3-C6-cycloalkyl or C(O)-(CH2)n-aryl, and aryl and n are as defined above, for example, by the reaction of Mitsunobu (O. Mitsunobu, Synthesis 1981, 1) with the formation of the compounds of formula I or Ib, R2 is not equal to N

or

b) compound of the formula R2-C(O)-C1 or R2-C(O)-Br, or R2-C(O)-O-(O)-C-R2 enter into reaction with the compound of the formula I or Ib, R2 = H by the esterification reaction of the alcohol (Houben-Weyl, Methods der Organischen Chemie, Georg Thieme Verlag Stuttgart, vol E5, pp. 656-715).

The compounds of formula I or Ib R2 N, which is obtained according to ba)-bc). as described above, or are precipitated as insoluble additive salt of the acid is then sucked off, washed with a small amount of a suitable solvent and dried or remain in solution. The treatment can be carried out so that the reaction mixture after formation of ester of the formula I or Ib, R2 is not equal to N, neutralize inorganic or organic is ayrout on silica gel. Thus obtained pure basis of formulas I or Ib R2 is not equal to N, may, as described above for compounds of formula I or Ib, R2 = H, can be translated into an additive salt of the acid.

Educt of the formula III in most cases described in the literature (see Houben-Weyl, Methods der organischen Chemie, volume 9, page 384; 4 Aufl.; 1955 or DOS 2640358 (16.03.1978)).

In compounds of formula II as the remainder of the activated complex ester Z consider, for example, CL, Br, J, O-C(O)-C6H4-4-NO2,- SO2-CH3,- SO2-CF3O-SO2-C6H4-4-CH3O-SO2-C6H4. They can be obtained in several ways:

sa) diazo ketones of General formula VIII

can be translated using the halogen acids in compounds of General formula II (Z = C1, Br, J; R3 = H). This method as well as some of the compounds of formula II are known from the literature (for example, J. Am. Chem. Soc. 80, 2255 (1958); J. Indian Chem. Soc. 42, 115 (1965)), other compounds of formula II can be obtained and transformed accordingly. Diazo ketones of General formula VIII can then be known from literature methods through hydroxycodone General formula IX

translated into the corresponding joint in which R3 remains limited to hydrogen, the compounds of formula II, preferably, receive in such a way that compounds of General formula X

enter into reaction with a suitable halogenation agent, such as elemental chlorine or bromine, chloride Sulfuryl, monochloroamine, N-chlorosuccinimide, copper bromide-II, bromine complex with dioxane, N-bromosuccinimide, known from the literature conditions. The initial compounds of formula X are either known or can be obtained as described in the literature methods.

As halogenation means consider, for example, elemental chlorine, chloride Sulfuryl, monochloroamine, N-chlorosuccinimide, bromine complex with dioxane, N-bromo-succinimide, in particular, elemental bromine or bromide of copper-II. When galogenirovannyie preferably added dropwise bromine, if necessary diluted with an inert solvent to the solution or suspension of equimolar amounts of compounds of formula X in an inert solvent. As such it is, for example, about galogenovodorodov, such as di - or trichloromethane or 1,2-dichloroethane, but, preferably, acetic acid or lower Akilova ether acetic acid, or mixtures of the mentioned solvents. The reaction temperature find the respectfully, if the components of the reaction mix with a catalytic amount of acid, for example, Hydrobromic acid, or after adding dropwise a small amount of bromine, the reaction mixture was first heated to discoloration of halogen and then bromilow further.

When bromirovanii compounds of formula X copper bromide-II can act similarly to the method described in J. Org. Chem. 29, 3459 (1964) or J. Org. Chem. 40, 1990 (1975).

As glorieuses means suitable, in particular, chloride Sulfuryl, which is usually injected into the reaction solution or suspension of the compounds of formula X in a solvent, such as, for example, three or tetrachlorethane or simply ether, such as diethyl ether or tert-butyl methyl ether, in a temperature range between 20 and 80 C. and Then mixed with ice water and process as usual. When used as halogenation means of chlorine into a solution of the compounds of formula X in a polar solvent, for example glacial acetic acid or dimethylformamide or N-methyl-2-pyrrolidone, first pass gaseous hydrogen chloride as catalyst, and then at a temperature of from 0 to 25 With an equivalent amount of chlorine. Reaction time is 2-24 hours Then mix the nimid, the compounds of formula X, preferably in a polar solvent, such as glacial acetic acid, is introduced into reaction with 1-2 equivalents of N-chlorosuccinimide, after addition of catalytic amounts of hydrochloric acid, at about 50 C for 2-12 hours After it is mixed with ice water and process as usual.

cc) the compounds of formula II can finally get in such a way that hydroxyketone General formula XI,

which are either known (Chem. Ber. 83, 390), or can be received in a suitable way, enter into reaction with activated derivatives of organic and inorganic acids, such as acid chloride of methansulfonate, the acid chloride of triftoratsetata, the acid chloride of econsultancy, the acid chloride of benzosulfimide, acid chloride, p-toluenesulfonic acid, thienylboronic, phosphorus trichloride, tribromide phosphorus, phosphorus oxychloride, p-nitrobenzoate.

Thus obtained solution or suspension of the compounds of formula II, it is advisable to was evaporated under reduced pressure and purify the compounds of formula II by crystallization from an inert solvent, such as benzene, toluene, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, cyclone silica gel, but it is desirable to use as the eluent heptane, diethyl ether, tert-butyl methyl ether, toluene, ethyl ester acetic acid, or their mixture.

The compounds of formula II can also be used in the following stage without further purification.

The compounds of formula X,

where R3 is not equal to hydrogen, are available in a variety of ways:

da) the compounds of formula X, where R3 = fluoro, can be, for example, obtained by reacting compounds of formula X, where R3 = H, with an electrophilic fluorinating reagent. As electrophilic fluorinating reagent (see also: W. E. rnette, J. Am. Chem. Soc. 106, 452-454 (1984)), for example, triplet 1-fluoro-2,4,6-trimethylpyridine, triplet 3,5-dichloro-1-torpedine, triplet 1-torpedine, tetrafluoroborate 1-torpedine, pyridineboronic 1-torpedine, N-fluoro-N-methyl-p-toluensulfonate, N-fluoro-N-propyl-p-toluensulfonate, N-forbindelsesfaneblad, N-forbindelseshastighed [NFSi], bis(tetrafluoroborate) 1-fluoro-4-hydroxy-1,4-diazoniabicyclo-2.2.2]octane (NFTh). The fluorination reaction is conducted so that the solution or suspension of the compounds of formula X, where R3 = H, in a nonpolar aprotic solvent such as benzene, toluene, hexane or Hatay ether or tert-butyl methyl ether, or their mixture is added an equivalent amount of base, with which the compound of the formula X (R3 = H) was transferred to the enolate of the compound of the formula X (R3 = H). As grounds for this reaction, suitable n-utility, hexamethyldisilazane potassium or sodium, sodium hydride, potassium hydride, tert-butyl potassium, motility, hydroxide, Tetra-n-butylamine. A suitable reaction temperature is a temperature from -78 to 25 C. To the solution or suspension formed in this way isolate the compounds of formula X (R3 = H) is then added dropwise at a temperature of from -78 to 100 C, preferably at a temperature of from -50 to 80, 1 to 2, preferably 1.5 equivalent of one of these fluorinating reagents, dissolved in one of the abovementioned solvents or solvent mixtures, preferably dissolved in toluene or di-chloromethane. The order of addition of the component reactions can be reversed, i.e., the solution or suspension isolate the compounds of formula X (R3 = H) are added dropwise to a solution of fluorinating reagent at the indicated temperatures. Depending on the selected reaction temperature, the reaction ends in a period from 15 minutes to 48 hours Interaction, especially N-forbindelsesfanebladet, can alienology the ester compounds of the formula X, where R3 = H (for example, trimethylsilylpropyne or trimethylsilyloxy ether of triftoratsetata in toluene at a temperature of from -78 to 80 With the addition of one equivalent of base, such as triethylamine) and then add fluorinating reagent, dissolved in dichloromethane or toluene, at room temperature, and after about 12 hours the reaction (at room temperature) process. Processing of the reaction mixture may be carried out in such a way that after neutralization of the excess entered the base, the reaction mixture was evaporated and then mixed with solvent, such as ethyl ester, acetic acid or heptane, and shaken with policecontributing solution of sodium bicarbonate. The organic phase after drying over magnesium sulfate evaporated, and the reaction product to further purification can either be recrystallized from a solvent such as hexane or heptane, or subjected to chromatographic purification on a column of silica gel with leaching, for example, mixtures of dichloromethane with heptane or ethyl ester of acetic acid with heptane.

Interaction with bis(tetrafluoroborate) 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane (NFTh) can be Prov is.

db) the compounds of formula X, where R3 = (C1-C6)-alkyl or (CH2)n-aryl, and n=1-5, and aryl, as defined above, can be, for example, obtained by reacting compounds of formula X, where R3 = H, with a strong base and an alkylating agent of General formula R3-X, with X = Br, J, O-C(O)-C6H4-4-NO2,- SO2-CH3,- SO2-CF3O-SO2-C6H4-4-CH3O-SO2-C6H4. To ensure this alkylation is only desired monoalkylamines, the compounds of formula X (R3 = H), preferably, make connections, for example, formula XII, XIII or XIV.

Compounds of the type formula XII (R3 = H) can be obtained according to the method described by F. Henin and other Tetrahedron, 50, 2849-2864 (1994). Any type of formula XIII (R3 = H), and R’-R ' = (CH2)4-, - (CH2)5-, - CH2-CH2-O-CH2-CH2- it is possible to obtain, for example, in accordance Stork and others J. Am. Chem. Soc. 85, 207 (1963). The compounds of formula XIV (R3 = H) are available according to known literature method, for example, P. W. Hickmott, Chem. Ind. (London), 731 (1974). Connection type formulas XII and XIV (R3 = H) after translating them into anions by means of a strong base can be turned alkylating agent about what about the hydrolysis of hydrazones (XII) or hydrolysis and decarboxylation-ketoesters (XIV) in the compounds of formula X, where R3 = H. The compounds of formula XIII (R3 = H) can in an inert solvent, such as trichloromethane or toluene, after addition of base, such as triethylamine, with an alkylating funds General formula R3-X after acid hydrolysis-alkylated the enamine of formula XIII (R3 = H) can be converted into compounds of formula X, where R3 = H.

The compounds of formula X, where R3 = SOON3SOON2CH3, COOH, CONH2THE N3, SOP(CH3)2it is possible to obtain through the compounds of formula XII and the formula XIII are known from the literature methods by reacting, for example, CL-C(O)-O-CH2-CH3.

dd) the Compounds of General formula X, where R3 = CN, can be obtained by known literature methods (M. E. Kuehne, J. Org. Chem. 81, 5400-5404 (1959) by reaction of compounds of formula XIII with harzianum.

de) compounds of General formula X, where R3 = O-(C1-C6)-alkyl, can be obtained by known literature methods (J. Chan Lee and others, Synth. Commun. 21, 4085-90 (1997)), starting from compounds of General formula X, where R3 = H, so that the compound of the formula X (R3 = H) is refluxed with [hydroxy(p-nitrobenzenesulfonate)iodine]benzene [HNJB] in acetonitrile 2-6 h, and the resulting intermediate product is introduced into reactione.

df) Similarly possible to obtain compounds of General formula X, where R3 = O(O)CLO3. And described in de) intermediate product is converted into acetic acid by adding catalytic amounts of silver carbonate in the compound of formula X, where R3 = O(O)CLO3.

dg) compounds of General formula X, where R3 = N3it is possible to obtain either by nucleophilic exchange with azides from the corresponding compounds of formula X, where R3 = CL or Br (K. Van Sant, M. S. South; Tetrahedron Lett. 28, 6019 (1987)), but better by analogy with T. Patonay and R. V. Hoffman, J. Org. Chem. 59, 2902-2905 (1994) from enolacetate compounds X (R3 = H) or enamines compounds X (compounds of formula XIII (R3 = H) through-toiletry and subsequent reaction with sodium azide.

dh) the compounds of formula X, where R3 = (C2-C6)-quinil, can be obtained via 1,3-dicarbonyl compounds of General formula XIV. By analogy with the known from the literature (M. Ochiai, T. Ito, Y. Takaoka, Y. Masaki, M. Kunishima, S. Tani, Y., Nag;

J. Chem. Soc., Chem. Commun. 118-119 (1990), with compounds of formula XIV (R3 = H), first under the action of a strong base such as tert-butyl potassium tert-butanol or tert-butyl potassium in tetrahydrofuran was transferred to their enolate anions and then injected into the reaction tetrafluoroborate ethinyl(FeNi formula X, where R3 = SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, S-(C1-C6)-alkyl, S-(CH2)n-phenyl, and n=0-3, can be obtained by known literature methods by interaction generated under the action of strong bases, such as diisopropylamide lithium in a mixture of solvents, such as hexane/pyridine, the enolate anion of the compounds of formula X, where R3 = H, with the corresponding dialkyl-, di(aralkyl) or diphenyldisulfide at low temperatures. Thus obtained compounds of formula X, where R3 = S-(C1-C6)-alkyl or S-(CH2)n-phenyl, and n=0-3, can be recycled with Nadzaladevi acid into the corresponding sulfoxidov (R3 = SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl) (J. Drabowicz, M. Mikolajczyk; Synthesis 1978, 758) and with a solution of 30% hydrogen peroxide, or by reaction with meta-chloroperoxybenzoic acid in dichloromethane in the corresponding sulfones (R3 = SO2-(C1-C6)-alkyl, SO2-(CH2)nis phenyl.

The compounds of formula X (R3 = H), which are used as starting products for producing compounds of formula II where R3 = H, F, CN, N3, O-(C1-C6)-alkyl, (CIl, (C2-C6)-quinil, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, SO-(C1-C6)-alkyl; SO-(CH2)n-phenyl, S-(C1-C6)-alkyl, S-(CH2)n-phenyl, and n=0-3, With(O)och3WITH(O)OCH2CH3WITH(ABOUT)IT, C(O)NH2WITH(O)N3WITH(O)N(CH3)2O(O)CLO3and Z have the above values, can be purchased or accessible by analogy with various well-known from the literature methods (scheme 1):

Scheme 1

EA) compounds of General formula XV, where R1, R1’, X and Y have the above values and where W represents carbonylations group, such as halogen, for example, C1 or Br, or or, or O-C(O)-R", and R" = alkyl, for example, CH3or aryl, e.g. phenyl, may known from the literature, for example, Houben-Weyl, Methods der Organischen Chemie, Thieme Verlag Stuttgart, 1973, volume VII/2a, page 111) to close the ring under the action of proton acids or Lewis acids with the formation of the corresponding compounds of General formula Ha.

b) Compounds of the General formulae X and XA, where R1 and/or R1’ mean S-(C1-C6)-alkyl, S-phenyl, SO-(C1-C6)-alkyl, SO-phenyl, SO2-(C1-C6)-alkyl, SO2-phenyl, S-(CH2)n(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2can be obtained by known literature methods (Houben-Weyl, Methods der Organischen Chemie, volume XI/1, page 422, and 475, Thieme publishing house, Stuttgart) thus, in order to bring about the restoration of correspondingly substituted compounds of formula X or XA, where R1 and/or R1’ = NO2for example, Raney Nickel and hydrogen in a solvent such as ethanol or glacial acetic acid, or zinc in glacial acetic acid or tin or chloride of tin-(II) in hydrochloric acid to amine of formula X or XA, where R1 and/or R1’ = NH2and then diazotization by adding sodium nitrite in hydrochloric acid and then turning action CuCl2and SO2in glacial acetic acid to the correspondingly substituted anhydrides of sulfonic acids. The latter can be converted under standard conditions recovery in the alkaline environment in the relevant sulfinamide acid, which then can be known from literature methods processed in the compounds of formula X or XA, where R1 and/or R1’ = S-(C1-C6)-alkyl, S-phenyl, SO-(C1-C6)-alkyl, SO-phenyl, SO2-(C1-C6)-alkyl, SO2-phenyl, S-(CH2)n-phenyl, SO-(CH2-alkyl, SO2N[(C1-C6)-alkyl]2.

The compounds of formula X or XA, where R1 and/or R1’ = O-(C1-C6)-alkyl, O-CH2-CF3, O-CH2-CF2-CF3, O-(C4-C6)-alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine, or hydrogen may be replaced by HE, O-C(O)CH3, O-CH2-Ph, NH2or N (SOON2PH)2, O-(CH2)n-phenyl, and n=0-6, S-(C1-C6)-alkyl, S-phenyl, S-(CH2)n-phenyl, and n=0-6, available by nucleophilic substitution of compounds of General formula X or XA, where R1 and R1’ = F or Br, with compounds of the General formula R1-M or R1’-M where R1 and/or Rl’ have the above meanings and M denotes an atom of an alkali metal, such as Na, or chetyrehkolenny the nitrogen atom, as, for example, (n-Bu)4N. it is injected into the reaction, for example, the compound of formula X or XA, where R1 and/or R1’ denotes F, mostly in the polar aprotic solvent such as dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide, with the compound of the formula R1-H or R1’is H, and R1 and R1’ is as defined above, with addition of a base, such as sodium carbonate or potassium, sodium hydride, hexomat the temperature from 50 to 150 and then usually treated.

Such compounds are also available, if the compounds of formula X or XA, where R1 and/or R1’ = VG, is introduced into the reaction under the conditions of catalysis of the transfer phase (E. V. Dehmlow and S. S. Dehmlow, Phase Transfer Catalysis, 2nd edition, Verlag Chemie, Weinheim, 1983) with compounds of formula R1-H and/or Rl’-H with, for example, a catalyst such as Aliquat 336, in a mixture of toluene with 50%th aqueous solution of sodium hydroxide or 15-crown-5 in toluene with a 50% aqueous solution of sodium hydroxide in about 2 h and then treated as usual (A. J. Serio Duggan, E. J. J. Grabowski, W. K. Russ: Synthesis 573-5 (1980); A. Ohta, Y. Iwasaki, Y. Akita: Synthesis 828-9 (1982); W. Chin-Hsien, L. Xiang-Te, C. Xiao-Hun: Synthesis 858-61 (1982); H. Alsaidi, R. Gallo, J. Metzger: Synthesis 921-4 (1980)).

After normal processing of compounds of General formula X or XA, where R1 and/or R1’ = O-(C1-C6)-alkyl, O-CH2-CF3, O-CH2-CF2-CF3ABOUT-(C4-C6)-alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine, or one hydrogen may be replaced by HE, OC(O)CH3, O-CH2-Ph, NH2or N(COOCH2Ph)2, O-(CH2)n-phenyl, and n=0-6, S-(C1-C6)-alkyl, S-phenyl, S-(CH2)n-phenyl, and n=0-6, can be selected.

Compounds of General formulae X and XA, where R1 and/or R1’ = CN, can be obtained by standard methods (L. Friedman, H. Shec is recorded with a metal cyanide, as, for example, NaCN, KCN, Cu(I)-CN. As the solvent used for this polar aprotic environment, as, for example, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide. A suitable reaction temperature is a temperature from 150 to 200 C.

it) compounds of General formula XV and XA, where R1 and R1’ indicates if necessary substituted aryl or heteroaryl residue can be obtained by known literature methods from the corresponding compounds of formulas XV and XA, where R1 and/or R1’ is bromine, iodine or tripterocalyx. By analogy with N. Miyaura and A. Suzuki, Chem. Rev. 95, 2457-83 (1995) or the So-Oh-e, N. Miyaura and A. Suzuki, J. Org. Chem. 58, 2201-08 (1993), such compounds may be derived from a bromine - or iodine(hetero)aryleno or (hetero) aritifical formula XV or Ha, where R1 and/or R1’ is bromine, iodine, tripterocalyx, by interacting with arylboronic acids or their esters or arboreality General formula R1-B or R1’-B where R1 and/or R1’ may be, if necessary, substituted aryl residue, such as, for example, phenyl, teinila, pyridium or fullam, and means boron residue, such as B(OH)2IN(OCH3)2(O-(CH2)3-O) (OC(CH3)2- (CH3organic base, as, for example, triethylamine, or inorganic bases, such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, barium hydroxide, cesium fluoride or tetrabutylammonium fluoride, in a mixture of solvents such as toluene and water or acetone and water or dimethoxyethane and water or in solvents such as toluene, benzene, dimethoxyethane, tetrahydrofuran, dioxane, acetone or dimethylformamide with the addition of palladium catalyst at a temperature of from 20 to 150 C. as palladium catalysts are used, for example, Pd(OAc)2, PD(h3)4, PdCl2(h3)2the complex of palladium(II)-[1,1’-bis(diphenylphosphino)-ferrocene]-chloride-methylene chloride, Pd[P(2-methoxyphenyl)3]4or d (DBA)2/[(MeO)3-C6H2]PPh2([DBA= dibenzylideneacetone]).

ed) in Addition, the compounds of formulas XV and XA, where R1 and/or R1’ means, if necessary substituted, aryl or heteroaryl residue, can also be obtained from corresponding compounds of formulas XV and XA, where R1 and/or R1’ represents a boron residue, such as In(och3)2or(OS(CH3)2- (CH3)2-O). The last received R1 and/or R1’ - bromine or iodine, by interacting pinacoline ether ziborovoy acid [(Me4WITH2O2)BB-(O2WITH2IU4)] or by interaction with 4,4,5,5-Tetra-methyl-1,3,2-dioxa-borolane. The solvent preferably used dimethyl sulfoxide, dimethylformamide, dioxane or toluene or a mixture thereof. The reaction temperature is from about 80 to 100 C. In the reaction mixture is then added to a weak base, such as potassium acetate and a palladium catalyst, such as, for example, a complex of palladium(II)-[1,1’-bis(diphenylphosphino)-ferrocene]-chloride-methylene chloride or PdCl2-(PPh3)2. Thus obtained compounds of formulas XV and XA, where R1 and/or R1’ means a boron residue, such as In(och3)2or(OS(CH3)2- (CH3)2-O), can then be as described in the EU), subjected to reaction in combination with a compound R1 is Br, R1 is J, R1-OTf with the formation of compounds of formulas XV and XA, where R1 and/or R1' means, if necessary substituted, aryl or heteroaryl residue.

Compounds of formulas XV and XA, where R1 and/or R1’ means a boron residue, such as B(OH)2IN(OCH3)2(O-(CH2)3-O) (OC(CH3)2- (CH3its Another way of obtaining compounds of formula Ha, where R1 and/or R1’ are, if necessary substituted, aryl or heteroaryl residue, is that the compounds of formula XVI, where R1 has the previously indicated meaning, and Sn(alkyl)3for example, denotes Sn(n-butyl)3by reaction of a combination of the Steele in accordance with known literature method described by J. K. Stille, Angewandte Chemie, 98, 504-519 (1986), T. N. Mitchell, Synthesis, 803-815 (1992) or from T. Gan, etc., Tetrahedron Lett. 38, 8453-56 (1997), is introduced into reaction with the compound R1’is Br or R1’-J, and R1’ is, if necessary substituted, aryl2, PdCl2(PhCN)2or PdCl2-(CH3SP)2, in a solvent, such as tetrahydrofuran, toluene or dimethylformamide at temperatures between 20 and 150 C.

ORGANOTIN compounds of the formula XVI, for their part, are available from, for example, brominated or yugirovannykh in the ring predecessors by interacting with the derivatives of the bi-trialkylamine, for example, istributional (Bu3SnSnBu3) known from the literature method (J. K. Stille, Angewandte Chemie, 98, 504-519 (1986); T. Gan and others, Tetragedron Lett. 38, 8453-56 (1997)). And add palladium catalyst, such as Pd(PPh3)4. The solvent can be, for example, toluene; the reaction temperature support between 20 and 110 C. in Addition ORGANOTIN compounds of the formula XVI, and Sn(alkyl)3may be, for example, Sn(CH3)3can be obtained by analogy with the known literature methods (M. Gielen and others Rev. Silicon Germanium Tin Lead Compd. 3, 9 (1997); M. Gielen, Rev. Silicon Germanium Tin Lead Compd. 5, 6 (1981)) by reacting the corresponding brominated in the nucleus predecessors with tributylstannyl sodium at about 0 C.

ef) similarly the compounds of formula Ha, where R1 and/or R1’ are, if necessary Zam R1’ - bromine or iodine, is injected into reaction with aryl - or heteroarylboronic General formula R1-Sn(alkyl)3or R1’-Sn(alkyl)3where R1 and R1’ may be substituted, aryl or heteroaryl residue, under conditions described below).

ed) the compounds of formula Ha, where R1 and/or R1’ = (C2-C6)-quinil or (C2-C6)-alkenyl can be obtained by known literature methods, as described in the EU) and its), catalyzed by palladium interaction, for example, trimethylsilylacetamide or alkynes (K. Sonagashira, etc., Tetrahedron Lett. 4467 (1975); S. Takahashi and others. Synthesis 627 (1980)), alkenylsilanes (E. Negishi, etc., J. Org. Cliem. 62, 8957-60 (1997)) or dialkylaminoalkyl, trialkylaluminium or allyl compounds, 1-alkenylboronic compounds or vinyl compounds (A. Hassner and others, J. Org. Chem. 49, 2546 (1984)) with compounds of formula Ha, where R1 and/or Rl’ is bromine, iodine or OTf.

Obtained by each of these methods, the solution or suspension of the compounds of formula II, it is advisable to was evaporated under reduced pressure and purify the compounds of formula II by crystallization from an inert solvent, such as benzene, toluene, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, cyclohexane, pentane, heptane. Preferably takiveikata with from 1 to 1.5-fold amount of the thiourea of formula III by the way, described above under a).

Described in the production method of (b) coordination compounds of the formula IV is carried out in a solvent with known compounds of the formula V. as such solvents suitable lower alcohols with 1 to 4 carbon atoms as well as lower alkalemia esters of acetic acid with 1 to 4 carbon atoms in the alkyl part, such as, for example, particularly suitable methyl ester of acetic acid and ethyl ester of acetic acid. The interaction is usually conducted in the temperature range between 0 and 60, preferably between 15 and 35 C, and the duration of reaction is between 5 and 60 hours

The compounds of formula I can be recrystallized from a suitable inert solvent, such as acetone, methyl ethyl ketone, acetonitrile, nitromethane. However, particularly preferably, deposition from a solvent, such as dimethylformamide, dimethylacetamide, nitromethane, acetonitrile, methanol, ethanol, isopropanol. Free base of General formula I can also with advantage be purified chromatographically on silica gel. As eluents suitable mixture of dichloromethane with methanol, ethyl ester acetic acid, with heptane, ethyl ester of acetic acid with methanol.

Connections form the Oia formula I to make pure acid at temperatures between 0 and 40, because they are liquid or have a melting point slightly higher than 40 C. However, it is preferable to work in a solvent, such as water or an organic solvent, such as dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, lower alkilany ether acetic acids with 1-4 carbon atoms in the alkyl part, acetonitrile, nitromethane, acetone, methyl ethyl ketone or a lower alcohol with 1 to 4 carbon atoms. Moreover, per mole of the compounds (I use about 1-1 .5 mole of acid (H-Z; but you can also use large quantities of acid. Typically operate at temperatures between 0 and 40, preferably between 10 and 25 C.

When working in aqueous solution after addition of the acid H-Z usually occurs simultaneous dissolution of the compounds of formula I and only rarely loss of the corresponding additive compounds acid. It is advisable to select the proposed salt in the formation of a solution by careful evaporation of the water, preferably by freeze-drying. When working in organic solvents insoluble additive, acid salts precipitated many times after addition of the appropriate acid H-Z. In other cases, additive compounds, see

The additive products of the acids with a very high degree of purification fall sometimes also in the form of viscous oils or amorphous glassy product. These amorphous products can be crystallized by treating with an organic solvent at a temperature of from 40 to 80 C. are suitable For this, in particular, dialkylamide, such as acetone or methyl ethyl ketone, lower dialkyl ethers, as well as acetonitrile, nitromethane and, if necessary, as lower alcohols.

The additive products of the acids can be deprotonirovannym by treatment with bases in the compounds of General formula I. as grounds consider, for example, solutions of inorganic hydroxides such as lithium hydroxide, sodium, potassium, calcium or barium, carbonate or hydrocarbonate, such as sodium carbonate or potassium bicarbonate, sodium or potassium, ammonia and amines, such as triethylamine, Diisopropylamine, dicyclohexylamine, piperidine, morpholine, methyldicyclohexylamine.

When working in the aquatic environment free basic compound I often trudnorastvorimy, are precipitated and can be separated by filtration or extraction with an organic solvent, preferably ethyl ether, acetic acid, mi carbon preferably, methanol, ethanol and isopropanol; can also be used ethyl ester acetic acid, diethyl ether, tetrahydrofuran, dioxane, dimethyl ether of ethylene glycol, dimethylformamide. Work at temperatures from -35 to 60, preferably between 0 and 25 C. When using a solvent, miscible with water, if necessary after pre-con-centering of the reaction mixture, the free base of formula I is precipitated by adding water. When using not miscible with water solvent after the reaction, the reaction mixture was washed with water, and the organic solvent evaporated.

The following examples explain the invention, but not limit it. The measured melting temperature and decomposition (i.e. square) has not been restated and are generally dependent on the heating rate.

Examples are given in table. 1.

The compounds of formula I have a favorable effect on lipid metabolism, in particular, they are applicable as a means of suppressing appetite/tools for weight loss. These compounds can be used individually or in combination with other products for weight loss (as they, for example, is of type II diabetes.

The activity of compounds tested as follows:

Biological test method:

Test suppressing appetite actions carried out on male NMRI mice. After a 24-hour cancellation feeding through a stomach tube was introduced trial medication. Individually with free access to drinking water to the animals 30 min after giving the drug suggested condensed milk. Consumption of condensed milk was determined every Polo for 7 hours and observed the General condition of the animals. The measured consumption of milk was compared with untreated control animals (see table. 2).

From table. 2 shows that the compounds of formula I show a very good reduce appetite action. Reduces appetite action is much improved compared with the comparative example.

Next described in detail for some compounds, other compounds of formula I were obtained similarly:

Example 1 (compound A4):

5-Methanesulfonyl-3-phenyl-2-phenylimino-2,3,8,8-Tetra-hydro-indeno[1,2-d]thiazol-3A-ol:

a) the acid chloride indan-1-one-6-sulfonic acid:

To a suspension of 10.7 g of commercially available 6-aminoindan-1-she's in 100 ml policecontributing hydrochloric acid is added dropwise to a mixture of 6.4 g of CuCl22H2O in 20 ml of water and 195 ml of a saturated solution of SO2in glacial acetic acid. After the weakening of nitrogen excretion is stirred for 1 h at room temperature. By adding 400 ml of water reaches the crystallization of the desired product (acid chloride indan-1-one-6-sulfonic acid), which is sucked off and washed with a small amount of cold water. The product has a melting point of 75 C.

b) Indan-1-one-6-Sultanova acid:

Dissolve 2.1 g of solid NaOH and 18.1 g NS3in 53 ml of water. Add at the same time 2 n NaOH and portions make 8 g of acid chloride of indan-1-one-6-sulphonic acid so that the pH remained at 7-7,2. The temperature rises to about 35 C. and Then stirred for 2 h at room temperature, carefully acidified with concentrated hydrochloric acid and evaporated to dryness, the residue is boiled twice with about 200 ml of methanol, and the filtrate is again evaporated. The residue is triturated with a small amount of acetone, sucked off and dried in vacuum. Get indan-1-one-6-sulinowo acid, which decomposes at 275 C.

c) 6-Methanesulfonyl-indan-1-it:

0.75 g of Sodium are dissolved in 75 ml of anhydrous methanol. Add portions of 5.9 g of indan-1-one-6-sulinowo kislota boiling under reflux. After standing over night, evaporated, the residue is shaken with water and CH2Cl2, the organic phase is dried, evaporated, and the residue is subjected to crystallization with diiso-propyl ether. After extraction and drying receive a 6-methanesulfonyl-indan-1-he with a melting point of 155 C.

d) 2-Bromo-6-methanesulfonyl-indan-1-it:

3,15 g 6-Methanesulfonyl-indan-1-it is suspended in 50 ml of glacial acetic acid and mixed with 0.4 ml of 48% aqueous solution NVG. Added at room temperature to 0.92 ml of bromine in 10 ml of glacial acetic acid and stirred for 2 h then Poured onto ice, the precipitate is sucked off and washed with cold water. The product was then purified by chromatography on a column with SiO2with dichloromethane. As a first fraction have a little dibromopropanol and as the main product 2-bromo-6-methanesulfonyl-indan-1-he with a melting point of 120 C.

e) 5-Methanesulfonyl-3-phenyl-2-phenylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol:

1.45 g of 2-Bromo-6-methanesulfonyl-indan-1-it is dissolved in 15 ml of acetone and mixed with stirring with 1.25 g of N,N’-diphenylthiophene in 25 ml of acetone. From a clear solution after about 2 h, distilled hydrobromide 5-methanesulfonyl-3 is washed by a small amount of acetone. 1.7 g of the hydrobromide (so pl. 247) dissolved in 10 ml of methanol and mixed with 0.8 ml of triethylamine. After 15 minutes, add 150 ml of water, stirred for 30 minutes under ice cooling. The resulting product is sucked off and washed with a small amount of cold water. Get a 5-methane-sulfonyl-3-phenyl-2-phenylimino-2,3,8,8-tetrahydro-indeno-[1,2-d]thiazol-3A-ol with a melting point of 172 C.

Example 2 (compound A9):

3-Ethyl-2-ethylimino-5-(propane-1-sulfonyl)-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol

a) 6-(Propane-1-sulfonyl)-indan-1-it:

0.25 g of sodium are dissolved in 50 ml of anhydrous methanol. Add portions 1,96 g indan-1-one-6-sulinowo acid (see above) and stirred for 30 min at room temperature. Then add to 1.87 g of 1-iodine-propane and stirred for 4 h while boiling under reflux. To end the interaction evaporated in vacuo, mixed with 5 ml of jumproping and 10 ml of toluene and heated for 2 hours under reflux. Then evaporated, the residue is shaken with water and CH2Cl2, the organic phase is dried, evaporated, and the residue purified by filtration column (SiO2; cyclohexane/ethyl acetate = 2/1). Get 6-(propane-1-sulfonyl)-indan-1-he with a melting point of 100 C.

-1-sulfonyl)-indan-1-it is carried out similarly to obtain 2-bromo-6-methanesulfonyl-indan-1-it. The crude product is purified by crystallization and subsequent washing of the low-boiling petroleum ether. Get 2-bromo-6-(propane-1-sulfonyl)-indan-1-he with a melting point 87-89 C.

c) 3-Ethyl-2-ethylimino-5-(propane-1-sulfonyl)-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol:

951 mg of 2-Bromo-6-(propane-1-sulfonyl)-indan-1-it was dissolved in 20 ml of acetone and mixed with stirring with 528 mg of N,N’-lifetimeeven in 10 ml of acetone. After about 10 min, distilled hydrobromide 3-ethyl-2-ethyl-imino-5-(propane-1-sulfonyl)-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol. Stirred for further 1 h at room temperature, is sucked off and washed with a small amount of acetone. After drying receive hydrobromide 3-ethyl-2-ethyl-imino-5-(propane-1-sulfonyl)-2,3,8,8-tetrahydro-indeno[1,2-a]thiazol-3A-ol with a melting point of 146 C. the Latter is dissolved in 10 ml of methanol and mixed with 0.4 ml of triethylamine. After 15 min add 50 ml of water and stirred for 1 h in an ice bath. The resulting crystallized sucked off, washed with water and purified by filtration column (SiO2; ethyl acetate/methanol 3/1). Get 3-ethyl-2-ethylimino-5-(propane-1-sulfonyl-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol with a melting point of 136 C.

With the, the 17 (use of 4-amino-indan-1-it), A, A48 motorway (5-chloro-6-nitro-indan-1-it) is obtained similarly.

Example 3 (compound A21)

The hydrobromide 3-ethyl-2-ethylimino-6-phenyl-2,3,8,8-Tetra-hydro-indeno[1,2-d]thiazol-3A-ol:

a) 5-Phenyl-indan-1-it:

4,22 g of 5-Bromo-indan-1-it, 2,44 g phenylboronic acid and are 4.24 g of sodium carbonate are suspended in a mixture of 100 ml of toluene with 20 ml ethanol and 20 ml of water. After addition of 450 mg of palladium acetate-II and 1.05 g of triphenylphosphine, the mixture is heated 5 h under reflux. After that, the ethanol portion of the reaction mixture is distilled off in vacuo, the reaction mixture is mixed with 50 ml of 0.5 n sodium hydroxide and stirred for 15 min at room temperature. The organic phase is separated and the aqueous part is shaken twice with toluene. The combined organic phases are washed with water, then saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuum. The residue is stirred with n-heptane, sucked off, washed with n-pentane and dried in vacuum at room temperature. Get 5-phenyl-indan-1-he with a melting point of 75 C.

b) 2-Bromo-5-phenyl-indan-1-it:

3,19 g 5-Phenyl-indan-1-dissolve it in 25 ml of glacial acetic acid. Add 10 ál 48%-but ssnoi acid with stirring at room temperature. The reaction mixture next two hours was stirred at room temperature prior to addition 0,057 ml of bromine, mix h and then the reaction mixture was poured on ice water (15 g of water, 45 g of ice, 150 mg of sodium bicarbonate). The precipitation is sucked off and chromatographic on silica gel with toluene/ethyl ester, acetic acid 10/1. Get 2-bromo-5-phenyl-indan-1-he with a melting point of 99-100 C.

(C) hydrogen bromide 3-ethyl-2-ethylimino-6-phenyl-2,3,8,8-Tetra-hydro-indeno[1,2-d]thiazol-3A-ol:

718 mg of 2-Bromo-5-phenyl-indan-1-it was dissolved in 20 ml of dry acetone. To this solution at 5 added dropwise over 5 min a solution of 397 mg of N,N’-diethyltoluamide in 10 ml of dry acetone. The reaction mixture was stirred 2 h at room temperature, the precipitate is then sucked off and washed with acetone. Get hydrobromide 3-ethyl-2-ethylimino-6-phenyl-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol with a melting point 140-141 C (decomposition).

Starting from 5-bromo-indan-1-it is similarly obtained compound A22, A24, A25, A26, A29, A30, A31, A32, A34, A36, A37, A38.

Example 4 (compound A39):

The hydrobromide 3-methyl-2-methylamino-7-(4-triptoreline)-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol

a) 4-(4-Triptoreline)-indan-1-he:b) 2-Bromo-4-(4-triptoreline)-indan-1-it:

2.76 g of 4-(4-Triptoreline)-indan-1-dissolve it in 20 ml of glacial acetic acid. Add 10 μl of 48% solution of Hydrobromic acid in glacial acetic acid and slowly added dropwise a solution of 0,516 ml of bromine in 5 ml of glacial acetic acid. The reaction mixture is stirred 3 h at room temperature and then poured into a mixture of 100 ml of water, 100 g of ice and 100 mg of sodium bicarbonate. Aqueous suspension of TSA is cromatografia on silica gel with dichloromethane/n-heptane 3/1. Get 2-bromo-4-(4-trifluoromethyl-phenyl)-indan-1-he with a melting point 94-97 C.

(C) hydrogen bromide 3-methyl-2-methylamino-7-(4-trifluoromethyl-phenyl)-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol:

426 mg of 2-Bromo-4-(4-triptoreline)-indan-1-she and 131 mg of N,N’-dimethyltitanocene in 10 ml of acetone combine at room temperature and stirred for 4 hours the precipitation is sucked off, washed with acetone and dried in vacuum. Get hydrobromide 3-methyl-2-methylamino-7-(4-triptime-terphenyl)-2,3,8,8-tetrahydro-indeno-[1,2-d]thiazol-3A-ol with a melting point 202-204 C.

On the basis of 4-bromo-indan-1-it is likewise the compound obtained A40.

Example 5 (compound a)

Hydrochloride 3-methyl-2-methylamino-6-pyridin-3-yl-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol

a) 5-Pyridin-3-yl-indan-1-it:

13,26 g 3-Bromopyridine dissolved in 160 ml of diethyl ether and cooled to -60 C. To this solution for 30 minutes added dropwise 52 ml of a 1.6 molar solution of n-utility in n-hexane. Leave the solution to warm to -30 C and at this temperature, added dropwise with stirring to 9.5 ml trimethylol ester of boric acid. The reaction mixture is heated for 3 h under reflux, then cooled to 0 C and add the sulfonic acid, and stirred for further 30 minutes then add 20 g of celite, heat the mixture to room temperature, filtered, the filtrate evaporated, the residue is stirred with 700 ml of toluene, again filtered and the solvent is distilled off in vacuum. 4.1 g of the residue (3-[1,3,2]dioxaborolan-2-yl-pyridine) without further purification together with 4,22 g 5-bromantan-1-it and are 4.24 g of sodium carbonate dissolved in a mixture of 100 ml of toluene with 20 ml ethanol and 20 ml of water. The solution Tegaserod with argon and then added 112 mg of palladium acetate-II and 262 mg of triphenylphosphine. The reaction mixture is boiled for 4 hours under reflux, the ethanol portion of the mixture is distilled in vacuum. Then added with stirring 50 ml of 0.5 n sodium hydroxide, the organic phase is separated, and the aqueous phase is shaken with toluene. The combined organic phases are successively shaken with water and saturated saline, dried over magnesium sulfate, evaporated in vacuo and purify by chromatography on silica gel with ethyl ether acetic acid/n-heptane 1/1. Get 5-pyridin-3-yl-indan-1-he with a melting point 103-106 C.

b) 2-Chloro-5-pyridin-3-yl-indan-1-it:

3,22 g 5-Pyridin-3-yl-indan-1-it is dissolved in 160 ml of dichloromethane and at 0 C for 15 min, mixed dropwise with perature, before slowly add 50 ml of a saturated solution of sodium bicarbonate. The organic phase is separated, washed with water, dried over magnesium sulfate, evaporated in vacuo and purify by chromatography on silica gel with dichloromethane/methanol 50/1. Get (along with 2,2-dichloro-5-pyridin-3-yl-indan-1-one with a melting point of 109 (C) 2-chloro-5-pyridin-3-yl-indan-1-he with a melting point 103-105 C.

c) the Hydrochloride of 3-methyl-2-methylamino-6-pyridin-3-yl-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol:

366 mg of 2-Chloro-5-pyridin-3-yl-indan-1-she and 235 mg of N,N’-dimethyltitanocene dissolved in 5 ml of methanol and boiled for 7 hours under reflux. The reaction mixture is cooled and evaporated in vacuum. The residue is mixed with 5 ml of acetone, stirred for 30 min in an ultrasonic bath and then sucked off. The residue is washed with acetone and dried in vacuum. Receive hydrochloride 3-methyl-2-methylamino-6-pyridin-3-yl-2,3,8,8 a-tetrahydro-indeno[1,2-d]thiazol-3A-ol with a melting point 253-255 C.

Example 6 (compound A41):

The hydrobromide 3-methyl-2-methylamino-6-triptoreline-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol

a) Methyl ester of 3-triptoreline-cinnamic acid:

to 9.15 g of 3-Cryptomaterial acid are dissolved in 90 the Cooled solution is then gently mixed with 0.9 g of sodium bicarbonate, stirred for 5 min and then evaporated in vacuum. The rest make 250 ml of ethyl ether, acetic acid, washed twice using 50 ml of water and dried over magnesium sulfate. The solution is evaporated in vacuo, and the remaining light oil is used without further purification.

b) Methyl ester of 3-(3-trifloromethyl)propionic acid:

9.6 g of Methyl ester of 3-cryptomaterial acid are dissolved in 200 ml of methanol. Added 750 mg of palladium on coal (10%) and hydronaut at normal pressure. After conventional treatment get methyl ester 3-(3-Cryptor-methoxyphenyl)propionic acid as light oil.

C) 5-Triptoreline-indan-1-it:

9,37 g Methyl ester 3-(3-trifloromethyl)-propionic acid are dissolved in 50 ml of ethanol with 25 ml of water. Add 3,74 g of potassium hydroxide and boiled for 45 min under reflux. The cooled solution is evaporated, the residue is mixed with 25 ml of water and added with stirring, concentrated hydrochloric acid to achieve a pH of 1. Water the reaction mixture is shaken twice with 75 ml of dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, evaporated and dried in vacuum. Get 3-(3-trifloromethyl)PR the reed and boiled for 1 h under reflux. The cooled reaction mixture is evaporated, the residue bring in 5 ml of toluene and again evaporated. Get the acid chloride 3-(3-trifloromethyl)propionic acid, which without further purification was dissolved in 30 ml dichloromethane and at 0-5 With added dropwise with stirring over 15 min to a suspension of 5.49 g of anhydrous aluminum trichloride in 40 ml of dichloromethane. The reaction mixture is stirred one hour at 0 C and then bring in 40 ml of ice water. The organic phase is separated, and the aqueous phase is again shaken with 40 ml of dichloromethane. The combined organic phases are washed with 40 ml saturated sodium hydrogen carbonate solution and water, dried over magnesium sulfate, evaporated in vacuo and purify by chromatography on silica gel with toluene/ethyl ester, acetic acid 20/1. Get a 5-three-formatosi-indan-1-it is in the form of a light yellow oil.

a) 2-Bromo-5-triptoreline-indan-1-it:

5.3g 5-Triptoreline-indan-1-dissolve it in 50 ml of glacial acetic acid, mixed with 110 ál of Hydrobromic acid (48% in glacial acetic acid) and at room temperature is mixed dropwise with a solution 1,305 ml of bromine in 12 ml of glacial acetic acid. The reaction mixture is stirred for 90 min at room temperature and ZAT the water, dried over magnesium sulfate, evaporated in vacuum and chromatographic on silica gel with toluene/ethyl ester, acetic acid 50/1. Get 2-bromo-5-triptoreline-indan-1-it is in the form of wax.

(e) hydrobromide 3-methyl-2-methylamino-6-triptoreline-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol:

0,197 mg of 2-Bromo-5-triptoreline-indan-1-she 0.104 g g N,N’-dimethyltitanocene dissolved in 5 ml of acetone and boiled for 5 hours under reflux. The resulting suspension is stirred for further 1 h at 0 C and then sucked off; the residue is washed with acetone and evaporated in vacuum. The hydrobromide 3-methyl-2-methylamino-6-triptoreline-2,3,8,8-tetrahydro-into[1,2-d]thiazol-3A-ol melts at 162 With decomposition.

Example 7 (compound A35):

The hydrobromide 5-tert-butyl-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol:

a) Methyl ester of 3-(4-tert-butylphenyl)acrylic acid:

3-(4-Tert-butylphenyl)acrylic acid in methanol analogously to example 6A) is subjected to interaction with sulfuric acid to methyl ester 3-(4-tertbutylphenyl)acrylic acid. Ether has a waxy texture with a melting point of about 35 C.

b) Methyl ester of 3-(4-tert-butylphenyl)propionic acid:

10.0 g Metrov the CSOs h gain of 2.45 g of magnesium turnings, and a mixture of three hours was stirred at room temperature. Then add 380 ml of magnesium turnings are added and stirred for one hour. After cooling (ice bath) carefully added dropwise with stirring to 90 ml of 2 n hydrochloric acid. Thereafter, the methanol is removed in vacuo, the residue is extracted twice using 200 ml of dichloromethane, the dichloromethane phase is washed with water until neutral (2 50 ml), dried over magnesium sulfate and evaporated. Get methyl ester 3-(4-tert-butylphenyl)propionic acid as a colourless waxy compounds.

c) 3-(4-Tert-butylphenyl)propionic acid:

9,90 g of Methyl ester of 3-(4-tert-butylphenyl)propionic acid are dissolved in a mixture of 30 ml of ethanol with 15 ml of water, mixed with 4,46 g of potassium hydroxide, heated for 45 minutes under reflux and then evaporated in vacuo, mixed with 30 ml of water and cooled in an ice bath, adjusted pH to 1 with concentrated hydrochloric acid. The aqueous solution is shaken out three times with 100 ml dichloromethane, washed with water until neutral, dried over magnesium sulfate and evaporated in vacuum. The residue is stirred with 100 ml of 25% acetic acid, cooled to 10 With and sucked off and dried in vacuum. Get 3-(4-tert-butylphenyl)propionate:

The acid chloride acid get analogously to example 6C) and without further purification enter the next stage.

e) 6-Tert-butyl-indan-1-it:

From carboxylic acid 7d receive 6-tert-butyl-indan-1-on, as described in 6C). 6-Tert-butyl-indan-1-it has a melting point of 94-96 C.

f) 2-Bromo-6-tert-butyl-indan-1-it:

According to the method described in 6d), 6-tert-butyl-indan-1-make it 2-bromo-6-tert-butyl-indan-1-it; it has a melting point 58-61 C.

d) the hydrobromide 5-tert-butyl-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol:

The interaction of 267 mg of 2-bromo-6-tert-butyl-indan-1-one with 156 mg of N,N’-dimethyltitanocene in 10 ml of acetone gives the hydrobromide 5-tert-butyl-3-methyl-2-methylimino-2,3,8,8-indeno-[1,2-d]thiazol-3A-ol with a melting point 277-279 C.

Example 8 (compound A23):

The hydrobromide 3A-hydroxy-3-methyl-2-methylamino-3,3 a,8,8A-tetrahydro-2H-indeno[1,2-d]thiazole-6-carbonitrile:

a) 1-Oxo-indan-5-carbonitrile:

9.5 g of 5-Bromantan-1-she and 4.93 g of CuCN suspended in 10 ml of dimethylformamide and 4 h refluxed. To chilled, dark brown viscous suspension with stirring was added dropwise a solution of 18 g of ferric chloride III in 5 ml of concentrated Sol is 50 ml of toluene, and the combined organic phases are shaken with 50 ml of 2 n hydrochloric acid and 50 ml of 2 n sodium hydroxide and then with water until neutral. Toluene extract is dried over magnesium sulfate, evaporated in vacuo, and the residue is recrystallized from n-heptane. Get 1-oxo-indan-5-carbonitrile with a boiling point of 123-125 C.

b) 2-Bromo-1-oxo-indan-5-carbonitrile:

Bromination of 1-oxo-indan-5-carbonitrile carried out analogously to example 6d) and get 2-bromo-1-oxo-indan-5-carbonitrile with a melting point 115-118 C.

c) hydrogen bromide 3A-hydroxy-3-methyl-2-methylamino-3,3 a,8,8A-tetrahydro-2H-indeno[1,2-d]thiazole-6-carbonitrile:

236 mg of 2-Bromo-1-oxo-indan-5-carbonitrile dissolved in 10 ml of acetone and 0-5 mixed with 210 mg of N,N’-dimethylthiophene. The mixture is stirred for 3 h at room temperature and 1 h at 0 C. the reaction Product is sucked off, washed with acetone and dried in vacuum. Get hydrobromide 3A-hydroxy-3-methyl-2-methyl-imino-3,3 a,8,8A-tetrahydro-2H-indeno[1,2-d]thiazole-6-carbonitrile with a melting point 282-284 C (decomposition).

In a similar way received connection A12 from 6-bromo-indan-1-it.

Example 9 (compound A18):

3-Methyl-2-methylimino-5-methylsulphonyl-6-phenylthio-2,3,8,8-tetr is of 4.9 g of 5-chloro-6-methylsulphonyl-1-indanone 1.4 g of anhydrous milled potassium carbonate and 50 ml of DMF, are added dropwise in an argon atmosphere with stirring to 2.55 ml thiophenol and heat, still stirring, for about 10 h at 80 C. After addition of 500 ml of water at room temperature, the crystals are filtered and purified by dissolving in acetone, treatment with activated carbon and subsequent sedimentation of water. Light yellow crystalline substance, melting point 211-212 C.

b) 2-Bromo-6-methylsulphonyl-5-phenylthio-1-indanone obtained by adding dropwise a mixture of of 0.39 ml of bromine in 10 ml of glacial acetic acid to a stirred solution of 2.4 g of 6-methylsulphonyl-5-phenylthio-1-indanone, 0.2 ml of concentrated aqueous Hydrobromic acid and 30 ml of glacial acetic acid, the subsequent pouring the reaction mixture into a slurry of water and ice and subsequent filtration of the crystalline product. Slightly yellow crystalline substance, melting point 158-160 C.

c) hydrogen bromide 3-methyl-2-methylimino-5-methylsulphonyl-6-phenylthio-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol

Into a solution of 2.7 g of 2-bromo-6-methylsulphonyl-5-phenylthio-1-indanone in 30 ml of acetone contribute to 0.72 g of N,N’-dimethylthiophene, stirred for one hour at whom the m

a) 3-Methyl-2-methylimino-5-methylsulphonyl-6-phenylthio-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol

The hydrobromide 3-methyl-2-methylimino-5-methylsulphonyl-6-phenylthio-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol are suspended in methanol and mixed with 3-fold molar excess of triethylamine. The resulting solution is filtered and cause crystallization by trituration with a glass rod. A colorless crystalline compound, melting point 142-143 With decomposition.

Example 10 (compound A48 motorway):

The hydrobromide 8-chloro-5A-hydroxy-3,4-dihydro-7-methyl-sulfonyl-indeno[2,1-b]imidazo[1,2-d]thiazolidine

a) 5-Chloro-6-nitro-1-indanone:

86 g of 5-Chloro-1-indanone contribute with stirring and external cooling in 540 ml of fuming nitric acid with a density of 1.52 g/ml so that the internal temperature was maintained between -15 and -10 C. the Reaction mixture was poured into stirred slurry of ice water and filtered yellow crystalline substance. Purification by dissolving in a mixture of 2 parts of acetone and 5 parts of ethanol, treatment with activated carbon and subsequent removal parts acetone by distillation under reduced pressure. Melting point 126-128 C.

b) 6-Amino-5-chloro-1-indanone:

c) 5-Chloro-6-chlorosulfonyl-1-indanone:

To a suspension of 26.8 g of 6-amino-5-chloro-1-indanone in 200 ml of 20% hydrochloric acid are added dropwise with good stirring and cooling a solution of 10.4 g of sodium nitrite in 30 ml of water, and the temperature of the support between 0 and 5 C. thus obtain a solution, which after further stirring at 0 portions with stirring to make a solution of 12.7 g of dihydrate of chloride of copper-II, 50 ml of water and 400 ml of saturated sulfur dioxide glacial acetic acid at 0-5 C. Stirred for further one hour without external cooling, connect then with 600 ml of water and filtered, the crystals washed several times on the filter with cold water and then dried in vacuum. A colorless crystalline substance, melting point 147-148 C.

d) 5-Chloro-1-indanone-6-Sultanova acid:

To a solution of 26 g of sodium hydrosulphate and 3 g of NaOH in 75 ml of water in portions with stirring PM 2 n sodium hydroxide so, so that the pH was maintained between 7 and 7.5. After this set of concentrated hydrochloric acid to pH 1-2, cooled to 0 C -5 C, the crystals are filtered and washed with water. Melting point >300 With blackening at 170 C.

e) 5-Chloro-6-methylsulphonyl-1-indanone:

To a solution of sodium methylate, which was obtained from 150 ml of methanol and 1 g of sodium is added first of 9.2 g of 5-chloro-1-indanone-6-sulinowo acid and then 15 g of methyl iodide, and the mixture is heated with an efficient reflux 10 h to a boil. After removal of the solvent the residue is mixed with 200 ml of water, the crystals are filtered and the product washed thoroughly with water.

A colorless crystalline substance from methanol after treatment with activated carbon, melting point 197-198 C.

f) 2-Bromo-5-chloro-6-methylsulphonyl-1-indanone:

receive from 6.8 g of 5-chloro-6-methylsulphonyl-1-indanone and 1.45 g of bromine in glacial acetic acid. From colorless to light brown crystalline substance, melting point of 144 C.

d) the hydrobromide 8-chloro-5A-hydroxy-3,4-dihydro-7-methylsulphonyl-indeno[2,1-b]imidazo[1,2-d]thiazolidine

To a solution of 3,24 g of 2-bromo-5-chloro-6-methylsulphonyl-1-indanone in 50 ml of acetone was added when paramesh room temperature. Colorless crystalline compound is filtered off and washed several times with acetone. The decomposition temperature of 135 C.

h) 8-Chloro-5A-hydroxy-3,4-dihydro-7-methylsulphonyl-indeno[2,1-b]imidazo[1,2-d]thiazolidin get analogously to example 9 of the hydrobromide 8-chloro-5A-hydroxy-3,4-dihydro-7-methylsulphonyl-indeno[2,1-b]imidazo[1,2-d]thiazolidine and triethylamine in methanol. A colorless crystalline substance, the decomposition temperature of 192 C.

Example 11 (compound A27):

The hydrochloride of 6-(4-chlorophenoxy)-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol

a) 5-(4-Chlorophenoxy)-1-indanone:

2,82 g of 4-Chlorophenol after dissolution in 60 ml of anhydrous dimethylacetamide is stirred from 8.2 g and powdered anhydrous potassium carbonate 1/2 h at room temperature. After addition of 1.5 g of 5-forindiana stirred for 10 hours at 120-130 C, and distilled after cooling, the solvent under reduced pressure. The residue is mixed with water and extracted several times with ethyl acetate. The organic phase is washed with 2 n NaOH and then with water, then stirred for 15 min after addition of activated charcoal, and the solvent after drying over anhydrous magnesium sulfate distilled off under reduced pressure. Partially crystallisa ethyl acetate and toluene. Brown crystals, melting temperature of 75-80 C.

b) 2-Bromo-5-(4-chlorophenoxy)-1-indanone:

To a solution of 1.3 g of 5-(4-chlorophenoxy)-1-indanone in 30 ml ethyl ester of acetic acid are added dropwise in about 1/2 ml of a solution of 0.25 ml of bromine in 5 ml of ethyl ether, acetic acid and slowly heated to discoloration bromine or to begin the selection NVG. Then cooled and added dropwise at room temperature, the remaining bromine, leave to mix for another 2 h, and the solvent is distilled off under reduced pressure. The remaining dark oil is used without further purification.

c) the hydrobromide 6-(4-chlorophenoxy)-3-methyl-2-methylimino-2,3,8,8 a-tetrahydro-indeno[1,2-d]thiazol-3A-ol obtained by the interaction 1,69 g of 2-bromo-5-(4-chlorophenoxy)-1-indanone and 0.52 g of n, N’-dimethyltitanocene in 25 ml of ethyl acetate in the form of light yellow to colorless crystalline precipitate. Melting point 252-255 C.

d) 6-(4-Chlorophenoxy)-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol are obtained by treatment of a solution of 1.5 g of the hydrobromide 6-(4-chlorophenoxy)-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol in 40 ml of methanol and 2.3 ml of triethylamine. The solvent is distilled off, and the rest of the re is s)-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol is obtained by addition of a solution of HCl gas in a simple diethyl ether to a solution of 1.2 g of 6-(4-chlorophenoxy)-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d] thiazol-3A-ol in 30 ml of ethyl acetate to strongly acidic reaction in the form of a colorless crystalline precipitate. Melting point 247-250 C.

Example 12 (compound A28):

The hydrobromide 6-{2,2,2-triptoreline)-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol

a) 5-(2,2,2-Triptoreline)-1-indanone:

2.2 ml 2,2,2-triptoreline add to stir a mixture of 3.5 g of 5-forindiana, 20 ml of anhydrous dimethylformamide and 4.1 g and powdered anhydrous potassium carbonate and stirred for 10 h at 80 C. the Solvent is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, and the organic phase is washed several times with water. Get indanone derivative in the form of a brown crystalline solid after chromatography on silica gel with a mixture of equal parts of ethyl acetate and toluene as eluent. Melting point 93-97 C.

b) 2-Bromo-5-(2,2,2-triptoreline)-1-indanone produced by the interaction of 0.9 g of 5-(2,2,2-triptoreline)-1-indanone with 0.2 ml of bromine in 25 ml of glacial acetic acid. The compound is used without further purification.

(C) hydrobromide 6-(2,2,2-triptoreline)-3-methyl-2-methyl-imino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol is produced by the interaction of 1.2 g of 2-bromo-5-[2,2,2-triptoreline)-1-indanone and 0.4 g of N,N’-dimethyltitanocene in 25 ml of ethyl acetate in the form of light-JMeter-2-methylimino-2,3,8,8 a-tetrahydro-indeno[1,2-d]the thiazol-3A-ol hydrobromide is obtained from 6-(2,2,2-triptoreline)-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol and triethylamine. Colorless crystalline solid, melting point 138-140 C.

e) of the Hydrochloride of 6-(2,2,2-triptoreline)-3-methyl-2-methyl-imino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol is obtained from 6-(2,2,2-triptoreline)-3-methyl-2-methyl-imino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol and a solution of HCl gas in a simple ether. Colorless crystals, melting point 274-276 C.

Example 13 (compound A45):

Hydrochloride 5-(2,2,3,3,4,4,4-getAttributes)-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol

a) 5-(2,2,3,3,4,4,4-GetAttributes)-1-indanone:

obtain 6.5 g of 5-forindiana and 35.6 g and powdered anhydrous potassium carbonate in 50 ml of anhydrous dimethylacetamide in the form of oil color of honey.

b) 2-Bromo-5-(2,2,3,3,4,4,4-getAttributes)-1-indanone

produced by interaction of 4.16 g of 5-(2,2,3,3,4,4,4-getAttributes)-1-indanone with 0,69 ml of bromine in 110 ml of ethyl acetate. The connection is allocated in the form of a brown oil and used without further purification.

c) the hydrobromide 6-(2,2,3,3,4,4,4-getAttributes)-3-methyl-2-methylimino-indeno[1,2-d]thiazol-3A-ol is produced by the interaction of 1.4 g of 2-bromo-5-(2,2,3,3,4,4,4-getAttributes)-1-indanone and 0.36 g of N,N’-dimethyltitanocene in 40 ml acetic acid ethyl ester as light yellow to BL-2 methylimino-2,3,8,8 a-tetrahydro-indeno[1,2-d]the thiazol-3A-ol hydrobromide is obtained from 6-(2,2,3,3,4,4,4-getAttributes)-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno-[1,2-d]thiazol-3A-ol and triethylamine. Colorless crystalline solid, melting point 138-140 C.

e) of the Hydrochloride of 6-(2,2,3,3,4,4,4-getAttributes)-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol

obtained from 6-(2,2,3,3,4,4,4-getAttributes)-3-methyl-2-methylimino-2,3,8,8 a-tetrahydro-indeno[1,2-d]thiazol-3A-ol and ethereal hydrochloric acid. Colorless crystals, melting point 248-250 C.

Example 14 (compound B1):

6-Chloro-8-fluoro-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol:

a) 5-Chloro-2-fluoro-indan-1-it:

To a solution of 5.24 g of Diisopropylamine in 60 ml of dry tetrahydrofuran is slowly added dropwise at a temperature of <-50 C. and Then slowly added the solution 6,33 g of 5-chloro-indan-1-she's in 60 ml of dry tetrahydrofuran, and the mixture is stirred for 20 min at -50 C. Finally, are added dropwise 11.4 g of N-fluoro-dibenzoylethylene dissolved in 60 ml of dry tetrahydrofuran. With stirring, leave the mixture was heated for 2 h to 0, are added dropwise to 120 ml of a saturated solution of sodium bicarbonate, distilled tetrahydrofuran in vacuo, and the residue is shaken twice with 150 ml ethyl ester of acetic acid. The organic phase is washed with water and a saturated solution pavarino firom/n-heptane 1/1. Along with the 5-chloro-2,2-debtor-indan-1-one get 5-chloro-2-fluoro-indan-1-he with a melting point of 102-104 C.

b) 5-Chloro-2-bromo-2-fluoro-indan-1-it:

Bromination of 5-chloro-2-fluoro-indan-1-it is carried out similarly 6d), and get 5-chloro-2-bromo-2-fluoro-indan-1-he with a melting point 104-105 C.

c) 6-Chloro-8-fluoro-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol:

263 mg of 5-Chloro-2-bromo-2-fluoro-indan-1-she and 156 mg of N,N’-dimethyltitanocene dissolved in 5 ml of acetone and stirred for 90 min at room temperature and then 2 hours at 50 C. the Reaction mixture is cooled and evaporated in vacuum. To the residue add 5 ml of toluene and the mixture is heated for 2 hours under reflux, cooled, mixed with 152 mg of triethylamine and stirred for 2 h at room temperature. The residue is sucked off, washed with a small amount of water and dried in vacuum. Get 6-chloro-8-fluoro-3-methyl-2-methylimino-2,3,8,8 a-tetrahydro-indeno[1,2-d]thiazol-3A-ol with a melting point 189-190 C.

Example 15 (compound B2):

The hydrochloride of 6-chloro-8-fluoro-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-it:

1 g (4,47 mmole) of 6-Chloro-8-fluoro-3-methyl-2-methylimino-1,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol are dissolved in 120 ml of warm isopropanol evaporated, and the residue triturated with acetone, sucked off, and the residue is dried in vacuum. Receive hydrochloride 6-chloro-8-fluoro-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-a]thiazol-3A-ol with a melting point 205 (decomp.).

Example 16 (compound B1(-) and B1(+):

100 mg of racemic mixture of compound B1 is divided into column high-performance liquid chromatography (CSP Chiralpak AD 250 4,6) with n-hexane/ethanol 10+1 for the enantiomers. Receive (-)-torque enantiomer B1(-) with retention time of 7.9 min with a melting point 175-79 C (decomp.) and (+)-torque enantiomer B1 (+) retention time 8,84 min with a melting point 172-77 C (decomp).

Example 17 (compound C1 and C6):

(6-Chloro-3A-methoxy-3-methyl-3,3 a,8,8A-tetrahydro-indeno[1,2-d]thiazole-2 - ilidene)methylamine (hydrochloride):

5 g of the Hydrochloride of 6-chloro-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol are dissolved in 200 ml of methanol and heated for three days under reflux. The cooled reaction mixture is evaporated in vacuo, the residue is triturated with 50 ml of acetone and filtered. The filtrate is evaporated, suspended in 100 ml of ethyl ether, acetic acid and mixed with 100 ml of saturated solution of sodium bicarbonate. The organic phase is separated, washed with water, dried over Get 6-chloro-3-methyl-2-methylimino-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol with a melting point of 94-96 C.

The hydrochloride of this compound (compound C6) thus receive the free base is dissolved in methyl tert-butyl ether, and with stirring and cooling in an ice bath, add ethereal hydrochloric acid to achieve a pH of about 1. After that the reaction mixture is stirred for further 3 h at room temperature, the solvent is distilled off, the residue is mixed with acetone and filtered. The filtrate is evaporated in vacuo, the residue is dried in vacuum. Receive hydrochloride 6-chloro-3-methyl-2-methylimino-2,3,8,8 a-tetrahydro-indeno[1,2-d]thiazol-3A-ol with a melting temperature of 65-70 C.

Connection C2-C5 receive a similar way.

Example 18a and b (compound C1(+) and C1(-)):

100 mg of racemic mixture of compound C1 (free base) shared by high-performance liquid chromatography (CSP Chiralpak AD h,6) n-hexane/2-propanol 25/1 with 0.1% diethylamine the enantiomers. Receive (+)-torque enantiomer C1(+) retention time 7,38 min and the value of specific rotation 237,5 (=10,3 mg/2 ml in trichloromethane) with a melting point of 70-71 C and (-) - torque enantiomer C1(-) with retention time of 8.06 min and the value of specific rotation -229,1 (=9,9 mg/2 ml in trichloromethane) with a melting point 71-72 C.

Example 19 (connected to the) 2,3-Dibromo-3-(2-chlorophenyl)propionic acid

obtained by the addition dropwise of a solution of 7.8 g of bromine to a suspension of 9 g of 2-harkerite acid in 250 ml of chloroform upon irradiation with 500-watt fluorescent lamp and subsequent evaporation of the solvent. The melting point of 183-185 C.

b) acid chloride 2,3-dibromo-3-(2-chlorophenyl)propionic acid is obtained by boiling 10 g of 2,3-dibromo-3-(2-chlorophenyl)propionic acid in 70 ml of thionyl chloride with stirring and distillation of the liquid in the form of oily-amorphous residue.

C) 2-Bromo-3-(2-chlorophenyl)-1-indanone

In a mixture of 4.1 g of anhydrous benzene and 30 ml of carbon disulfide make under argon atmosphere 6.6 g of anhydrous active aluminum chloride and then cooled to -20 C. While maintaining the cooling in this suspension is added dropwise a solution of 15 g of acid chloride of 2,3-dibromo-3-(2-chlorophenyl)propionic acid in 50 ml of carbon disulfide, incubated 5 h at 0 C and leave for the next 16 hours in a refrigerator at a temperature of 4-8 C. the Reaction mixture is poured with stirring into a mixture of ice and water, strongly acidified with concentrated Hcl, extracted with chloroform, the organic phase is washed with water and finally dried over magnesium sulfate. After removal of the solvent viscous amorphous residue contribute in diethyl ether, and a few who Argonaut solvent. Viscous amorphous substance.

a) hydrobromide 8-(2-chlorophenyl)-3-methyl-2-methylimino-2,3,8,8 a-tetrahydro-indeno[1,2-d]thiazol-3A-ol

4 g of 2-Bromo-3-(2-chlorophenyl)-1-indanone in acetic ether is mixed with 1.2 g of N,N’-dimethylthiophene and stirred for 2 days at room temperature. Pale-yellow crystalline substance, melting point 163 C.

Example 20 (compound D14):

The hydrobromide 3A-hydroxy-3-methyl-2-methylamino-8-phenyl-3A,8,9,9 a-tetrahydronaphthyl[2,1-b]thiazolidine

a) 2-Bromo-4-phenyl-1-tetralone

produced by reactions 4,43 g of 4-phenyl-1-tetralone and 3.2 g of bromine in containing NVG ethyl acetate in the form of a viscous amorphous product.

b) the hydrobromide 3A-hydroxy-3-methyl-2-methylamino-8-phenyl-3A,8,9,9 a-tetrahydronaphthyl[2,1-b]thiazolidine

receive by interacting 26 g of 2-bromo-4-phenyl-1-tetralone and 5 g of N,N’-dimethyltitanocene in 60 ml of ethyl acetate in the form of light yellow to colorless crystalline precipitate. Melting point 229-231 C (With decomposition).

Connection D1 obtained in the same way.

Example 21 (compound D16):

1-Ethyl-2-ethylimino-9-nitro-1,2,4,5-tetrahydro-an-6-oxa-3-thia-1-azabenzo[e]azulene-10b-ol:

a) the acid chloride of 4-proximalen acid:

504,6 g of 4-FEM mixture is distilled in vacuum and get the acid chloride 4-proximalen acid with a boiling point 145-147 C at a pressure of 10-12 mm RT.article.

b) 6,7,8,9-Tetrahydrobenzaldehyde-5-it:

Suspended 192 g of aluminium chloride-III 1.6 l of dry 1,2-dichloroethane and slowly added dropwise under a protective argon atmosphere with stirring, a solution of 238 g of acid chloride of 4-proximalen acid in 300 ml of 1,2-dichloroethane for 5.5 hours at a temperature of -5 C. the reaction Product is subjected to hydrolysis by pouring into a mixture of 2 l of water and 2 l of concentrated hydrochloric acid. Stirred for 30 min, precipitated and sucked off. The organic phase is separated, and the aqueous phase is shaken out three times with 1,2-dichloroethane. The organic extract is washed with water, dilute bicarbonate solution and finally with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuum. The residue is distilled in vacuum. Get 6,7,8,9-tetrahydrobenzaldehyde-5-he with a boiling point 79-84 C at a pressure of 0.001 mm RT.article in the form of a transparent liquid.

c) 7-Nitro-3,4-dihydro-2H-benzo[b]oxepin-5-it:

25 g of 6,7,8,9-Tetrahydrobenzaldehyde-5-it is dissolved in 280 ml of concentrated sulfuric acid at -10 C. With vigorous stirring at -10 To contribute portions x 16.75 g of sodium nitrate. The dark reaction mixture is stirred for 45 min at 0 C; while the remainder of the sodium nitrate slowly percivall and neutralized with water. The air-dried residue to clean recrystallized from isopropanol. Get 7-nitro-3,4-dihydro-2H-benzo[b]oxepin-5-he who is subjected to further processing.

d) 4-Bromo-7-nitro-3,4-dihydro-2H-benzo[b]oxepin-5-it:

2,07 g of 7-Nitro-3,4-dihydro-2H-benzo[b]oxepin-5-she dissolved in 10 ml dichloromethane and cooled in an ice bath with stirring, mixed with 1.7 g of bromine dissolved in 10 ml of dichloromethane (addition over 3 hours). The reaction mixture contribute in 30 ml of a saturated solution of sodium bicarbonate, the organic phase is separated, and the aqueous phase is repeatedly extracted with dichloromethane. The combined organic extracts washed with saturated sodium chloride solution, dried over sodium sulfate, evaporated and the residue recrystallized from butyl ester of acetic acid and get 4-bromo-7-nitro-3,4-dihydro-2H-benzo[b]-oxepin-5-he with a melting point 115-118 C.

e) 1-Ethyl-2-ethylimino-9-nitro-1,2,4,5-tetrahydro-an-6-oxa-3-thia-1-azabenzo[e]azulene-10b-ol:

5 g of 4-Bromo-7-nitro-3,4-dihydro-2H-benzo[b]oxepin-5-it is heated with 2.4 g of N,N’-diethyltoluamide in 30 ml of butane-2-it 30 min under reflux. The precipitate is sucked off, stirred with a saturated solution hydrocarbonbearing salt, dried over sodium sulfate, evaporated and the residue is recrystallized from methanol/water. Get 1-ethyl-2-ethylimino-9-nitro-1,2,4,5-tetrahydro-an-6-oxa-3-thia-1-azabenzo[e]azulene-10b-ol with a melting point 125-127 C. Similarly, the compounds D12, D15, D17-D20, D22-D23, D26-D31 from the corresponding derivatives of benzocycloheptene or benzocycloheptene.

Example 22 (compound D21):

1-Methyl-2-methylimino-6,6-dioxo-1,2,3 and 4,5,6 hexahydrite-1-Aza-benzo[e]azulene-10b-ol:

a) the acid chloride of 4-phenylsulfanyl acid:

54,9 g of 4-Phenylsulfanyl acid are dissolved with 0.5 ml of dimethylformamide in 280 ml of toluene. Added dropwise to 36.5 ml oxalicacid and the reaction mixture is stirred 2 h at room temperature and one hour at 65-70 C. and Then distilled in vacuum toluene and excess oxalicacid. The brown oily residue is distilled in high vacuum and get the acid chloride 4-phenylsulfanyl acid with a boiling point of 116 to 119 C at a pressure of 0,008 mm RT.article.

(b) 3,4-Dihydro-2H-benzo[b]thiepin-5-it:

38,2 g of Anhydrous aluminium chloride-III are suspended in 260 ml of dichloromethane. At 0 under stirring slowly added a solution of 51.1 g of acid chloride of 4-peninsulae-yellow solution. This solution with vigorous stirring contribute in ice-cold mixture of 1 l of water and 1 l of concentrated hydrochloric acid. After stirred for 30 min, the mixture is extracted three times with 200 ml of diethyl ether. The combined organic phase is shaken out with water and with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuum. The oil obtained is distilled and receive 3,4-dihydro-2H-benzo[b]thiepin-5-he with a boiling point of 93-94 C at a pressure of 0.002 mm RT. Art.

c) 1,1-Dioxo-1,2,3,4-tetrahydrobenzo[b]thiepin-5-it:

10 g of 3,4-Dihydro-2H-benzo[b]thiepin-5-Oh are dissolved in 125 ml of glacial acetic acid. At room temperature under stirring slowly added dropwise and 11.2 ml of 35% hydrogen peroxide. After stirring for 2 h at room temperature are added dropwise 11 ml of 35% hydrogen peroxide. The reaction mixture was then stirred over night. Carefully remove the solvent in vacuo, and the residue is mixed with ice and with stirring, gently mixed with 1 n potassium bicarbonate. Aqueous suspension gently saturated with sodium chloride, was sucked off, washed with water and dried in vacuum. Receive 1,1-dioxo-1,2,3,4-tetrahydrobenzo[b]thiepin-5-he temperature of Pavlenko[b]thiepin-5-it is dissolved with stirring in 200 ml of glacial acetic acid. Add a 8.9 g of N-bromosuccinimide and heat the mixture for 8 hours at 75-80 C. After the reaction, the solvent is evaporated in vacuo, and the oily residue is mixed under stirring with ice-cold solution of sodium bicarbonate. After 30-minute stirring sucked off, and the residue is washed with water. After drying in vacuo get 4-bromo-1,1-dioxo-1,2,3,4-tetrahydrobenzo[b]thiepin-5-he with a melting point 132-136 C.

e) 1-Methyl-2-methylimino-6,6-dioxo-1,2,3 and 4,5,6 hexahydro-dithia-1 azabenzo[e]azulene-10b-ol:

4,34 g of 4-Bromo-1,1-dioxo-1,2,3,4-tetrahydrobenzo[b]-thiepin-5-it is suspended 15 ml of butane-2-it. The mixture is heated to 60-70 and With portions added 1.8 g of N,N’-dimethylthiophene. The solution is boiled for 2 hours under reflux, then cooled, and the precipitate is sucked off and washed with butane-2-one. The residue is stirred with 100 ml of saturated sodium hydrogen carbonate solution and extracted with ethyl ester of acetic acid. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuum. Connect with a small amount of ethyl ester of acetic acid, sucked off and dried in vacuum. Get 1-methyl-2-methylimino-6,6-dioxo-1,2,3 and 4,5,6 hexahydro-dithia-1 azabenzo[e]and the N-(10b-hydroxy-1-methyl-2-methylamino-1,2,3 and 4,5,10 b-hexahydro-6-oxa-3-thia-1-azabenzo[e]azulene-9-yl)-ndimethylacetamide:

a) N-(5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepin-7-yl)-ndimethylacetamide:

16 g of 7-Nitro-3,4-dihydro-2H-benzo[b]oxepin-5-she dissolved in 400 ml of methanol, mixed with 270 ml of palladium on active coal (10%) and hydronaut at normal pressure. After filtration and removal of solvent in vacuo get prone to oxidation 7-amino-3,4-dihydro-2H-benzo[b]oxepin-5-it is in the form of a yellow oil. This oil is dissolved in 150 ml of dichloromethane; add 8 g of triethylamine and then, with ice cooling slowly added dropwise with vigorous stirring to 8.1 g of acetic anhydride. The reaction mixture is stirred for another hour at room temperature. The solution is evaporated in vacuo, and the residue contribute in ethyl ester acetic acid, washed with water and saturated sodium chloride solution, dried over sodium sulfate and again evaporated. After crystallization from ethyl ether-acetic acid N-(5-oxo-2,3,4,5-tetrahydrobenzo[b]-oxepin-7-yl)-ndimethylacetamide melts at 130-132 C.

b) N-(4-bromo-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl)-ndimethylacetamide:

1 g of N-(5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl)-ndimethylacetamide dissolved in 6 ml dichloromethane. At 0 under stirring slowly added dropwise 0,8075 g of bromine dissolved in 5 ml dichloromethane. The reaction is the target of sodium bicarbonate and extracted several times with dichloromethane. The organic phase is washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuum. The residue is recrystallized from isopropanol and get N-(4-bromo-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl)-ndimethylacetamide with a melting point 157-160 C.

(C) the Hydrochloride of N-(10b-hydroxy-1-methyl-2-methylamino-1,2,3 and 4,5,10 b-hexahydro-6-oxa-3-thia-1-azabenzo[e]azulene-9-yl)ndimethylacetamide:

7 g of N-(4-bromo-5-oxo-2,3,4,5-tetrahydrobenzo[b]-oxepin-7-yl)ndimethylacetamide and 2.5 g of N,N’-dimethyltitanocene in 60 ml of butane-2-it is boiled for 4 hours under reflux. The cooled suspension is filtered, and the residue is stirred with 200 ml of saturated solution of potassium bicarbonate. Add a little ethyl ester acetic acid, sucked off, the residue is washed with water to give N-(10b-hydroxy-1-methyl-2-methyl-imino-1,2,3 and 4,5,10 b-hexahydro-6-oxa-3-thia-1-azabenzo[e]-azulene-9-yl)ndimethylacetamide with a melting point of 186-188 C. the Free base is dissolved in 30 ml of 2 n hydrochloric acid. After about 10 minutes, stirring falls hydrochloride N-(10b-hydroxy-1-methyl-2-methylamino-1,2,3 and 4,5,10 b-hexahydro-6-oxa-3-thia-1-azabenzo[e]azulene-9-yl)ndimethylacetamide. It melts with decomposition at 270 C.

Example 24 (compound E2):

The hydrobromide 6-chlorine is an-1-she 1,17 g of 1,3-bis-(4-methoxyphenyl)thiourea suspended in 50 ml of dry dichloromethane, 4 h and stirred at room temperature and one hour at the temperature of the ice bath. The precipitate is sucked off, washed with dichloromethane and dried in vacuum. Get hydrobromide 6-chloro-3-(4-methoxy-phenyl)-2-(4-methoxy-phenylimino)-2,3,8,8-tetrahydro-indeno[1,2-d]thiazol-3A-ol, which melts with decomposition at 230-235 C.

Connections E1 and E3-E5 obtained in a similar way.

1. It is a polycyclic thiazolidin-2-radenovi amines of the formula I

where mean:

A)

Y - a simple link;

X - CH2;

R1 - (C2-C6)-alkyl, in which one hydrogen may be replaced by OS(O)CH3; AND (C2-C6)-alkenyl; and (C2-C6)-quinil; O-CF3, O-CH2-CF3, O-CH2-CF2-CF3, O-CH2-CF2-CF2-CF3ABOUT-(C4-C6)-alkyl, and alkyl residues, one, more, or all hydrogen(s) may be replaced by fluorine;

S - (C1-C6)-alkyl, S-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl,

and n = 0-1, and phenyl residue up to two times may be substituted (C1-C6)-alkyl; phenyl, O-(CH2)n-phenyl,

and n = 0-1, 1 - or 2-naphthyl, 2-, 3 - or 4-PI is 6)-alkyl, SO2-CH3ABOUT-(C1-C6)-alkyl;

R1’ is H;

R2 is H;

R3 is H;

R4 - (C1-C6)-alkyl;

R5 - (C1-C6)-alkyl;

or

In)

Y - a simple link;

X - CH2;

R1 and R1’ independently of each other H, Cl, (C1-C6)alkyl, in which one hydrogen is replaced by HE,

R2 is H;

R3 is F, C(O)och3With(ABOUT)HE;

R4 - (C1-C6)-alkyl, (CH2)n-phenyl, and n = 1;

R5 - (C1-C6)-alkyl, (CH2)n-phenyl, and n = 1;

or

C)

Y - a simple link;

X - CH2;

R1 and R1’ independently of each other H, Cl, phenyl, substituted CF3;

R2 - (C1-C6)-alkyl, (C2-C8)-alkenyl;

R3 is H, F;

R4 - (C1-C6)-alkyl, (CH2)n-phenyl, and n = 0 and phenyl may be substituted by Cl, O-(C1-C6)-alkyl;

R5 - (C1-C6)-alkyl, (CH2)n-phenyl, and n = 0 and phenyl may be substituted by Cl, O-(C1-C6)-alkyl;

or

D)

Y is a simple bond, -CH2- or-CH2-CH2-;

X - CH(phenyl), and the phenyl residue can>-C6)-alkyl, SO2-(CH2)n-phenyl, and n = 0;

2 - N;

R3 is H;

R4 - (C1-C6)-alkyl;

R5 - (C1-C6)-alkyl;

or R4 and R5 together can mean-CH2-CH2- or-CH2- (CH3)2-

or

E)

Y - a simple link;

X - CH2;

R1 is - Cl;

R1’ is H;

R2 is H;

R3 is H;

R4 is phenyl, and the phenyl residue may be substituted up to two times F, Cl, O-(C1-C3)-alkyl, (C1-C6)-alkyl;

R5 - phenyl, and the phenyl residue may be substituted up to two times F, Cl, (C1-C6)-alkyl, O-(C1-C3)-alkyl,

and their physiologically acceptable salts.

2. The compounds of formula I on p. 1, characterized in that the mean

A)

Y - a simple link;

X - CH2;

R1 - (C2-C6)-alkyl, in which one hydrogen may be replaced by OS(O)CH3; AND (C2-C6)-alkenyl; and (C2-C6)-quinil; O-CF3, O-CH2-CF3, O-CH2-CF2-CF3, O-CH2-CF2-CF2-CF3ABOUT-(C4-C6)-alkyl, and alkyl residues one or more the eat n = 0-1, and phenyl residue up to two times may be substituted (C1-C6)-alkyl;

phenyl, O-(CH2)n-phenyl, and n = 0-1, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, and phenyl cycles can be from one to three times substituted by F, Cl, CF3, OCF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl;

R1’ is H;

R2 is H;

R3 is H;

R4 - (C1-C6)-alkyl;

R5 - (C1-C6)-alkyl;

or

In)

Y - a simple link;

X - CH2;

R1 and R1’ independently of each other H, Cl, (C1-C6)alkyl, in which one hydrogen is substituted for IT;

R2 is H;

R3 is F, C(O)och3With(ABOUT)HE;

R4 - (C1-C6)-alkyl, (CH2)n-phenyl, and n = 1;

R5 - (C1-C6)-alkyl, (CH2)n-phenyl, and n = 1;

or

C)

Y - a simple link;

X - CH2;

R1 and R1’ independently of each

H, Cl, phenyl, substituted CF3;

R2 - (C1-C6)-alkyl, (C2-C8)-alkenyl;

R3 is H, F;

R4 - (C1-C6)-alkyl, (CH2)n-phenyl, and n = 0 and

phenyl may be substituted by Cl, O-(C1-C6)-alkyl;

1-C6)-alkyl;

or

D)

Y is a simple bond or-CH2-;

X - CH(phenyl), and the phenyl residue may be substituted by Cl;

O, S, SO2,

R1 and R1’ independently of each other H, Cl, CN, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, n = 0,

R2 is H;

R3 is H;

R4 - (C1-C6)-alkyl;

R5 - (C1-C6)-alkyl;

or

E)

Y - a simple link;

X - CH2;

R1 is - Cl;

R1’ is H;

R2 is H;

R3 is H;

R4 is phenyl, and the phenyl residue may be substituted up to two times F, Cl, O-(C1-C3)-alkyl, (C1-C6)-alkyl;

R5 - phenyl, and the phenyl residue may be substituted up to two times F, Cl, (C1-C6)-alkyl, O-(C1-C3)-alkyl,

and their physiologically acceptable salts.

3. The compounds of formula I under item 1 or 2, characterized in that they indicate

A)

Y - a simple link;

X - CH2;

R1 - (C2-C6)-alkyl, in which one hydrogen may be replaced by OS(O)CH3; AND (C2-C6)-alkenyl; and (C2-C6)-quinil; O-CH2-CF3, O-CH2-CF1-C6)-alkyl, S-(CH2)n-phenyl, and n = 0-1, and phenyl residue up to two times may be substituted (C1-C6)-alkyl; phenyl, O-(CH2)n-phenyl, and n = 0-1, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, and phenyl cycles can be one to two times substituted by F, Cl, CF3, OCF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl;

R1’ is H;

R2 is H;

R3 is H;

R4 - (C1-C6)-alkyl;

R5 - (C1-C6)-alkyl;

or

In)

Y - a simple link;

X - CH2;

R1 and R1’ independently of each other H, Cl, (C1-C6)alkyl, in which one hydrogen is substituted for IT;

R2 is H;

R3 is F, C(O)och3With(ABOUT)HE;

R4 - (C1-C6)-alkyl, (CH2)n-phenyl, and n = 1;

R5 - (C1-C6)-alkyl, (CH2)n-phenyl, and n = 1;

or

C)

Y - a simple link;

X - CH2;

R1 and R1’ independently of each

H, Cl, phenyl, substituted CF3;

R2 - (C1-C6)-alkyl, (C2-C8)-alkenyl;

R3 is H, F;

R4 - (C1-C6)-alkyl, (CH2)n-phenyl, and n = 0 and

the dryer is B>-phenyl, and n = 0 and

phenyl may be substituted by Cl, O-(C1-C6)-alkyl;

or

D)

Y is a simple bond or-CH2-;

X - CH(phenyl), and the phenyl residue may be substituted by Cl;

O, S, SO2,

R1 and R1’ independently of each other H, Cl, CN, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n = 0;

R2 is H;

R3 is H;

R4 - (C1-C6)-alkyl;

R5 - (C1-C6)-alkyl;

or

E)

Y - a simple link;

X - CH2;

R1 is - Cl;

R1’ is H;

R2 is H;

R3 is H;

R4 is phenyl, and the phenyl residue may be substituted up to two times F, Cl, O-(C1-C3)-alkyl, (C1-C6)-alkyl;

R5 - phenyl, and the phenyl residue may be substituted up to two times F, Cl, (C1-C6)-alkyl, O-(C1-C3)-alkyl,

and their physiologically acceptable salts.

4. The compounds of formula I on PP.1, 2 or 3, characterized in that the mean: Y - simple bond; X is CH2; R1 - (C1-C6)-alkyl, in which one hydrogen may be replaced by OS(O)CH3; AND (C2-C6)-alkenyl; and (C2-C6)-quinil; CF(s) may be replaced by fluorine; SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n = 0-1,-(CH2)n-phenyl, and n = 0-1, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, and phenyl cycles may be substituted by F, Cl, CF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl; R1’ is H; R2 is H; R3 is H; R4 - (C1-C6)-alkyl; R5 - (C1-C6)-alkyl, and their physiologically acceptable salts.

5. The compounds of formula I according to one or more paragraphs.1-4, characterized in that they are defined: R1 is 6-Cl; R1’ is H; R2 is H; R3 is - F; R4 is CH3; R5 is CH3; X - CH2Y - a simple link, as well as their physiologically acceptable salts.

6. The compounds of formula I according to one or more paragraphs.1-5, representing hydrochloride compounds of formula I.

7. Drug to suppress appetite and/or weight loss containing compound according to one or more paragraphs.1-6.

8. Medicinal product for the prevention and treatment of diabetes type II containing the compound according to one or more paragraphs.1-6.

9. Compounds according to one or more paragraphs.1-6, suitable for the treatment of obesity.

10. Compounds according to one or more paragraphs.1-6, suitable for prevention or treatment of type II diabetes.

11. The method of obtaining the medication is more with a pharmaceutically acceptable carrier and the mixture result in a usable form.

 

Same patents:

The invention relates to a method for producing [1,2,4]triazolo[3,4-b][1,3]benzothiazol-3(2H)-thione of the formula

including fusion [1,2,4]triazolo[3,4-b][1,3]benzothiazole with excess sulfur in for 5-20 minutes at a temperature of 180-200With subsequent isolation of the target product

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to tetrahydro-gamma carbolines formula (I), where R1, R2D, Alk and n are such as defined in the claims

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The invention relates to novel ortho-sulfonamidophenylhydrazine heteroaryl hydroxamic acids of the formula

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where W and X are both carbon, T is nitrogen, U represents CR1where R1represents hydrogen, or alkyl containing 1-8 carbon atoms, R represents-N(CH2R5)-SO2Z, Q represents -(C=O)-NHOH, with

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is a benzene ring, or is a heteroaryl ring of 5 to 6 atoms in the cycle, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the heteroatom of nitrogen, denoted as W, where benzene or heteroaryl ring may optionally contain one or two substituent R1where permissible; Z is phenyl, which is optionally substituted by phenyl, alkyl with 1-8 carbon atoms, or a group OR2; R1represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl from 1 to 4 carbon atoms, phenyl, optionally substituted by 1-2 groups OR2group-NO2group -(CH2)nZ, where Z is a phenyl which allows an alkyl with 1-8 carbon atoms, phenyl, optionally substituted with halogen, or heteroaryl radical containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; R5represents hydrogen, alkyl with 1-8 carbon atoms, phenyl, or heteroaryl containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; or their pharmaceutically acceptable salts

The invention relates to new derivatives of 5H-thiazole[3,2-a]pyrimidine of the General formula I, where R1means (ness.)alkyl or benzyl; R2means (ness.) alkyl, (ness.)alkoxygroup, -O(CH2)nN(R13)(R14or-N(R15)(CH2)nN(R13)(R14); R3-R14each denotes hydrogen, halogen, (NISS

The invention relates to new tricyclic pyrazole derivative or its pharmaceutically acceptable salt

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

The invention relates to billnum compounds or substituted pyridinium formula (I), where X denotes N or CR8where R8denotes hydrogen, halogen, phenyl, alkyl, alkoxy, alkoxycarbonyl, carboxy, formyl or-NR4R5where R4and R5denote hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, naphthyl; R1aand R1Brepresent trifluoromethyl, alkyl, alkenyl, quinil, cycloalkyl, alkanoyl; R2denotes alkyl, alkenyl, quinil, cycloalkyl; R3denotes hydroxy, TRIFLUOROACETYL, alkanoyl, alkenyl; AG denotes an aromatic or heteroaromatic ring, for example phenyl, naphthyl, pyridyl, furanyl, thiophenyl

The invention relates to new non-steroidal compounds which are high-affinity modulators of steroid receptors

The invention relates to new derivatives of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula I, in which R1means a hydrogen atom, a C1-4alkyl group or phenyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxy-group, nitro group, WITH1-4alkoxygroup, (C1-4alkyl) amino and di(C1-4alkyl)amino group; or a group of formula (a) Z means a hydrogen atom or a C1-4alkoxygroup, R0means a group of the formula Alk-NR4R5where Alk is alkalinous group having a straight or branched C1-6chain, one of R2and R3is amino and the other is an amino group or a 5-6-membered saturated heterocyclic group containing one or two atom(s) of nitrogen and/or oxygen and attached via its nitrogen atom, and the specified heterocyclic group may be substituted WITH1-4alkyl group, phenyl group or kalogeropoulou group, or the last of the R2and R3is a group of the formula - SR

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is
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