Substituted 8,8a-dihydro-3ah-indeno[1,2-d]thiazoles, method for their preparing and their using as medicinal agents

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted 8,8a-dihydro-3aH-indeno[1,2-d]thiazoles and to their physiologically acceptable salts and physiologically functional derivatives also. Invention describes compounds of the formula (I): wherein R1 and R1' mean independently of one another H, F, Cl, Br, J; R2 and R3 means H; R4 means phenyl hat can be replaced with hydroxyl group (OH); R5 means hydrogen atom (H); R6 means OH. Also, invention describes a method for preparing these compounds. Compounds can be used as anorexic agents for prophylaxis and treatment of obesity.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

5 cl, 2 tbl, 1 ex

 

The invention relates to substituted 8,8A-dihydro-an-indeno[1,2-d]triazolam, and their physiologically acceptable salts and physiologically functional derivatives.

In the prior art already described derivatives of thiazolidine with anorexically action (patent Austria No. 365181).

The task of the invention to provide other compounds that are therapeutically suitable anorexically action.

The invention relates, therefore, to compounds of formula (I):

where

R1, R1' denote, independently of one another, H, F, Cl, Br, J, CF3, NO2, 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, and alkyl, alkenyl or etkinlik the remains of one, several or all of the hydrogen atoms may be replaced by fluorine atoms, or one hydrogen atom may be replaced by HE, OC(O)CH3, OS(O)H, O-CH2-phenyl, NH2, NH-CO-CH3or N(SOON2-phenyl)2; SO2-NH2, SO2NH-(C1-C6)-alkyl, SO2N-[(C1-C6)-alkyl]2S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C 6)-alkyl, SO2-(CH2)n-phenyl, and n may be 0-6 and the phenyl residue up to twice may be substituted with F, Cl, Br, HE, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2; NH2, NH-(C1-C6)-alkyl, N-[(C1-C6)-alkyl]2, NH-(C1-C7)-acyl, phenyl, biphenyl, O-(CH2)n-phenyl, and n may be 0-6; 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl or 2 - or 3-thienyl, and phenyl, biphenylyl, nattily, peredelnyj, farnily or thienyl cycles, respectively, can be up to three times substituted with F, Cl, Br, J, HE, CF3, NO2CN, OCF3, 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 position 1, 2 or 3 may be replaced by stands or benzyl; tetrazol-5-yl, and tetrazole the ring in position 1 or 2 can be replaced by stands or benzyl; 1,3,4-oxadiazol-2-yl; 2-amino-1,3,4-oxadiazol-5-yl, the amino group once or twice may be substituted with (C1-C6)-alkyl, -C(O)-(C1-C6)-alkyl, -C(O)-(C3-C7)-cycloalkyl, -C(O)-phenyl, -(O)-NH-(C 1-C6)-alkyl, -C(O)-NH-(C3-C7)-cycloalkyl or C(O)-NH-aryl, and aryl means phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl or 2 - or 3-furanyl; -C(O)-morpholine-4-yl, -C(O)-piperidine-1-yl, -C(O)-piperazine-4-yl, -C(O)-1-methylpiperazin-4-yl, -C(O)-1-benzylpiperazine-4-yl, -SO2-(C1-C6)-alkyl or-SO2-phenyl, and the phenyl ring up to twice may be substituted with F, Cl, Br, CN, CF3HE OCF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, (CH2)n-phenyl or O-(CH2)n-phenyl, and n may be 0-6, NH2, NH-(C1-C6)-alkyl, N-[(C1-C6)-alkyl]2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;

R2 denotes H, (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, C(O)-(C1-C6)-alkyl, C(O)-(C3-C6-cycloalkyl, C(O)-(CH2)n-phenyl, C(O)-(CH2)n-thienyl, C(O)-(CH2)n-pyridyl, C(O)-(CH2)n-furyl, and n may be equal to 0-5 and where the phenyl, thienyl, pyridyl, furyl, respectively, up to twice may be substituted with Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

R3 denotes H, (C1-C 6)-alkyl, F, Cl, Br, CN, N3, O-(C1-C6)-alkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, and n may be equal to 0-5 and where the phenyl, thienyl, pyridyl, furyl, respectively, up to twice may be substituted with Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl, (C2-C6)-quinil, (C2-C6)-alkenyl, OC(O)CH3, (CH2)n-C(O)O-(C1-C6)-alkyl, (CH2)n-C(O)HE, (CH2)n-C(O)NH2, (CH2)n-C(O)NHCH3, (CH2)n-C(O)N(CH3)2moreover , n may be equal 0-3;

R4 means (C1-C6)-alkyl, (C3-C7-cycloalkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, (C4-C7)-cycloalkenyl, and in the alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine atoms or one hydrogen atom may be replaced by HE, OC(O)CH3, OS(O)H, O-CH2-phenyl or-(C1-C4)-alkyl; (CH2)n-pyrrolidin-1-yl, (CH2)n-piperidine-1-yl, (CH2)n-morpholine-4-yl, (CH2)n-piperazine-1-yl, (CH2)n-N-4-methylpiperazin-1-yl, (CH2)n-N-4-benzylpiperazine-1-yl, (CH2)n-phthalimide, and n can be 1-6; (CH2 )n-aryl, and n may be 0-6 and the aryl may mean phenyl, biphenyl, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, 2-, 4 - or 5-thiazolyl, 2-, 4 - or 5-oxazolyl, 1-pyrazolyl, 3 - or 5-isoxazolyl, 2-or 3-pyrrolyl, 2 - or 3-pyridazinyl, 2-, 4 - or 5-pyrimidinyl, 2-pyrazinyl, 2-(1,3,5-triazinyl), 2 - or 5-benzimidazolyl, 2-benzothiazolyl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, tetraol-5-yl, indol-3-yl, indol-5-yl or N-Mei-2-, -4 - or-5-yl and aryl residue or heteroaryl residue up to twice may be substituted with F, Cl, Br, HE, CF3, NO2CN, OCF3, O- (C1-C6)-alkyl, S-(C1-C6)-alkyl, SO-(C1-C6)-alkyl, (CH2)n-SO2-(C1-C6)-alkyl, (CH2)n-SO2-NH2, (CH2)n-SO2-N=CH-N(CH3)2), where n may be 0-6; (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COOH, COO-(C1-C6)-alkyl, COO-(C3-C6)-cycloalkyl, CONH2, CONH-(C1-C6)-alkyl, CON-[(C1-C6)-alkyl]2, CONH-(C3-C6)-cycloalkyl, NH2, NH-CO-(C1-C6)-alkyl, NH-CO-phenyl, NH-SO2-(C1-C6)-alkyl, NH-SO2-phenyl, and the phenyl ring up to twice may be substituted with F, Cl, CN, (C1-C6)-alkyl, O-(C1-C6)-Alki is a, CF3, COOH, COO-(C1-C6)-alkyl or CONH2; pyrrolidin-1-yl, morpholine-1-yl, piperidine-1-yl, piperazine-1-yl, 4-methylpiperazin-1-yl, (CH2)n-phenyl, O-(CH2)n-phenyl, S-(CH2)n-phenyl, SO2-(CH2)n-phenyl, and n may be equal to 0 to 3; (CH2)n-A-R8, and n can be 1-6;

A represents O, NH, N-(C1-C6)-alkyl, NCHO, N-(CH3), S, SO, SO2;

R8 means (C1-C8)-alkyl, (C3-C8-cycloalkyl, and in the alkyl residues of one or more hydrogen atoms may be replaced by fluorine atoms or one hydrogen atom may be replaced by HE, OC(O)CH3, OS(O)H, O-CH2-phenyl or-(C1-C4)-alkyl; (CH2)m-aryl, and m=0-6, and the aryl may mean phenyl, thienyl or pyridyl and aryl part up to twice may be substituted with F, Cl, Br, HE, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, S-(C1-C6)-alkyl, SO-(C1-C6)-alkyl, (CH2)n-SO2-(C1-C6)-alkyl, (CH2)n-SO2-NH2, (CH2)n-SO2-N=CH-N(CH3)2), (CH2)n-SO2-NH-[(C1-C8)-alkyl], (CH2)n-SO2-N-[(C1-C6)-alkyl]2, (CH2)n-SO2-NH-[(C3-C8)-cycloalkyl], (the H 2)n-SO2-N-[(C3-C8-cycloalkyl]2and n may be 0-6; (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COOH, COO-(C1-C6)-alkyl, COO-(C3-C6)-cycloalkyl, CONH2, CONH-(C1-C6)-alkyl, CON-[(C1-C6)-alkyl]2, CONH-(C3-C6)-cycloalkyl, NH2, NH-(C1-C6)-alkyl, N-[(C1-C6)-alkyl]2, NH-CO-(C1-C6)-alkyl, NH-CO-phenyl, NH-SO2-phenyl, and the phenyl ring up to twice may be substituted with F, Cl, CN, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, COOH, COO-(C1-C6)-alkyl or CONH2; NH-SO2-(C1-C8)-alkyl, N-[(C1-C6)-alkyl] -SO2-(C1-C8)-alkyl, pyrrolidin-1-yl, morpholine-1-yl, piperidine-1-yl, piperazine-1-yl, 4-methylpiperazin-1-yl, (CH2)p-phenyl, O-(CH2)p-phenyl, S-(CH2)pis phenyl or SO2-(CH2)p-phenyl, and R may be equal 0-3;

R5 means a hydrogen atom;

R6 denotes Cl, Br, HE, O-(C1-C6)-alkyl, O-(CH2)n-aryl, and n may be 0-6 and the aryl may mean phenyl, 2-, 3 - or 4-pyridyl or 2 - or 3-thienyl; O-C(O)-H, O-C(O)-(C1-C6)-alkyl, O-C(O)-(C3-C8-cycloalkyl, O-C(O)-aryl, where the aryl may mean f the Nile, pyridyl, thienyl or furanyl; -O-α- or -β-glucuronic acid, SH, S-(C1-C6)-alkyl, S-(CH2)n-phenyl, and n is 0-6; S-C(O)-(C1-C6)-alkyl, S-C(O)-(C3-C8-cycloalkyl, S-C(O)-phenyl; SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, and n may be 0-6; SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n is 0-6; NH2, NH-(C1-C6)-alkyl, NH- (C3-C7-cycloalkyl, N-[(C1-C6)-alkyl]2, morpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl, 1-methylpiperazin-4-yl, 1-benzylpiperazine-4-yl, NH-phenyl, NH-CH2-phenyl, NH-C(O)-(C1-C6) -alkyl, NH-C(O)-phenyl;

or

R5 and R6 together form =O,and n is 2-6.

and their physiologically acceptable salts and physiologically functional derivatives.

Preferred compounds of formula (I), where

R1, R1' denote, independently of one another, H, F, Cl, Br, J, CF3, NO2, 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, and alkyl residues one, several or all of the hydrogen atoms may be replaced by atoms CFT is RA, or one hydrogen atom may be replaced by HE, OC(O)CH3, OS(O)H, O-CH2-phenyl, NH2, NH-CO-CH3or N(SOON2-phenyl)2; SO2-NH2, SO2NH-(C1-C6)-alkyl, SO2N- [(C1-C6)-alkyl]2S-(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 may be 0-6 and the phenyl residue up to twice may be substituted with F, Cl, Br, HE, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2; NH2, NH-(C1-C6)-alkyl, N-[(C1-C6)-alkyl]2, NH-(C1-C7)-acyl, phenyl, biphenyl, O-(CH2)n-phenyl, and n may be 0-6; 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2-or 3-furanyl or 2 - or 3-thienyl, and phenyl, biphenylyl, nattily, peredelnyj, farnily or thienyl cycles, respectively, can be up to three times substituted with F, Cl, Br, J, HE, CF3, NO2CN, OCF3, 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 position 1, 2 of the 3 can be replaced by stands or benzyl;

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

R2 denotes H, (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, C(O)-(C1-C6)-alkyl, C(O)-(C3-C6-cycloalkyl, C(O)-(CH2)n-phenyl, C(O)-(CH2)n-thienyl, C(O)-(CH2)n-pyridyl, C(O)-(CH2)n-furyl, and n may be equal to 0-5 and where the phenyl, thienyl, pyridyl, furyl, respectively, up to twice may be substituted with Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O- (C1-C6)-alkyl;

R3 denotes H, (C1-C6)-alkyl, F, Cl, Br, CN, N3, O-(C1-C6)-alkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, and n may be equal to 0-5 and where the phenyl, thienyl, pyridyl, furyl, respectively, up to twice may be substituted with Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C3)-alkyl, (C2-C6)-quinil, (C2-C6)-alkenyl, OC(O)CH3, (CH2)n-C(O)O-(C1-C6)-alkyl, (CH2)n-C(O)HE, (CH2)n-C(O)NH2, (CH2)n-C(O)NHCH3, (CH2)n-C(O)N(CH3/sub> )2moreover , n may be equal 0-3;

R4 means (C1-C8)-alkyl, (C3-C7-cycloalkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, (C4-C7)-cycloalkenyl, and in the alkyl residues one, several or all hydrogen atoms may be replaced by fluorine atoms or one hydrogen atom may be replaced by HE, OC(O)CH3, OS(O)H, O-CH2-phenyl or-(C1-C4)-alkyl; (CH2)n-pyrrolidin-1-yl, (CH2)n-piperidine-1-yl, (CH2)n-morpholine-4-yl, (CH2)n-piperazine-1-yl, (CH2)n-N-4-methylpiperazin-1-yl, (CH2)n-N-4-benzyl-piperazine-1-yl, (CH2)n-phthalimide, and n can be 1-6; (CH2)n-aryl, and n may be 0-6 and the aryl may mean phenyl, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl and aryl residue or heteroaryl residue up to twice may be substituted with F, Cl, Br, HE, CF3, O-(C1-C6)-alkyl, (CH2)n-SO2-(C1-C6)-alkyl, (CH2)n-SO2-NH2, (CH2)n-SO2-N=CH-N(CH3)2), where n may be 0-6; NH-SO2-(C1-C6)-alkyl, NH-SO2-phenyl, and the phenyl ring up to twice may be substituted with F, Cl, CN, (C1-C6)-alkyl, O-(C1 -C6)-alkyl, CF3, COOH, COO-(C1-C6)-alkyl or CONH2; (C1-C6)-alkyl, COOH, COO-(C1-C6)-alkyl or CONH2; (CH2)n-A-R8, and n can be 1-6;

A represents O, NH, (C1-C6)-alkyl, SO2;

R8 means (C1-C8)-alkyl, (C3-C8-cycloalkyl, and in the alkyl residues of one or more hydrogen atoms may be replaced by fluorine atoms or one hydrogen atom may be replaced by HE, OC(O)CH3, OS(O)H, O-CH2-phenyl or-(C1-C4)-alkyl; (CH2)m-aryl, and m=0-6, and the aryl may mean phenyl, thienyl or pyridyl and aryl part up to twice may be substituted with F, Cl, Br, HE, CF3, O-(C1-C6)-alkyl, (CH2)n-SO2-(C1-C6)-alkyl, (CH2)n-SO2-NH2, (CH2)n-SO2-N=CH-N(CH3)2), where n may be 0-6; NH-SO2-(C1-C6)-alkyl, NH-SO2-phenyl, and the phenyl ring up to twice may be substituted with F, Cl, CN, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, COOH, COO-(C1-C6)-alkyl, CONH2and n may be 0-6; COOH, COO-(C1-C6)-alkyl or CONH2;

R5 means a hydrogen atom;

R6 denotes Cl, Br, HE, O-(C1-C 2)-alkyl, O-(CH2)n-aryl, and n may be 0-6 and the aryl may mean phenyl, 2-, 3 - or 4-pyridyl or 2 - or 3-thienyl; O-C(O)-H, O-C(O)-(C1-C6)-alkyl, O-C(O)-(C3-C8-cycloalkyl, O-C(O)-aryl, where the aryl may mean phenyl, pyridyl, thienyl or furanyl; -O-α- or -β-glucuronic acid, SH, S-(C1-C6)-alkyl, S-(CH2)n-phenyl, and n is 0-6; S-C(O)-(C1-C6)-alkyl, S-C(O)-(C3-C8-cycloalkyl, S-C(O)-phenyl; SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, and n may be 0-6; SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n is 0-6; NH2, NH-(C1-C6)-alkyl, NH-(C3-C7-cycloalkyl, N-[ (C1-C6)-alkyl]2, morpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl, 1-methylpiperazin-4-yl, 1-benzylpiperazine-4-yl, NH-phenyl, NH-CH2-phenyl, NH-C(O)-(C1-C6)-alkyl, NH-C(O)-phenyl;

or

R5 and R6 together form =O,moreover, n is 2-6,

and their physiologically acceptable salts and physiologically functional derivatives.

Especially preferred compounds of formula (I), where

R1, R1' denote, independently of one another, H, F, Cl, Br, HE, O-(C1-C6)-alkyl, (C1-C6) -alkyl, and alkyl residue which one hydrogen atom may be replaced by IT;

R2 denotes H, (C1-C6)-alkyl, C(O)-(C1-C6)-alkyl;

R3 denotes Cl, Br, (CH2)n-COO-(C1-C6)-alkyl, (CH2)n-COOH, (CH2)n-CONH2and n can be 0 or 1;

R4 means (C1-C4)-alkyl or (C3-C6-cycloalkyl, and in the alkyl residues one hydrogen atom may be replaced by IT; (CH2)n-aryl, and n may be 0-6 and the aryl may mean phenyl, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl and aryl residue or heteroaryl residue up to twice may be substituted with F, Cl, Br, HE, CF3, O-(C1-C6)-alkyl, SO2-(C1-C6)-alkyl, (CH2)n-SO2-NH2and n may be 0-6; (C1-C6)-alkyl, COOH, COO-(C1-C6)-alkyl or CONH2; (CH2)n-A-RS, and n can be 1-6;

And means ON, SO2;

R8 means (C1-C8)-alkyl, (C3-C8-cycloalkyl, and in the alkyl residues one hydrogen atom may be replaced by IT; (CH2)m-aryl, and m=0-6, and the aryl may mean phenyl or thienyl and aryl part up to twice may be substituted with F, Cl, Br, HE, CF3, O-(C1-C6)-alkyl, SO2-(C1-C6)-alkyl, SO2-NH2, COOH, COO-(C1-C6)-is Lila or CONH 2;

R5 means a hydrogen atom;

R6 means HE, O-(C1-C6)-alkyl, O-C(O)-(C1-C6)-alkyl, O-C(O)-aryl, where the aryl may mean phenyl or thienyl; -O-α- or -β-glucuronic acid; SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n may be 0-6; NH2, morpholine-4-yl, NH-C(O)-(C1-C6)-alkyl, NH-C(O)-phenyl;

or

R5 and R6 together form =O ormoreover, n may be equal to 2-6;

and their physiologically acceptable salts.

The invention relates to compounds of formula (I) in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and their mixtures.

Alkyl, alkeline and alkyline residues in the substituents R1, R1', R2, R3, R4, R6, R8 and can be both linear and branched.

Pharmaceutically acceptable salts on the basis of their higher water solubility compared to the baseline, respectively, the basic compounds are particularly suitable for applications in medicine. These salts must include pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable additive salts with acids proposed according to the invention compounds are salts of inorganic acids as hydrochloric acid, Hydrobromic acid, phosphoric acid, metaphosphoric to the slot, nitric acid, acid and sulfuric acid, and organic acids, such as acetic acid, benzosulfimide, benzoic acid, citric acid, econsultation, fumaric acid, gluconic acid, glycolic acid, setinova acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonate, succinic acid, p-toluensulfonate, tartaric acid and triperoxonane acid. For medical purposes especially preferably using salt and hydrochloric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (like sodium and potassium salts), and salts of alkaline earth metals (as magnesium salt and calcium).

Salts with a pharmaceutically unacceptable anion is also included in the scope of the invention as useful intermediates for obtaining or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example in vitro, applications.

Used herein, the term "physiologically functional derivative" refers to any physiologically acceptable derivative proposed according to the invention the compounds of formula (I), for example, ester, which when administered to a mammal, such as man, is able (directly or indirectly) obrazovyvat the compound of formula (I) or its active metabolite.

To physiologically functional derivatives are also proletarienne form proposed according to the invention compounds. Such proletarienne forms in vivo can be metabolised to offer according to the invention compounds. These proletarienne forms themselves may or may not be active.

Proposed according to the invention compounds may be present in various polymorphic forms, for example as amorphous and crystalline polymorphous forms. All polymorphic forms proposed according to the invention compounds are included in the scope of the invention are the subject matter of the invention.

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

The number of compounds according to formula (I)needed to achieve the desired biological effect depends on a number of factors, for example, selected from specific connections, intended use, type of administration and the clinical condition of the patient. In General, the daily dose amount in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, for example, 3-10 mg/kg/day. Intravenous dose of the composition is better value for example, in the range from 0.3 mg/kg to 1.0 mg/kg, which prigodnye you can enter in the form of infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may include, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter of the compounds according to formula (I). Single doses may contain, for example, from 1 mg to 10 g of biologically active substances. Thus, ampoules for injection may contain, for example, from 1 mg to 100 mg, and oral input of the dosage form in the form of single doses, as, for example, tablets or capsules, may contain, for example, from 1.0 mg to 1000 mg, typically from 10 mg to 600 mg of biologically active substances. In the case of pharmaceutically acceptable salts of the above mass data refer to mass produced from salt ion dihydrothiazolo. For the prevention or therapy of the abovementioned conditions, the compounds of formula (I) can be used by themselves in the form of compounds, however, preferably together with an acceptable carrier in the form of pharmaceutical compositions. The media, of course, must be acceptable, in the sense that it is compatible with other components of the composition and is not harmful to the health of the patient. The carrier may be solid or liquid or both, and is preferably used together with the compound to obtain the dosage form in the form of the gas dose for example in the form of a tablet, which may contain from 0.05 to 95 wt.% biologically active substances. There also may be other pharmaceutically active agents, including other compounds according to formula (I). Proposed according to the invention pharmaceutical compositions can be obtained by one of the known pharmaceutical methods, which essentially consist in the fact that the components are mixed with pharmacologically acceptable carriers and/or auxiliary substances.

Proposed according to the invention pharmaceutical compositions suitable for oral, rectal, local, peroral (for example sublingual), or parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable route of administration in each individual case depends on the type and severity of the treated condition and the kind used in each case, the compounds according to formula (I). In the scope of the invention also includes the index of the dosage form and index prolonged dosage forms. Preferred are resistant to acid and gastric juice dosage forms. Suitable, resistant to gastric juice coating include acetated cellulose, polyvinylacetate, hydroxypropylmethylcellulose and anionic polymers met krylovii acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration may be in the form of separate units, such as capsules, membrane wafers, tablets for sucking or tablets, which contain, respectively, a certain number of compounds according to formula (I); as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an emulsion oil-in-water or water-in-oil. These compositions, as already mentioned, can be prepared by any suitable pharmaceutical method which includes a step, in the case where the biologically active substance and the carrier (which may consist of one or more additional components) is introduced into the contact. In General, the compositions are obtained by uniform and homogeneous mixing of the biologically active substance with a liquid and/or finely dispersed solid carrier, after which the product, if necessary, is formed. For example, the tablet can get that powder or granules of the compound is pressed or molded, if necessary, together with one or more additional components. Molded tablets can be obtained by tabletting suitable connection device in a freely flowing form, such as in the form of a powder or granulate, if necessary, mixed with a binder, giving the chip is scost tablets substance, inert diluent and/or one (several) of surface-active/dispersing agent. Molded tablets can be obtained by molding in a suitable device, powder, moistened with an inert liquid diluent connection.

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

Suitable pharmaceutical compositions for parenteral administration preferably include sterile aqueous compositions of the compounds according to formula (I), which preferably is isotonic with the blood provided the recipient. These compositions are preferably injected intravenously, although the introduction can be made subcutaneously, intramuscularly or intradermally in the form of injections. These compositions preferably you can obtain the fact that the compound is mixed with water and the resulting solution make sterile and isotonic with blood. Introduced by injection proposed according to the invention the compositions contain, in General, 0.1 to 5 wt.% active connection.

A suitable formats ticheskie compositions for rectal injection are preferably in the form of suppositories with disposable dose. You can get them to the fact that the compound according to formula (I) is mixed with one or more conventional solid carriers, such as cocoa butter, and an appropriate mixture of mold.

Suitable pharmaceutical compositions for local application on the skin are preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil. As a carrier, you can apply vaseline, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. Biologically active substance, in General, is in a concentration of 0.1-15 wt.%, for example, 0.5 to 2 wt.%, in the calculation of the composition.

It is also possible percutaneous introduction. Suitable pharmaceutical compositions for percutaneous applications can be in the form of individual patches that are suitable for long-term close contact with the epidermis of the patient. These patches are more suitable way contain biologically active substance in water, if necessary, buffered solution, dissolved and/or dispergirovannom in adhesive means or dispergirovannom in the polymer. A suitable concentration of biologically active substances is about 1-35%, preferably about 3-15%. As a special ability, biologically active substance, such as, for example, described in Pharmaceutical Research, 2 (6), 318 (1986), freed of the shackles of the m electric or electrophoresis.

The object of the invention, then, is a method of obtaining compounds of General formula (I), characterized in that compounds of the formula (I) are obtained according to the following reaction scheme:

For this purpose, compounds of General formula (II):

where R1, R1' and R3 have the specified value, using N-bromosuccinimide transferred to the compound of formula (III).

The compounds of formula (III), then, using the metal salts of organic acids (Moezel), as, for example, silver acetate, transferred to the compounds of formula (IV). On the other hand, the compounds of formula (III) by nucleophilic exchange with O-, S - or N-nucleophiles can be converted into the corresponding O-, S - or N-substituted compounds of the formula (VI), where the residues R1, R1', R3, R5 and R6 have described the value.

The compounds of formula (IV), for example, by acid hydrolysis can be converted to compounds of formula (V).

Compounds of formulas (V) and (VI) under standard conditions by reaction with bromine can be translated into the appropriate α-brometane formula (VII), where, for example, R5 may denote a hydrogen atom and R6 may mean IT.

Interaction thioamides formula R4-C(S)-NH2where R4 has the above meanings, with compounds of General formula (VII) leads to compounds of General formula (I), where R2 means a hydrogen atom. These connections when using the standard methods can be converted into compounds of formula (I), where R2 has the other of the above values.

For salt formation as inorganic acids, for example, use: halogen acids as hydrochloric acid and Hydrobromic acid, and also sulfuric acid, phosphoric acid and amidosulfonic.

As organic acids for salt formation should for example be mentioned: formic acid, acetic acid, benzoic acid, p-toluene-acid, benzosulfimide, succinic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, citric acid, L-ascorbic acid, salicylic acid, izational acid, methanesulfonate, triftormetilfullerenov, 1,2-benzisothiazol-3(2H)-he, 6-methyl-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide.

The above method is preferably carried out so that the compounds of the formula (VII) enter into interaction with thioamides R4-C(S)-NH2in a molar ratio of from 1:1 to 1:1,5. The reaction is preferably carried out in an inert solvent, for example, in polar organic solvents, such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, nitromethane or diethylethylenediamine ether. As a particularly preferred solvents, however, are methyl acetate and ethyl acetate, alcohols briefly with the chain, as methanol, ethanol, propanol, isopropanol, and the lowest dealkylation, as, for example, acetone, butane-2-one or hexane-2-it. You can also use a mixture of these reaction media; as it is also possible to use mixtures of these solvents with solvents that are less suitable for individual use, 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, accordingly, the more polar the solvent is better to use in excess. Components of the reaction can be suspended or dissolved in an appropriate reaction medium. In principle, the components of the reaction can also be entered into cooperation without solvent, particularly when the appropriate thioamide has low melting point. The reaction proceeds only weakly exothermically and it can be performed at a temperature of from -10°to 150°C, preferably from 30°to 100°C. as particularly favorable, as a rule, is the range of temperatures from 50°to 90°C.

The duration of reaction largely depends on the reaction temperature and ranges from 2 minutes to 3 days when Bo is high, accordingly, the lower temperatures. In favorable temperatures, the duration of the reaction is, in General, from 5 minutes to 48 hours.

The compounds of formula (I) in the form of their insoluble additive salts with acid often are precipitated during the reaction, it is sensible to add a suitable precipitant. As such, using, for example, hydrocarbons like benzene, toluene, cyclohexane or heptane, or carbon tetrachloride; especially as particularly suitable are alkalemia the acetic acid esters as ethyl acetate or n-butyl acetate, or a simple dialkyl ethers like 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, the salts of the compounds of formula (I), if necessary after concentration of the reaction solution, the precipitated using one of these precipitators. Next, a solution of the reaction mixture also preferably can be entered under stirring in a solution of one of these precipitators. Processing of the reaction mixture can also be implemented in such a way that the reaction mixture is alkalinized with the addition of organic bases, such as, for example, triethylamine or diisobutylamine or ammonia or morpholine or piperidine, or 1,8-diazabicyclo[5,4,0]und the C-7-ene, and the reaction product after concentration purify by chromatography, for example, when using a column with silica gel. As a suitable eluting environments for this purpose are, for example, mixtures of ethyl acetate with methanol, mixtures of dichloromethane with methanol, mixtures of toluene with methanol or ethyl acetate or a mixture of ethyl acetate with hydrocarbons as heptane. If purification of the crude product exercise described at the end of the way, from the thus obtained pure Foundation of the compounds of formula (I) additive product with the acid compounds of formula (I) can be obtained in such a way that the base is dissolved or suspended in an organic proton solvent as methanol, ethanol, propanol or isopropanol, or in an organic aprotic solvent like ethyl acetate, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, acetone, or butane-2-it, and this mixture is then mixed with at least equimolar amounts of an inorganic acid, as, for example, hydrogen chloride, dissolved in an inert solvent, such as diethyl ether or ethanol, or another of the above inorganic or organic acids.

The compounds of formula (I) can precrystallization of a suitable inert solvent, such as acetone, butane-2-it, acetonitrile, nitromethane. CCA is i.i.d. preferred however, is pereosazhdeniya of solvent, such as, for example, dimethylformamide, dimethylacetamide, nitromethane, acetonitrile, preferably methanol or ethanol.

The reaction of compounds of formula (VII) with thioamides R4-C(S)-NH2can also be carried out in such a way that the reaction mixture are added in at least equimolar amount of base, such as, for example, triethylamine, and the thus obtained free base of formula (I) then, if necessary, transferred to their additive products with acid.

Additive products with acid compounds of the formula (I) by treatment with bases can be converted into a free base of General formula (I). As the bases used, for example, solutions of inorganic hydroxides, as the hydroxide of lithium, sodium, potassium, calcium or barium; carbonates or bicarbonates like sodium carbonate or potassium bicarbonate, sodium or potassium, ammonia and amines as triethylamine, Diisopropylamine, dicyclohexylamine, piperidine, morpholine, methyldicyclohexylamine.

Thioamides of General formula R4-C(S)-NH2either available commercially, or they can be obtained for example by reacting the corresponding carboxylic acid amide with pentasulfide phosphorus in pyridine (R.N.Hurd, G.Delameter, Chem. Rev., 61, 45 (1961)) or with Lawesson reagent in toluene, pyridine, triamide hexamer fosforos acid [Scheibye, Pedersen and Lawesson, Bull. Soc. Chim. Belges, 87, 229 (1978)], preferably in a mixture of tetrahydrofuran with 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or 1,3-dimethyl-2-imidazolidinone. This is a hydroxyl group, an amino group or an additional carbonyl group better protect using again tsepliaeva protective group, such as, for example, using benzyl, tert-butoxycarbonyl, benzyloxycarbonyl residue, respectively, by changing, if necessary, in a cyclic acetal. Methods for doing this are described, for example, the manual Th.W.Greene and P.G.M.Wuts "Protective Groups in Organic Synthesis", second edition, 1991, John Wiley and Sons, new York.

Thioamides of formula R4-C(S)-NH2also get the fact that the NITRILES of General formula R4-CN enter into interaction with hydrogen sulfide (Houben-Weil, IX, 762) or thioacetamide (..Taylor, J.A.Zoltewicz, J. Am. Chem. Soc., 82, 2656 (1960)) or O,O-Diethyldithiophosphoric acid. Interaction with hydrogen sulfide is preferably carried out in an organic solvent like methanol or ethanol; interaction with thioacetamide is carried out in a solvent as dimethylformamide adding hydrochloric acid; interaction with Oh,O-Diethyldithiophosphoric acid is carried out in a solvent like ethyl acetate in acidic conditions, for example, HCl, at room temperature or when heated.

The following examples p is assaut the invention, however, do not limit the scope of protection. The measured melting temperature, respectively, the decomposition (TPL) are without amendment, and, in General, depend on the heating rate.

Table 1

Examples

ExampleR1; R1'R2R3R4R5R6SolTPL [°]
16-Cl; HHHphenylHOH-152
2H; HHHphenyl-2-HEHOH-110
(decomposition)

The compounds of formula (I) are favourable effects on fat metabolism, in particular they are suitable as anorexically funds. The compounds can be used individually or in combination with other anarxicheskij biologically active substances. Such other anorexicskin biologically active substances indicated in the example, in the "Roten Liste", Chapter 01, section "Tools for weight loss/Means for lowering the appetite." Compounds suitable for prevention and particularly for the treatment of obesity. The compounds are suitable, furthermore, for prevention and particularly for the treatment of type II diabetes.

The effectiveness of the compounds was tested as follows.

Biological test model

Testing anoreksighennogo actions carried out on female NMRI mice. After being deprived of food for 24 hours through the gastric tube was administered the test drug. When an individual content and with free access to drinking water to the animals 30 minutes after administration of the drug was offered condensed milk. The consumption of condensed milk was determined every half hour for 1.5 hours and watched the General health of animals. The measured consumption of milk was compared with that of untreated control animals.

Table 2

Anorexically the action defined as a reduction of the cumulated consumption of milk treated compared with untreated animals.
Connection/

Example

Oral dose [mg/ng]Number of animals/ the cumulated consumption they say the ka treated animals N/[ml] Number of animals/ the cumulated consumption of milk untreated control animals

N/[ml]
The reduction of the cumulated consumption of milk in % relative to the control
Example 1305/1,065 / 1,5431%

From the table it can be seen that the compounds of formula (I) show a very good anorexically action.

Below describes in detail the receipt of certain compounds, other compounds of formula (I) are obtained in a similar manner.

Example 1 (compound I):

6-chloro-2-phenyl-8, 8A-dihydroindeno [1, 2-d] thiazol-3A, 8-diol

a) 3-Bromo-5-Clorinda-1-he:

with 8.33 g (50 mmol) of 5-Clorinda-1-she, along with 8.9 g (50 mmol) of N-bromosuccinimide suspended in 175 ml of carbon tetrachloride is mixed with 1 g of benzoyl peroxide and refluxed under stirring for 3 hours. The cooled reaction solution is filtered, shaken twice with water, each time with 100 ml of water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is dissolved when heated in 120 ml of a mixture in the ratio 1:1 of n-heptane and cyclohexane, boiled with activated charcoal, filtered and the filtrate conc the Ute in a vacuum. Get 3-bromo-5-Clorinda-1-he with a melting point of 96-97°C.

b) 3-acetoxy-5-Clorinda-1-he:

4,91 g (20 mmol) 3-bromo-5-Clorinda-1-she, along with 3,34 g (20 mmol) of silver acetate are suspended in 100 ml of acetic acid and refluxed under stirring for 5 hours. The cooled reaction solution was concentrated in vacuo and the residue purified chromatographically using silica gel using a mixture of toluene and acetone in a ratio of 10:1. Get 3-acetoxy-5-Clorinda-1-he with a melting point 65-67°C.

c) 5-chloro-3-hydroxyine-1-he:

1.98 g (8,8 mmol) 3-acetoxy-5-Clorinda-1-dissolve it in 10 ml of acetonitrile, with the addition of 50 ml of 3 n HCl. The reaction mixture is stirred for 48 hours at room temperature. Then used as the solvent acetonitrile is distilled off under vacuum and precipitated precipitated crude product is filtered and purified chromatographically using silica gel using a mixture of toluene and acetone in the ratio of 5:1. The product, 5-chloro-3-hydroxyine-1-he melts at the temperature 125-128°C.

d) 2-bromo-5-chloro-3-hydroxyine-1-he:

0,69 g (of 3.78 mmol) 5-chloro-3-hydroxyine-1-dissolve it in 100 ml of diethyl ether. With stirring, add 1 drop of bromine and stirred until the discoloration. Then cooled to a temperature of -5°and within 30 the minutes added dropwise 0,194 ml (of 3.78 mmol) of bromine in 2 ml of dichloromethane. Then stirred for 30 minutes, mixed with water (50 ml), the organic phase is separated, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue dried in vacuum. Get 2-bromo-5-chloro-3-hydroxyine-1-he with a melting point 118-119°C.

e) 6-chloro-2-phenyl-8,8A-dihydroindeno[1,2-d]thiazol-3A,8-diol:

0.6 g (2.3 mmol) of 2-bromo-5-chloro-3-hydroxyine-1-she, along with 0,473 g (of 3.45 mmol) thiobenzamide dissolved in 5 ml of isopropanol. After adding 0,478 ml (of 3.45 mmol) of triethylamine is stirred for 12 hours at room temperature and then for 8 hours at a temperature of 50°C. the Cooled reaction mixture was concentrated in vacuo and the residue purified chromatographically using silica gel using first a mixture of n-heptane and ethyl acetate in a ratio of 3:1 and then using a mixture of toluene and acetone in the ratio of 5:1. Get 6-chloro-2-phenyl-8,8A-dihydroindeno[1,2-d]-3A,8-diol with a melting point (decomposition) 151-153°C.

1. The compounds of formula (I)

where R1, R1' mean independently from each other H, F, Cl, Br, J;

R2 denotes H;

R3 denotes H;

R4 denotes phenyl, which can be substituted for IT;

R5 means a hydrogen atom;

R6 means HE,

and their physiologically acceptable salt is a physiologically functional derivatives.

2. Compounds according to claim 1 for use as a drug for the prophylaxis or treatment of obesity.

3. A drug for the prophylaxis or treatment of obesity containing one or more compounds according to claim 1.

4. The drug according to claim 3, characterized in that it additionally contains one or more other anorexically biologically active substances.

5. Method of preparing compounds according to claim 1, characterized in that, according to the following scheme:

the compound of formula (VII), where the residues have the above for formula (I) values, using thioamide formula R4-C(S)-NH2where R4 is specified for formula (I) is, converted into compounds of General formula (I), where R2 means a hydrogen atom.



 

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11 cl, 3 dwg, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of glucopyranosyloxybenzylbenzene represented by the formula (I): wherein R1 represents hydrogen atom or hydroxy(lower)alkyl; R2 represents lower alkyl group, lower alkoxy-group and lower alkylthio-group being each group is substituted optionally with hydroxy- or (lower)alkoxy-group, or to its pharmaceutically acceptable salts. Also, invention relates to pharmaceutical composition eliciting hypoglycemic activity and to a method for treatment and prophylaxis of hyperglycemia-associated diseases, such as diabetes mellitus, obesity and others, and to their intermediate compounds. Invention provides preparing new derivatives of glucopyranosyloxybenzylbenzene that elicit the excellent inhibitory activity with respect to human SGLT2.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 tbl, 2 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to polycyclic dihydrothiazoles of formula I , containing in substituted alkyl residues in 2-posiiton, as well as physiologically accepted salts thereos, having anorexia action. In formula Y is direct bond; X is CH2; R1 and R1' are independently H, Cl; R2 and R3 are H; R4 is (C8-C16-cycloalkyl, (CH2)n-A-R8, wherein n = 1-6, excepted group of formula -CH2-O-CH2-phenyl with unsubstituted phenyl; A is O, S; R8 is methyl or (CH2)m-aryl, where in m = 0-6; and aryl may represent phenyl, wherein aryl group may be optionally substituted with one or two substituents, selected from Cl, O-(C1-C6)-alkyl or (C1-C6)-alkyl. Also disclosed is method for production thereof.

EFFECT: new anorexia pharmaceuticals.

5 cl, 4 ex, 2 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention represents ligands MC-4 and/or MC-3 of the formula (I): , wherein X means hydrogen atom, -OR1, -NR1R1' and -CHR1R1' wherein R1 and R1' are taken among the group: hydrogen atom, (C1-C6)-alkyl and acyl; (1) each R2 is taken independently among the group: hydrogen atom, (C1-C6)-alkyl; or (2) (a) R2 bound with carbon atom that is bound with X and Z1 and substitute R5 can be optionally bound to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; or (b) R2 bound with carbon atom that is bound with ring Ar can be bound with R7 to form ring condensed with ring Ar; each among Z1, Z2 and Z3 is taken independently from the following groups: -N(R3e)C(R3)(R3a)-, -C(R3)(R3a)N(R3e)-, -C(O)N(R3d)-, -N(R3d)C(O)-, -C(R3)(R3a)C(R3b)(R3c)-, -SO2N(R3d)- and -N(R3d)SO2- wherein each among R3, R3a, R3b and R3c, R3d, R3e when presents is taken independently among hydrogen atom and (C1-C6)-alkyl; p is a whole number from 0 to 5 wherein when p above 0 then R4 and R4' are taken among hydrogen atom, (C1-C6)-alkyl and aryl; R5 represents 5 substitutes in phenyl ring J wherein each R5 is taken among hydrogen atom, hydroxy-, halogen atom, thiol, -OR12, -N(R12)(R12'), (C1-C6)-alkyl, nitro-, aryl wherein R12 and R12' are taken among hydrogen atom and (C1-C6)-alkyl; or two substitutes R5 can be bound optionally to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; q = 0, 1, 2, 3, 4 or 5 wherein when q above 0 then R6 and R6' are taken among hydrogen atom and (C1-C6)-alkyl; Ar is taken among the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine; R7 are substitutes at ring Ar wherein each R7 is taken among hydrogen, halogen atom, -NR13R13', (C1-C6)-alkyl and nitro- wherein R13 and R13' are taken among hydrogen atom and (C1-C6)-alkyl; r is a whole number from 0 to 7 wherein when r is above 0 then R8 and R8' are taken among hydrogen atom and (C1-C6)-alkyl; B is taken among -N(R14)C(=NR15)NR16R17, -NR20R21, heteroaryl ring and heterocycloalkyl ring wherein R14-R17, R20 and R21 are taken independently among hydrogen atom and (C1-C6)-alkyl; s = 0, 1, 2, 3, 4 or 5 wherein when s is above 0 then R and R9' are taken among hydrogen atom and (C1-C6)-alkyl; R10 is taken among the group consisting of optionally substituted bicyclic aryl ring and optionally substituted bicyclic heteroaryl ring; D is taken among hydrogen atom, amino- and -C(O)R11 wherein R11 is taken among the following group: hydroxy-, alkoxy-, amino-, alkylamino-, -N(R19)CH2C(O)NH2 wherein R19 represents (C1-C6)-alkyl, -NHCH2CH2OH and -N(CH3)CH2CH2OH, or its isomers, salts, hydrates or biohydrolysable ester, amide or imide.

EFFECT: valuable medicinal properties of compounds.

18 cl, 107 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new heterocyclylsulfonyl alkylcarboxylic acids and their derivatives of the general formula (1): or their pharmaceutically acceptable salts, N-oxides or hydrates possessing the inhibitory effect on kinase activity and to the focused library for search of active leader-compounds comprising at least abovementioned compound. In the general formula 91) W represents optionally substituted heterocyclic radical, among them: pyrrole-3-yl, thiophene-2-yl, isooxazole-4-yl, pyrazole-4-yl, imidazole-4-yl, pyridine-3-yl, 1H-2,4-dioxopyrimidine-5-yl, 2,3-dihydro-1H-indole-5-yl, 2,3-dihydro-1H-indole-7-yl, 1,3-dihydro-2-oxoindole-5-yl, 2,3-dioxo-1H-indole-5-yl, 2-oxo-3H-benzoxazole-6-yl, benzothiazole-6-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazole-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinoline-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxoquinoxaline-6-yl, 3-oxo-4H-benzo[1,4]oxazine-7-yl, 3-oxo-4H-benzo[1,4]thiazine-7-yl, 2,4-dioxo-1H-quinazoline-6-yl, 2,4-dioxo-1,5-dihydrobenzo[b][1,4]diazepine-7-yl or 2,5-dioxo-3,4-dihydrobenzo[b][1,4]diazepine-7-yl; Y represents optionally substituted methylene group; R1 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; n = 1, 2 or 3; or Yn represents carbon atom of optionally substituted (C3-C7)-cycloalkyl or optionally substituted (C4-C7)-heterocyclyl. Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injections placed into pharmaceutically acceptable package.

EFFECT: valuable properties of compounds.

5 cl, 3 sch, 5 tbl, 6 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to polycyclic dihydrothiazole and to their physiologically acceptable salts and physiologically functional derivatives. Invention describes compounds of the formula (I): wherein R1 and R1' mean independently of one another atoms of hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) and iodine (J); R2 and R3 mean hydrogen atom (H); R4 means (CH2)n-R5 wherein n can be = 0-6; R5 means phenyl that can be substituted with NH-SO2-(C1-C6)-alkyl, NH-SO2-phenyl being phenyl ring up to twice-fold can be substituted with chlorine atom (Cl), (CH2)m-SO2-NH2, (CH2)-SO2-NH-(C1-C6)-alkyl, (CH2)m-SO2-N-[(C1-C6)-alkyl]2 or (CH2)m-SO2-N-[=CH-N(CH3)2] wherein m can be = 0-6, and a method for their preparing. Compounds are useful, for example, as anorexic agents used in prophylaxis or treatment of obesity.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

5 cl, 12 tbl, 2 ex

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