Derivatives of 1,10b-dihydro-2-(aminocarbonylphenyl)-5h-pyrazolo[1,5-c][1,3]benzoxasin-5-yl)phenylmethylmethanon as inhibitors of hiv virus replication

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are derivatives of 5H-pyrazolo[1,5-c][1,3]benzoxasin-5-yl)phenylmethanon of formula , possessing ability to inhibit HIV replication, where values of R1, R2, R3 substitutes are given in invention formula. Also describes is pharmaceutical preparation and application of compound for obtaining medication applied for treatment of conditions associated with HIV infection.

EFFECT: claimed compounds are applicable for prevention or treatment of HIV-produced infection and for AIDS treatment.

15 cl, 3 tbl, 5 ex

 

The present invention relates to derivatives of 5H-pyrazolo[1,5-c][1,3]benzoxazin-5-yl)phenylmethanone as inhibitors of viral replication of HIV virus, methods for their preparation and to pharmaceutical compositions, their use as medicines and diagnostic kits containing them. The present invention also concerns combinations of these HIV inhibitors with other antiretrovirals. It also refers to the use of their tests as compounds and reagents. Compounds of the present invention is applicable for the prevention or treatment of infection by HIV and the treatment of AIDS.

The number of people living with HIV /AIDS, consisted in December 2001, approximately 40 million people, which included more than 37 million adults and approximately 2.7 million children under 15 years. The number of people infected with HIV, only in 2001, reached 5 million people, while the number of deaths from AIDS in 2001 was $ 3 million. In modern chemotherapy in the treatment of people with HIV/AIDS, use of inhibitors of the fusion of the virus, as well as enzymes reverse transcriptase (RT) and protease. In light of the emergence of HIV strains resistant to inhibitors of the thread generating the merge RT and protease, there is a growing pot is ebest in the development of new anti-virus tools with new mechanisms of action.

The present invention relates to compounds having formula (I),

and their N-oxides, stereoisomeric forms and salts,

where

"a" takes on the values 0, 1, 2, 3, 4 or 5;

R1represents hydrogen, C1-10alkyl, C2-10alkenyl,2-10quinil,3-12cycloalkyl, Het, aryl or1-10alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-12cycloalkyl, amino and mono - or disubstituted amino, where the amino substituents each individually selected from C1-10of alkyl, C2-10alkenyl,3-12cycloalkyl, Het and aryl;

R2represents hydrogen, C1-10alkyl, C2-10alkenyl,2-10quinil,3-12cycloalkyl, Het, aryl or1-10alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-12cycloalkyl, amino and mono - or disubstituted amino, where the amino substituents each individually selected from C1-10of alkyl, C2-10alkenyl,3-12cycloalkyl, Het and aryl; or

R1and R2together with the nitrogen atom to which they are attached form a (5-12)-membered saturated or partially saturated a heterocycle, this heterocycle can be optionally substituted C1-10the alkyl, C2-10alkenyl,2-10the quinil,3-12cyclol the sludge, With1-6allyloxycarbonyl, Het, aryl or1-10by alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-12cycloalkyl, amino and mono - or disubstituted amino, where the amino substituents each individually selected from C1-10of alkyl, C2-10alkenyl,3-12cycloalkyl, Het and aryl;

R3is carboxyl, halogen, nitro, C1-10alkyl, C3-12cycloalkyl, polyhalo1-10alkyl, cyano, amino, mono - or disubstituted amino, aminocarbonyl, mono - or disubstituted aminocarbonyl,1-10alkyloxy,1-10alkylthio,1-10alkylsulfonyl, pyrrolidinyl, piperidinyl, homopiperazine, morpholine, thiomorpholine or piperazinil, optionally substituted C1-10the alkyl, where the substituents of any of the amino groups, each individually, are selected from C1-10of alkyl, C2-10alkenyl,3-12cycloalkyl, Het and aryl;

aryl represents phenyl, optionally substituted by one or more substituents selected from the group consisting of C1-10of alkyl, polyhalo1-10of alkyl, C1-10alkyloxy,1-10alkylthio,1-10alkylsulfonyl, nitro, cyano, halo, C3-7cycloalkyl,1-10alkylcarboxylic, carboxyl,1-10allyloxycarbonyl, amino, mono - or disubstituted amino, aminocarbonyl,mono - or disubstituted aminocarbonyl, where any of the substituents of the amino groups, each individually selected from phenyl,1-10of alkyl, C2-10alkenyl,3-7cycloalkyl, pyrrolidinyl, piperidinyl, homopiperazine or piperazinil, optionally substituted C1-10by alkyl;

Het represents a 5 - or 6-membered aromatic, saturated or partially saturated, monocyclic or bicyclic a heterocycle with one or more heteroatoms, of which each individually selected from nitrogen, oxygen, or sulfur; and each heterocycle can be optionally substituted with one or where possible more substituents selected from the group consisting of C1-10of alkyl, polyhalo1-10of alkyl, C1-10alkyloxy,1-10alkylthio,1-10alkylsulfonyl, nitro, cyano, halo, C3-7cycloalkyl,1-10alkylcarboxylic, carboxyl,1-10allyloxycarbonyl, amino, mono-or disubstituted amino, aminocarbonyl, mono - or disubstituted aminocarbonyl, where the substituents of any of the amino groups, each individually selected from phenyl,1-10of alkyl, C2-10alkenyl,3-7cycloalkyl, pyrrolidinyl, piperidinyl, homopiperazine or piperazinil, optionally substituted C1-10the alkyl.

In this document the term ”halo” or ”halogen” is used to refer to the group is whether part of the group, entered as fluorine, chlorine, bromine or iodine. The term “polygala” used as a prefix, which denotes the substitution by one or more halogen atoms. The examples that used the prefix "polygala"include, for example, polyhalo1-10alkyl, polyhalo1-6alkyl, polyhalo1-4alkyl and the like. Especially interesting are polygamously as deformity and trifluoromethyl.

The term "C1-4alkyl"related to the group or part of a group, refers to saturated monovalent hydrocarbon radical with unbranched and branched chain, containing from 1 to 4 carbon atoms. Examples of such1-4alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like.

The term "C1-6alkyl"related to the group or part of a group, refers to saturated monovalent hydrocarbon radical with unbranched and branched chain, containing from 1 to 6 carbon atoms. Examples of such1-6alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 2-methylbutyl, pentyl, isoamyl, hexyl, 3-methylpentyl and the like.

The term "C1-10alkyl"related to the group or part of a group, refers to saturated monovalent hydrocarbon radicals with ner is Svetlanas and branched chain, containing from 1 to 10 carbon atoms. Examples of such1-10alkyl radicals include examples With1-6alkyl radicals and heptyl, octyl, nonyl, decyl, 3-atergatis and the like.

The term "C2-6alkenyl"referring to a group or part of a group, denotes a monovalent hydrocarbon radical with unbranched and branched chain, having at least one double bond and containing from 2 to 6 carbon atoms. Examples of such2-6alkenyl radicals include ethynyl, propenyl, 1-butenyl, 2-butenyl, Isobutanol, 2-methyl-1-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 3-methyl-2-pentenyl and the like.

The term "C2-10alkenyl"referring to a group or part of a group, denotes a monovalent hydrocarbon radical with unbranched and branched chain, having at least one double bond and containing from 2 to 10 carbon atoms. Examples of such2-10alkenyl radicals include

examples2-6alkenyl and 2-heptenyl, 3-heptenyl, 3-octenyl, 4-octenyl, 4-nonanol, 4-decenyl and the like.

The term "C2-6quinil"referring to a group or part of a group, denotes a monovalent hydrocarbon radical with unbranched and branched chain, having at least one triple bond and containing from 2 to 6 ATO is s carbon. Examples of such2-6etkinlik radicals include ethinyl, PROPYNYL, 1-butynyl, 2-butynyl, Isobutanol, 2-methyl-1-butynyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 3-methyl-2-pentenyl and the like.

The term "C2-10quinil"referring to a group or part of a group, denotes a monovalent hydrocarbon radical with unbranched and branched chain, having at least one triple bond and containing from 2 to 10 carbon atoms. Examples of such2-10etkinlik radicals include

examples2-6the quinil and 2-heptenyl, 3-heptenyl, 3-octenyl, 4-octenyl, 4-nonenal, 4-decenyl and the like.

The term "C3-7cycloalkyl"referring to a group or part of a group, denotes a carbocyclic or zerocarboncity monovalent hydrocarbon radicals having from 3 to 7 carbon atoms in the main chain carbocycle or pyrocarbonate. Examples of such3-7cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Spiro[2,4]heptenyl, cycloheptyl and the like.

The term "C3-12cycloalkyl"referring to a group or part of a group, denotes a carbocyclic or zerocarboncity monovalent hydrocarbon radicals having from 3 to 12 carbon atoms in the main chain carbocycle or pyrocarbonate. PR is measures such 3-12cycloalkyl radicals include examples With3-7cycloalkyl and cyclooctyl, cycloneii, Spiro[4,4]nonyl, Spiro[4,5]decyl, Spiro[5,5]undecyl, cyclododecyl, Spiro[5,6]dodecyl, and the like.

Examples of 5 - or 6-membered heterocycles, referred to as Het, include, among others, pyridine, pyrimidine, pyridazine, pyrazin, triazine, imidazole, thiazole, oxazole, oxadiazole, thiadiazole, isothiazol, isoxazol, pyrazole, furan, thiophene, pirol, quinoline, isoquinoline, benzoxazol, samesexual, benzothiazole, IsoBuster, benzimidazole, benzotriazole, tetrahydroquinolin, tetrahydroisoquinoline, piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, homopiperazin, homopiperazin, tetrahydrofuran and tetrahydrothieno.

When used herein, the term "C(=O)" refers to a carbonyl part, and the term "S(=O)2" defines sulfonyloxy part. The term "hydroxy"as used herein means-OH, the term "nitro" means-NO2the term "cyano" means-CN, and the term "thio" means-S, the term "oxo" means =O.

Any use of the terms "one or more substituents" or "substituted", in the definition of compounds of formula (I), assume that when the atom indicated in the expression using turnover "one or more substituents, or substituted, one, or carried the only hydrogen atoms substituted selected from a specified group substituents; provided that you are not exceeding the principal valence of the specified atom, and the substitution leads to a chemically stable compound, i.e. the compound which is sufficiently stable to be isolated from the reaction mixture with the desired degree of purity and can be converted into a therapeutic tool.

For therapeutic use apply such salts of the compounds of the present invention, in which the counterion is pharmaceutically or physiologically acceptable. However, salts with pharmaceutically unacceptable counterion may also find use, for example, upon receipt or purification of pharmaceutically acceptable compounds of the present invention. All salts, regardless of whether they are pharmaceutically acceptable or not included in the scope of the present invention.

Pharmaceutically acceptable or physiologically-tolerated form of acid additive salts, which are capable of forming compounds of the present invention, can be easily obtained by using such appropriate acids as, for example, such inorganic acids as kaleidostone acid, for example hydrochloric or Hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, propanoic, glycoles what I lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, reklamowa, salicylic, p-aminosalicylic, AMOVA and similar acids.

These forms of acid additive salts when processing an appropriate basis can be transformed back into the form of a free base.

Compounds of the present invention containing an acidic proton may also be converted into non-toxic form of the additive metal salt or amine by treatment with appropriate organic and inorganic bases. Appropriate forms basic salts include, for example, ammonium salts, Quaternary ammonium salts, salts of alkali and alkaline earth metals, such as lithium salts, sodium, potassium, magnesium, calcium and the like, salts with organic osnovaniyami, for example salt, benzathine, N-methyl-D-glucamine, geranamine and salts with amino acids such as, for example, arginine, lysine and the like.

These forms are basically additive salts in the processing of the corresponding acid can be back transformed to the form of the free acid.

The term “salt” also includes hydrates and forms an additive salts of the solvent that can form a joint the present invention. Examples of such forms are, for example, hydrates, alcoholate, and the like. The term “salt” also includes the quaternization of the nitrogen atoms of these compounds. The basic nitrogen atom can be quaternity with any agent known to technicians in the field, including, for example, the lowest alkylhalogenide, diallylsulfide, halides, long-chain and arylalkylamine.

The N-oxide forms of the present compounds include compounds in which one or more atoms of nitrogen oxidized to the so-called N-oxide.

These compounds can also exist in tautomeric forms. These forms, although they are not explicitly indicated in the above formula, I believe is included in the scope of the present invention.

Whenever used in this patent application, the terms “real connection”, “connection of the present invention”, “compounds of formula (I)” or similar terms include the compounds of formula (I), their N-oxides, their stereoisomeric forms, their salts or any of its subgroups.

Interesting compounds of formula (I) are such compounds or any subgroup, where "a" takes the value of zero, 1 or 2;more interesting, in particular, are such compounds where "a" takes the value of zero or 1.

Interesting compounds are the so is E. the compounds of formula (1), in which R1represents hydrogen, C1-6alkyl, C2-6alkenyl,2-6quinil,3-7cycloalkyl, Het, aryl or C1-6alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-7cycloalkyl, amino and mono - or disubstituted amino, where the amino substituents each individually selected from C1-6the alkyl or C3-7cycloalkyl;

where R1in particular represents a C1-6alkyl, C3-7cycloalkyl, Het, aryl or

C1-6alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-7cycloalkyl, and mono - or disubstituted amino, where the amino substituents each individually selected from C1-6the alkyl.

Interesting compounds are those compounds of formula (I) or any subgroup in which R2represents hydrogen, C1-10alkyl, C2-10alkenyl, C2-10quinil,3-12cycloalkyl, or C1-10alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-7cycloalkyl, amino and mono - or disubstituted amino, where the amino substituents each individually selected from C1-6of alkyl;

where R2in particular represents hydrogen, C1-6alkyl, C2-6alkenyl, or C1-6alkyl, substituted Deputy selected is from the group consisting of aryl.

Interesting compounds are those compounds of formula (I) or any subgroup in which R1and R2together with the nitrogen atom to which they are attached, form a (5-12)-membered saturated or partially saturated a heterocycle, this heterocycle can be optionally substituted C1-6the alkyl, C2-6alkenyl,

C2-6the quinil,3-7cycloalkyl, C1-6allyloxycarbonyl, Het, aryl or C1-6by alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-7cycloalkyl, amino and mono - or disubstituted amino, where the amino substituents each individually selected from C1-6of alkyl, C2-6alkenyl, C2-6alkenyl,3-7cycloalkyl, Het and aryl;

where, in particular, R1and R2together with the nitrogen atom to which are attached, form a (5-12)-membered saturated or partially saturated a heterocycle, this heterocycle can be optionally substituted C1-6the alkyl, C1-6allyloxycarbonyl or C1-6the alkyl substituted by aryl;

in more detail, the compounds in which R1and R2together with the nitrogen atom to which are attached, form a heterocycle selected from the group consisting of piperazinil, homopiperazine, piperidine, homopiperazine, morpholine, thiomorpholine, p is rolidone, indolinyl, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline; this heterocycle can be optionally substituted C1-6the alkyl, C2-6alkenyl, C2-6the quinil,3-7cycloalkyl, C1-6allyloxycarbonyl, Het, aryl, or C1-6by alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-7cycloalkyl, amino and mono - or disubstituted amino, where the amino substituents each individually selected from C1-6of alkyl, C2-6alkenyl,3-7cycloalkyl, Het and aryl.

And even in more detail, the compounds in which R1and R2together with the nitrogen atom to which are attached, form a heterocycle selected from the group consisting of piperazinil, homopiperazine, piperidine, homopiperazine, morpholine, thiomorpholine, pyrrolidine, indoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline; this heterocycle can be optionally substituted C1-6the alkyl, C1-6allyloxycarbonyl or C1-6the alkyl substituted by aryl.

Interesting compounds are those compounds of formula (I) or any subgroup in which R3is carboxyla, halogen, nitro, C1-6the alkyl, C3-7cycloalkyl, polyhalo1-4the alkyl, cyano, amino, mono - or disubstituted amino, aminocarbonyl, mono is whether disubstituted by aminocarbonyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkylsulfonyl, pyrrolidinium, piperidinium, homopiperazine, morpholinium, thiomorpholine or piperazinil, optionally substituted C1-6the alkyl, where the substituents of any of the amino groups is chosen, each individually, from C1-6of alkyl, C2-6alkenyl,3-7cycloalkyl, Het and aryl;

where R3in particular represents halogen, nitro, C1-6alkyl, C3-7cycloalkyl, polyhalo1-4alkyl, cyano, C1-6alkyloxy, C1-6alkylthio, C1-6alkylsulfonyl, piperidinyl, morpholinyl.

Interesting compounds are those compounds of formula (I) or any sub-group, in which aryl is phenyl, optionally zameshannym one or more substituents selected from the group consisting of C1-6of alkyl, polyhalo1-6of alkyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkylsulfonyl, nitro, cyano, halo, C3-7cycloalkyl, C1-6alkylcarboxylic, carboxyl, C1-6allyloxycarbonyl, amino, mono - or disubstituted amino, aminocarbonyl, mono - or disubstituted aminocarbonyl, where the substituents of any of the amino groups, each individually selected from phenyl, C1-6of alkyl, C2-6alkenyl,3-7cycloalkyl, pyrrolidinyl, piperidinyl, homopiperazine or p is of pyrazinyl, optionally substituted C1-6by alkyl;

where, in particular, the aryl is phenyl, optionally substituted one, two or three substituents selected from the group consisting of C1-6of alkyl, C1-6alkyloxy, nitro, cyano, halo, amino, mono - or disubstituted amino, where the substituents of any of the amino groups, each individually, are selected from C1-6the alkyl.

Interesting compounds are those compounds of formula (I) or any subgroup in which Het represents a 5 - or 6-membered aromatic, saturated or partially saturated, monocyclic or bicyclic a heterocycle with one or more heteroatoms, where each individually selected from nitrogen, oxygen, or sulfur; and the heterocycle may be optionally substituted one or where possible more substituents selected from the group consisting of C1-6of alkyl, polyhalo1-6of alkyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkylsulfonyl, nitro, cyano, halo, C3-7cycloalkyl, C1-6alkylcarboxylic, carboxyl, C1-6allyloxycarbonyl, amino, mono - or disubstituted amino, aminocarbonyl, mono - or disubstituted aminocarbonyl, where the substituents of any of the amino groups, each individually selected from phenyl, C1-6of alkyl, C2-6alkenyl,3-7cycloalkyl, pyrrole is inila, piperidinyl, homopiperazine or piperazinil, optionally substituted C1-6by alkyl;

where, in particular, Het represents a 5 - or 6-membered aromatic, saturated or partially saturated, monocyclic or bicyclic a heterocycle with one or more heteroatoms, where each individually selected from nitrogen, oxygen, or sulfur; and the heterocycle may be optionally substituted C1-6the alkyl.

In more detail, when Het represents a heterocycle selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, pyrrolyl, furanyl, teinila, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, imidazolyl, tetrahydropyranyl, tetrahydrofuryl, imidazoline, DIOXOLANYL, pyrrolidinyl, piperidinyl, homopiperazine, piperazinil, homopiperazine, dioxane, morpholine, thiomorpholine; this heterocycle can be optionally substituted with one or where possible more substituents selected from the group consisting of C1-6of alkyl, polyhalo1-6of alkyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkylsulfonyl, nitro, cyano, halo, C3-7cycloalkyl, C1-6alkylcarboxylic, carboxyl, C1-6allyloxycarbonyl, amino, mono - or disubstituted amino, aminocarbonyl, mono - or diseasesand the th aminocarbonyl, where any of the substituents of the amino groups, each individually selected from phenyl, C1-6of alkyl, C2-6alkenyl,3-7cycloalkyl, pyrrolidinyl, piperidinyl, homopiperazine or piperazinil, optionally substituted C1-6by alkyl;

even more detail, where Het represents a heterocycle selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, pyrrolyl, furanyl, teinila, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, imidazolyl, tetrahydropyranyl, tetrahydrofuryl, imidazoline, DIOXOLANYL, pyrrolidinyl, piperidinyl, homopiperazine, piperazinil, homopiperazine, dioxane, morpholine, thiomorpholine; this heterocycle can be optionally substituted C1-6the alkyl.

More interesting compounds are those compounds of formula (I) or any subgroup in which Het represents a heterocycle selected from the group consisting of pyridinyl, furanyl, teinila, tetrahydrofuranyl, pyrrolidinyl, piperidinyl; this heterocycle can be optionally substituted with one or where possible more substituents selected from the group consisting of C1-6of alkyl, polyhalo1-6of alkyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkylsulfonyl, nitro, cyano, halo, C3-7is cloacina, C1-6alkylcarboxylic, carboxyl, C1-6allyloxycarbonyl, amino, mono - or disubstituted amino, aminocarbonyl, mono - or disubstituted aminocarbonyl, where the substituents of any of the amino groups, each individually selected from phenyl, C1-6of alkyl, C2-6alkenyl,3-7cycloalkyl, pyrrolidinyl, piperidinyl, homopiperazine or piperazinil, optionally substituted C1-6by alkyl;

where, in particular, Het represents a heterocycle selected from the group consisting of pyridinyl, furanyl, teinila, tetrahydrofuranyl, pyrrolidinyl, piperidinyl; this heterocycle can be optionally substituted C1-6the alkyl.

An interesting group of compounds are those compounds of formula (I)where the use of one or more of the following limitations:

1. "a" takes on the values zero or l;

2. R1represents a C1-10alkyl, C3-12cycloalkyl, Het, aryl or C1-10alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-12cycloalkyl and mono - or disubstituted amino in which the amino substituents each individually selected from C1-10of alkyl;

3. R2represents hydrogen, C1-10alkyl, C2-10alkenyl or C1-10alkyl, substituted aryl;

4. R1and R2together with the nitrogen atom to motorolaringtones, form (5-12)-membered saturated or partially saturated a heterocycle, this heterocycle can be optionally substituted C1-10the alkyl, C1-6allyloxycarbonyl or C1-10the alkyl substituted by aryl;

5. R3represents halogen, nitro, C1-10alkyl, C3-12cycloalkyl, polyhalo1-10alkyl, cyano, C1-10alkyloxy, C1-10alkylthio, C1-10alkylsulfonyl, piperidinyl, morpholinyl;

6. Aryl represents phenyl, optionally substituted by one or more substituents selected from the group consisting of C1-10alkyloxy, halo, mono - or disubstituted amino, where the Deputy of any of the amino groups, each individually, are selected from C1-10of alkyl;

7. Het represents a 5 - or 6-membered aromatic, saturated or partially saturated, monocyclic or bicyclic a heterocycle with one or more heteroatoms, where each individually selected from nitrogen, oxygen, or sulfur; and the heterocycle may be optionally substituted C1-10the alkyl.

Specific compounds are compounds of formula (I) or any subgroup, such as interesting connections defined above, in which the-C(=O)-NR1R2the part is in the para - position in the phenyl ring, attached to position 2 of the frame 1,9b-dihydro-5-oxa-3,3a-diabetic is openta[a]naphthalene (also known as frame 1,10b-dihydro-5H-pyrazolo[1,5-c][1,3]benzoxazine), as you can see in the compound of formula (Ia)shown in the figure below.

Specific compounds are compounds of formula (I) or any subgroup, such as interesting compounds indicated above, in which "a" takes on the values zero or 1, and R3is halogen, nitro, C1-10the alkyl, C3-12cycloalkyl, polyhalo1-10the alkyl, cyano, C1-10alkyloxy, C1-10alkylthio, C1-10alkylsulfonyl, piperidinium, morpholinium.

Specific compounds are compounds of formula (I) or (Ia) or any subgroup, such as interesting compounds indicated above, in which R1is C1-10the alkyl, C3-12cycloalkyl, Het, aryl or C1-10by alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-12cycloalkyl and mono - or disubstituted amino in which the amino substituents each individually selected from C1-10of alkyl; R2represents hydrogen, C1-10alkyl, C2-10alkenyl or C1-10alkyl, substituted aryl;

or R1and R2together with the nitrogen atom to which are attached, form a (5-12)-membered saturated or partially saturated a heterocycle, this heterocycle can be optionally substituted C1-10the alkyl, C16 allyloxycarbonyl or C1-10the alkyl substituted by aryl.

The preferred compounds are the compounds of formula (I) or (Ia) or any subgroup, such as interesting and particular compounds defined above, in which

"a" takes the value of zero or 1;

R1is C1-10the alkyl, C3-12cycloalkyl, Het, aryl or C1-10by alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-12cycloalkyl and mono - or disubstituted amino in which the amino substituents each individually selected from C1-10of alkyl;

R2represents hydrogen, C1-10alkyl, C2-10alkenyl or C1-10alkyl, substituted aryl; or

R1and R2together with the nitrogen atom to which are attached, form a (5-12)-membered saturated or partially saturated a heterocycle, this heterocycle can be optionally substituted C1-10the alkyl, C1-6allyloxycarbonyl or C1-10the alkyl substituted by aryl;

R3represents halogen, nitro, C1-10alkyl, C3-12cycloalkyl, polyhalo1-10alkyl, cyano, C1-10alkyloxy, C1-10alkylthio, C1-10alkylsulfonyl, piperidinyl, morpholinyl.

The preferred compounds are the compounds of formula (I) or (Ia) or any subgroup, such as the interest is diversified and specific compounds defined above, in which

"a" takes on the values zero or 1;

R1is C1-10the alkyl, C3-12cycloalkyl, Het, aryl or C1-10by alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-12cycloalkyl and mono - or disubstituted amino in which the amino substituents each individually selected from C1-10of alkyl;

R2represents hydrogen, C1-10alkyl, C2-10alkenyl or C1-10alkyl, substituted aryl; or

R1and R2together with the nitrogen atom to which they are attached, form a (5-12)- membered saturated or partially saturated a heterocycle, this heterocycle can be optionally substituted C1-10the alkyl, C1-6allyloxycarbonyl or C1-10the alkyl substituted by aryl;

R3represents halogen, nitro, C1-10alkyl, C3-12cycloalkyl, polyhalo1-10alkyl, cyano, C1-10alkyloxy, C1-10alkylthio, C1-10alkylsulfonyl, piperidinyl, morpholinyl;

aryl represents phenyl, optionally substituted by one or more substituents selected from the group consisting of C1-10alkyloxy, halo, mono - or disubstituted amino, where the substituents of any of the amino groups, each individually, are selected from C1-10of alkyl;

Het represents a 5 - or 6-membered ring is aromatic, saturated or partially saturated, monocyclic or bicyclic a heterocycle with one or more heteroatoms, where each individually selected from nitrogen, oxygen, or sulfur; and the heterocycle may be optionally substituted C1-10the alkyl.

More preferred compounds are the compounds of formula (I) or (Ia) or any subgroup, such as interesting and particular compounds defined above, in which

"a" takes on the values zero or 1;

R1is C1-6the alkyl, C3-7cycloalkyl, Het, aryl or C1-6by alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-7cycloalkyl and mono - or disubstituted amino in which the amino substituents each individually selected from C1-6of alkyl;

R2represents hydrogen, C1-6alkyl, C2-6alkenyl or C1-6alkyl, substituted Deputy selected from the group consisting of aryl; or

R1and R2together with the nitrogen atom to which they are attached, form a heterocycle selected from the group consisting of piperazinil, homopiperazine, piperidine, homopiperazine, morpholine, thiomorpholine, pyrrolidine, indoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline; this heterocycle can be optionally substituted C-6 the alkyl, C1-6allyloxycarbonyl or C1-6the alkyl substituted by aryl;

R3represents halogen, nitro, C1-6alkyl, C3-7cycloalkyl, polyhalo1-4alkyl, cyano, C1-6alkyloxy, C1-6alkylthio, C1-6alkylsulfonyl, piperidinyl, morpholinyl;

aryl represents phenyl, optionally substituted one, two or three substituents selected from the group consisting of C1-6of alkyl, C1-6alkyloxy, nitro, cyano, halo, amino, mono - or disubstituted amino, where the substituents of any of the amino groups, each individually, are selected from C1-6of alkyl;

Het represents a heterocycle selected from the group consisting of pyridinyl, furanyl, teinila, tetrahydrofuranyl, pyrrolidinyl, piperidinyl; this heterocycle can be optionally substituted C1-6the alkyl.

Other more preferred compounds are the compounds of formula (I) or (Ia) or any subgroup, such as interesting, specific and preferred compounds defined above, in which R1is cyclopentyl, and R2is hydrogen.

Other more preferred compounds are the compounds of formula (I) or (Ia) or any subgroup, such as interesting, specific and preferred compounds defined above, in which "a" and EET value 1, and R3is halogen, cyano, C1-4the alkyl, C1-4alkylthio; morpholinium, C1-4alkyloxy, nitro, C1-4alkylsulfonyl, trifluoromethyl.

The most preferred compounds are

4-[5-(4-perbenzoic)-1,10b-dihydro-5H-pyrazolo[1,5-c][1,3]benzoxazin-2-yl]-N-[(4-methoxyphenyl)methyl]-N-methylbenzamide;

4-[5-(4-cyanobenzoyl)-1,10b-dihydro-5H-pyrazolo[1,5-c][1,3]benzoxazin-2-yl]-N-cyclopentylmethyl;

4-[5-(4-propylbenzoyl)-1,10b-dihydro-5H-pyrazolo[1,5-c][1,3]benzoxazin-2-yl]-N-cyclopentylmethyl;

4-[5-(4-methylsulfonylbenzoyl)-1,10b-dihydro-5H-pyrazolo[1,5-c] [1,3]benzoxazin-2-yl]-N-cyclopentylmethyl;

4-[5-(4-atienzar)-1,10b-dihydro-5H-pyrazolo[1,5-c][1,3]benzoxazin-2-yl]-N-cyclopentylmethyl;

4-[5-(4-tert-butylbenzoyl)-1,10b-dihydro-5H-pyrazolo[1,5-c][1,3] benzoxazin-2-yl]-N-cyclopentylmethyl;

4-[5-(4-nitrobenzoyl)-1,10b-dihydro-5H-pyrazolo[1,5-c][1,3]benzoxazin-2-yl]-N-cyclopentylmethyl;

4-[5-(4-methansulfonate)-1,10b-dihydro-5H-pyrazolo[1,5-c] [1,3]benzoxazin-2-yl] -N-cyclopentylmethyl;

4-[5-(4-trifloromethyl)-1,10b-dihydro-5H-pyrazolo[1,5-c][1,3]benzoxazin-2-yl]-N-cyclopentylmethyl

or their N-oxides, stereoisomeric forms or salt.

Due to the fact that the compounds of formula (I) are inhibitors of HIV replication, the compounds of formula (I) are suitable for the treatment of warm-blooded animals, in particular the people, infected with HIV. Conditions associated with HIV, which can be prevented or cured by the compounds according to the present invention include AIDS, AIDS-associated complex (ARS), progressive generalized lymphadenopathy (PGL), such as chronic diseases of the CNS caused by retroviruses, such as HIV mediated dementia and multiple sclerosis.

Therefore, compounds of the present invention can be used as drugs counteracting the above-mentioned conditions, or in the way of their treatment. Such use as a medicine or method of treatment comprises the systemic introduction of an effective therapeutic amount of the compounds of formula (I) HIV-infected warm-blooded animals, in particular HIV-infected people. Therefore, the compounds of the present invention can be used to obtain the medicinal product applied in the treatment of conditions associated with HIV infection.

In one embodiment, the invention relates to the use of compounds of the present invention to obtain a drug to prevent HIV transmission or HIV infection, or disease associated with HIV infection of warm-blooded animals, in particular humans, which, in particular, transmission or through sexual intercourse or close intimate contact between partners. Thus, the invention also relates to a method of preventing HIV transmission or HIV infection, or disease associated with HIV infection, in particular, sexual transmission, or close intimate contact between partners, including the introduction of a warm-blooded animal, including man, an effective prophylactic amount of a compound of formula (I).

The term "stereochemical isomeric forms of the compounds of the present invention", as used previously in this document, defines all possible compounds made up of the same atoms connected in the same sequence of relationships, but having different three-dimensional structures which are not interchangeable and which can have compound of the present invention.

If not mentioned or stated otherwise, the chemical designation of compounds comprises a mixture of all possible stereochemical isomeric forms. This mixture may contain all of the diastereomers and/or enantiomers basic molecular structure of the compounds. All stereochemical isomeric forms of the compounds of the present invention, both in pure form and in the form of a mixture with each other, included in the scope for the present invention.

Pure stereoisomeric forms of the compounds and intermediates mentioned herein, is defined as isomers, essentially containing no other enantiomeric or diastereoisomeric forms of the same basic molecular structure of these compounds or intermediates. In particular, the term "stereoisomer pure" refers to compounds or intermediates having excess stereoisomer, constituting at least 80% (i.e. minimum number of one isomer is 80%, and the maximum number of other possible isomers is 20%) to 100% excess stereoisomer (i.e. 100% of one isomer, in the absence of other isomers); in more detail, the compounds or intermediates having excess stereoisomer of 90% to 100%, even more detail, with excess stereoisomer of 94% up to 100% and, in most detail, with excess stereoisomer of 97% to 100%. The terms "enantiomerically pure" and "diastereomers clean" should be understood in the same way, but given the enantiomer excess and surplus diastereoisomer in this mixture.

Pure stereoisomeric forms of the compounds and intermediates of this invention can be obtained using techniques known in this field. For example, the enantiomers can be about who divided from each other by the selective crystallization of their diastereomeric salts, using optically active acids. Alternatively, the enantiomers can be separated by chromatographic methods using chiral stationary phase. These pure stereochemical isomeric forms may also be derived from the corresponding pure stereochemical isomeric forms of the appropriate starting compounds, provided that the reaction proceeds as stereospetsifichno. If you want a specific stereoisomer, preferably, when the specified connection will synthesize stereospecificity methods of getting. In these ways will be mainly used enantiomerically pure source materials.

Diastereomers racemic mixture of compounds of the present invention can be obtained separately by conventional methods. Appropriate physical separation, which mainly can be used are, for example, selective crystallization and chromatography, for example, column chromatography.

The compounds can contain one or more asymmetric centers and therefore may exist in different stereoisomeric forms. The absolute configuration of each asymmetric center, which can be present in joints, can be indicated with the stereochemical descriptors R S; this R - and S-symbol conforms to the rules described in Pure Appl. Chem. 1976, 45, 11-30.

The present invention also is intended to include all isotopes of atoms present in these compounds. Isotopes include atoms that have the same sequence number but different mass number. As a generic example, without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include13C and14C.

Useful properties of these compounds is related to their ability to inhibit replication of the HIV virus, can be illustrated using the test virus replication, which directly measure the ongoing HIV replication of wild-type virus in MT4 cells specific interaction of HIV-tat with LTR sequence connected with GFP (MT4-LTR-EGFP cells). Using the test virus replication, cited above, found that these compounds inhibit the replication of viruses that are resistant to the compounds inhibiting reverse transcriptase, compounds which inhibit the protease, or compounds inhibiting both (so-called viruses multidrug-resistant).

As for the mechanism of action by which these compounds inhibit viral replication, the measurement time is the new addition was shown to that these compounds inhibit the initial phase of the viral replication. Experiments on determination of time adding allow you to understand at what point in time the test compound inhibits viral replication in the cellular environment. In particular, the tested compounds of the present invention was added with different time intervals to MT4 cells infected with HIV-1 expressing the reporter gene of HIV-1 LTR-luciferase (MT4-LTR-Luc) or MT4 cells expressing HTV-1-LTR-EGFP reporter gene (MT4-LTR-EGFP). The first addition of the test compounds (first time point) occurred 30 minutes after the synchronization of the virus.

Moreover, it was found that these compounds have negligible activity or did not find activity in reporter test on the introduction of the virus (ERA), which measure the inhibition of fusion between cells of the cell line, stably expressing HIV (effector cell line), and a cell line expressing CD4 and CXCR4 (cell line target)containing LTR-EGFP, using as a reader laser analyzer cells (FACS).

Test for toxicity, in which reduced expression of the GFP reporter protein (MT4-CMV-EGFP cells) serves as a marker of cell toxicity of the tested compounds, can be used to assess the toxicity of n is standing connections.

Generally speaking, the compounds of the present invention can be obtained by the sequence of reactions for the synthesis depicted in scheme 1.

Scheme 1

In scheme 1, the intermediate of formula 1.2 can be obtained by a combination of an amine of the formula NH(R1)(R2) and benzoic acid of the formula 1.1. This reaction can be performed in such an appropriate inert to the reaction solvent as acetonitrile, dichloromethane, tetrahydrofuran or any other solvent which dissolves the reactants, in the presence of a binding agent, such as EDCI (ethyldimethylammonium) and HOBt (hydroxybenzotriazole) or their functional equivalent. The intermediates of formula 1.2 can then be subjected to condensation with salicylic aldehyde of formula 1.3, in the presence of an appropriate base such as an inorganic base, such as potassium hydroxide or sodium hydroxide in an appropriate solvent system, such as, for example, a mixture of alcohol and water, for example a mixture of ethanol and water. Or can be used such organic base, as pyrrolidin in an appropriate solvent such as tetrahydrofuran or dichloromethane. Variable “PG” in the intermediate 1.3 means a protective group for a hydroxy-group, such as methoxymethyl, tert-butoxy the Tyl, tetrahydropyranyl or methoxyethoxymethyl (MEM). The best yields were observed when using protected salicylic aldehydes of formula 1.3. Particularly suitable protective group is, for example, MEM. Scheme 2 shows the reaction procedure of obtaining the intermediate of formula 1.3, where the protecting group is MEM. The intermediate obtained in the above condensation reaction, is Halcon formula 1.4 (also described in J. Med. Chem, 2000, 43, 4868-4876). The protective group can be removed from a secure chalcone formula 1.4, in acidic medium, for example, using hydrochloric acid in an appropriate solvent, such as, for example, tetrahydrofuran, dichloromethane or an alcohol, thereby obtaining the intermediate of formula 1.5. Then intermediate 1.5 can be subjected to interaction with hydrazine in an appropriate mixing with the water solvent, such as dioxane, toluene or an alcohol such as ethanol, to obtain dihydropyrazolo formula 1.6 (J. Ind. Chem. Soc, 1989, 66, 893-896). The compound of formula (1) can then be obtained through a combination of dihydropyrazolo formula 1.6 with the corresponding glyoxal formula 1.7 in an appropriate solvent, such as toluene or dioxane, in the presence of catalytic amount of acid, such as para-toluensulfonate.

Scheme 2

The preparation is t of the intermediate of formula 1.3 with MEM as a protective group can be obtained by the interaction of salicylic aldehyde 2.1, which is commercially available, with harmacokinetics, in the presence of a base such as sodium hydride or potassium hydride, in the presence of a suitable solvent, such as N,N-dimethylformamide or tetrahydrofuran.

Scheme 3

Getting glyoxal of formula 1.7 can be done on the basis of the intermediate of formula 3.1, method or similar method described in J. Het. Chem. 1987, 24, 441-451. In more detail, acetyl formula 3.1 can be oxidized to glyoxal of formula 1.7 in a solvent such as dioxane, using as oxidizing agent, the oxide of selenium.

The compounds of formula (I) can also be obtained through the sequence of reactions for the synthesis depicted in scheme 4.

Scheme 4

According to scheme 4, the intermediate of formula 4.1 can be subjected to condensation with salicylic aldehyde of formula 4.2, in the presence of such a suitable base, inorganic base such as potassium hydroxide or sodium hydroxide, in such an appropriate solvent system, such as alcohol or mixture of alcohol and water, for example a mixture of ethanol and water. This condensation leads to the release of chalcone formula 4.3. This Halcon formula 4.3 can then be subjected to interaction with hydrazine in such a suitable mixing with the water solvent, for example, as dioxane, toluene or an alcohol such as ethanol, to obtain dihydropyrazol formula 4.4. The intermediates of formula 4.5 can be obtained by a combination of dihydropyrazolo formula 4.4 with the corresponding glyoxal 1.7 in a suitable solvent, such as toluene, N,N-dimethylformamide or dioxane, in the presence of catalytic amount of acid such as para-toluensulfonate. Then benzoic acid of formula 4.5 can be subjected to reaction combination with an amine of the formula NH(R1)(R2) in an appropriate inert to this reaction, a solvent such as acetonitrile, dichloromethane, tetrahydrofuran or any other solvent which dissolves the reactants, in the presence of such binding agent, such as EDCI and HOBt, or their functional equivalent, to obtain the compounds of formula (I).

In the methods of manufacturing described above, the reaction products can be separated from the reaction medium and then, if necessary, further purified according to methods widely known in this field, such as extraction, crystallization, distillation, grinding into powder and chromatography.

The compounds of formula (I)obtained by the methods described above in the present description, can be synthesized as a mixture of stereoisomeric forms, in particular in the form of racemic mixtures of enantiomers which m is able to be separated from one another, following well-known in the field methods of separation. Racemic compounds of the formula (I) can be converted into the appropriate form diastereomeric salts by reaction with an appropriate chiral acid. These form the diastereomeric salts are then separated, for example, selective or fractional crystallization, and the enantiomers separated with alkali. An alternative way of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. These pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting compounds, provided that the flowing reaction stereospetsifichno. If you want a specific stereoisomer, preferably, the specified connection was synthesized stereospecifically methods of getting. These methods are mainly used enantiomerically pure source materials.

Thus, the compounds of the present invention can be used in animals, preferably mammals, and in particular to humans as pharmaceuticals, by themselves, in mixtures with one another or in the form of pharmaceutical preparations.

Moreover, the present invention relates to the pharmaceutical is a mini-drugs, which contain as active ingredients parts of an effective dose of at least one of the compounds of formula (I), in addition to the customary pharmaceutically innocuous excipients and auxiliary agents. Typically, the pharmaceutical preparations contain from 0.1 to 90 wt.%. this compound. The pharmaceutical preparations can be obtained in a manner that is itself known to professionals in this field. For this purpose, at least one compound of the present invention, together with one or more solid or liquid pharmaceutical excipients and/or auxiliary means, and, if necessary, in combination with other pharmaceutically active compounds, transferred to suitable for administration form or dosage form which can then be used as a pharmaceutical in human medicine or veterinary medicine.

Pharmaceutical preparations which contain the compound according to the invention can be administered orally, parenterally, for example intravenously, rectally, by inhalation, or topically; the preferred route of administration depends on the individual case, for example, a particular flow violations subject to treatment. Oral introduction is preferred.

On the basis of their special knowledge of professional this area knows auxiliary means, which is suitable for the desired pharmaceutical preparation. In addition to solvents, gel-forming agents, bases for suppositories, tablet auxiliaries and other active carriers compounds used as antioxidants, dispersing agents, emulsifiers, protivovspenivayushchie substances, corrigentov, preservatives, soljubilizatory, agents for achieving a depot effect, buffer substances or dyes.

Compounds of the present invention may also find application in the inhibition of the samples, ex vivo, containing HIV or who is believed to be exposed to HIV. Therefore, these compounds may be used for inhibition of HIV present in the sample of body fluids, which contains or believe that contains HIV or exposed to HIV.

As a drug may also be used in combination antiretroviral compounds and compounds of the present invention. Thus, the present invention relates also to a product containing (a) compound of the present invention and (b) another antiretroviral compound, in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of retroviral infections. Thus, in order l is given or to fight HIV infections, or infection and disease associated with HIV infections, such as acquired immunodeficiency syndrome (AIDS) or AIDS-associated complex (ARC), the compounds of this invention can be put together in combination, for example, such inhibitors binding, as, for example, extrasolar, suramin, polyanion, soluble CD4, an agent that binds gpl20, such as BMS378806, anti-CD4 Ab compounds such as PRO-542 or TNX-355; inhibitors of the merger, such as, for example, T20, T1249, inhibitors, binding to receptors such as, for example, AK-602, SCH-C, SCH-D, AMD 3100 (Bellamy), AMD-070, 779, 220, UK-427-857, PRO-140; RT inhibitors (reverse transcriptase inhibitors), such as, for example, foscarnet and prodrugs; nucleoside RTIs, such as, for example, AZT, 3TC, DDC, DDI, D4T, abacavir, FTC, FTC, DAPD, the dOTC; the nucleotide RTIs, such as, for example, PMEA, PMPA, tenofovir; NNRTIs, such as nevirapine, delavirdine, efavirenz, teveren, lowered, etravirine, dapivirine, R278474, MKC-442, UC 781, capravirine (Capravirine), DPC-961, DPC963, DPC082, DPC083, calanolide A, SJ-3366, TSAO, 4”-diaminononane TSAO; inhibitors of RNase H, such as, for example, SP1093V, PD126338; TAT inhibitors, such as, for example, RO-5-3335, K12, K37; integrase inhibitors, such as, for example, L 708906, L 731988; protease inhibitors, such as, for example, darunavir, APV ritonavir, nelfinavir, shinaver, indina is Il, lopinavir, latinovic, ATV, BMS 186316, DPC 681, DPC 684, tipranavir, AG1776, DMP 450, L 756425, PD178390, PNU 140135; inhibitors of glycosylation, such as, for example, castanospermine, deoxynojirimycin.

Of particular interest are products containing (i) a compound of formula (I) and (ii) darunavir, and (iii) ritonavir as a combined preparation for simultaneous, separate or sequential use in the treatment of retroviral infections.

Of particular interest are products containing (i) a compound of formula (I) and (ii) etravirine, as a combined preparation for simultaneous, separate or sequential use in the treatment of retroviral infections.

Of particular interest are products containing (i) a compound of formula (I) and (ii) dapivirine, as a combined preparation for simultaneous, separate or sequential use in the treatment of retroviral infections.

Of particular interest are products containing (i) a compound of formula (I) and R278474 in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of retroviral infections.

To reduce the intensity of symptoms of the disease, HIV infection, or delete the infection and its symptoms compounds of the present invention can also be introduced in combination is immunomodulators (e.g., bropirimine, antibodies to human alpha-interferon, IL-2, mentionedearlier, interferon alpha, and naltrexone) or antibiotics (for example, pentanedinitrile).

For forms of oral administration of compounds of the present invention is mixed with appropriate additives, such as excipients, stabilizers or inert diluents, and using conventional methods result in such forms suitable for administration, such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions. Examples of suitable inert carriers are Arabian gum, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, the drug may be in the form of both dry and wet granules. Suitable oily excipients or solvents are vegetable or animal fat, such as sunflower oil or cod-liver oil. Suitable solvents for aqueous or alcohol solutions are water, ethanol, sugar solutions, or mixtures thereof. For other forms of introduction as additional auxiliary means applies the glycols and polypropylenglycol.

For subcutaneous or intravenous administration, the active connection is transferred into a solution, suspension, or emulsion, if desired, instead of the ones with such common substances as soljubilizatory, emulsifiers or other assistive technology. The compounds may be subjected to lyophilization, and the resulting lyophilizate use, for example, to obtain drugs for injection and infusion. Suitable solvents are, for example, water, saline solution or alcohols, e.g. ethanol, propanol, glycerol, and, in addition, sugar solutions such as glucose or mannitol, or various mixtures of these solvents.

Suitable pharmaceutical preparations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of these compounds or their physiologically acceptable salt in a pharmaceutically acceptable solvent such as ethanol or water, or a mixture of these solvents. If necessary, the product may also contain other pharmaceutical AIDS such as surfactants, emulsifiers and stabilizers, as well as the propellant. This product usually contains the active compound in concentrations of from about 0.1 to 50%, in particular from about 0.3 to 3 wt.%.

In order to increase the solubility and/or stability of the compounds in pharmaceutical compositions, it can be useful the use of α-, β - or γ-cyclodextrins or their proizvoditelja such co-solvents, as the alcohols can improve the solubility and/or stability of the compounds in pharmaceutical compositions. When receiving water compositions additive salts of the considered compounds, due to their better solubility in water, obviously, are more suitable.

Appropriate cyclodextrins are α-, β - or γ-cyclodextrins (CDs) or ethers or mixed ethers in which one or more hydroxyl groups of the structural units of glucose residues cyclodextrin substituted by alkyl, in particular, stands, ethyl or isopropyl, e.g. randomly methylated β-CD; hydroxyalkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxylation, in particular, carboxymethyl or carboxyethyl; alkylcarboxylic, in particular, acetyl; allyloxycarbonyl or carboxymethyloxyamino, in particular, carboxyphenoxypropane or carboxitherapy; alkylcarboxylic, in particular, 2-acetylaminophenol. Especially noteworthy as complexing agents and/or soljubilizatory β-CD, randomly methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and (2-carboxymethoxy)-propyl-β-CD, and in particular 2-hydroxypropyl-β-CD (2-HP-β-CD).

The term "simple mixed ether" denotes a derivative of a cyclodextrin in which, at least two of the hydroxy-group of the cyclodextrin tarifitsirovana different groups, such as, for example, hydroxypropyl and hydroxyethyl.

Interesting way of forming combinations of the present compounds with cyclodextrin or its derivatives has been described in EP-A-721331. Although described therein drugs contain active antifungal ingredients, they are equally interesting for the development of compounds according to the present invention. The preparations described therein, in particular, suitable for oral administration and contain the active antifungal ingredient, a sufficient amount of cyclodextrin or its derivative as a solubilizer, water acidic environment as the volume of a liquid medium and an alcohol co-solvent, greatly facilitating access to the composition. In addition, these drugs adding sweeteners and/or corrigentov, pharmaceutically acceptable, can be made more pleasant.

Other handy ways to increase the solubility of the compounds of the present invention in pharmaceutical compositions is described in WO94/05263, PCT application No. PCT/EP98/01773, EP-A-499299 and WO 97/44014, which are all put into this document by reference.

In more detail, the present compounds can be formulated in a pharmaceutical composition comprising a therapeutically effective quantity is of particles, consisting of a solid dispersion containing (a) compound of the present invention and (b) one or more pharmaceutically acceptable water-soluble polymers.

The term “solid dispersion” defines a system in a solid state (as opposed to liquid or gaseous state), containing at least two components, where one component is dispersed more or less evenly by another component or components. When the specified variance of the components is such that the system throughout is chemically and physically uniform or homogenous or consists of one phase, as it is defined in thermodynamics, such a solid dispersion is defined as "solid solution". Solid solutions are preferred physical systems, because their components are usually readily bioavailable to organisms in which they entered.

The term “solid dispersion” also includes dispersion, which throughout less homogeneous than solid solutions. Such dispersions are not all over chemically and physically homogeneous and contain more than one phase.

Conveniently, when a water-soluble polymer in the form of particles is a polymer that has an apparent viscosity of 1 to 100 MPa·s when dissolved in 2% aqueous solution when the temperature is e dissolution, component 20°C.

Preferred water-soluble polymers are hydroxypropylmethylcellulose or HPMC. HPMC, having a degree of methoxyamine constituting from about 0.8 to about 2.5 molar rate of substitution by hydroxypropyl, comprising from about 0.05 to about 3,0, usually soluble in water. The term "degree of methoxyamine" denotes the average number of groups of simple methyl ester per one glucose residue of a molecule of cellulose. The term "molar rate of substitution by hydroxypropyl" denotes the average number of moles of propylene oxide, which interacts with each glucose residue of the cellulose molecules.

Particles defined above in the present description, can be obtained first in the form of a solid dispersion of the components, and then an optional grinding or crushing of this dispersion. There are different methods of producing solid dispersions, including extrusion from the melt, spray drying and evaporation of the solution.

Additionally, it may be convenient to form the present compound in the form of nanoparticles on the surface are adsorbed to the surface modifier in an amount sufficient to maintain an effective average particle size average of less than 1000 nm. Considered acceptable m is defecatory surface include such modifiers, physically sticking to the surface of the antiretroviral agent is not associated with antiretroviral agent chemically.

Acceptable surface modifiers, preferably, can be selected from known organic and inorganic pharmaceutical excipients. Such fillers include various polymers, oligomers of low molecular weight, natural compounds and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

However, another interesting way of formation of these compounds includes a pharmaceutical composition, with which the compounds according to this invention is introduced into hydrophilic polymers, and this mixture is applied as a covering film on many small balls, thereby obtaining a composition having good bioavailability, which can be easily obtained and which is suitable for the production of pharmaceutical dosage forms for oral administration.

These balls contain (a) located in a Central, rounded or spherical core, (b) covering the film of hydrophilic polymer and an antiretroviral agent and (c) tightly covering polymer layer.

Substances suitable for use as the e core balls, varied, provided that these substances are pharmaceutically acceptable and have the correct size and strength. Examples of such substances are polymers, inorganic substances, organic substances and sugars and their derivatives.

Another aspect of the present invention relates to a collection or container containing the compound of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit the implementation of the HIV virus, HIV, or both. This aspect of the invention may find application in pharmaceutical research programs.

The dose of these compounds or their physiologically acceptable salt(s), which is injected depends on the individual case, and, as usual, it should be adapted, for optimum effect, the conditions in the individual case of the disease. Thus, it is, of course, depends on the frequency of administration and the effectiveness and duration of action of the compounds used in each case for therapy or prophylaxis; but it also depends on the nature and severity of the infection and symptoms of the disease, gender, age, weight and individual perceived is mcepaste person or animal, subject to treatment, as well as on whether the management of acute or preventive. Usually, the daily dose of a compound of the present invention when administered to a patient weighing approximately component 75 kg, is in the range between 1 mg and 5 g, preferably between 10 mg and 2 g, more preferably, between 20 mg and 1 g Dose may be entered as a single dose or can be divided into several, for example two, three, four, or even more separate doses.

Experimental part

EXAMPLE 1. Synthesis of 4-[5-(4-cyanobenzoyl)-1,10b-dihydro-5H-pyrazolo[1,5-c] [1,3]benzoxazin-2-yl]-N-cyclopentylamine, in accordance with scheme 1 (compound 44)

Synthesis of 4-acetyl-N-cyclopentylamine 1.2.a

A mixture of 4-acetylbenzoic acid 1.1.a (10 mmol), cyclopentylamine (11 mmol), EDCI (11 mmol) and HOBt (2 mmol) in CH2Cl2(100 ml) was stirred at room temperature for 20 hours. To the obtained reaction mixture was added water, and the organic layer was separated. The aqueous layer three times was extracted with dichloromethane. The combined organic layers were dried over MgSO4, was filtered, and the solvent evaporated to dryness. The residue was purified column chromatography over silica gel (eluent: CH2Cl2/methanol: 95/5). Pure fractions were collected and the solvent evaporated, receiving 90% of the product 1.2.a.

Synthesis of 2-(2-methoxyethoxy the toxi)benzaldehyde 1.3.a

Intermediate 2.1 (20 mmol) was dissolved in N,N-dimethylformamide (150 ml). The resulting mixture was cooled to 0°C. was Added sodium hydride (30 mmol)and the mixture was stirred at room temperature for 1 hour, and added harmacokinetics (20 mol). The mixture was stirred at room temperature for 16 hours. Was added water (200 ml)and the mixture was extracted with dichloromethane. The organic layer was separated, dried over MgSO4), filtered, and the solvent evaporated to dryness. The residue was purified on silica gel using dichloromethane as eluent. The solvent was removed to obtain a connection 1.3.a with the release of 95%.

Synthesis of N-cyclopentyl-4-{3-[2-(2-methoxyethoxyethoxy) phenyl]acryloyl}benzamide 1.4.a

Intermediate 1.2.a (5 mmol) was dissolved in ethanol (100 ml) and then added intermediate 1.3.a (5 mmol). The mixture was stirred at room temperature and was added dropwise a solution of potassium hydroxide (10 mmol) in water (50 ml). The mixture was heated up to 80°C for 12 hours. After cooling to room temperature the solution was added ammonium chloride (50 ml), and ethanol was removed and replaced by ethyl acetate. The mixture was extracted with ethyl acetate and dried with magnesium sulfate. Removal of solvent and purification on silica gel using CH2Cl2and methanol, used as eluent resulted in the receipt of product 1.4.a (70%) in the form of oil.

Synthesis of N-Cyclopentyl-4-[3-(2-hydroxyphenyl)acryloyl] benzamide 1.5.a

Intermediate 1.4.a (5 mmol) was dissolved in tetrahydrofuran (100 ml) and was added dropwise a solution of hydrochloric acid (2 molar). The mixture was stirred at room temperature overnight. Was added water (100 ml)and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried by magnesium sulfate, and the solvent evaporated to dryness, obtaining intermediate 1.5.a (80 %) in powder form.

Synthesis of N-cyclopentyl-4-[5-(2-hydroxyphenyl)-4,5-dihydro-1H-pyrazole-3-yl]benzamide 1.6.a

Intermediate 1.5.a (4 mmol) was dissolved in ethanol (100 ml). To the reaction mixture was added dropwise hydrazine (4.4 mmol). The mixture was then stirred at 70°C for 4 hours. After cooling to room temperature the mixture was filtered, receiving the intermediate 1.6.a in the form of a white powder (90%).

Synthesis of 4-(2-oxoacyl)benzonitrile 1.7.a

To a mixture of dioxane (75 ml) and water (7.5 ml)was added selenium oxide (100 mmol). The mixture was stirred at 50°C to dissolve the oxide of selenium. Then was added para-cyanoacetate (100 mmol). The mixture was stirred at 90°C for 12 hours. The warm solution was filtered and the solvent was removed. The obtained residue was dissolved in dichloromethane and added water. The organic layer was separated, dried over magnesium sulfate, and the solvent was removed, the receiving interm is diat 1.7.a in the form of a solid (85%).

Synthesis of compound 44

Intermediate 1.6.a (4 mmol) was dissolved in toluene (50 ml), then was added intermediate 1.7.a (4.4 mmol) and para-toluensulfonate (5%). The reaction mixture is boiled in a flask under reflux for 8 hours. After cooling to room temperature, added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried by magnesium sulfate, filtered, and the solvent evaporated to dryness. The residue was purified column chromatography over silica gel (eluent: CH2Cl2/methanol: 95/5). Fractions of product were collected, and the solvent evaporated, receiving 85% of compound 44.

EXAMPLE 2. Synthesis of 4-[5-(4-cyanobenzoyl)-1,10b-dihydro-5H-pyrazolo[1,5-c] [1,3]benzoxazin-2-yl]-N-cyclopentylamine, in accordance with scheme 4 (compound 44)

Synthesis of 4-[3-(2-hydroxyphenyl)acryloyl]benzoic acid 4.3.a

Method A. 4-acetylbenzoic acid 4.1.a (10 mmol) was dissolved in ethanol (100 ml) and then added salicylic aldehyde (10 mmol). The mixture was stirred at room temperature and was added dropwise a solution of potassium hydroxide (50 mmol) in water (30 ml). The mixture was heated up to 80°C for 12 hours. After cooling to room temperature was added water (100 ml), and ethanol was removed and replaced by ethyl acetate. The mixture was acidified to pH 4 by adding an aqueous solution of hydrochloric acid. Reacciona the mixture was then extracted with ethyl acetate, and the organic layer was dried with magnesium sulfate. The solvent is evaporated, and the residue was purified column chromatography on silica gel (eluent: CH2Cl2/methanol: 80/20)to give the intermediate of 4.3.a in the form of a white powder (20%).

Method C. 4-acetylbenzoic acid 4.1.a (10 mmol) was dissolved in tetrahydrofuran (100 ml) and then added salicylic aldehyde 4.2 (10 mmol). The mixture was stirred at room temperature, and was added dropwise pyrrolidine (20 mmol). The mixture was heated up to 80°C for 12 hours. After cooling to room temperature was added water (100 ml) and ethyl acetate (100 ml). The mixture was extracted with ethyl acetate and dried with magnesium sulfate. The solvent is evaporated, and the residue was purified column chromatography on silica gel (eluent: CH2Cl2/Meon: 80/20)to give the intermediate of 4.3.a in the form of a white powder (35%).

Synthesis of 4-[5-(2-hydroxyphenyl)-4,5-dihydro-1H-pyrazole-3-yl]benzoic acid 4.4.a

Intermediate 4.3.a (33 mmol) was dissolved in ethanol (150 ml) and was added dropwise hydrazine (134 mmol). The mixture was stirred at 70°C for 4 hours. After cooling to room temperature the mixture was filtered, receiving the intermediate 4.4.a in the form of a white powder (90%).

Synthesis of 4-[5-(4-cyanobenzoyl)1,10b-dihydro-5H-pyrazolo[1,5-c][1,3] benzoxazin-2-yl]benzoic acid 4.5.a

Intermediate 4.4.a (5 mmol) was dissolved in toluene (50 ml), the eat was added intermediate 1.7.a (6 mmol) and para-toluensulfonate (5%). The mixture was boiled in a flask with reflux for 8 hours. After cooling to room temperature, added water, and the mixture was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and the solvent was removed. The residue was purified on silica gel using CH2Cl2and methanol as eluent, obtaining intermediate 4.5.a in the form of a powder (81%).

Synthesis of compound 44

Carboxylic acid 4.5.a (2.4 mmol) was dissolved in tetrahydrofuran (20 ml). Then was added EDCI (2,64 mmol) and HOBT (10%). The mixture was stirred 10 minutes at room temperature and was added cyclopentylamine (2,64 mmol). Then the mixture was stirred at room temperature overnight. Was added water, and the mixture was extracted with ethyl acetate, dried with magnesium sulfate, and the solvent was removed. The crude residue was purified column chromatography on silica gel using dichloromethane and methanol as eluent, receiving the connection 44 in the form of a powder (82%).

The compounds listed in the tables below were obtained analogously to the methods described in examples 1 or 2.

Table 1

Table 2

EXAMPLE 3. Virological properties of the compounds according to the present invention

Antiviral activity of compounds was determined using cell test MT4-LTR-EGFP cells. The test showed that these compounds find strong anti-HIV activity against laboratory HIV strain (HIV-1 strain LAI) and HIV-1 virus (HIV-1-MDR), multidrug-resistant. Cell test was carried out in accordance with the following method.

HIV-positive or false-infected MT4-LTR-EGFP cells were incubated for three days in the presence of different concentrations of inhibitor. During infection with GFP reporter is activated by the viral tat protein. At the end of the incubation period was estimated level of GFP. In samples of virus control (in the absence of any inhibitor) received the maximum fluorescence level. Inhibitory activity of the compounds was observed in virus infected cells and was expressed as EC50and EC90. These values represent the number of connections required for protection against viral infections, respectively 50% and 90% of the cells. The toxicity of the compounds was measured on false-infection is different cells and expressed as CC 50that represents the concentration of compound required to inhibit cell growth by 50%. Index selectivity (SI) (ratio CC50/EC50) is an indicator of the selectivity of the anti-HIV activity inhibitor.

td align="center"> 17 In
Table 3
Compounds having the value of pEC50(which is defined as the negative logarithm of the expression EC50exceeding 6 belong to the class of activity A. Compounds having the value of pEC50greater than or equal to 5 but less than or equal to 6, belong to the class of activity B. Compounds having the value of pEC50smaller than 5, belong to the class activity With. For some compounds of the present invention, carried out several tests. In this case, to determine the activity classes used the average value of EC50. An empty cell in table 3 indicates that no data
The connection numberClass activity when tested on HTV-1-LAIClass activity when tested on HTV-1-MDR
1In
2
3
4In
5And
6And
7In
8
9And
10
11
12In
13In
14
15
16
And
18And
19In
20InIn
21
22And
23
24InIn
25InIn
26InIn
27AndAnd
28AndAnd
29InAnd
30
31In
32In
33AndAnd
34In
35And
36And
37In
38AndIn
39*AndIn
40In
41In
42In
43In
44AndAnd
45AndAnd
46 AndAnd
47AndAnd
48InIn
49
50AndAnd
51And
52AndAnd
53AndAnd
54InIn
55AndAnd
58AndAnd

EXAMPLE 4. The measurement of time adding

MT4-LTR-EGFP or MT4-LTR-Luc cells were infected multiple infection (MOI) by centrifugation for 10 min at 1200g. Free virus was removed with two-stage wash at 4°C to synchronize the infection. After 30 minutes after infection under test connect the tion was added at different times in parallel cultures in microtitration tablets. In the case of MT4-LTR-EGFP cells, fluorescence in cultures was evaluated under the microscope 24 hours after infection and collected the supernatant (supernatant). HIV replication was assessed quantitatively in samples of the supernatant liquid by measuring the concentration of viral antigen p24, when using the purchase of a set, in accordance with the Protocol for its use (NEN). Because of the high MOI used in this type of experiments, the concentrations of inhibitors were not less than 100 times higher than their value EC50within the scan cell test. In the case of MT4-LTR-Luc cells, HIV inhibitors with a concentration that meets

EC90was added at different time intervals to HIV-1 infected MT4 cells expressing the HIV-1 LTR-luciferase reporter gene. HIV-1 infection find, determining the luciferase. After 24 hours of incubation, was added to the luciferase substrate and measured the level of chemiluminescence. In those time points where compounds were detected activity, the level of luciferase was reduced.

Compounds of the present invention, which were tested, inhibited viral replication earlier than three hours after synchronization.

Example 5. The pharmaceutical composition

Capsules

The active ingredient, in casu, the compound of formula (I)dissolved in an organic solvent, such as ethanol, methane is or methylene chloride, preferably a mixture of ethanol and methylene chloride. Such polymers as copolymers of polyvinylpyrrolidone with vinyl acetate (PVP-VA) or hypromellose (HPMC), usually 5 MPa·s, is dissolved in such organic solvents as ethanol, methanol, methylene chloride. Acceptable, when the polymer is dissolved in ethanol. The polymer solutions and compounds are mixed and then dried by spray drying. The ratio of compound/polymer chosen in the range from 1/1 to 1/6. For the intermediate, this interval is from 1/1,5 to 1/3. A suitable ratio is the ratio of 1/6. Dried spray dried powder, the solid dispersion is then filled capsules, intended for insertion into the body. Download drug one capsule is, depending on the size of the used capsules, from 50 to 100 mg.

Tablets, film-coated

GETTING the CENTRAL PART TABLET

A mixture of 100 g of the active ingredient, in casu, the compounds of formula (I), 570 g lactose and 200 g starch mix well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. Wet powder mixture was sieved, dried and again sieved. Then was added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All was well mixed and extruded in the tabletki, getting 10,000 tablets, each tablet contained 10 mg of the active ingredient.

SHELL

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The last solution is added to the previous one and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated suspensions of the dye, and the whole homogenized. The Central part of the tablets covered with a mixture thus obtained, a special apparatus for cover.

1. Derivatives of 1,10b-dihydro-2-(aminocarbonylmethyl)-5H-pyrazolo[1,5-c][1,3]benzoxazin-5-yl)phenylmethanone having the formula

his or their salt
where "a" takes on the values zero, 1;
R1represents hydrogen, C1-10alkyl, C2-10alkenyl or1-10alkyl, substituted Deputy selected from the group consisting of amino and mono-or disubstituted amino, where the amino substituents each individually selected from C1-10of alkyl;
R2represents a C1-10alkyl, C3-12cycloalkyl, pyridinyl, piperidinyl, phenyl, substituted by the Deputy, is selected from C1-10alkyloxy, disubstituted aminor PPI, With1-10alkyl, substituted Deputy selected from pyridinyl, tetrahydrofuranyl, teinila, furanyl, pyrrolyl,3-12cycloalkyl, phenyl, substituted Deputy selected from C1-10alkyloxy, halogen;
R1and R2together with the nitrogen atom to which they are attached, form homopiperazin, 1,2,3,4-tetrahydroisoquinoline, piperazinil, substituted C1-10the alkyl, C1-10allyloxycarbonyl;
R3represents halogen, nitro, C1-10alkyl, C3-12cycloalkyl, polyhalo1-10alkyl, cyano, amino, mono - or disubstituted With1-10alkyloxy,1-10alkylthio,1-10alkylsulfonyl, piperidinyl, morpholinyl.

2. The compound according to claim 1, in which R1represents a C1-10alkyl, C2-10alkenyl or1-10alkyl, substituted Deputy selected from the group consisting of amino and mono - or disubstituted amino, where the amino substituents each individually selected from C1-10of alkyl;
R2represents a C1-10alkyl, C3-12cycloalkyl, pyridinyl, piperidinyl, phenyl, substituted by the Deputy, is selected from C1-10alkyloxy, disubstituted amino, C1-10alkyl, substituted Deputy selected from pyridinyl, tetrahydrofuranyl, teinila, furanyl, pyrrolyl,3-12cycloalkyl, phenyl, substituted for what estealam selected from C 1-10alkyloxy, halogen;
R1and R2together with the nitrogen atom to which they are attached, form homopiperazin, 1,2,3,4-tetrahydroisoquinoline, piperazinil, substituted C1-10the alkyl, C1-10allyloxycarbonyl.

3. The compound according to claim 1, in which R3represents halogen, nitro, C1-10alkyl, C3-12cycloalkyl, polyhalo1-10alkyl, cyano, C1-10alkylthio,1-10alkylsulfonyl, piperidinyl, morpholinyl.

4. The compound according to claim 1, where the compound has the formula

5. The compound according to claim 4, where "a" takes on the values zero or 1;
R1represents hydrogen, C1-10alkyl, C2-10alkenyl or1-10alkyl, substituted Deputy selected from the group consisting of amino and mono - or disubstituted amino, where the amino substituents each individually selected from C1-10of alkyl;
R2represents a C1-10alkyl, C3-12cycloalkyl, pyridinyl, piperidinyl, phenyl, substituted by the Deputy, is selected from C1-10alkyloxy, disubstituted amino, C1-10alkyl, substituted Deputy selected from pyridinyl, tetrahydrofuranyl, teinila, furanyl, pyrrolyl,3-12cycloalkyl, phenyl, substituted Deputy selected from C1-10alkyloxy, halogen;
R1and R2together with ATO is ω nitrogen, to which they are attached, form homopiperazin, 1,2,3,4-tetrahydroisoquinoline, piperazinil, substituted C1-10the alkyl, C1-10allyloxycarbonyl;
R3represents halogen, nitro, C1-10alkyl, C3-12cycloalkyl, polyhalo1-10alkyl, cyano, amino, mono - or disubstituted With1-10alkyloxy,1-10alkylthio,1-10alkylsulfonyl, piperidinyl, morpholinyl.

6. Connection by claims 4 and 5, in which "a" takes on the values zero or 1;
R1represents hydrogen, C1-10alkyl, C2-10alkenyl or1-10alkyl, substituted Deputy selected from the group consisting of amino and mono - or disubstituted amino, where the amino substituents each individually selected from C1-10of alkyl;
R2represents a C1-10alkyl; or
R1and R2together with the nitrogen atom to which they are attached, form homopiperazin, 1,2,3,4-tetrahydroisoquinoline, piperazinil, substituted C1-10the alkyl, C1-10allyloxycarbonyl;
R3represents halogen, nitro, C1-10alkyl, C3-12cycloalkyl, polyhalo1-10alkyl, cyano, amino, mono - or disubstituted With1-10alkyloxy,1-10alkylthio, C1-10alkylsulfonyl, piperidinyl, morpholinyl.

7. The compound according to claims 1 or 5, in which
"a" takes the value 1;
R1 represents hydrogen, C1-10alkyl, C2-10alkenyl or1-10alkyl, substituted Deputy selected from the group consisting of amino and mono - or disubstituted amino, where the amino substituents each individually selected from C1-10of alkyl;
R2represents a C1-10alkyl; or
R1and R2together with the nitrogen atom to which they are attached, form homopiperazin, 1,2,3,4-tetrahydroisoquinoline, piperazinil, substituted C1-10the alkyl, C1-10allyloxycarbonyl;
R3represents halogen, nitro, C1-10alkyl, C3-12cycloalkyl, polyhalo1-10alkyl, cyano, amino, mono - or disubstituted With1-10alkyloxy,1-10alkylthio,1-10alkylsulfonyl, piperidinyl, morpholinyl.

8. The compound according to claims 1, 4 or 5 in which "a" has a value of 1, a R3represents halogen, cyano, amino, mono - or disubstituted With1-10alkyloxy,1-10alkylthio,1-10alkylsulfonyl, piperidinyl, morpholinyl.

9. The compound according to claim 1, having the structure:
4-[5-(4-perbenzoic)-1,10b-dihydro-5H-pyrazolo-[1,5-C][1,3]benzoxazin-2-yl]-N-[(4-methoxyphenyl)methyl]-M-methylbenzamide;
4-[5-(4-cyanobenzoyl)-1,10b-dihydro-5H-pyrazolo-[1,5-C][1,3]benzoxazin-2-yl]-N-cyclopentylmethyl;
4-[5-(4-propylbenzoyl)-1,10b-dihydro-5H-pyrazolo-[1,5-C][1,3]benzoxazin-2-yl]-N-cyclopentyl benzamid;
4-[5-(4-methylsulfonylbenzoyl)-1,10b-dihydro-5H-pyrazolo[1,5-C][1,3] benzoxazin-2-yl]-N-cyclopentylmethyl;
4-[5-(4-ethylbenzoyl)-1,10b-dihydro-5H-pyrazolo[1,5-C][1,3]benzoxazin-2-yl]-N-cyclopentylmethyl;
4-[5-(4-tert-butylbenzoyl)-1,10b-dihydro-5H-pyrazolo[1,5-C][1,3]benzoxazin-2-yl]-N-cyclopentylmethyl;
4-[5-(4-nitrobenzoyl)-1,10b-dihydro-5H-pyrazolo[1,5-C][1,3]benzoxazin-2-yl]-N-cyclopentylmethyl;
4-[5-(4-methansulfonate)-1,10b-dihydro-5H-pyrazolo[1,5-C][1,3]benzoxazin-2-yl]-N-cyclopentylmethyl;
4-[5-(4-trifloromethyl)-1,10b-dihydro-5H-pyrazolo[1,5-C][1,3]benzoxazin-2-yl]-N-cyclopentylmethyl.

10. The compound according to any one of claims 1 to 9 as a drug with the ability to inhibit HIV replication.

11. The use of compounds according to any one of claims 1 to 9 to get a medicinal drug used to treat conditions associated with HIV infection.

12. The use of compounds according to any one of claims 1 to 9 when receiving a drug that is suitable for preventing the transmission of HIV, or HIV infection, or preventing diseases associated with HIV infection.

13. Pharmaceutical drug that has the ability to inhibit HIV replication, which contains as active ingredients an effective dose of a compound according to any one of claims 1 to 9, in addition to generally is ATiM pharmaceutically innocuous excipients and auxiliary agents.

14. The compound according to any one of claims 1, 2, 10, in which R3represents halogen, nitro, C1-10alkyl, C3-12cycloalkyl, polyhalo1-10alkyl, cyano, C1-10alkylthio, piperidinyl, morpholinyl.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I with anti-HIV activity , where R1 represents C1-6(Ar1)alkyl or C1-6(Ar1)oxyalkyl; R2 represents hydrogen or OR14; R3 represents hydrogen, halogen, hydroxyl, cyano, C1-6alkyl, C5-7cycloalkenyl, C1-6halogenalkyl, C1-6alkoxy, C1-6alkylthio, N(R8)(R9), NHAr2, N(R6)COR7, OCON(R8)(R9), OCH2CON(R9)(R9), CO2R6, CON(R8)(R9), SOR7, S(=N)R7, SO2R7, SO2N(R6)(R6), PO(OR6)2, C2-4(R12)alkynyl, R13, Ar2 or Ar3; R4 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R5 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R6 represents hydrogen or C1-6alkyl; R7 represents C1-7alkyl; R8 represents hydrogen or C1-6alkyl; R9 represents hydrogen, C1-6alkyl, C1-6hydroxyalkyl or C1-6(C1-6dialkylamino)alkyl; or N(R8)(R9) taken together represent azetidinyl, pyrrolydinyl, (R10)-piperidinyl, N-(R11)-piperazinyl, morpholinyl or dioxothiazinyl; R10 represents hydrogen; R11 represents hydrogen, C1-6alkyl, COR6 or CO2R6 ; R12 represents hydrogen, hydroxyl, N(R6)(R6), OSO2R7 or dioxothiazinyl; R13 represents dioxothiazinyl; R4 represents hydrogen or C1-6alkyl; Ar1 represents ,,,,,,,,; or Ar2 represents tetrazolyl, triazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, furanyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl or indolyl, and is substituted with 0-2 substitutes selected from a group consisting of halogen, benzyl, C1-6alkyl, C1-6alkoxy, N((R8)(R9), CON(R8)(R9) and CO2R8; Ar3 represents phenyl substituted with 0-2 substitutes selected from a group consisting of halogen, cyano, hydroxy, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)methyl, C1-6halogenalkoxy, N(R8)(R9), CON(R6)(R6) and CH2N(R8)(R9), or represents dioxolanylphenyl; and X-Y-Z represents C(R14)2OC(R14)2C(R14)2, C(R14)2OC(R14)2C(R14)2C(R14)2; or pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition.

EFFECT: bicyclic heterocycles are disclosed, as well as their use HIV integrase inhibitors.

21 cl, 38 dwg, 8 tbl, 282 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relates to benzopyran derivatives of formula or

or their pharmaceutically acceptable salts, where R1 and R2 independently represent a hydrogen atom or a C1-6alkyl group, R3 is a hydroxyl group, R4 is a hydrogen atom, m is an integer ranging from 1 to 4, n is an integer ranging from 0 to 4, V is a single bond, CR7R8 or NR9, R5 is a hydrogen atom, R6 is a hydrogen atom, C1-6alkyl group, C3-8cycloalkyl group, C3-8cycloalkenyl group, amino group, C1-6alkylamino group, C6-14aryl group, C2-9heteroaryl group or C2-9heterocyclic group, A is a 5- or 6-member ring condensed with a benzene ring, and the ring can contain an oxygen atom, a nitrogen atom or a sulphur atom numbering from 1 to 3 or separately, or combined, the number of unsaturated bonds in the ring equals 1, 2 or 3, including the unsaturated bond in the condensed benzene ring, carbon atoms in the ring can represent carbonyl or thiocarbonyl.

EFFECT: compounds can be used as antiarrhythmic agents.

47 cl, 1 tbl, 98 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on HsEg5. In formula (I) A is C=O or CH2; B is optionally substituted C1-6alkyl, D is O or N, where O is substituted with one R8, and where N is substituted with one or more R8, R1 and R2 together with the carbon atoms with which they are bonded form optionally substituted isothiazole or isoxazole, condensed with a pyrimidine ring, optionally substituted with a substitute which is C1-6 alkyl. Values of the rest of the radicals are given in the formula of invention.

EFFECT: invention relates to use of disclosed compounds in making medicinal agents with inhibitory effect on HsEg5, to a method of obtaining inhibitory effect on HsEg5, to a pharmaceutical composition which contains the disclosed compound as an active ingredient.

22 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 2,3-dihydro-6-nitroimidazo[2,1-b]oxazol of general formula (1), as well as to their optically active forms and pharmacologically acceptable salts: where values of R1, R2 and n are given in i.1 of invention formula.

EFFECT: development of compounds, which have bactericidal action against Mycobacterium tuberculosis, polyresistant Mycobacterium tuberculosis and can be applied as antituberculosis medication.

3 cl, 16 ex, 183 tbl, 1515 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: novel chemical compounds of formula (I) or their pharmaceutically acceptable salts possess inhibiting activity with respect to kinase p-38 MAP and kinase FGFR, and can be used in treatment of such diseases as arthritis, obstructive lung disease, Alzheimer's disease or oncological and other diseases. In general formula (I) , R1 is hydrogen, R2 is 6-member oxygen-containing heterocyclyl, aryl, selected from unsubstituted phenyl or phenyl substituted with aliphatic acyl group which contains 1-6 carbon atoms, halogen cyano, hydroxyl, C1-6alkylsulfinyl, C1-6alkylsulfonyloxy, C1-6alkylsulfonyl, C1-6alkylsulfanyl, tret-butydimethylsilanyloxy, 6-member heterocyclyl, containing 1-2-heteroatoms, selected from nitrogen and oxygen, R3 is C1-6alkyl, Ar1 is phenyl, substituted with 1-2 substituents, selected from atoms of halogen, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, X1 is oxygen and X2 is chemical bond.

EFFECT: efficient application of invention compounds in pharmaceutical composition.

13 cl, 1 tbl, 64 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relate to oxabispidinic compounds of formula I, ,where R1 is C1-12alkyl (where the given alky group is substituted with a group selected from phenyl, Het1, N(R5a)R6, -OR5c, -S(O)2N(R9b)R9c and -N(R9b)S(O)2R9d); R5a is H; R5c is C1-6alkyl (which is substituted with phenol) or phenyl; R6 is H or -C(O)OR10b; R10b is C1-6alkyl; R9b in each case where it is used in the given description of the invention represents H or C1-6alkyl; R9c and R9d in each case it is used in the given description of the invention independently presents C1-6alkyl (possibly substituted with one or more substitutes, selected from halogen or phenyl), phenyl or Het7, or R9c is H; R2 is H or OR13; R3 is H; R13 is H; Het1 and Het7 independently represent 5-12-member heterocyclic groups containing one or more heteroatoms, selected from oxygen and nitrogen, where these groups are possibly substituted with one or more substitutes selected from halogen and C1-6alkyl; A is a direct bond, -J-, J-S(O)2N(R19b)- or -J-N(R19c)S(O)2- (where in the last two groups -J is bonded to the nitrogen of an oxabispidinic ring); B is Z-{[C(O)]aC(H)(R20a)}b-, -Z-[C(O)]cN(R20b)-, -Z-N(R20c)S(O)2-, -Z-S(O)2N(R20d)-, -Z-S(O)n-, -Z-O- (where in the last six groups Z is bonded to a carbon atom, carrying R2 and R3), -N(R20e)-Z-, -N(R20f)S(O)2-Z-, -S(O)2N(R20g)-Z- or -N(R20h)C(O)O-Z- (where in the last four groups Z is bonded to a phenyl group which is possibly substituted with a R4 group); J is C1-6alkylene, possibly broken by a -S(O)2N(R19d)- or -N(R19e)S(O)2- group and/or possibly substituted with a substitute selected form -OH; Z is a direct bond or C1-4alkylene, possibly broken by a -N(R20i)S(O)2- or -S(O)2N(R20j)- group; a, b and c possibly represent 0 or 1; n is 0, 1 or 2; R19b-R19e in each case where used in the given description of the invention independently represents H or C1-6alkyl; R20a is H or together with the only substitute R4 on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, represents C2-4alkylene, possibly broken or ending with O, N(H) or N(C1-6alkyl) group; R20b is H or C1-6alkyl; R20c-R20j in each case when used in the given description of the invention independently represents H or C1-6alkyl; or R20g and R20i independently represent C1-6alkyl, substituted with 3,5-dimethylisoxazolyl; G is CH; R4 is one or more possible substitutes selected from cyano, halogen, C1-4alkyl and C1-6alkoxy, possibly substituted with one or more hanogen and a R4 substitute on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, together with R20a can represent C2-4alkylene; broken or ending with O or N(H) or a N(C1-6alkyl) group; R41-R46 independently represent H; where each phenyl group is possibly substituted with one or more substitutes selected from halogen, cyano, C1-6alkyl and C1-6alkoxy (where the last two groups are possibly substituted with one or more halogen atoms); or to their pharmaceutically acceptable salts. The invention also relates to methods of producing said compounds, as well as to a pharmaceutical composition based on said compounds, with HERG-channel blocking activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for preventing and treating arrhythmia, particularly cardiac and ventricular arrhythmia.

32 cl, 1 tbl, 15 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to pharmaceutical industry and concerns an antidepressant composition containing medicinal substance based on Azaphen. The composition contains the following components, mg/tbl: Azaphen 155.4-158.7; Metocel 80.0-100.0; Microcrystalline cellulose 98.7-102.0; Aerosil 3.7-14.8; Kollidon 25 3.7-11.1; Talc 5.55-11.1; Magnesium stearate 1.85-3.7.

EFFECT: invention provides production of the pharmaceutical composition with prolonged release of the active pharmaceutical component that allows stabilising concentration of the preparation in a human body within 24 hours and thereby reducing frequency rate of the preparation intake within 24 hours to attain the required therapeutic effect.

2 cl, 3 ex, 1 tbl, 1 dwg

FIELD: medicine.

SUBSTANCE: carboxylic acid compounds are presented by formula (I) where R1 represents (1) hydrogen atom, (2) C1-4alkyl; E represents -CO-; R2 represents (1) halogen atom, (2) C1-6 alkyl, (3) trihalogen methyl; R3 represents (1) halogen atom, (2) C1-6alkyl; R4 represents (1) hydrogen atom; R5 represents (1) C1-6alkyl; represents phenyl; G represents (1) C1-6alkylene; represents 9-12-merous bicyclic heterocycle containing heteroatoms, chosen of 1-4 nitrogen atoms, one or two oxygen atoms; m represents 0 or an integer 1 to 4, n represents 0 or an integer 1 to 4, and i represents 0 or an integer 1 to 11 where R2 can be identical or different provided m is equal to 2 or more, R3 can be identical or different provided n is equal to 2 or more, and R5 can be identical or different provided i is equal to 2 or more; both R12 and R13, independently represent (1) C1-4alkyl, (2) halogen atom, (3) hydroxyl or (4) hydrogen atom, or R12 and R13 together represent (1) oxo or (2) C2-5alkylene and where provided R12 and R13 simultaneously represent hydrogen atom, carboxylic acid compound presented by formula (I), represents a compound chosen from the group including the compounds (1) - (32), listed in cl.1 of the patent claim. Besides the invention concerns a pharmaceutical composition based in the compound of formula I and to application of the compound of formula I for making the pharmaceutical composition.

EFFECT: there are produced new carboxylic acid derivatives with antagonistic activity with respect to DP receptor.

14 cl, 74 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I-a), where R1 and R2, each independently, represent -COORA (where RA is hydrogen or C1-8 alkyl), -CONRBSO2RC (where RB is hydrogen or C1-8 alkyl, RC is C1-8 hydrocarbon), -D-R1 is -CO-(CH2)2-R1, -CO-(CH2)3-R1, -CO-(CH2)4-R1 or C1-4alkylene-R1; E is a bond or C1-4alkylene; ring formula represents a 3,4-dihydro-2H-1,4-benzoxazine or 1H-indole ring; V is , where R110 is hydrogen or C1-8 alkyl, and the arrow shows that it is bonded to ring A; the group with formula is a phenyl group, which can contain a group with formula , where ring 2 is a C5-10 mono- or bicyclic aromatic carbocyclic ring, which can be partially or completely saturated, spirobicyclic carbocyclic ring, or a carbocyclic ring bonded by a bridge bond; where W is -O-CH2-, -O-(CH2)2, -O-(CH2)3, -O-(CH2)4, -O-(CH2)5, -CH2-O, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -O-(CH2)3-O-, -O-(CH2)4-O-, -O-(CH2)5-O-, C1-6 alkylene, its N-oxide, its salt or its solvate. The invention also relates to a pharmaceutical composition based on formula I-a compound and its use.

EFFECT: obtaining new derivatives of benzoxazine and indole, with antagonistic effect on cysLT2 and which are useful for preventing and/or curing respiratory diseases, such as bronchial asthma, chronic obstructive lung diseases.

8 cl, 57 tbl, 261 ex

FIELD: medicine.

SUBSTANCE: neuropathy pain is managed by introducing the compound selectively activating muscarine receptors subtype M(1) however not easing the acute pain.

EFFECT: possibility to manage neuropathy pain without reducing common stimulus sensory ability.

10 cl, 3 ex, 3 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) or to its pharmaceutically acceptable salts or to it solvates, where m is equal 0 to 3, X stands for N, Y stands for -SO2-, each R1 independently stands for halogen, C1-C12alkyl, halogen(C1-C12)alkyl, hydroxy(C1-C6)alkyl, R2 stands for aryl or heteroaryl which represents monocyclic radical containing 5 to 12 atoms in a cycle, including one, two or three nitrogen heteroatoms in a cycle optionally substituted with halogen or cyano, each R3 and R4 independently stands for C1-C12alkyl, or R3 and R4 together with carbon atom whereto they are attached, form the cyclic group containing 3-6 atoms in a cycle, and each R5, R6, R7, R8 and R9 stands for hydrogen. Besides, the invention concerns the pharmaceutical composition.

EFFECT: preparation of the new biologically active compounds with antagonistic action to 5-NT6 receptor.

15 cl, 6 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine and pharmaceutics and concerns combined anti-tuberculosis composition in form of solid medicinal form including as active components riphampicin, levofloxacin, isoniazide, pyrazinamide and pyridoxine hydrochloride.

EFFECT: increased treatment efficiency.

8 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to quinobenzoxazin analogues with general formula (1) where V represents H, halo-, or NR1R2; NH2, or NR1-(CR12)n-NR3R4; A represents H, fluoro-, or NR12; Z represents O, S, NR1 or CH2; U represents NR1R2; X represents NR1R2 or halo-; n=1-6; where in NR1R2, R1 and R2 can form 5-7-member heterocyclic ring which is optionally substituted and has 1-2 heteroatoms, selected from group consisting of N, O and S; R1 represents H or C1-6alkyl; R2 represents C1-10alkyl optionally including one or more non-adjacent heteroatoms N or O and is optionally substituted with if necessary substituted 3-6-member carbocyclic or 5-14-member heterocyclic ring; or R2 is 5-14-member heterocyclic ring, which has 1-2 heteroatoms, selected from group consisting of N, O or S, 6-member aryl or 5-7member heteroaryl ring, which contains 1-3 heteroatoms, selected from group consisting of N, O and S, each of which can be, if necessary, substituted; R3 represents H or C1-6alkyl; R4 represents H, C1-6alkyl, optionally substituted with 3-6 carbocyclic or 5-14-member heterocyclic ring, or 6-member aryl, R4 and R3, if necessary, can form optionally 5-7-member substituted heterocyclic ring, which contains 1-2 heteroatoms selected from N and O; W represents substituent, such as described in i.1 of invention formula, where Q, Q1, Q2, and Q3 represents independently CH or N; Y represents independently O or CH; R5 represents substituent in any position of closed ring in form of H or OR2; on condition that U is not morpholinyl or 2,4-difluoroaniline, when X represents F or pyrrolidinyl, A is F, Z represents O, and W represents phenylene; each obligatorily substituted fragment being substituted with one or more halogen, C1-6-alkoxy, amino, carbamate, C1-10alkyl, C2-10alkenyl, each of which is optionally substituted with halogen, =O, 6-member aryl or one or more heteroatom, selected from N and O; 6-member aryl, 3-6-member carbocyclic ring or 5-7-member heterocyclic ring containing 1-2 heteroatoms, selected from group, consisting of N and O; or its pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition based on formula (1) compound and to method of treatment of proliferative cell diseases using formula (1) compounds.

EFFECT: obtaining novel quinobenzoxazin analogues possessing useful biological properties.

48 cl, 3 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

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

13 cl, 1 tbl, 30 ex

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