Condensed derivative indiana, the retrieval method and the composition having antitumor activity

 

(57) Abstract:

The invention relates to novel condensed derivative indana formula I

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in which A represents an optionally substituted benzene ring, naphthalene ring or benzene ring condensed with the lowest alkylenedioxy; ring B represents an optionally substituted benzene, Y = -N= CR or CR=N-. Derivative indana produced by interaction of derivatives of 6-halogenide [2,1-c] quinoline with an amine or alcohol in the presence or absence of a suitable solvent. The compounds may find use as anticancer agents in pharmaceutical compositions containing a derivative Indiana and a pharmaceutically acceptable carrier. 3 S. and 12 C.p. f-crystals, 7 PL.

The technical field to which the invention relates

The present invention relates to novel condensed derivative Indiana, their pharmaceutically acceptable salts, process for the preparation of such derivatives, compositions and antitumor means containing such derivatives and to a method of treating tumors in mammals. Compounds of the invention have an excellent antitumor activity and therefore are useful in the framework of indeno/2,1-C/quinoline known, for example, compounds substituted piperazinilnom group in position 6, described in Med. Chem. Res. , 3, 44 - 51 (1993). Although disclosed their antiserotonin activity, it is not reported and does not describe the antitumor activity of these compounds. Therefore, the antitumor activity of condensed derivatives Indiana invention is unknown.

The aim of the present invention is to provide compounds which have an excellent antitumor activity and is useful as a drug for the treatment of tumors.

Disclosure of the invention the present invention have conducted studies and found that condensed derivative indana show excellent antitumor activity and are useful as anticancer agents. Thus accomplished the present invention.

The present invention provides a condensed derivative indana represented by formula (1) or their pharmaceutically acceptable salts.

< / BR>
In this formula, ring A represents an optionally substituted benzene ring or naphthalene ring, or a benzene ring having a bottom is a great ring, having lower alkylenedioxy. Y represents-N=CR or CR=N-, R represents a group-NR1R2, optionally substituted nitrogen-containing heterocyclic group or a group-OR3where R1and R2are the same or different, and each represents a hydrogen atom; a phenyl group; optionally substituted nitrogen-containing heterocyclic group; lower alkyl group which may be substituted by at least one Deputy, selected from the group consisting of optionally substituted amino, lower alkyloxy, phenyl group, nitrogen-containing heterocyclic group, aminoacides group, a substituted lower alkyl group or a hydroxyl group; R3represents a lower alkyl group optionally substituted by a substituted amino group, provided that ring A and ring B are a benzene ring having no substituents when R represents an optionally substituted nitrogen-containing heterocyclic group.

Compounds of the present invention, depicted mentioned formula (1), have excellent antitumor activity and are effective in the treatment of m is estvo compounds of the above formula (1) or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier for them.

The present invention provides, in particular, an antitumor agent containing an effective amount of the compounds of the aforementioned formula (1) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier for them.

The present invention also provides a method of treating tumors in mammals which comprises the administration to a mammal an effective amount of compounds of the aforementioned formula (1) or its pharmaceutically acceptable salt.

Examples of the groups in the above formula (1), denoted by R1, R2and R3and other groups described in the description, below.

Examples of groups of deputies, included in the benzene ring and naphthalene ring, designated as ring A and ring B are halogen atom, a lower alkyl group, lower alkoxygroup, a hydroxyl group, a nitro-group, amino group, lower alloctype, benzyloxy lowest alluminare, cyano, carboxyl group, lower alkoxycarbonyl group, and preferred are a halogen atom, a lower alkyl group, lower alkoxygroup, a hydroxyl group, a nitrogroup, aminostyrene can be placed in any position of each ring, which may be the same or different 1-4 substituent. As for the ring A, the preferred positions are the positions of 8-, 9 - and 10-indeno/2,1-c/-quinoline rings and indeno/2,1-c/isoquinoline ring. As for ring B, preferred are similar to the 2-, 3 - and 4-positions. The number of groups of substituents in each ring is preferably 1 and 2, respectively.

The structure and position of substituents in indeno/2,1 - C/ - quinoline are given below in table. 1, and the structure and position of substituents in indeno/2,1-C/ - isoquinoline are given below in table. 2.

Examples of the lower alkylenedioxy are methylendioxy, atlantoxerus, trimethylenediamine, tetramethylthiourea and such alkylenedioxy containing 1 to 4 carbon atoms. The provisions of substitution lower alkylenedioxy are preferably regulations 8, 9, or 9, 10 indeno/2,1-C/quinoline ring and indeno/2,1-C/isoquinoline ring if ring A; and similarly position 2, 3 or 3, 4 in the case of ring B. When ring A represents an optionally substituted naphthalene ring, provisions for attachment of substituents in the other benzene ring, which is part of nafta the options that is, the position 8 - 9 9 - 10 10 - 11 ring A.

Examples of the halogen atom include fluorine atom, chlorine atom, bromine atom and iodine atom.

Examples of the lower alkyl groups are linear or branched alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.

Examples of the lower alkoxygroup are linear or branched alkoxygroup containing from 1 to 6 carbon atoms, such as methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, second-butoxypropan, tert-butoxypropan, pentyloxy, hexyloxy etc.

Examples of the lower acyloxy are linear or branched alloctype containing from 1 to 6 carbon atoms, such as formyloxy, acetoxygroup, propionyloxy, butyryloxy, 2-methylpropyloxy, pivaloyloxy, partnershop, 3-methylbutyraldehyde, hexaniacinate etc.

Examples of the lower acylamino are linear or branched alluminare containing from 1 to 6 carbon atoms, manograph, pivaloylpyruvic, partnerlinktype, 3-methylbutylamine, exonerating etc.

Examples of the lower alkoxycarbonyl groups are linear or branched alkoxycarbonyl group containing from 2 to 7 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, solutionline, second-butoxycarbonyl, tert-butoxycarbonyl, ventilatsiooniga, hexyloxymethyl group, etc.

Examples of groups of deputies, included in the nitrogen-containing heterocycles represented by R, R1and R2are lower alkyl groups, lower alkyl groups containing hydroxyl group (hydroxyl group), preferably lower alkyl groups.

Examples of the groups of substituents in the substituted amino groups, called the "optionally substituted amino group", referring to R1and R2and called the "lower alkyl group optionally substituted by a substituted amino group" represented by R3are the lower alkyl group, lower cycloalkyl group, di- (lower alkyl)aminoalkyl group, hydroxy-lower is I an alkyl group, di(lower alkyl)aminoalkyl group, hydroxy-lower alkyl group and benzyloxycarbonyl group. Mentioned substituted amino group can be monosubstituted or disubstituted, preferably disubstituted.

Examples of the lower alkyl groups containing substituted for the amino group, are methylaminomethyl, ethylaminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, diethylaminomethyl, diethylaminoethyl-2-yl, dipropylamine, dibutylamine, dibutylamine and similar mono - or dialkylaminoalkyl group containing 1 or 2 (C1-C6)-alkyl; N-dimethylaminoethyl-N-methylaminomethyl group, acetylamino, acetaminophen, propionylcarnitine, propiomelanocortin, pivaloyloxymethyl, pihlajaniemi and similar alkyl groups, substituted C2-C6-aceraminophen; cyclopropylamine, cyclopentylamine, cyclopentylmethyl, cyclohexylmethyl, cyclohexylamine and similar alkyl groups, substituted C3-C6-cycloalkylation; hydroxyethylaminomethyl, 2-hydroxyethylaminomethyl, 3 is oxibutinina and similar alkyl groups, substituted (C1-C4-hydroxyethylaminophenol; benzyloxycarbonylamino, benzyloxycarbonylamino, N-benzyloxycarbonyl-N-methylaminomethyl and similar alkyl groups, substituted benzyloxycarbonylamino.

Examples of the lower alkyl groups containing lower alkoxygroup are ethoxymethylene, ethoxyethylene, propoxymethyl, methoxyaniline, ethoxyaniline, methoxypropyl group and similar linear or branched (C1-C6)-alkyl groups, substituted C1-C6-alkoxygroup.

Examples of lower alkyl groups, the substituted phenyl group are benzyl, phenethyl, 2-phenethyl, phenylpropyl, benzhydryl, triticina group and similar linear or branched (C1-C4)-alkyl groups, substituted by 1-3 phenyl groups.

Examples of nitrogen-containing heterocyclic groups represented by the groups R, R1and R2are preferably 5 - or 6-membered heterocyclic monocyclic group type containing 1 to 4 nitrogen atom and 0 or 1 oxygen atom or a sulfur atom, for example pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, pyrazolyl, imidazolyl, oxadiazolyl, cadralazine, pyrrolidyl, imidazolidinyl, imidazolyl, pyrazolidine, pyrazoline, piperidyl, piperidino, piperazinil, morpholinyl, morpholinopropan, etc., preferably 5 - or 6-membered heterocyclic monocyclic group type containing 1 to 3 nitrogen atom and 0 or 1 oxygen atom, in particular pyridyl, pyrrolidinyl, piperidyl, piperidino, piperazinil, morpholinyl, morpholinopropan, 1,2,4-triazoline group.

Examples of substituted nitrogen-containing heterocyclic groups are 4-methylpiperazine, 4-ethylpiperazine, 4-methyl-piperidino, 4-ethylpiperidine, 2-hydroxyethylpyrrolidine, 2-(2-hydroxyethyl)pyrrolidine etc.

Examples of the lower alkyl groups containing nitrogen-containing heterocyclic group represented by the group R1and R2are 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl, 3-pyridylethyl, 4-pyridylethyl, pyrrolidinyl, pyrrolidinyl, piperidinomethyl, piperidinoethyl, piperazinylmethyl, piperidinomethyl, morpholinomethyl, morpholinoethyl and similar linear or branched (C1-C6)-alkyl groups having a nitrogen-containing heterocyclic group.

Examples aminoxide groups, the I, dimethylaminoacetyl, diethylaminoacetate, dibutylaminoethanol group, and similar mono - or dialkylaminoalkyl groups in which the alkyl part contains 1 to 4 carbon atoms.

Examples of the lower alkyl groups containing aminoacids group, a substituted lower alkyl group, are methylaminomethyl, methylaminomethyl, ethylaminomethyl, ethyleneoxide, dimethylaminoacetyl, dimethylaminoacetyl, diethylaminoacetate, diethylaminoacetate, dibutylaminoethanol and similar linear or branched (C1-C6)-alkyl groups containing mono - or dialkylaminoalkyl group in which the alkyl part contains 1 to 4 carbon atoms.

Examples of the lower alkyl groups containing a hydroxyl group include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3 - dihydroxypropyl, 4-hydroxybutyl, 2,3-dihydroxybutyl, 5 - hydroxyphenyl, 2,3-dihydroxyphenyl, 6-hydroxyhexyl, 2,3 - dihydroxyethylene group and similar linear or branched (C1-C6) is an alkyl group containing 1 or 2 hydroxyl groups.

Examples of salts of compounds of the invention are not specifically limited to the mi acids, such as formic acid, acetic acid, propionic acid, triperoxonane acid, tartaric acid, malic acid, maleic acid, fumaric acid, succinic acid, oxalic acid, methanesulfonate acid, p-toluensulfonate acid; and inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid.

As for the compounds represented by formula (1),

ring A is preferably a benzene ring, optionally substituted with hydroxyl group (or groups) or atom (atoms), halogen, or a benzene ring having a lower alkylenedioxy, preferably represents a benzene ring, optionally substituted by 1 or 2 hydroxyl groups and/or halogen atoms, or a benzene ring containing lower alkylenedioxy;

ring B is preferably a benzene ring substituted by a hydroxyl group (or groups), preferably represents a benzene ring substituted by 1 or 2 hydroxyl groups;

Y preferably represents-CR=N-;

R preferably represents a group-NR1R< - predstavljaet a group-NR1R2;

- R1and R2are the same or different, and each represents preferably a hydrogen atom, a phenyl group or a lower alkyl group, optionally substituted by an optionally substituted amino group, nitrogen-containing heterocyclic group, aminoacides group, a substituted lower alkyl group or a hydroxyl group, and preferably represent hydrogen atoms or lower alkyl groups, optionally substituted di(lower alkyl)substituted amino groups or nitrogen-containing heterocyclic groups, in particular R1represents a lower alkyl group substituted by dimethylaminopropoxy, diethylaminopropyl or pyridinoline group, and R2represents a hydrogen atom; and

- R3represents preferably a lower alkyl group, optionally substituted di(lower alkyl) substituted amino group.

Preferred compounds of the invention are derived indeno/2,1-C/quinoline represented by the formula (1) in which ring A represents a benzene ring, unsubstituted or substituted by 1 or 2 hydroxyl groups which defaults to a benzene ring, substituted by 1 or 2 hydroxyl groups; Y represents-CR=N-, R represents a group-NR1R2(where R1and R2are the same or different, and each represents a hydrogen atom or a lower alkyl group, optionally substituted di(lower alkyl)substituted amino group or nitrogen-containing heterocyclic group), piperazinilnom group, a substituted lower alkyl group, or a group OR3(where R3represents a lower alkyl group, optionally substituted di(lower alkyl)substituted amino group).

More preferred compounds of the invention are derived indeno/2,1-C/quinoline represented by formula (1) in which ring A represents a benzene ring, unsubstituted or substituted by 1 or 2 hydroxyl groups and/or halogen atoms, or a benzene ring containing lower alkylenedioxy; ring B is a benzene ring substituted by 1 or 2 hydroxyl groups; Y represents-CR=N-, R represents a group-NR1R2(where R1represents a lower alkyl group, a substituted di(lower alkyl)substituted amino group or a nitrogen-containing gamepay or pyrrolidinyloxy group, R2represents a hydrogen atom).

Compounds of the present invention, of the formula (1) can be obtained in accordance with the following reaction scheme 1.

< / BR>
where ring A, ring B and Y are as defined above. Z represents-CX=N - or-N=CX, X represents a halogen atom.

Stage A

The target compound of the present invention of formula (1) are obtained by reacting the derivative of 6-halogenide/2,1-C/-quinoline or a derivative of 5-halogenide/2,1-C/isoquinoline of the formula (2), with the amine RH (which corresponds to NH(R1)(R2or optionally substituted nitrogen-containing heterocyclic group), or with alcohol (R3HE) in the presence or in the absence of a suitable solvent for amination or alkoxysilane. When carrying out the amination reaction can be used sodium hydride, tert-piperonyl potassium, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, etc. in a suitable solvent. When carrying out the reaction alkoxysilane alcohol can be used in the form of the free alcohol or in the form of an alcoholate obtained by adding sodium, sodium hydride, tert-butoxide, tert-butanol and the like alcohols, dimethylformamide, dimethylacetamide, pyridine, toluene, benzene, acetonitrile, tetrahydrofuran, water, etc., Solvents are used each separately or as a mixture of two or more of them.

When carrying out the reaction of the amine or alcohol is used in amounts of 0.1 - 100 mm, preferably 1 - to 10-fold from the molar amount of the compounds of formula (2). The reaction temperature is in the range 0 - 200oC, preferably 50 to 150oC, and the reaction time is from 0.1 to 100 hours, preferably 1 to 60 hours. Such conditions are favorable for the reaction.

When ring A or ring B in the compounds of formula (1) obtained in accordance with reaction scheme 1, contains as substituents of lower CNS group or benzyloxy, the substituents can be converted into a hydroxyl group in the interaction of the compound with Hydrobromic acid, Modesto-hydrogen acid chloride-hydrogen acid, sulfuric acid, etc. in the presence or in the absence of a suitable solvent. Examples of solvents are acetic acid and water that can be used individually or in mixtures. In the implementation of the company used in an amount of 0.1 - 1000 pieces (about/weight), preferably 5 to 100 parts (vol/wt), the number of lower alkoxygroup or benzyloxy. The reaction temperature lies in the range 0 - 200oC, preferably 50 to 150oC, and the reaction time is from 0.1 to 100 hours, preferably 0.5 to 60 hours. Such conditions are favorable for the reaction.

When ring A or ring B in the compounds of formula (1) obtained according to reaction scheme 1, contains as a substituent a nitro-group, a nitrogroup, if desired, can be converted into the amino group by recovery. The reduction can be performed in a suitable solvent, using tin chloride, in the presence of hydrochloride. Examples of the solvent are methanol, ethanol and like alcohols, dimethylformamide, etc., When carrying out the reaction the molar amount of the hydrochloride is preferably 1 to 100-fold from the molar quantity of the nitro group, and the molar quantity of the chloride of tin is preferably 1 - to 10-fold from the molar quantity of the nitro group. The reaction temperature lies in the range 0 - 50oC, and the reaction time is 0.1 to 100 hours, preferably 1 to 12 hours. Such conditions are blagoprijatstviju with reaction scheme 1, contains, as substituents, a hydroxyl group, if desired, the hydroxyl group can be converted into alkoxygroup, benzyloxy or alloctype by alkylation, benzylidene or acylation, respectively. The alkylation reaction and the reaction benzylidene can be carried out in a suitable solvent when exposed to alkylating agent or agent benzylidene, moreover, in the presence of a base. Examples of solvents are dimethoxyethane, dioxane, tetrahydrofuran, dimethylformamide, acetone, etc., Examples of the base include potassium carbonate, sodium carbonate, potassium hydroxide, etc., Examples of the alkylation agent is a halide, sulfate ester and sulfonate-ester optionally substituted alkanes. Examples of agents benzylidene are benzylchloride etc. When the reaction molar amount of base is 1 - to 5-fold, molar amount of alkylation agent or agent benzylidene is 1 - to 5-fold from the molar amount of hydroxyl groups. The reaction temperature lies in the range 0 - 80oC, and the reaction time is 0.1 to 24 hours, preferably 0.5 to 10 hours. Such conditions are the two whom accordance with reaction scheme 1, contains an amino group, a substituted lower alkyl group, amino group, substituted lower alkyl group, can be converted into aminoacids group, a substituted lower alkyl group, the interaction of the amino group with an oxidant in a suitable solvent. The solvent has no particular restrictions, if it has no harmful effect on the course of the reaction. Examples of the solvents include ether, tetrahydrofuran and like ethers, methylene chloride, chloroform and like halogenated hydrocarbons, acetone, methyl ethyl ketone and similar alkylene, methanol, ethanol and like alcohols, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile and the like aprotic polar solvents, acetic acid, water, etc. that can be used individually or as mixtures of two or more of them. Oxidants have no particular restrictions, but include manganese dioxide, sodium hypochlorite, CAN /cerium (IV)ammoniumnitrate/, DDQ /2,3-dichloro-5,6-dicyano-1,4-benzoquinone/ chloranil /2,3,5,6-tetrachloro-1,4-benzophenon/ complex DMSO-pyridine-sulfur trioxide, reagent Jones (Jones), pyridine-chlorproma, pyridinediamine, dimethylsulfoxide-oxalicacid, hydrogen peroxide, tert-butylhydroperoxide and this pen is the notes), which can be used individually or in mixtures with each other.

When carrying out the reaction of the oxidizing agent is used in quantities of 1 to 100 equivalents, preferably 1 to 10 equivalents of the compound represented by formula (1). The reaction temperature ranges from a temperature under cooling with ice to the boiling point of the solvent, and the reaction time is 0.1 to 96 hours, preferably from 0.1 to 1 hour. Such conditions are favorable for the reaction.

The acylation reaction is carried out by interaction of compounds with the desired carboxylic acid or its reactive derivative. When using the reactive derivative, the reaction is carried out in a suitable solvent, optionally in the presence of a base to accelerate the reaction, although the reaction conditions are changed in accordance with the kind of the reactive derivative and the source of phenolic derivatives. Examples of the reactive derivative include acid anhydrides, mixed anhydrides, acid anhydrides, etc., Examples of solvents are chloroform, dichloromethane, dioxane, tetrahydrofuran, dimethylformamide, pyridine, etc., Examples of bases are carbonates on the my molar quantity is preferably to the base 1 - 5-fold, for Alliluyeva agent 1 to 5-fold from the molar amount of hydroxyl groups. The reaction temperature is in the range of 0 - 50oC, and the reaction time is 0.1 to 24 hours, preferably 0.5 to 3 hours. Such conditions are favorable for the reaction.

When ring A or ring B in the compounds of formula (1) obtained in accordance with reaction scheme 1, contains an amino group as a substituent, the amino group may optionally be converted into alluminare by acylation. The acylation reaction is carried out by reaction with the desired carboxylic acid or its reactive derivative. When using the reactive derivative, the reaction is carried out in a suitable solvent, optionally in the presence of a base to accelerate the reaction, although the reaction conditions are changed in accordance with the kind of the reactive derivative and the original unionpromoted. Examples of the reactive derivative include acid anhydrides, mixed anhydrides, acid chlorides, etc., Examples of solvents are chloroform, dichloromethane, dioxane, tetrahydrofuran, dimethylformamide, etc., Examples of bases are sodium bicarbonate, sodium carbonate is radiated molar quantity is preferable for the base 1 - 5-fold, for Alliluyeva agent 1 to 5-fold from the molar amount of amino groups. The reaction temperature is in the range of 0 - 50oC, and the reaction time is 0.1 to 100 hours, preferably 0.5 to 10 hours. Such conditions are favorable for the reaction.

In the compound of formula (1) obtained according to reaction scheme 1, by means of nitration can be entered nitro. The nitration reaction is conducted using Niteroi agent, such as fuming nitric acid and nitric acid in the presence or in the absence of sulfuric acid. When the reaction molar amount of the nitration agent is preferably 1 to 100 times the molar amount of the compounds of formula (1). The reaction temperature is in the range of 0 - 30oC, and the reaction time is 0.1 to 20 hours, preferably 0.5 to 5 hours. Such conditions are favorable for the reaction.

When R in the compound of formula (1) obtained in accordance with reaction scheme 1, contains a protective group, such as benzyloxycarbonyl group, a lower acyl group, etc., protective groups can be removed by the interaction of the protective group with Hydrobromic acid, jodies solvent. Among the solvents include acetic acid, water, etc. that are used individually or as a mixture of two or more of their number.

When carrying out the reaction of Hydrobromic acid, Modesto-hydrogen acid chloride-hydrogen acid, sulfuric acid, etc. are used in quantities of 1 to 1000 (R/W), preferably 5 - 100 (vol/weight) parts on the number of protective groups. The reaction temperature is in the range 0 - 200oC, preferably 50 to 150oC, and the reaction time is 0.1 to 100 hours, preferably 0.5 to 60 hours. Such conditions are favorable for the reaction.

Compounds of the invention obtained by the mentioned reactions can be converted into their salts in accordance with conventional methods, the interaction of compounds with the above-mentioned organic or inorganic acids in suitable solvents. Examples of solvents are water, methanol, ethanol, dichloromethane, tetrahydrofuran, etc., the reaction Temperature is preferably in the range of 0 - 50oC.

Derivatives of 6-halogenide/2,1-C/quinoline of formula 1, used as starting materials in reaction scheme 1, can be poluchenii 2 (see at the end of the description) ring A, ring B and X are as defined above. R4represents a lower alkyl group.

Stage B

Carboxylic acid of the formula (4) can be obtained by hydrolysis of compounds of formula (3) in a suitable solvent in the presence of a base.

The compound of the formula (3) can be obtained according to the method, opened not in the examined patent publication Japan N 3-223254.

Examples of the solvent is not specifically limited if the solvent does not render harmful influence on the course of the reaction, and include methanol, ethanol, propanol and like alcohols, dioxane, tetrahydrofuran, dimethoxyethane and similar ethers, and water, which are used individually or as mixtures of two or more of them. Examples of bases are sodium hydroxide, potassium hydroxide, barium hydroxide and the like hydroxides of alkali and alkaline-earth metals.

When the reaction molar amount of base is preferably 1 to 10 times the molar amount of the compounds of formula (3). The reaction temperature is in the range 0 - 100oC, preferably 50 - 100oC, and the reaction time is 0.5 - 1>Stage C

The compounds of formula (5) or (6) can be obtained by interaction of halogenation agent with compounds of the formula (3) or (4), usually in the absence of solvent, or optionally in an inert solvent, respectively. Examples of the inert solvent is not specifically limited if the solvent does not render harmful influence on the course of the reaction, and include chloroform, benzene, toluene, xylene, etc., Examples of halogenation agents are thionyl chloride, thienylboronic, oxychloride, chloride of phosphorus, phosphorus bromide, pentachloride phosphorus, pentabromide phosphorus, etc. To accelerate the reaction can be added pyridine or dimethylformamide.

When the reaction molar amount of halogenation agent is preferably 1 to 100 times the molar amount of the compounds of formula (3) or (4). The reaction temperature is in the range 0 - 200oC, preferably 50 to 150oC, and the reaction time is 0.5 - 100 hours, preferably 0.5 to 10 hours. Such conditions are favorable for the reaction.

The compound of the formula (5) or equation (6) does not necessarily isolate and purify, but they can be used in the next stage without purification.

Examples of the inert solvent is not specifically limited if the solvent does not render harmful influence on the course of the reaction, and include nitrobenzene, xylene, dichloromethane, carbon tetrachloride, etc., Examples of proton acids are sulfuric acid, phosphoric acid, polyphosphoric acid, Hydrobromic acid, etc., Examples of the Lewis acid is aluminum chloride, tin chloride, ferric chloride, etc.

When the reaction molar quantity of used proton acid or a Lewis acid is 1 to 1000-fold, preferably 1 to 100-fold amount of the molar amount of the compounds of formula (5) or (6). The reaction temperature is in the range of 0 - 200oC, and the reaction time is 0.5 - 50 hours, preferably 0.5 to 20 hours. Such conditions are favorable for the reaction.

In the reaction scheme 3 (see end of description) ring A, ring B, X, and R4are as defined above. R5represents a lower alkyl group.

Stage E

The compound of formula (9) receive saimiri solvent is not specifically limited, if the solvent does not render harmful influence on the course of the reaction, and include methanol, ethanol, propanol and like alcohols, benzene, toluene, xylene, dioxane, tetrahydrofuran, etc.

When the reaction molar amount of compound (8) is preferably 0.5 to 2-fold molar amount of the amount of the compounds of formula (7). The reaction temperature is within a 20 - 150oC, preferably 90 to 130oC. the reaction Time is 0.1 - 50 hours, preferably 0.1 to 2 hours. Such conditions are favorable for the reaction.

Stage F

The compound of formula (10) are obtained by reacting the compounds of formula (9) obtained in stage E, the proton acid is usually in the absence of solvent, optionally in the presence of an inert solvent.

Examples of the inert solvent is not specifically limited if the solvent does not render harmful influence on the course of the reaction, and include nitrobenzene, xylene, etc., Examples of proton acids are sulfuric acid, phosphoric acid, polyphosphoric acid, Hydrobromic acid, etc.

When carrying out the reaction, the amount of used proton acid is one the formula (9). The reaction temperature is in the range of 90 - 150oC. the reaction Time is 0.5 - 50 hours, preferably 1 to 10 hours. Such conditions are favorable for the reaction.

Stage G

The compound of formula (10) is also produced by the interaction of the compounds of formula (3) or (4) proton acid is usually in the absence of solvent, optionally in the presence of an inert solvent.

Examples of inert solvents for this reaction is not particularly limited if the solvent does not render harmful influence on the course of the reaction, and include nitrobenzene, xylene, etc., Examples of proton acids are sulfuric acid, phosphoric acid, polyphosphoric acid, Hydrobromic acid, etc.

When carrying out the reaction, the amount of used proton acid is, as the amount of solvent, preferably a 5 - to 15-fold amount of the compounds of formula (3) or (4). The reaction temperature is in the range of 50 - 200oC. the reaction Time is 0.5 - 50 hours, preferably 0.5 to 10 hours. Such conditions are favorable for the reaction.

Stage H

The compound of the formula (2a) are obtained by reacting the compound is optionally in the presence of an inert solvent.

Examples of inert solvents have no special restrictions, if the solvent does not render harmful influence on the course of the reaction, but include chloroform, benzene, toluene, xylene, etc., Examples of halogenation agents are thionyl chloride, thienylboronic, oxychloride phosphorus, chloride of phosphorus, phosphorus bromide, pentachloride phosphorus, pentabromide phosphorus, etc. To accelerate the reaction can be used pyridine, dimethylformamide, etc.

When the reaction molar amount of halogenation agent is preferably 1 to 100-fold from the molar amount of the compounds of formula (10). The reaction temperature is in the range 0 - 200oC, preferably 50 to 150oC. the reaction Time is 0.5 - 50 hours, preferably 0.5 to 10 hours. Such conditions are favorable for the reaction.

Derivatives of 5-halogenide/2,1-C/isoquinoline, depicted by formula (2), which are used as starting substances in the reaction scheme 1, can be obtained in accordance with reaction scheme 4 below.

In the reaction scheme 4 (see end of description) ring A, ring B and X are as defined above.

Stage I

Carboxylic key which can be carried out by a known method, opened in Bolletino Chimico Farmaceutico, 125, 437 (1986).

In addition, the compounds of formula (11) can be synthesized in accordance with the description in Boll. Sedute Accad. Gioenia Sci. Nat. Catania, 6, 606 (1960) or by publication of the last examination of the Japan patent N 5-132463.

Examples of solvents have no special restrictions, if the solvent does not render harmful influence on the course of the reaction, but include methanol, ethanol, propanol and like alcohols, etc.

When carrying out the reaction the molar quantity of ammonia used is 1 to 1000-fold, preferably 10 - 100-fold from the molar amount of the compounds of formula (11). The reaction temperature is in the range 0 - 100oC, preferably about room temperature, and the reaction time is 0.5 - 100 hours, preferably 2 to 20 hours. Such conditions are favorable for the reaction.

Stage J

The compounds of formula (13) are obtained by reacting compounds of the formula (12) obtained in stage 1, with a proton acid or a Lewis acid in the absence of solvent, or optionally in the presence of an inert solvent.

Examples of inert solvents have no special restrictions, if the solvent does not render BP is tan, etc. Examples of proton acids include hydrogen fluoride, sulfuric acid, phosphoric acid, phosphorus oxide, polyphosphoric acid, etc., Examples of Lewis acids include aluminum chloride, iron chloride, tin chloride (4), zinc chloride, boron fluoride, etc.,

When the reaction molar quantity of the proton acid is 5 to 15-fold, and the Lewis acid 1 - to 10-fold from the molar amount of the compounds of formula (12). The reaction temperature is in the range 0 - 200oC, and the reaction time is 0.5 - 50 hours, preferably 0.5 to 20 hours. Such conditions are favorable for the reaction.

Stage K

The compounds of formula (2b) are obtained by reacting the compounds of formula (13) obtained in stage J, with a halogenation agent is usually in the absence of solvent, optionally in the presence of an inert solvent.

Examples of inert solvents have no special restrictions, if the solvent does not render harmful influence on the course of the reaction, and include chloroform, benzene, toluene, xylene, etc., Examples of halogenation agents are thionyl chloride, thienylboronic, oxychloride phosphorus, chloride of phosphorus, phosphorus bromide, pentachloride phosphorus, pentabromide phospho reaction molar amount of halogenation agent is preferably 1 - 100-fold from the molar amount of the compounds of formula (13). The reaction temperature is in the range 0 - 200oC, preferably 50 to 150oC. the reaction Time is 0.5 - 50 hours, preferably 0.5 to 10 hours. Such conditions are favorable for the reaction.

Compounds of the invention and other compounds obtained by any of the aforementioned methods, may be extracted and purified by usual methods of separation and purification used in the relevant field of technology, for example, by concentration, extraction with solvent, filtration, recrystallization, various chromatographic methods, etc.

When the compounds of the invention are used as drugs for the case of malignant tumors in mammals, the compounds can be prepared in the form of various pharmaceutical dosage forms in accordance with the purposes of treatment. Examples of pharmaceutical dosage forms are preparations for oral administration such as tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, and preparations for parenteral administration such as injections, suppositories, ointments, is the field of technology.

In the preparation of compositions in tablet form as carriers using excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders, such as ordinary syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinylpyrrolidone; disintegrators such as dry starch, sodium alginate, powdered agar, powdered laminaran, sodium bicarbonate, calcium carbonate, polyoxyethylenesorbitan esters of fatty acids, sodium lauryl sulfate, monoglycerides of stearic acid, cacao butter, hydrogenated oil; absorption promoters such as Quaternary ammonium bases, sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactate, kaolin, bentonite, colloidal silicon dioxide; lubricants such as purified talc, salts of stearic acid, borax, and polyethylene glycol. Tablets can be made optional in the form of tablets, on which is applied a conventional coatings, such as tablets, sugar coated tablets with gelatin coated tablets, etc.

In the preparation of pills as carriers used excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin and talc; binders such as powdered Arabian gum, powder tragakant, gelatin; disintegrators, such as laminaran, agar.

Capsules can be manufactured in a usual way by mixing the compounds of the invention with the aforementioned media, followed by filling with a mixture of hard gelatin capsules, soft elastic capsules, etc.

For compositions suppositories as carriers use polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc.

In the preparation of injection liquids, emulsions and suspensions are preferably sterile and isotonic to blood. In the preparation of the above-mentioned preparations are used diluents, such as water, ethanol, macrogol, propylene glycol, ethoxylated isostearoyl alcohol, polioksidony isostearoyl alcohol, polyoxyethylenesorbitan esters of fatty acids, etc. To medicines add not only sodium chloride, glucose or glycerin in number, the aesthetics, etc.

Ointments can be prepared by conventional means by optional mixing with the compound of the invention basics, stabilizer, wetting agent, preservative, etc., and the resulting composition mixed to obtain drugs-ointment. Examples of bases are liquid paraffin, white petrolatum, white beeswax, paraffin, etc., Examples of preservatives are methyl-4-hydroxybenzoate, ethyl-4-hydroxybenzoate, propyl-4-hydroxybenzoate etc.

The patches are prepared by applying the above ointments, pastes, creams, gels, etc. on conventional media. Examples of the media /substrates/ are appropriately woven fabric and nonwoven fabric made of cotton, staple fiber or some other chemical fiber, film, or foam sheets, made of plasticized polyvinyl chloride, polyethylene, polyurethane, etc.

The formulations of drugs can be added optional colorants, preservatives, perfumes, flavoring, podslushivala and other medicines.

A number of compounds of the invention in the formulations of drugs are not specifically limited, but is is not particularly limited, but will properly be determined by the type of drug, age, gender and other data of the patient, severity of disease, etc., for Example, tablets, pills, liquids, suspensions, emulsions, granules, capsules administered orally. Injection given intravenously, either separately or in mixture with conventional additives, such as glucose, amino acids and other Injections can be administered intramuscularly, intracutaneously, subcutaneously or administered intraperitoneally in the form only of this drug. Suppositories injected into the rectum. Ointments applied to the skin, the mucous membrane of the nose (oris), etc.

A number of compounds of the present invention, which include in each dosage unit varies depending on the patient's symptoms or type of drug. The preferred amount per unit is from 1 to 1000 mg for oral preparations, from 0.1 to 500 mg injection, or 5 to 1000 mg for suppositories. The daily dosage of the drug in the above-mentioned dosage forms varies according to the symptoms, body weight, age, gender, and other patient data, but typically is in the range from 0.1 to 5000 mg, preferably from 1 to 1000 mg, for an adult. The drug is administered preferably the e treated by injection of medications containing compounds of the invention are not limited specifically, but these include head and neck cancer, ezofagealnaya carcinoma, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, or cholangioma, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, bladder cancer, prostate cancer, cancer of the testes, osteochondroma, malignant lymphoma, leukemia, cervical cancer, skin cancer, brain cancer, etc.

The best option of carrying out the invention

Listed below are reference examples, examples, examples, pharmacological test and examples of dosage forms of the present invention.

Reference example 1

Synthesis of 1,2-dihydro-4-(3,4 - methylenedioxyphenyl)-2-oxo-3-quinoline-carboxylic acid.

A mixture of ethyl ester of 1, 2-dihydro-4-(3,4-methylenedioxyphenyl)-2-oxo-3-quinoline-carboxylic acid (40 g, 118,6 mmol), methanol (200 ml), water (300 ml) and potassium hydroxide (33,3 g, 593,5 mmol) is refluxed for 40 hours. To the reaction mixture add 110 ml of 6N HCl to acidify the mixture, and separating the precipitated crystals by filtration. The resulting crystals are washed with diethyl ether, and obtain 35 g (yield 95.4 percent) named m), to 7.35 (1H, d, j=8 Hz), 7,13 (1H, m), 7,06 (1H, d, j=8 Hz), 6,98 (1H, d, j=8 Hz), 6.87 in (1H, s), 6,76 (1H, d, j=8 Hz), between 6.08 (2H, s).

IR (KBr) cm-1: 3440, 1646, 1577, I486, 1441, 1395, 1238, 1039.

Reference example 2

Synthesis of 6-chloro-9,10-methylenedioxy-7H-indeno/2,1-C/quinoline-7-it.

A mixture of 1,2-dihydro-4-(3,4-methylenedioxyphenyl) -2-oxo-3-quinoline-carboxylic acid obtained in reference example 1 (10 g, and 32.3 mmol) and phosphorus oxychloride (100 ml, 1.07 mol) is refluxed for 4 hours. The reaction mixture is distilled until a dry residue, and washed several times with n-hexane. To the resulting residue are added 50 g of polyphosphoric acid, and the mixture is heated at 90oC for 2 hours. The reaction mixture was poured into a mixture of ice water, and filtered off the precipitated crystals. The resulting crystals are dissolved in tetrahydrofuran, filtered off any insoluble substances, purified column chromatography on silica gel (eluent chloroform) and obtain 6.0 g (yield 59.9 per cent) named in the connection header.

So pl. 265 - 270oC.

1H NMR (CDCl3) : a 8.34 (1H, d, j=8 Hz), of 8.04 (1H, d, j=8 Hz), to 7.84 (1H, d-d, j=8.7 Hz), 7,66 (1H, d-d, j=8 Hz), 7,58 (1H, s,), of 7.23 (1H, s), 6,17 (2H, s).

IR (KBr) cm-1: 3450, 1713, 1556, 1504, 1478, 1420, 1384, 1335, 1266, 1037.

SS is ether 1,2 - dihydro-4-phenyl-2-oxo-3-quinoline-carboxylic acid (5 g, 17 mmol), ethanol (20 ml), water (40 ml) and potassium hydroxide (5 g, 89 mmol) is refluxed for 1.5 hours. To the reaction mixture add 60 ml of 2N HCl to acidify, and separating the precipitated crystals by filtration. The obtained crystals are recrystallized from ethanol and gain of 4.2 g (yield of 92.9%) named in the connection header.

So pl. 246 - 254oC (decomp.).

1H NMR (DMSO-d6) : 13,10 (1H, sh.C.), to 12.28 (1H, s), 7,60-7,05 (9H, m ).

IR (KBr) cm-1: 3000, 2970, 2950, 2880, 2850, 2840, 2790, 1699, 1653, 1608, 1598, 1557, 1506, 1488, 1435, 1411, 1262, 1100, 753, 709, 591.

Reference example 4

Synthesis of 5H-indeno/2,1-C/quinoline-6,7-dione.

A mixture of 1,2-dihydro-4-phenyl-2-oxo-3-quinoline-carboxylic acid obtained in reference example 3 (2 g, 7.5 mmol), and polyphosphoric acid (20 g) is injected into the reaction at 130oC for 4 hours. The reaction mixture was poured into ice water and separated by filtration of the precipitated crystals. The obtained crystals periostat with methanol, and obtain 1.7 g (yield 91.2 per cent) named in the connection header.

So pl. >290oC.

1H NMR (DMSO-d6) : 12,12 (1H, sh.C.), 8,55 (1H, d, j=8 Hz), 8,40 (1H, d, j=8 Hz), 7,78-7,33 (6H, m).

IR (KBr) cm-1: 2860, 1724, 1652, 1618, 1601, 1585, 1503, 1484, 1404, 763, 743, 576.

So pl. >290oC.

1H NMR (DMSO-d6) : a 12.03 (1H, sh.C.), to 8.41 (1H, d, j=8 Hz), at 8.36 (1H, d, j= 7 Hz), 7,70-7,17 (5H, m), is 2.44 (3H, s).

IR (KBr) cm-1: 3440, 1711, 1643, 1599, 1580, 1543, 1481, 1465, 1437, 1404.

Reference example 6

Synthesis of 6-chloro-3-methyl-7H-indeno/2,1-C/quinoline-7-it/

A mixture of 3-methyl-5H-indeno/2,1-C/quinoline-6,7-dione, obtained in reference example 5 (700 mg, 2.7 mmol) and phosphorus oxychloride (10 ml, 107 mmol) is refluxed for 1.5 hours. The reaction mixture is distilled until a dry residue. To the residue water is added after filtration to obtain the precipitated crystals. The resulting crystals are washed with water and dissolved in chloroform, and filtered off any insoluble matter. By recrystallization from benzene obtain 550 mg (yield 73.4 per cent) named in the connection header.

So pl. 208 - 211oC.

1H NMR (CDCl3-1: 1718, 1623, 1557, 1494, 1460, 1413, 1064, 915, 867, 755, 715.

Reference example 7

Synthesis of 1,3 - dioxo-3'-methoxy-2-indocarbocyanine.

To a suspension of 2 - etoxycarbonyl-1,3-indandion (2.7 g, 12.5 mmol) in toluene (100 ml) is added m-anisidine (1.7 g, of 13.8 mmol) and the mixture is refluxed for 0.5 hours. Distilled approximately half the amount of the solvent, and is obtained by filtering the precipitated crystals. The obtained crystals are recrystallized from ethanol, and obtain 1.7 g (yield 46,0%) named in the connection header.

So pl. 128 - 138oC.

1H NMR (CDCl3) : 9,52 (1H, sh.C.), 7,70-of 7.55 (4H, m), 7,31 (1H, d, j= 8 Hz), 7,17 (1H, d-d, j=2.2 Hz), 7,10-6,74 (2H, m), 3,84 (1H, s).

IR (KBr) cm-1: 1658, 1604, 1584, 1563, 1537, 1496, 1455, 1416.

Reference example 8

Synthesis of 3-methoxy-5H-indeno/2,1-C/quinoline-6,7-dione.

A mixture of 1,3-dioxo-3'-methoxy-2-indocarbocyanine (1.6 g, 5.4 mmol) obtained in reference example 7, and polyphosphoric acid (18 g) is reacted at 120oC for 1.5 hours. The reaction mixture was poured into a mixture of ice water, and is obtained by filtering the precipitated crystals. The resulting crystals are washed with tetrahydrofuran, and obtain 1.0 g (yield of 66.6%) named in the connection header.

IR (KBr) cm-1: 1705, 1640, 1621, 1585, 1480, 1415, 1394,

Reference example 9

Synthesis of 6-chloro-3-methoxy-7H-indeno/2,1-C/quinoline-7-it.

A mixture of 3-methoxy-5H-indeno/2,1-C/quinoline-6,7-dione (550 mg, 2.0 mmol) obtained in reference example 8, and phosphorus oxychloride (20 ml, 214 mmol) is refluxed in the presence of catalytic amounts of N, N-dimethylformamide for 4 hours. The reaction mixture is distilled until a dry residue. To the residue water is added, and is obtained by filtering the precipitated crystals. The resulting crystals are dissolved in chloroform and filtered off any insoluble matter. By recrystallization from benzene obtain 460 mg ( yield 78.4 per cent) named in the connection header.

So pl. 261 - 266oC.

1H NMR (CDCl3) : 8,39 (1H, d, j=9 Hz), 8,11 (1H, d, j=8 Hz), 7,81 (1H, m), of 7.64 (1H, d-d-d, j=8 and 8.1 Hz), 7,53 (1H, m),7,41 (1H, d, j= 2 Hz), 7,33 (1H, d-d, j=9,2 Hz), of 4.00 (3H, s).

IR (KBr) cm-1: 1706, 1618, 1564, 1496, 1474, 1464, 1428, 1208, 1186, 1157, 1122, 1060, 1012,

Reference example 10

Synthesis of ethyl ester of 1,2-dihydro-7-methoxy-4-phenyl-2-oxo-3-quinoline-carboxylic acid.

A mixture of 2-amino-4-methoxybenzophenone /20 g, 88 mmol/, diethylmalonate /26,7 ml, 176 mmol/, 1,8-diazabicyclo /5,2,0/-undeca-7-ene /on the air. To the cooled mixture ethanol /30 ml/, and is removed by filtering the precipitated crystals. The resulting crystals are washed with ethanol, and get to 25.7 g /exit 90,2%/ called in the connection header.

So pl. 175 - 177oC.

1H NMR (CDCl3) : 12,60 (1H, sh.C.), of 7.48-to 7.35 (5H, m), 7,18 (lH, d, j= 9 Hz), 6,91 (1H, d, j=3 Hz), 6,72 (lH, d-d, j=9, 3 Hz), 4,08 (2H, K., j=7 Hz), 3,90 (3H, s), of 0.97 (3H, T., j=7 Hz).

IR (KBr) cm-1: 2980, 2940, 1735, 1642, 1597, 1516, 1238, 1213, 1094.

Reference example 11

Synthesis of 1,2-dihydro-7-methoxy-4-phenyl-2-oxo-3-quinoline-carboxylic acid.

Ethyl ester of 1,2-dihydro-7-methoxy-4-phenyl-2-oxo-3-quinoline-carboxylic acid 3.0 g/ obtained in reference example 10, is injected into the interaction and treated by the same procedure, which is outlined in reference example 1, the product is washed with ethanol, and obtain 2.7 g /exit 99,0%/ called in the connection header.

So pl. 292 - 294oC.

1H AMP (DMSO-d6) : 13,23 (1H, s), 12,25 (1H, s), 7,54-7,44 (3H, m), 7,31-7,27 (2H, m), 6,99-of 6.90 (2H, m), to 6.80 (1H, m), 3,83 (3H, s).

IR (KBr) cm-1: 3170, 1731, 1625, 1476, 1403, 1243, 1212, 847.

Reference example 12

Synthesis of 6-chloro-3-methoxy-7H - indeno/2,1-C/quinoline-7-it (another way).

Mentioned 1,2-dihydro-7 - methoxy-4-phenyl-2-oxo-3-hee is the method what is described in the reference example 2, and get called in the header connection. Physico-chemical properties of the compounds obtained are similar to the properties of the compound of reference example 9.

Reference example 13

Synthesis of 6-chloro-3-hydroxy-7H-indeno/2,1 - C/quinoline-7-it.

A mixture of 6-chloro-3-methoxy-7H-indeno/2,1-C/quinoline-7-she (10.0 g, 33.8 mmol) obtained in reference example 9 and 100 ml conc. sulfuric acid is stirred with heating at 160oC for 2 hours. The reaction mixture was poured into a mixture of ice water to get filtered precipitated crystalline substance. The resulting crystals are washed with water and ethanol in this order, and obtain 8.5 g (yield 89.4 per cent) named in the connection header.

So pl.> 300oC.

1H NMR (DMSO-d6) : 11,18 (1H, sh.C.), 8,66 (1H, d, j=9 Hz), 8,43 (lH, d, j=8 Hz), to 7.77-to 7.59 (3H, m), 7,35 (1H, d-d, j= 9, 2 Hz), 7.23 percent (1H, d, j=2 Hz).

IR (KBr) cm-1: 3110, 1711, 1623, 1610, 1461, 1435, 1398, 1179, 1067, 750.

Reference example 14

Synthesis of 3-benzyloxy-6-chloro-7H-indeno/2,1-C/quinoline-7-it.

To a suspension of 6-chloro-3 - hydroxy-7H-indeno/2,1-C/quinoline-7 - she (500 mg, 1.8 mmol) obtained in reference example 13, and potassium carbonate (300 mg, 2.1 mmol) in N,N - dimethylformamide (5 the ect is poured into a mixture of ice water, and by filtering get loose crystalline substance. The resulting crystals are washed with water and 2-propanol in this sequence, and obtain 610 mg (yield 92.4 per cent) named in the connection header.

So pl. 212 - 214oC.

1H NMR (CDCl3) : to 8.40 (1H, d, j=9.5 Hz), 8,10 (1H, d, j=7.5 Hz), 7,80 (1H, d, j=7.5 Hz), to 7.67-7,31 (9H, m), of 5.24 (2H, s).

IR (KBr) cm-1: 3090, 1711, 1623, 1570, 1461, 1435, 1397, 1179, 1067, 750.

Reference example 15

Synthesis of 1,2-dihydro-4-phenyl-1-oxo-3-ethinlestradiol acid.

To a solution of 4-phenylisocyanate-3-carboxylic acid (36.2 g, 136 mmol) in methanol (50 ml) was added 100 ml of a saturated solution of ammonia in methanol, and the mixture is stirred at room temperature for 8 hours. The mixture is distilled to remove the solvent. To the residue add 300 ml of methanol and 100 ml of 4N solution of hydrogen chloride in ethyl acetate is added to acidify the mixture. The solvent is removed by distillation. To the residue water is added to obtain by filtering the precipitated crystals. The resulting crystalline substance is recrystallized from ethanol with water, and get 32,0 g (yield 88.7 per cent) named in the connection header.

So pl. >300oC.

1H NMR (DMSO-d6) : 13,51598, 1468, 1446, 1307, 761, 706.

Reference example 16

Synthesis of 6H-indeno/2,1-C/isoquinoline-5,7-dione.

A mixture of 1,2-dihydro-4-phenyl-1-oxo-3-ethinlestradiol acid (32 g) obtained in reference example 15, and polyphosphoric acid (300 g) enter into interaction with the 100oC for 5 hours. The reaction mixture was poured into a mixture of ice water and is produced by filtering the precipitated crystals. The resulting crystals are washed with ethyl acetate and get to 26.6 g (yield of 89.2%) named in the connection header.

So pl. > 300oC.

1H NMR (DMSO-d6) : 12,18 (1H, sh.C.), 8,40-8,35 (2H, m), 7,94-7,88 (2H, m), 7,73 (1H, d-d, j=8,8 Hz), 7,54-7,46 (2H, m), 7,24 (1H, d-d, j=7, 7 Hz).

IR (KBr) cm-1: 3060, 1716, 1681, 1645, 1620, 1604, 1598, 1588, 1462, 1328, 716.

Reference example 17

Synthesis of 5-chloro-7H-indeno/2,1-C/isoquinoline-7-it.

A mixture of 6H-indeno/2,1-C/isoquinoline-5,7-dione, obtained in reference example 16 (26,6 g, 108 mmol) and phosphorus oxychloride (300 ml) is refluxed in the presence of 1 ml of n, N-dimethylformamide for 2 hours. The reaction mixture is distilled until a dry residue. To the residue add a mixture of water with ice, and is produced by filtering the precipitated crystals. The obtained crystalline material was washed with water, peracre is SUP>oC.

1H NMR (CDCl3) : 8,51-of 8.47 (2H, m), 7,99-of 7.82 (3H, m), 7,74 (1H, d, j=7 Hz), to 7.59 (1H, d-d, j=8, 8 Hz), 7,40 (1H, d-d, j=8, 7 Hz).

IR (KBr) cm-1: 1738, 1722, 1615, 1602, 1461, 1412, 1347, 1253, 765, 713, 682, 616.

Reference example 18

The following compounds are synthesized using the compounds of reference examples 1-17.

*2,6-Dichloro-7H-indeno/2,1-C/quinoline-7-on.

So pl. 282 - 284oC.

1H NMR (CDCl3) : 8,46 (1H, d, j=8 Hz), 8,11 (1H, d, j=7 Hz), 8,03 (1H, d , j=9 Hz), 7,84-7,79 (2H, m), of 7.69 (1H, d-d, j=8, 8, 1 Hz), EUR 7.57 (1H, d-d, j=7, 7 Hz).

*6-Chloro-2-methoxy-7H-indeno/2,1-C/quinoline-7-on.

So pl. 261 - 262oC.

1H NMR (CDCl3) : of 8.06 (1H, d, j=8 Hz), 8,00 (1H, d, j=9 Hz), 7,82 (1H, d, j=7 Hz), 7.68 per-7,50 (4H, m), 4,06 (3H, s).

*6-Chloro-2-nitro-7H-indeno/2,1-C/quinoline-7-on.

So pl. > 300oC.

1H NMR (CDCl3) : for 9.47 (1H, d, j=2 Hz), 8,46 (1H, d-d, j=9, 2 Hz), of 8.25 (1H, d , j=8 Hz), 8,24 (2H, d, j=9 Hz), 7,88 (1H, d, j=7 Hz), 7,78 (1H, d-d, j=8, 8, 1 Hz), to 7.64 (1H, d-d, j=8, 8 Hz).

*6-Chloro-2,3-methylenedioxy-7H-indeno/2,1-C/quinoline-7-on.

So pl. > 300oC.

1H NMR (CDCl3) : 8,02 (1H, d, j=8 Hz), 7,81 (1H, d, j=7 Hz), 7,72 (1H, s ), to 7.64 (1H, d - d-d, j=8, 8, 1 Hz), 7,52 (1H, d-d, j=8, 8 Hz), 7,37 (1H, s), 6,23 (2H, s).

*6-: 8,00 (1H, D., j=7 Hz), 7,82 (1H, d, j=7 Hz), the 7.65 ( 1H, d-d, j=8, 8 Hz), to 7.61 (1H, s), 7,52 (1H, d-d, j=8, 7 Hz), 7,41 (1H, s), 4,14 (3H, s), 4,07 (3H, s).

*6-Chloro-3-fluoro-7H-indeno/2,1-C/quinoline-7-on.

So pl. 257 - 259oC.

1H NMR (CDCl3) : 8,55 (1H, m), 8,12 (1H, A., j=7 Hz), to 7.84 (1H, d, j= 7 Hz), 7,76-7,47 (4H, m).

*6-Chloro-3,9-dimethoxy-7H-indeno/2,1-C/quinoline-7-on.

So pl. 298 - 300oC.

1H NMR (CDCl3) : 8,31 (1H, d, j=9 Hz), 7,98 (1H, d, j=9 Hz), 7,37 (1H, d , j=3 Hz), 7,33 (1H, d, j=3 Hz), 7,29 (1H, d-d, j=9, 3 Hz), was 7.08 (1H, d-d, j=8, 3 Hz) to 3.99 (3H, s), of 3.94 (3H, s).

*3,6-Dichloro-7H-indeno/2,1-C/quinoline-7-on.

So pl. 250 - 252oC.

1H NMR (CDCl3) : to 8.40 (1H, d, j=9 Hz), 8,07 (1H, d, j=9 Hz), with 8.05 (1H, s), 7,80 (1H, d, j=7 Hz), 7,69-7,52 (3H, m).

*3-Benzyloxy-6-chloro-9,10-methylenedioxy-7H-indeno/2, 1 - C/quinoline-7-on.

So pl. 241 - 243oC.

1H NMR (CDCl3) : 8,19 (1H, d, j=9 Hz), 7,60-7,31 (8H, m), 7,19 (1H, s), x 6.15 (2H, s), a total of 5.21 (2H, s).

*6-Chloro-3-methoxy-9,10-methylenedioxy-7H-indeno/2, 1-C/quinoline-7-on.

So pl. > 300oC.

1H NMR (CDCl3) : by 8.22 (1H, d, j=9 Hz), 7,53 (1H, s), of 7.36 (1H, d, j= 3 Hz), 7,30 (1H, d, j=3 Hz), 7.23 percent (1H, s), 6,16 (2H, s), 3,98 (3H, s).

*6-Chloro-8-methoxy-7H-indeno/2,1 - C/quinoline-7-on.

So pl. 259 - 260(1H, D.-d-d, j= 8, 7, 1 Hz), 7,60 (1H, d-d, j=9, 8 Hz), to 7.09 (1H, d, j=9 Hz), Android 4.04 (3H, s).

*6-Chloro-8 - hydroxy-7H-indeno/2,1-C/quinoline-7-on.

So pl. 240 - 241oC.

1H NMR (CDCl3) : 8,83 (1H, s), 8,46 (1H, d, j=9 Hz), of 8.09 (1H, d, j= 9 Hz), 7,88 (1H, d-d-d, j=7, 7, 1 Hz), 7,73-the 7.65 (2H, m), 7,52 (1H, d-d, j=9, 7 Hz), 7,03 (1H, d, j=9 Hz).

*6-Chloro-9-methoxy-7H-indeno/2,1-C/quinoline-7-on.

So pl. 210 - 212oC.

1H NMR (CDCl3) : 8,39 (1H, d, j=8 Hz), 8,04-of 7.97 (2H, m), 7,83 (1H, d-d-d, j=9, 7, 1 Hz), the 7.65 (1H, d-d-d, j=8, 7, 1 Hz), 7,29 (1H, d, j= 3 Hz), 7,07 (1H, d-d, j=8, 3 Hz), 3,93 (3H, s).

*6-Chloro-10-methoxy-7H - indeno/2,1-C/quinoline-7-on.

So pl. 255 - 256oC.

1H NMR (CDCl3) : 8,43 (1H, d, j=9 Hz), 8,08 (1H, d, j=9 Hz), 7,86 (1H, d-d-d, j=9, 7, 1 Hz), 7,76 (1H, d, j=8 Hz), 7,69 (1H, d-d-d, j= 8, 7, 1 Hz), the 7.65 (1H, d, j=2 Hz), 6,94 (1H, d-d, j=8, 2 Hz) to 3.99 (3H, s).

*6-Chloro-10-hydroxy-7H-indeno/2,1-C/quinoline-7-on.

So pl. > 300oC.

1H NMR (DMSO-d6) : 8,64 (1H, d, j=8 Hz), 8,05-7,81 (4H, m), 7,63 (1H, d, j=8 Hz), to 6.95 (1H, d-d, j=8, 2 Hz).

*2-Aza-1-chloro-13H-dibenzo/s,i/fluorine-13-he.

So pl. 258 - 261oC.

1H NMR (CDCl3) : 9,00 (1H, d, j=8 Hz), 8,53 ( 1H, d, j=9 Hz), by 8.22 (1H, d, j=9 Hz), of 8.09 (1H, d, j=8 Hz), 8,03 (1H, d, j=9 Hz), 7,81 (1H, d , j=8 Hz), 7,71-7,47 (4H, m).

2">

To a suspension of 6-chloro-3-methoxy-7H-indeno/2,1-C/quinoline-7-she obtained in reference example 9 (2 g, 6.8 mmol) in pyridine (20 ml) is added N,N-dimethylethylenediamine (3 g, 33.8 mmol), and the mixture is stirred under heating at 100oC for 24 hours. The reaction mixture is distilled until a dry residue. To the residue water is added and the chloroform for extraction. The chloroform layer is dried over magnesium sulfate and evaporated. The residue is purified column chromatography on silica gel (eluent chloroform: ethanol = 10:1 (V/V)), and crystallized from ethanol, to obtain 1.3 g (yield 55.3%) is named in the title compound 1. Physico-chemical properties of this compound are given in table. 1.

The compound obtained is dissolved in a mixture of chloroform with methanol and filtered off any insoluble matter. The filtrate is acidified with 4N hydrogen chloride in ethyl acetate, and collecting the precipitated crystals. The obtained crystals are dried under reduced pressure, and get the salt of the compound 1 (compound 1) with a quantitative yield. Physico-chemical properties of this compound are given in table. 1.

Example 2

Synthesis of the hydrochloride of 6-(((dimethylamino)ethyl)amino)-3-fluoro - 7H-indeno/2,1-C/quinoline-7-she (compound 2).

To a suspension of 6-chloro-3-is), and the mixture is stirred under heating at 90oC for 12 hours. The reaction mixture is distilled until a dry residue. To the residue water is added and the chloroform for extraction. The chloroform layer is dried over magnesium sulfate and evaporated. The residue is purified column chromatography on silica gel (eluent chloroform: ethanol = 10:1 (V/V)). The purified substance was dissolved in 20 ml of tetrahydrofuran. To the solution was added 4N solution of hydrogen chloride in dioxane (2 ml) and the mixture is concentrated under reduced pressure. The resulting residue is crystallized from diethyl ether, and obtain 420 mg (yield of 34.3%) named in the connection header. Physico-chemical properties of this compound are given in table. 1.

Example 3

Synthesis of 6-(((dimethylamino)ethyl)amino)-3-hydroxy-7H - indeno-/2,1-C/quinoline-7-she (compound 3).

To a solution of 6-(((dimethylamino)ethyl)amino)-3-methoxy-7H-indeno/2,1-C/quinoline-7-she obtained in example 1 (3 g, 8.6 mmol) in acetic acid (40 ml) was added 47% aqueous Hydrobromic acid (40 ml) and the mixture is refluxed for 60 hours. The reaction mixture is distilled until a dry residue. To the residue water is added, and the pH of the solution was adjusted to 8 with an aqueous solution of ammonia, and then extracted with glia on silica gel (eluent chloroform:methanol:water = 8:3:1 (V/V/V)), and the product is crystallized from cyclohexane, to obtain 2.1 g (yield 73%) named in the connection header. Its physico-chemical properties are given in table. 1.

The compound obtained is dissolved in a mixture of chloroform with methanol and filtered off any insoluble matter. The filtrate is acidified with 4N hydrogen chloride in ethyl acetate, and collect the precipitated crystalline substance. The obtained crystals are dried under reduced pressure, and get salt compound 3 (compound 3, the output 89.4 per cent). Its physico-chemical properties are given in table. 1.

Example 4

Synthesis of 6-(((dimethylamino)ethyl)amino)-3-(pivaloyloxy)-7H-indeno/2,1 - C/quinoline-7-she (compound 4).

To a solution of 6-(((dimethylamino) ethyl) amino)-3-hydroxy-7H-indeno/2,1-C/quinoline-7-she obtained in example 3 (100 mg, 0.3 mmol), in dichloromethane (10 ml) is added 4-dimethylamino-pyridine (100 mg, 0.8 mmol) and pivaloate (37 μl, 0.3 mmol) and the mixture stirred at room temperature for 3 hours. To the reaction mixture, water is added to wash the organic layer is then dried over magnesium sulfate and evaporated. The residue is purified column chromatography on silica gel (eluent chloroform:ethanol = 10:1 (V/V)), and crystallized from hexane, CLASS="ptx2">

Example 5

Synthesis of 6-(((dimethylamino)ethyl)amino)-3-hydroxy-4-nitro-7H-indeno/2,1 - C/quinoline-7-she (compound 5).

A mixture of 6-(((dimethylamino)ethyl) amino)-3-hydroxy-7H-indeno/2,1-C/quinoline-7-she obtained in example 3 (100 mg, 0.3 mmol), conc. sulfuric acid (1 ml) and nitric acid (1 ml) was stirred at 5oC for 2 hours. The reaction mixture was poured into a mixture of ice water and the precipitated crystals are collected by filtration. The resulting crystalline substance is purified column chromatography on silica gel (eluent - the bottom layer of a mixture of chloro-form: methanol: water = 9:3:1 (V/V/V)) and crystallized from ethanol and diethyl ether, to obtain 60 mg (yield of 52.9%) named in the connection header. Its physico-chemical properties are given in table. 1.

Example 6

Synthesis of the hydrochloride of 6-((aminoethyl)amino)-3 - hydroxy-7H-indeno/2,1-C/quinoline-7-she (compound 59).

To compound 56 (1.1 g) add 20 ml conc. hydrochloric acid according to the procedure of example 1, and the resulting mixture reacts at an ambient temperature of 100oC for 12 hours. Then to the mixture isopropanol. The resulting mixture was allowed to cool, and collected by filtration of precipitated crude crystalline substance. subishi Chemical Co. Co., Ltd. ) and elute with a mixture of solvents (methanol: water = 1:1 with the addition of 1 drop of conc. hydrochloric acid). Erwerbende fractions are concentrated under reduced pressure. The precipitated crystals filtered off, washed with ethanol and dried under reduced pressure, receive 524 mg (yield of 63.7%) named in the connection header.

Example 7

Synthesis of trihydrochloride 6-(((methylamino)ethyl) amino)-3-hydroxy-7H-indeno/2,1-C/quinoline-7-she (compound 60).

A mixture of conc. hydrochloric acid and dioxane (10 ml - 10 ml) is added to the connection 57 (1.0 g) obtained by the procedure of example 1, and the resulting mixture reacts at an ambient temperature of 100oC for 3 hours. After completion of the reaction the mixture was concentrated under reduced pressure. To the residue again add 10 ml conc. hydrochloric acid, and the resulting mixture reacts at an ambient temperature of 100oC for 2 hours. After completion of the reaction to the mixture of 30 ml of isopropanol and collected by filtering the precipitated crude crystalline substance. The resulting crude crystals are dissolved in water. To the solution add 0.5 ml of conc. hydrochloric acid and 30 ml of isopropanol, and the mixture is stirred under ice cooling for crystallization, and get iluminated)ethyl)amino) -3-hydroxy-7H-indeno/2,1-C/quinoline-7-she (compound 61).

Compound 53 (2.0 g) obtained by the procedure of example 1, dissolved in 10 ml of chloroform. After stirring the solution under ice cooling to the solution is added a solution of m-chloroperbenzoic acid (1.2 g) in chloroform (10 ml) and the resulting mixture reacts at room temperature for 3 hours. The reaction product is purified column chromatography on alumina (eluent chloroform: methanol = 40: 1) and receive 6-(((dimethylaminoethoxy)ethyl)amino) -3-benzyloxy-7H-indeno/2,1-C/quinoline-7-on. To connect add 7.5 ml of conc. hydrochloric acid, and the mixture reacts at an ambient temperature of 100oC for 1.5 hours. After the reaction mixture to add 12 ml of ethanol, the resulting mixture is allowed to cool, and collected by filtering the precipitated crude crystals. The resulting crude crystalline substance is suspended in 15 ml of ethanol. The suspension is stirred under heating, allow it to cool, and collected by filtration crystalline substance. The resulting crystals are then suspended in 15 ml dichloromethane and stirred under heating. Suspension allow to cool, and collected by filtration of the crystalline substance of 1.34 g (yield 84,1%) named in the connection header.

P>/P>To a solution obtained by dissolving sodium (1.78 g, 77.4 mmol) in 2-dimethylaminoethanol (80 ml, 796 mmol), add 6-chloro-9,10-methylenedioxy-7H-indeno/2,1-C/quinoline-7-he (8 g, and 25.8 mmol) obtained in reference example 2, and the mixture is stirred under heating at 60oC for 24 hours. The reaction mixture was poured into a mixture of ice water and extracted with chloroform. The chloroform layer is dried over magnesium sulfate and evaporated. The residue is purified column chromatography on silica gel (eluent chloroform:methanol = 10:1 (V/V)), and crystallized from ethyl acetate, get 6,37 g (yield 68,1%) named in the connection header. Its physico-chemical properties are given in table. 2.

The compound obtained is dissolved in chloroform and filtered off any insoluble matter. The filtrate is acidified with 4N solution of hydrogen chloride in ethyl acetate, and collect the precipitated crystalline substance. The obtained crystals are dried under reduced pressure, and get salt compound 64 (compound 64) with a quantitative yield. Physico-chemical properties of this compound are given in table. 2.

Examples 10 - 74

Connection 6 - 58 and 62 - 63, shown in the table. 1, connection 65 - 72, shown in the table. 2, the connection 73, shown in ticks, described in examples 1-9.

In addition, compound (9-a, 23 -, 26 -, 28 -, 31 -, 41 -, 47 -, 49 -, 50-and 66-a and 73-and get as hydrochloride by the same methods described in examples 1, 3 and 9 to get hydrochloride compounds 1-a, 3-a and 64-A.

Example 75

Synthesis of 6-(1-(4-methylpiperazine))-7H-indeno/2,1-C/isoquinoline-7-she (compound 75).

A mixture of 5-chloro-7H-indeno/2,1-C/isoquinoline-7-she obtained in reference example 17 (1.0 g, 3.7 mmol), N-methylpiperazine (2 ml, 18 mmol) and n, N-dimethylformamide (10 ml) was stirred at 100oC for 4 hours. To the reaction mixture, water is added, and the mixture is extracted with ethyl acetate. An ethyl acetate layer is dried over magnesium sulfate and evaporated. The residue is purified column chromatography on silica gel (eluent chloroform:methanol = 100:1 (V/ V)) and crystallized from ethanol, to obtain 400 mg (yield 32,3%) named in the connection header. Its physico-chemical properties are given in table. 5.

Examples 76 - 80

Connection 76 - 80, which are listed in the table. 5, synthesized in accordance with the procedure of example 75 from the appropriate starting materials.

The test results of the compounds of the invention on the antitumor activity are listed below and explained on the phone or email.

Cells of mouse leukemia P388 placed in a 96-well plate at a density of 2103cells per well. Compounds of the invention are dissolved in purified water or dimethyl sulfoxide, and the solution was diluted with medium to various concentrations and added to the appropriate wells. After incubation tablet for 3 days in culture, fixed with glutaraldehyde, and the number of surviving cells determined by the method of crystal violet staining.

The cytotoxic effect of each connection is defined as the concentration at which the number of cells is reduced to 50% of the number of cells in the control sample, i.e., IC50. The results are given in table. 6.

Example 2 pharmacological tests. Antitumor effect.

Cells of mouse leukemia P388 (1106cells / mouse) administered intraperitoneally injected mouse CDF1. Each of the compounds of the invention, dissolved in 5% glucose or 5% dimethyl sulfoxide, in certain concentrations administered intraperitoneally injected at 1 and 5 days after injection of leukemic cells. Antitumor activity of the compounds of the invention was evaluated as the percentage increase in life-cycle (% ILS), compared with an average survival nearabout who we are. The capsule.

Capsules are prepared in the usual way with the following composition:

The compound 3-a - 200 mg

Lactose 30 mg

Corn starch 50 mg

Crystalline cellulose 10 mg

Magnesium stearate 3 mg

One capsule of 293 mg

Example 2 dosage forms. Tablets.

Tablets of the following composition is prepared in the usual way:

Connection 7 to 100 mg

Lactose - 47 mg

Corn starch 50 mg

Crystalline cellulose 50 mg

Hydroxypropylcellulose 15 mg

Talc 2 mg

Magnesium stearate 2 mg

Ethylcellulose 30 mg

The glycerides of unsaturated fatty acid 2 mg

Titanium dioxide 2 mg

On one tablet 300 mg

Example 3 dosage forms. Granules.

Granules of the following composition is prepared in the usual way:

The connection 28 to a - 200 mg

Mannitol - 540 mg

Corn starch 100 mg

Crystalline cellulose 100 mg

Hydroxypropylcellulose 50 mg

Talc 10 mg

One wrap - 1000 mg

Example 4 dosage forms. Small granules.

Small of the following composition granules are obtained in the usual way:

Compound 64-a - 200 mg

Mannitol, 5 mg

Talc 10 mg

On one pack 1000 mg

Example 5 dosage forms. The injection.

The injection solution of the following composition is prepared in the usual way:

The connection 41-a 100 mg

Distilled water for injection appropriate amount

One ampoule of 2 mg

Example 6 dosage forms. Suppositories.

Suppositories of the following composition is prepared in the usual way:

Connection 73-a - 200 mg

Witepsol S-55 (Witepsol S-55, a registered trade mark; a mixture of mono-, di - and triglycerides of saturated fatty acids from lauric up stearic acid; a product of Dynamit Nobel Co., Ltd.) - 1300 mg

One suppository - 1500 mg

1. Condensed derivative Indiana General formula I or their pharmaceutically acceptable salts

< / BR>
where ring a represents an optionally substituted benzene or naphthalene ring, imeyushee as substituents halogen atom, a lower CNS group, a hydroxyl group or a benzene ring condensed with the lowest alkylenedioxy;

the ring represents an optionally substituted benzene having as substituents, halogen atom, lower alkiline allmenalp, lower alkoxycarbonyl group or benzene ring condensed with the lowest alkylenedioxy;

Y = -N=CR or CR=N-,

where R represents (1) an optionally substituted nitrogen-containing heterocyclic group, (2) the group-NR1R2or (3) a group - OR3where R1and R2the same or different and each represents (a) hydrogen atom, (b) phenyl group, or (C) a lower alkyl group which may be substituted by at least one substituents selected from the group consisting of: (1) optionally substituted amino groups, (C-2) nitrogen-containing heterocyclic group, (C-3) aminoacides group, a substituted lower alkyl group, or (4) a hydroxyl group;

R3represents a lower alkyl group optionally substituted by a substituted amino group,

provided that when R is optionally substituted nitrogen-containing heterocyclic group, ring a and ring - unsubstituted benzene ring.

2. Condensed derivative indane or their pharmaceutically acceptable salts under item 1, in which the substituents in the ring And are selected from the group consisting of halogen atoms, lower CNS groups and hydroxyl is their CNS groups, hydroxyl group, nitro group, amino group, benzyloxy and lower acylamino.

3. Condensed derivative indane or their pharmaceutically acceptable salts under item 1 or 2, where R1and R2the same or different and each represents a hydrogen atom; a phenyl group; a lower alkyl group which may be substituted by an optionally substituted amino group, nitrogen-containing heterocyclic group, aminoxide group, a substituted lower alkyl group or a hydroxyl group (or groups).

4. Condensed derivative indana with indeno(2,1-C)quinoline structure, or their pharmaceutically acceptable salts under item 1 or 2, where Y = -CR= N-, R represents a group-NR1R2where R1and R2the same or different and each represents a hydrogen atom or a lower alkyl group, optionally substituted di (lower alkyl) substituted amino group or nitrogen-containing heterocyclic group, piperazinilnom group, a substituted lower alkyl group, or R - OR3group, where R3represents a lower alkyl group, optionally substituted di(NISSEI alkyl) substituted amino group.< represents a lower alkyl group, substituted di(lower alkyl) substituted amino group or nitrogen-containing heterocyclic group, R2represents a hydrogen atom.

6. Condensed derivative indane or their pharmaceutically acceptable salts under item 4, where R1represents a lower alkyl group substituted by dimethylaminopropoxy, diethylaminopropyl or pyrrolidinyl group.

7. Condensed derivative Indiana or pharmaceutically acceptable salt according to any one of paragraphs. 1 - 6, where the ring is a benzene ring substituted hydroxilic group (or groups).

8. Condensed derivative Indiana or pharmaceutically acceptable salt according to any one of paragraphs. 1 - 6, where ring a is a benzene ring, optionally substituted with hydroxyl group (or groups) or atom (atoms) halogen.

9. Condensed derivative Indiana or pharmaceutically acceptable salt according to any one of paragraphs. 1 - 6, where ring a is a benzene ring condensed with the lowest alkylenedioxy.

10. Condensed derivative indane having the structure indeno (2,1-C)quinoline, or their pharmaceutically acceptable salts under item 1, where Y = -CR= what each of them represents a hydrogen atom or a lower alkyl group, optionally substituted di(lower alkyl) substituted amino group or nitrogen-containing heterocyclic group; or R represents piperazino group, a substituted lower alkyl group, or a group OR3in which R3represents an alkyl group, optionally substituted di(lower alkyl) substituted amino group, the ring a represents a benzene ring, unsubstituted or substituted by 1 or 2 hydroxyl groups and/or atoms (atoms), halogen, or a benzene ring condensed with the lowest alkylenedioxy; a ring represents a benzene ring substituted by 1 or 2 hydroxyl groups.

11. Condensed derivative indane having the structure indeno (2,1-C)quinoline, or their pharmaceutically acceptable salts under item 1, where Y = -CR= N-, R represents a group-NR1R2in which R1represents a lower alkyl group, a substituted di(lower alkyl) substituted amino group or nitrogen-containing heterocyclic group, R2represents a hydrogen atom, ring a represents a benzene ring, unsubstituted or substituted by 1 or 2 hydroxyl groups and/or atoms (atoms), halogen, or benzene asenne 1 or 2 hydroxyl groups.

12. Condensed derivative indane having the structure indeno(2,1-C)quinoline, or their pharmaceutically acceptable salts under item 1, where Y = -CR=N-, R represents a group-NR1R2in which R1represents a lower alkyl group substituted by dimethylaminopropoxy, diethylaminopropyl or pyrrolidinyloxy group, R2represents a hydrogen atom, ring a represents a benzene ring, unsubstituted or substituted by 1 or 2 hydroxyl groups and/or atoms (atoms), halogen, or a benzene ring condensed with the lowest alkylenedioxy, the ring is a benzene ring substituted by 1 or 2 hydroxyl groups.

13. The composition having anti-tumor activity, characterized in that it contains condensed derived Indiana or its pharmaceutically acceptable salt p. 1, in an effective amount and a pharmaceutically acceptable carrier.

14. The composition according to p. 13, characterized in that it is useful in the treatment of malignant tumors in mammals.

15. The method of obtaining condensed derivatives indana formula I

< / BR>
where ring a is a benzene, naftalinovui optionally substituted benzene or has as substituents halogen atom or a lower alkoxygroup Y =-N=CR or CR=N-, where R represents (2) a group-NR1R2or (3) a group-OR3in which R1and R2- the same or different and each represents (a) hydrogen atom or (b) a lower alkyl group substituted by an optionally substituted amino group; R3represents a lower alkyl group substituted by a substituted amino group, consisting in the fact that the compound of formula II

< / BR>
where ring a And ring b have the above meanings;

Z=-CX=N - or-N=CXS-, where X represents a halogen atom,

subjected to interaction with the compound RH, where R has the values listed above.

 

Same patents:

The invention relates to 6-[X-(2-hydroxyethyl)aminoalkyl]-5,11-dioxo-5,6,-dihydro-11H - indeno[1,2-C]isoquinolines of the General formula I

< / BR>
in which

X represents the number of carbon atoms equal to 0-5 in aminoalkyl group, located at the nitrogen atom in the 6 position of the canonical formulas indrosophila, to their salts with inorganic and organic acids and method of production thereof
The invention relates to medicine, for treatment of allergic and diatopically diseases of the eyes and nose
The invention relates to medicine, for treatment of allergic and diatopically diseases of the eyes and nose

The invention relates to tetraethylammonium compounds of the formula I

< / BR>
and their pharmaceutically acceptable salts,

where R1represents one or more substituents selected from H, halogen, hydroxy, alkyl with 1 to 3 carbon atoms (optionally substituted by hydroxyl), alkoxyl with 1 to 3 carbon atoms, alkylthio with 1 to 3 carbon atoms, alkylsulfonyl with 1 to 3 carbon atoms, alkylsulfonyl with 1 to 3 carbon atoms, nitro, cyano, Polygalaceae with 1 to 3 carbon atoms, polyalkyloxy with 1 to 3 carbon atoms, phenyl (optionally substituted by one or more substituents selected from halogen, alkyl with 1 to 3 carbon atoms, alkoxy with 1 to 3 carbon atoms), or R1is carbamoyl, optional alkilirovanny one or two alkyl groups, each independently from 1 to 3 carbon atoms;

R2represents an aliphatic group containing 1 to 3 carbon atoms, optionally substituted by hydroxy or alkoxy containing 1 to 3 carbon atoms;

E represents alkylenes chain containing 2 to 5 carbon atoms, optionally substituted by one or more alkyl groups containing 1 to 3 atom is dinasovymi or different and are independently an alkyl of 1 3 carbon atoms, alkoxy with 1 to 3 carbon atoms, halogen, hydroxy, polyaluminum with 1 to 3 carbon atoms, polyalkyloxy with 1 to 3 carbon atoms, cyano, alkylthio with 1 to 3 carbon atoms, alkylsulfonyl with 1 to 3 carbon atoms, alkylsulfonyl with 1 to 3 carbon atoms, phenyl (optionally substituted by one or more substituents selected from halogen, alkyl with 1 to 3 carbon atoms or alkoxy with 1 to 3 carbon atoms), carbamoyl, optional alkilirovanny one or two alkyl groups, each of which is independently from 1 to 3 carbon atoms, or G represents a phenyl ring having condensed with him heterocyclic or aromatic carbocyclic ring,

and O-acylated derivatives
The invention relates to medicine, Nephrology

The invention relates to 6-[X-(2-hydroxyethyl)aminoalkyl]-5,11-dioxo-5,6,-dihydro-11H - indeno[1,2-C]isoquinolines of the General formula I

< / BR>
in which

X represents the number of carbon atoms equal to 0-5 in aminoalkyl group, located at the nitrogen atom in the 6 position of the canonical formulas indrosophila, to their salts with inorganic and organic acids and method of production thereof

The invention relates to water-soluble derivative of camptothecin described by formula (I)

< / BR>
where n = 1 or 2; 1) R1and R2taken separately, represent hydrogen, lower alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, lower alkoxy lower alkyl; 2) R1represents hydrogen, lower alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl or lower alkoxy lower alkyl; R2is-COR3where R3represents hydrogen, lower alkyl, pergola-lower alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl, lower alkyl, lower alkenyl, hydroxy lower alkyl, lower alkoxy, lower alkoxy lower alkyl; 3) R1and R2taken together with the connecting nitrogen atom form a saturated 3-7-atom heterocyclic group of formula 1A

< / BR>
where Y represents O, S, CH2, NR4where R4represents hydrogen, lower alkyl, pergola-lower alkyl, aryl, aryl substituted by one or more substituents selected from the group comprising lower alkyloxy lower alkyl, or COR5where R5represents hydrogen, lower alkyl, pergola-lower alkyl, lower alkoxy, aryl, aryl substituted by one or more substituents selected from the group comprising lower alkyl, pergola-lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl; and their pharmaceutically acceptable salts, their use for the treatment of tumors and methods of preparation

The invention relates to new chemical substances possessing valuable properties, in particular derivatives pyridyl General formula (I)

< / BR>
where

n is the number 2, 3, 4 or 5,

A - uglerodsesola communication or unbranched Allenova group with 1 to 4 carbon atoms, unsubstituted or substituted by one or two alkyl groups,

X - nitromethylene group, cyanomethylene group, unsubstituted or substituted by a residue R6with the following for R4values except tetrazole, or a group of formula =N-R7where R7is cyano, alkanesulfonyl group, phenylsulfonyl group, phenylalkylamine group, aminosulfonyl group, alkylaminocarbonyl group, dialkylaminoalkyl group, phenylcarbonylamino group, aminocarbonyl group, alkylaminocarbonyl group or dialkylaminoalkyl group,

Y - alkoxygroup, fenoxaprop, allylthiourea, phenylthiourea or a group of the formula-R8NR9where R8means a hydrogen atom, an unbranched or branched alkyl group with 1 to 10 carbon atoms, which is in the 2nd, 3rd or 4th position can be C is POI or peredelnoj group, alkyl group with 1 to 4 carbon atoms, which may optionally be substituted with hydroxyl group in the 2 nd, 3rd or 4th position, cycloalkyl group with 3 or 4 carbon atoms, cycloalkyl group with 5-8 carbon atoms, in which one ethylene bridge can be replaced on-phenylenebis group, bicycloalkyl group with 6 to 8 carbon atoms, unsubstituted or substituted 1, 2 or 3 alkyl groups, adamantly group, alkoxygroup or trimethylsilylethynyl group, and R9is a hydrogen atom or an unbranched alkyl group, or R8and R9together with in between the nitrogen atoms form an unsubstituted or substituted by one or two alkyl groups or phenyl group, cyclic alkalinising with 4 to 6 carbon atoms, in which one ethylene bridge in the provisions of 3.4 can be replaced on-phenylenebis group, morpholinopropan or piperazinone, unsubstituted or substituted in the 4-position of the alkyl group with 1 to 3 carbon atoms or phenyl group,

R1is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms,

R2and R3is a hydrogen atom or together form a carbon-carbon bond,

Pyr - Peregrina group, unsubstituted or sameena the group, alkylaminocarbonyl group, dialkylaminoalkyl group, group, translated in vivo metabolic by carboxyl group or carboxyl group, if Y represents the group R8NR9where R8and R9have the above meaning,

R5is a hydrogen atom or the halogen, alkyl, alkoxy or trifluoromethyl,

all of the aforementioned alkyl and CNS remains, if nothing else is mentioned, have 1 to 3 carbon atoms, and, if nothing else is mentioned, all the above-mentioned phenyl nuclei may be mono - or tizamidine identical or different substituents from the group comprising an atom of fluorine, chlorine, or bromine, alkyl, hydroxyl, alkoxyl, carboxyl, phenyl, nitro-, amino-, alkylamino, dialkylamino, alkanolamine, cyano, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl and dialkylaminoalkyl,< / BR>
their enantiomers, CIS - or TRANS-isomers, if R2and R3together denote a carbon-carbon bond, and their salts

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

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

13 cl, 3 tbl, 35 ex

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides antibacterial drug in the form of enveloped tablet with its nucleus containing ofloxacin as active substance and auxiliary ingredients: silica powder, calcium stearate, collidone, sodium carboxymethylcellulose, milk sugar, talc, and microcrystalline cellulose. Envelop of tablet contains collidone, hydroxypropylcellulose, talc, and titanium dioxide. Manufacture of tablet comprises mixing ofloxacin, silica powder, milk sugar, and microcrystalline cellulose; moistening resulting mixture with collidone solution; wet granulation; drying; dry granulation; and powdering of granules with mixture of calcium stearate and sodium carboxymethylcellulose. Afterward, granules are enveloped.

EFFECT: increased storage stability.

2 cl

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I): with the crystalline modification A and a drug eliciting effect against pathogenic microorganisms. The prepared crystalline modification shows stability and doesn't transform to another crystalline modification or amorphous form being even at prolonged storage.

EFFECT: improved and valuable properties of compound.

4 cl, 4 dwg, 6 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides composite therapeutical agent exhibiting antituberculous effect and made in the form of solid dosage form containing as active principle combination of lomefloxacin, isoniazid, pyrazinamide, ethambutol hydrochloride, and pyridoxine hydrochloride plus auxiliaries.

EFFECT: increased assortment of antituberculous drugs.

4 cl, 1 tbl, 4 ex

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