Tetrahydroisoquinoline compounds, methods for their preparation, pharmaceutical composition having antioxidant activity, anti-oxidant composition and method of stabilizing compounds susceptible to oxidation

 

(57) Abstract:

Usage: as a hydrophobic antioxidants on the basis of indecently patterns that can be used for fighting free radicals in lipids or lipid double phases, as well as for the stabilization of compounds susceptible to oxidative degradation. CIS-4b, 5, 9b, 10 - tetrahydro-5-ethyl-8-(N1N-diethylamino)-indeno [1,2-b]indole, yield 65%, the connection is unstable and the air turns blue and then dark red. CIS-4b, 5,9 b, 10-tetrahydro-5-methyl-8-tert-butylidene [1,2-b] indole, yield 96%, so pl. 74oC. 7 C. and 13 C.p. f-crystals, 3 tables.

The invention describes a new type of hydrophobic antioxidants based indeoendence patterns that are highly effective at restoring, i.e., the quenching of free radicals in lipids or lipid double phases, thus stopping the formation of peroxides in lipids and preventing the resulting process or related processes, conditions and diseases. The invention also describes compositions, especially pharmaceutical compositions containing as active ingredient at least one of the compounds of the invention or its salt, especially therapeuticsexplores active compounds in medical therapy, as well as for non-medical purposes. Especially important for non-medical applications would use to control or interrupt processes involving free radicals.

Some biological processes generate more or less stable intermediate products containing an unpaired electron, which can be either isolated or paired with additional electron from the environment. Such intermediates are called free radicals, and they can be products of different enzymatic or nonenzymatic reactions, some of which are vital for body functions, such as restoring ribonucleosides for DNA synthesis and the production of prostaglandins in the reaction prostaglandines. The latter is essential for the inflammatory response to cell damage and for a number of other functions. Other radical reactions include myeloperoxidase response in neutrophils and macrophages, which destroy bacteria and other invading particles and the transport of electrons in the mitochondrial respiratory chain. Most organisms contain chemical antioxidants, such as tocopherol (vitamin E), ascorbic acid and various radical and peroxide-enaknya radicals of various types are increasingly associated with a range of conditions and disorders such as ischemic or reperfusion disease, thrombosis, embolism, atherosclerosis, allergic/inflammatory condition type of bronchial asthma and rheumatoid arthritis, conditions related to Parkinson's disease, Alzheimer's disease or aging, cataracts, diabetes, tumors and toxicity of anticancer or immunosuppressive reagents and chemicals. One possible explanation of these conditions and diseases is that for reasons unknown, endogenous protectors from radical destruction insufficient to protect tissue from damage by radicals. Peroxidizable lipids, caused by excess production of these radicals can be the basis of one significant destructive mechanism that leads to the above conditions and diseases. Thus, the appointment of additional antioxidants, inhibiting radical reactions, i.e. peroxidizable lipids, would have given way to prevent or treat the above conditions and diseases. The invention describes new antioxidants indeoendence type that satisfy and demand accumulation in the membranes, i.e., they are quite hydrophobic, and they are potential inhibitors peroxidizable lipids.also be used for non-medical purposes for stabilizing compounds, susceptible to oxidative degradation, for example, in the means for skin care, nutritional supplements, preservatives, food and other products. The invention extends to a method of stabilization using indenolol, and the resulting stabilized compositions.

Previous inventions in this field

N-Methyl-4b, 5,9 b,10-tetrahydroindene[1,2-b] indole is described in J. Chem. Soc. Chem. Commun. p.647-48 (1981).

4b, 5,9 b, 10-tetrahydro-9b-ethylidene[1,2-b] indole is described in Beilsteins Handbuch Der Organishen Chemie, 4:e Edition of It. 200 EII, p.310-311 (1953).

Found that compounds with tetrahydroisoquinoline structure having formula IA (TGII) and IB (ISO-THII), effective as inhibitors of the process peroxidizable lipids and suitable as antioxidants, IA or IB can be represented in the form of a racemic mixture or in enantiomeric form, or

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in which R is hydrogen, an alkyl group or COR15, R1, R11and R12independently selected from hydrogen or lower alkyl groups, R3, R4, R5and R6independently selected from hydrogen, hydroxyl, halogen, lower alkyl groups, lower alkoxygroup, mono - or di-lower alkylamino, NH2or NR13Solo group, low alkoxygroup, mono - or di-lower alkylamino, NH2or NR13COR14, R13, R14and R15independently selected from hydrogen or lower alkyl groups with the proviso that when R is COR14then at least one of the substituents from R3to R10is hydroxyl or mono - or di-lower alkylaminocarbonyl, as well as enantiomers or salts of these compounds.

The new compounds of the invention have formula IA or IB, or

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in which R is hydrogen, an alkyl group or COR15,

R1, R2, R11and R12independently selected from hydrogen or lower alkyl groups,

R3, R4, R5and R6independently selected from hydrogen, hydroxyl, halogen, lower alkyl groups, lower alkoxygroup, mono - or di-lower alkylamino, NH2or NR13COR14,

R7, R8, R9and R10independently selected from hydrogen, hydroxyl, lower alkyl groups, lower alkoxygroup, mono - or di-lower alkylamino, NH2or NR13COR14,

R13, R14and R15independently selected from hydrogen or lower alkyl groups when the following conditions>is not hydrogen;

2) when R is hydrogen and R11is ethyl in formula IA, at least one of the radicals from R1to R10or R12is not hydrogen;

and enantiomers and salts of these compounds.

The following compounds of formula IA (TGII) and IB (ISO-THII), which are effective as inhibitors of the process peroxidizable lipids, especially suitable as antioxidants in medical therapy, or

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in which R is hydrogen, an alkyl group or COR15,

R1, R2, R11and R12independently selected from hydrogen or lower alkyl groups,

R3, R4,R5and R6independently selected from hydrogen, hydroxyl, halogen, lower alkyl groups, lower alkoxygroup, mono - or di-lower alkylamino, NH2or NR13COR14,

R7, R8, R9and R10independently selected from hydrogen, hydroxyl, lower alkyl groups, lower alkoxygroup, mono - or di-lower alkylamino, NH2or NR13COR14,

R13, R14and independently selected from hydrogen or lower alkyl groups,

with the proviso that when R is COR15then at least as well as enantiomers or pharmaceutically acceptable salts of these compounds.

Patterns of indenolol and ISO-indenolol of the invention have the following numbering of the atoms in the rings:

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4b,5,9 b,10-Tetrahydroindene[1,2-b]indole (TGII);

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5,5 a,6,10 b-Tetrahydroindene[2,1-b]indole (ISO-THII).

The alkyl group in the definition of R include an alkyl group having 1-24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexadecyl, octadecyl.

The term "lower" in the definition of substituents in the compound of the invention means that the number of carbon atoms not greater than 6, preferably not more than 4.

The lower alkyl group in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14and R15is an alkyl group having 1-6 carbon atoms, preferably 1-4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, preferred are methyl and ethyl.

The lower alkoxy group in the definition of R3, R4, R5and R6, R7, R8, R9and R10there alkoxy group having 1-6 carbon atoms, preferably 1-4 carbon atoms, such as IU Auda methoxyl and ethoxyl.

Halogen in the definition of R3, R4, R5and R6is chlorine, bromine, iodine or fluorine.

Mono - or di-lower alkylamino in the definition of R3, R4, R5, R7, R8, R9and R10include methylamino-, dimethylamino-, ethylamino, diethylamino, propylamino, dipropylamino, butylamino, dibutylamino, preferred are ethylamino or diethylaminopropyl.

Preferred groups of compounds of the invention are those in which R, R1, R2, R4and R6and R10are hydrogens and R5and/or R8is a lower alkoxygroup, especially methoxy, and/or R3, R5, R7, R9, R11and/or R12is a lower alkyl group, especially methyl, ethyl, isopropyl, and those compounds in which R5and/or R8there is a mono - or dialkylamino, especially ethylamino or diethylaminopropyl.

Preferred compounds having formula IA and IB tetrahydroindole, which are included in the invention are the following:

CIS-4b,5,9 b,10-tetrahydroindene[1,2-b]indole

CIS-4b,5,9 b,10-tetrahydro-6,8-dimethindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-5,8-dimethindene[1,2-b]indole;

CIS-4b,5,9 b,10-b,10-tetrahydro-8-isopropylidene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-5-methylindene[1,2-b]indole;

CIS-4b,5,9 b,10--tetrahydro-8-methoxyimino[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-10,10-dimethindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-9b-methylindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-4b,9b-dimethindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-4b,5,9 b-trimethylbenzene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-2-methoxy-1,3-dimethylbenzene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-2-methoxy-1,3-dimethyl-8-isopropylidene[1,2-b] indole;

CIS-4b,5,9 b,10-tetrahydro-4b-methylindene[1,2-b]indole;

CIS-4b, 5,9 b, 10-tetrahydro-2-hydroxy-1,3-dimethyl-8-isopropylidene[1,2-b] indole;

CIS-4b,5,9 b,10-tetrahydro-2-hydroxy-1,3-dimethylbenzene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-4b,8,9 b-trimethylbenzene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-isopropyl-4b,9b-dimethindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-isopropyl-4b-methylindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-2,8-dimethoxy-1,3,dimethindene-[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-4b,5,8,9 b-tetramethylbenzene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-tert-butylidene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-7,9-dimethindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-6-methylindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-diethylamino-5-this is util-4b-methylindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-Florentino[1,2-b]indole;

CIS-5,5 a,6b,10-tetrahydroindene[1,2-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-9-methoxyimino[1,2-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-9-isopropylidene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-4b,6-dimethindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-4b,5,6-trimethylbenzene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-5,6-dimethindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-6-isopropylidene[1,2-b]indole;

CIS-4b, 5,9 b, 10-tetrahydro-8-methoxy-4b-methyl-6-isopropylidene[1,2-b] indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-4,6-dimethylbenzene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-4,4 b,6-trimethylbenzene[1,2-b]indole;

CIS-4b, 5,9 b,10-tetrahydro-8-methoxy-4b,5,6,8,9 b-pentamethylbenzene[1,2-b] indole;

CIS-4b,5,9 b,10-tetrahydro-8-diethylamino-6-methylindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-diethylamino-4b,6-dimethindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-diethylamino-4b,5,6-trimethylbenzene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-6,10,10-trimethylbenzene[1,2-b]indole;

CIS-4b, 5,9 b, 10-tetrahydro-8-methoxy-4b,6,10,10-tetramethylbenzene[1,2-b] indole;

CIS-4b, 5,9 b, 10-tetrahydro-8-diethylamino-6,10,10-trimethylbenzene[1,2-b] indole;

CIS-4b, 5,9 b, 10-tetrahydro-8-diethylamino-4b, 6,10,10-Tetra is Idro-8-hydroxy-4b,7,9-trimethylbenzene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-hydroxy-7,9-decret-butylidene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-hydroxy-6,7,9-trimethylbenzene[1,2-b]indole;

CIS-4b, 5,9 b, 10-tetrahydro-8-hydroxy-4b, 6,7,9-tetramethylbenzene[1,2-b] indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-4b,6,9 b-trimethylbenzene[1,2-b]indole;

CIS-4b, 5,9 b, 10-tetrahydro--8-methoxy-4b,5,6,9 b-tetramethylbenzene[1,2-b] indole;

CIS-4b, 5,9 b, 10-tetrahydro-8-diethylamino-4b, 6,9 b-trimethylbenzene[1,2-b] indole;

CIS-4b, 5,9 b, 10-tetrahydro-8-diethylamino-4b, 5,6,9 b-tetramethylbenzene[1,2-b] indole;

CIS-5,5 a,6,10 b-tetrahydro--9-methoxy-7-methylindolo[2,1-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-9-methoxy-5a,7-dimethindene[2,1-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-9-diethylamino-7-methylindene[2,1-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-9-diethylamino-5a,7-dimethindene[2,1-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-9-hydroxy-8,10-dimethindene[2,1-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-9-hydroxy-7,8,10-trimethylbenzene[2,1-b]indole;

CIS-5,5 a, 6,10 b-tetrahydro-9-hydroxy-5a, 7,8,10-tetramethylbenzene[2,1-b] indole;

CIS-5,5 a,6,10 b-tetrahydro-9-diethylaminopentane[2,1-b]indole;

CIS-4b,5,9,10-tetrahydro-6-isopropylidene[2,1-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-9-methoxy-5,5,7-trimethylbenzene[2,1-b]indole;

CIS-5,5 a, 6,10 b-tetrahydro-9-diethylamino-5,5,7-trimethylbenzene[2,1-b] in isopropylidene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-4b-isopropyl-6-methylindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-isopropyl-5-methylindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-6-ethylidene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-3-methoxy-4b-methylindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-7-methoxy-4b-methylindene[1,2-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-3-hydroxy-2,4-dimethylbenzene[2,1-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-acetamido-6-methylindene[1,2-b]indole;

CIS-4b, 5,9 b,10-tetrahydro-2-acetamido-8-methoxy-6-methylindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-tert-butyl-5-methylindene[1,2-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-3-acetamidophenol[2,1-b]indole;

CIS-4b,5,9 b,10-tetrahydro-2-acetamidophenol[1,2-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-6-methylindene[2,1-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-6-ethyl-9-isopropylidene[2,1-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-9-Florentino[2,1-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-9-tert-butylidene[2,1-b]indole.

Preferred tetrahydroisoquinoline compounds of the invention having antioxidant activity, are the following:

CIS-4b,5,9 b,10-tetrahydroindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-6,6-dimethindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-5,8-dimethindene[1,2-b]indole;
CIS-4b,5,9 b,10-tetrahydro-8-isopropylidene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-5-methylindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxyimino[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-10,10-dimethindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-9b-methylindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-4b,9b-dimethindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-4b,5,9 b-trimethylbenzene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-2-methoxy-1,3-dimethylbenzene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-2-methoxy-1,3-dimethyl-8-isopropylidene[1,2-b] indole;

CIS-4b,5,9 b,10-tetrahydro-4b-methylindene[1,2-b]indole;

CIS-4b, 5,9 b, 10-tetrahydro-2-hydroxy-1,3-dimethyl-8-isopropylidene [1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-2-hydroxy-1,3-dimethylbenzene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-4b,8,9 b-trimethylbenzene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-isopropyl-4b,9b-dimethindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-isopropyl-4b-methylindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-2,8-dimethoxy-1,3-dimethylbenzene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-4b,5,8,9 b-tetramethylbenzene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-tert-butylidene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-7,9-dimethindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-methoxy-6-methylindene[1,inaintea[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-tert-butyl-4b-methylindene[1,2-b]indole;

CIS-4b,5,9 b,10-tetrahydro-8-Florentino[1,2-b]indole;

CIS-5,5 a,6,10 b-tetrahydroindene[2,1-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-9-methoxyimino[2,1-b]indole;

CIS-5,5 a,6,10 b-tetrahydro-9-isopropylidene[2,1-b]indole.

Compounds having formula IA and IB, can exist as such and in the form of pharmaceutically acceptable salts. For compounds with the General formula IA and IB, which are asymmetric, as pure enantiomers, mixtures of enantiomers and racemic mixtures are encompassed by the present invention.

Pharmaceuticals/

The compounds of formula IA and IB will normally be administered orally, rectally, through the skin or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic salts with an acid, such as hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulpham, citrate, tartrate, oxalate and the like, in a pharmaceutically acceptable dosage form. Dosage form may be solid, semisolid and liquid drug. Usually the active substance will be from 0.1 is from 0.2 to 50% by weight for preparations prescribed oral. In preparations for injection through the skin usually used is 0.1 to 5% by weight of active ingredient in a suitable binder.

To obtain pharmaceutical preparations containing the compound of formula I in a dosage form for oral application, the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches type of potato starch, corn starch or amylopectin, cellulose derivatives, a binder type of gelatin or polyvinylpyrrolidone, and the lubricant type stearate, calcium stearate, polyethylene glycol, waxes, paraffin and the like, and then pressed into tablets. If you need a tablet in the shell, the core, prepared as described above, can be coated with a concentrated sugar solution which may contain, for example, gum Arabic, gelatin, talc, titanium dioxide and the like substance. On the other hand, the tablet can be coated well-known expert in the field of polymer dissolved in a readily volatile organic solvent or mixture of organic solvents. In coating, you can add coloring materials in order to easily distinguish between tabka gelatin capsules, the active substance can be added to, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the active substance, using either of the above-mentioned excipients for tablets type lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. Drugs in liquid and semi-liquid form, you can also fill hard gelatin capsules. Dosage forms for rectal application can be a solution or suspension of, or be prepared in the form of suppositories comprising the active substance in a mixture with a neutral fat base, or gelatin rectal capsules that contain the active substance in a mixture with vegetable oil or paraffin oil.

Liquid preparations for oral administration can be in the form of syrups or suspensions, for example solutions containing from about 0.2 to about 20% by weight described here, the active substance, the rest is sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and karboksimetilcellyulozy for parenteral applications by injection can be prepared in the form of an aqueous solution of water-soluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of from about 0.5 to about 10% by weight. Such solutions may also contain stabilizing agents and/or damping agents and they can easily be prepared in the form of ampoules of different dosage.

The appropriate daily dose of the compounds of the invention in therapeutic treatment of humans are about 0.01 to 100 mg/kg body weight by oral appointment of 0.001 to 100 mg/kg of body weight at parenteral purpose.

Method of preparation.

Compounds of the invention can be obtained as described below, but the invention is not limited to these methods, the compounds can be obtained using the processes described earlier.

Methods, including the preparation of compounds THEY and ISO-THII of not THEY or ISO-THII the original substances.

a. 4b, 5,9 b, 10-tetrahydroindene[1,2-b] indole (TGII, IA) and analogues containing functional groups, atoms benzolamide rings and/or radicals in position C-10, such as lower alkyl, lower alkoxyl, can be obtained by restoring the corresponding 5,10-dihydroindeno[1,2-b] indole (DGII).

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R, R1, R2, R3, R4, R5, R6, R7, R8, R9and the ne mineral acid, such as hydrochloric acid, or more efficiently by the reaction with the reducing agent on the basis of boron type nitrobenzamide in a solvent, usually acetic acid, or BH3in tetrahydrofuran. Or you can use morpholinopropan in a solvent, often in tetrahydrofuran or dioxane, in the presence of a strong acid, for example hydrochloric acid. Or you can use trialkylsilyl. Upon completion of the reaction product can be distinguished by diluting the reaction mixture with water, neutralizing and either by filtration or extraction. Or recovery is achieved by hydrogenation catalyst type palladium, in this case, the product produce by removal of the catalyst and evaporation of the solvent under reduced pressure. THEY and its analogues can be cleaned by crystallization from a suitable solvent or by column chromatography on silica. DGII and its analogs are synthesized by the reaction of indomethacin Fisher from phenylhydrazine formula 2 and 1-indanone formula III, where R11is hydrogen. 5-Alkyl-4b,5,9 b,10-tetrahydroindene[1,2-b]indoles (N-alkyl-Tgiii) receive either N-alkylation of the corresponding DGII compounds to the reduction reaction of, any of their respective 5H-THII compounds by pramualratana their base before interaction with alkylhalogenide or alkylsulfate.

b. 4b,5,9,10-Tetrahydroindene[1,2-b]indole and analogues bearing a substituent at position C-9b, can be obtained using the synthesis of indoles Fisher and subsequent reduction of the intermediate indolenine (IV).

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R1, R2, R3, R4, R5, R6, R7, R8, R9, R10and R11defined as under formula IA, and, if necessary, with subsequent N-alkylation of R-halide or R-sulfate, where R is defined as in formula IA.

2-Substituted 1-indanone (III) or equivalent to the original materials, with the appropriate substitution of functional groups in benzolamide ring and in position C-3 can interact with phenylhydrazine (II) either in free base form or in salt form, often cleaners containing hydrochloride. Typically, the reagent is dissolved in a solvent, preferably an alcohol solvent type ethanol or propanol. In some cases, heating is required, while in others it is necessary to heat the reaction mixture at boiling for a period of time up to 1 h or more. Phenylhydrazones product can be selected by diluting the reaction mixture with water and separated by filtration or extraction with a suitable solvent. Further purification of the AET column chromatography on silica, you can use a number of eluting solvents.

Cyclization of phenylhydrazones in indolenine (IV) is achieved by re-dissolution in a suitable solvent, preferably an alcohol solvent type ethanol or propanol, and treatment solution of acid, such as hydrochloric acid, acetic acid or triperoxonane acid. This may require or not require heating. You can also use other cyclessa reagents comprising a Lewis acid such as zinc chloride, or reagents containing a phosphorus atom, for example, trichloride phosphorus, oxytrichloride phosphorus, polyphosphoric acid or polyphosphate. If you use salt phenylhydrazine instead of phenylhydrazine in reactions with indanone, the cyclization of the intermediate phenylhydrazones in indolenine can proceed spontaneously. In some examples observed that phenylhydrazone, obtained by the reaction of phenylhydrazones and 2-substituted 1-indanones, under conditions of heating in a high boiling solvent type diethylene give appropriate THII derivatives.

Recovery indolenine (IV) in THII derivative (V), substituted at C-9b position, is achieved with satanae. The products are then isolated and purified in the usual way.

c. 4b, 9b-Dialkyl-4b,5,9 b,10-tetrahydroindene[1,2-b]indoles (VI) and analogs can be synthesized directly by the reaction indolamines (IV) alkilani lithium (R12Li) in an aprotic solvent type dry tetrahydrofuran

< / BR>
where the substituents from R1to R12defined as under formula IA, and, if necessary, with subsequent N-alkylation of R-halide or R-sulfate, where R is defined as in formula IA.

d. 5,5 a, 6,10 b-Tetrahydroindene[2,1-b] indole (ISO-THII) and analogues can be obtained by recovery of the corresponding 5,6-dihydroindeno[2,1-b]indole (ISO-DGII) XII using the same methods as described in method a.

e. 10b-Substituted-5,5 a, 6,10 b-tetrahydroindene[2,1-b]indoles (IX) and analogs can be synthesized from indan-2-ones (VII) having a substituted group in position C-3, by reacting them with suitable phenylhydrazine (II) under the same conditions as when received indolenine (IV). Intermediate products are relevant indolenine (VIII), which are then dissolved in a suitable solvent, usually in ethanol, and treated with regenerating reagent such as sodium borohydride, receiving ISO-THII compounds (IX) carrying trevanian or by extraction with a suitable solvent.

< / BR>
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10and R11defined as under formula IB.

f. ISO-THII compounds (X), bearing alkyl substituents at positions C-5a and C-10b, received from the respective indolenine (VIII), through reaction with socialmiami (R12Li). Used the methodology previously described for 4b,9b-dialkylamines THII compounds (VI).

< / BR>
where the substituents from R1to R12defined as under formula IB.

g. 5-Alkyl-THEY or 6-alkyl-ISO-THII derivatives synthesized by N-alkylation of the corresponding 5H-THEY or 6N-ISO-THII compounds by dissolving them in an aprotic solvent, for example acetone, acetonitrile, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), optionally, but preferably in the presence of a strong base such as sodium hydride, and then treating the reaction mixture with alkylhalogenide or alkylsulfate. Or the corresponding 5-alkyl-THEY or 6-alkyl-ISO-THII connection can be restored by reaction with zinc and aqueous mineral acid, such as hydrochloric acid, or more efficiently by the reaction with the reducing agent on the basis of boron type nitrobenzamide in a solvent, most often in tetrahydrofuran or dioxane, and in the presence of a strong acid, for example hydrochloric acid. Or you can use trialkylsilyl. Upon completion of the reaction product produce by diluting the reaction mixture with water and either by filtration or extraction. Or restoration can be achieved by hydrogenation catalyst type palladium, in this case, 5-alkyl-DGII or 6-alkyl-ISO-DGII compound is dissolved in a suitable solvent, such as ethanol, acetic acid or ethyl acetate. In this case, the product produce by removal of the catalyst and evaporation of the solvent under reduced pressure. 5-Alkyl-THEY or 6-alkyl-ISO-THII compounds can be treated by crystallization from a suitable solvent or by column chromatography on silica.

h. 5-Alkyl-THEY or 6-alkyl-ISO-THII derivatives synthesized by simple recovery of the corresponding 5-aryl or 6-aryl derivatives using standard methods, for example, applying sociallyengaged.

i. THEY or ISO-THII connection with alkylaminocarbonyl in R3-R6and/or R7-R10can be obtained from the corresponding 5-acyl-THEY or 6-acyl-ISO-THII nitrocompounds using standard methods return the following acid hydrolysis of 5 - or 6-acyl groups for the 5 - or 6-unsubstituted compounds. Used nitro compounds can be obtained either from the corresponding DGII or ISO-DGII compounds in accordance with the above-described methods a. and b., or by nitration appropriately substituted THEE or ISO-THII connections.

j. The hydroxyl-substituted compound can be obtained from the corresponding alkoxy-substituted compounds by standard method dealkylation of ethers, for example, using different Lewis acid.

k. 4b-Alkyl THEE and ISO-THII, i.e., in which R12is a lower alkyl group and R substituents from R1to R11defined as in formula I, can be obtained from the relevant 4b-unsubstituted analogues by metallation, for example, butyllithium, carbonylation with carbon dioxide, the second metallation, for example, butyllithium, and alkylation of R12-halide or R12-sulfate with subsequent final hydrolysis of the resulting N-carboxylating intermediate product.

The processes of obtaining raw materials such as 5,10-dihydroindeno [1,2-b] indole (DGII) and 5,6-dihydroindeno [2,1-b] indole, and analogues containing functional groups is described in related patent application PCN/GB90/00948 that under the EQA, is not limited thereto. Temperature is given in degrees Celsius.

Example 1. CIS-4b,5,9 b,10-Tetrahydroindene[1,2-b]indole.

To a suspension of 5,10-dihydroindeno [1,2-b] indole 19,16 g, 93 mmol in glacial acetic acid (300 ml) portions within half an hour was added nitrobenzamide (24 g, 400 mmol). The mixture was stirred for 3 hours to dissolve all of the original substance. The solution was poured into ice water (500 ml) and was stirred for 1 h to destroy borhydride complex. A clear solution was carefully neutralized with sodium hydroxide, which led to the formation of a white precipitate. The precipitate was filtered and washed with water until complete absence of cyanide ion in the wash waters. Drying gave specified in the title compound as a white solid. Yield: 19 g (98%), So pl. 107oC.1H NMR (CDCl3) : 3,20 (1H, DD)), 3,51 (1H, DD), 3,99 (1H, W), 4.18 (1H, DDD), a 5.25 (1H, d), 6,60 (1H, d), 6,74 (1H, DD), of 6.99 (1H, DD), 7,15-7,22 (4H, m), 7,32 (1H, d,).

Example 2. CIS-4b,5,9 b,10-Tetrahydro-5-methylindene [1,2-b] indole.

In a flame dried flask was loaded sodium hydride (60 mg, 2.5 mmol) and tetrahydrofuran (THF) (5 ml) in a protective atmosphere of nitrogen. To the stirred suspension was added dropwise CIS-4b,5,9 b,10-tetrahydroindene [1,2-b] indole (allali itmean (0.2 ml) and the solution was stirred over night. Was added water (5 ml) and THF was removed in vacuum. Received such a way white solid was filtered and dried in a vacuum desiccator. The product was dissolved in 5% ethyl acetate in petroleum ether (60-80oC) and filtered through a layer of silicon dioxide. After evaporation of the solvent in vacuum has been specified in the title compound as a colourless solid. Yield: 450 mg (85%). So pl. 76-77oC.1H NMR (CDCl3) : 3,0(3H,s,), 3,1 (1H,DD), 3,4 (1H,DD), 4,1 (1H,DDD,), 4,9 (1H, d), to 6.4 (1H,d), 6,7 (1H, DD), 7,1-7,5 (6N,m).

Example 3. CIS-4b,5,9 b,10-Tetrahydro-8-methoxyimino[1,2-b]indole.

5,10-Dihydro-8-methoxyimino [1,2-b] indole (770 mg, 3.3 mmol) was treated with nitrobenzimidazole (1.0 g, 16 mmol) in solution in glacial acetic acid (17 ml). After 30 min the solution was poured into ice water, stirred for 1 h and neutralized with sodium hydroxide. The colorless reaction mixture was extracted with diethyl ether, the organic layers were dried (Na2SO4) and concentrated in vacuum. The residue was chromatographically in column (10% ethyl acetate in petroleum ether 60-80oC) receiving specified in the title compound as a colourless solid. Yield: 520 mg (66%). So pl. 101oC.1H NMR (CD9b,10-Tetrahydro-8-methoxy-5-methylindene[1,2-b]indole.

Using the procedure described in Example 2 CIS-4b,5,9 b,10-tetrahydro-8-methoxyimino[1,2-b]indole (239 mg, 1.0 mmol) was metilirovanie iodomethane using sodium hydride (25 mg, 1.1 mmol) as base in THF (2 ml). Extraction with diethyl ether and purification by high performance chromatography resulted in the transparent resin to yield 158 mg (63%), which otverdel after precondensation (180oC at 0.2 mm Hg), having specified in the header connection. So pl. 72oC. 1H NMR (CDCl3) : 2,87 (3H, s,), 3,03 (1H, DD ), to 3.36 (1H, DD), 3,70 (3H, s,), 4,08 (1H, DDD,), 4,80 (1H, d), 6,28 (1H, d), is 6.61 (1H, DD), 6,77 (1H, DD), 7,1-7,5 (4H, m).

Example 5. CIS-5,5 a,6,10 b-Tetrahydroindene[2,1-b]indole.

5,6-Dihydroindeno[2,1-b]indole (185 mg, 0.9 mmol) was treated with nitrobenzimidazole (310 mg, 5 mmol) in solution in glacial acetic acid (5 ml) for 6 hours the Solution was poured into ice water and was stirred for 1 h Then neutralized with sodium hydroxide, and the resulting white solid was collected by filtration, washed with water, dried and purified high-speed chromatography (10% EtOAc in petroleum ether 60-80oC, Rf30% EtOAc/petroleum ether (60-80oC) 0,6), having specified the title compound as a colourless solid washes the DDD,), 6,55 (1H, d), of 6.73 (1H, DDD,), of 7.00 (1H, DDD,) and 7.1 to 7.4 (4H, m).

Example 6. CIS-4b,5,9 b,10-Tetrahydro-10,10-dimethindene[1,2-b]indole.

5,10-Dihydro-10,10-indeno[1,2-b] indole (1,00 g, the 4.29 mmol) was treated with nitrobenzimidazole (1.0 g, 16 mmol) in solution in glacial acetic acid (20 ml) for 10 minutes the Solution was poured into water, stirred for 30 min and was extracted with diethyl ether. The organic phase was washed 10 times with water, dried (Na2SO4), and the solvent was removed in vacuum. The residue was dissolved in a mixture of 5% ethyl acetate and petroleum ether (60-80oC), filtered through a layer of silicon dioxide, getting after removal of solvent, the resin, which otverdel when pumping oil pump, giving specified in the title compound as a colourless solid. Output: 0,98 g (98%), So pl. 57-59oC.1H NMR (CDCl3) : of 1.17 (3H, s,), USD 1.43 (3H, s,), 3,86 (1H, d), a 3.9 (1H, Shir,), from 5.29 (1H, d), 6,59 (1H, d), of 6.71 (1H, DDD,), 7,02 (1H, DDD,), 7,2-7,3 (5H, m).

Example 7. CIS-4b,5,9 b,10-Tetrahydro-9b-methylindene[1,2-b]indole.

Phenylhydrazone 2-methyl-1-indanone (1.44 g, 6.1 mmol) was heated in diethylene glycol (20 ml) to a temperature close to the boiling point, until then, until an air condenser was not recovering the ammonia. The cooling solution is M hydrochloric acid, the aqueous phase was podslushivaet sodium hydroxide and re-extracted with diethyl ether. The extracts were evaporated and the residue was purified column chromatography using silica and elwira 5% EtOAc in petroleum ether, getting mentioned in the title compound as a colourless solid (Rf30% EtOAc/petroleum ether to 0.8). Output: (28%), So pl. 72oC.1H NMR (CDCl3) : of 1.46 (3H, s,), 3,10 (1H, d), 3,30 (1H, DD), of 4.05 (1H, s,), 4,69 (1H, s,), of 6.52 (1H, d), of 6.71 (1H, DDD,), to 6.95 (1H, DDD,), of 7.0 to 7.2 (5H, m).

Example 8. CIS-4b,5,9 b,10-Tetrahydro-4b,9b-dimethindene[1,2-b]indole.

Motility (1.5 ml, 2 EQ. 1.5 M solution in hexane) was added dropwise at -78oC to a solution of 9b,10-dihydro-9b-methyl-indeno[1,2-b]indole (260 mg, 1,19 mmol) in THF (10 ml). After stirring at -78oC for 1 h to dark red solution was added water (1 ml) and the reaction mixture was allowed to heat up. Upon reaching room temperature the color of the solution disappeared. The reaction was suppressed with a saturated solution of ammonium chloride (10 ml), the organic phase was separated and dried (Na2SO4). Evaporation of the solvent and high-performance chromatography (10% EtOAc/petroleum ether [60-80oC]) gave a colourless resin (Rf(10% EtOAc/petroleum ether [60-80oC]) 0.5), and Ko is ke compound as a colourless solid. Yield: 87 mg (31%).1H NMR (CDCl3) : of 1.35 (3H, s,), of 1.46 (3H, s,), of 3.07 (1H, d), to 3.36 (1H, d ), 4,27 (1H, Shir,), 6,53 (1H,), OF 6.71 (1H, DDD,), of 6.96 (1H, DDD,), 7,1-7,3 (5H, m).

Example 9. CIS-4b,5,9 b,10-Tetrahydro-6,8-dimethindene[1,2-b]indole.

5,10-Dihydro-6,8-dimethindene[1,2-b]indole (323 mg, 1.38 mmol) was treated with nitrobenzimidazole (400 mg, 5 EQ) in solution in glacial acetic acid (7 ml) for 30 minutes the Solution was poured into ice water and stirred for a further 30 minutes the Aqueous solution was neutralized with sodium hydroxide, the suspension was extracted with diethyl ether. The organic extracts were washed with water, dried (Na2SO4) and was evaporated in vacuum. Purification by high performance chromatography gave specified in the title compound as a colourless solid. Output: 2,44 mg (75%). So pl. 147oC (from EtOAc/petroleum ether (60-80oC)),1H NMR (CDCl3) : 2,03 and 2.07 (3H, s,), 3,18 (1H, DD), of 3.48 (1H, DD), 4,16 (1H, DDD,), of 5.24 (1H, d), of 6.66 (1H, s,), at 6.84 (1H, s, ), and 7.1 to 7.4 (4H, m).

Example 10. CIS-4b,5,9 b,10-Tetrahydro-8-methylindene[1,2-b]indole.

5,10-Dihydro-8-methylindene[1,2-b]indole (10 g, 46 mmol) was stirred at room temperature in glacial acetic acid (150 ml). Nitrobenzamide (8.6 g, 3 equivalents) was added in portions over 30 who I for 30 min acidic solution was made basic by adding sodium hydroxide, and the resultant solid substance was separated by filtration. The solid is abundantly washed with water until complete leaching of cyanide ion and then dried in a vacuum oven, getting mentioned in the title compound as a colourless solid. Yield: 7.5 g (73%), So pl. 110oC (from ethanol/water),1H NMR (CDCl3) : of 2.24 (3H, s,), 3,20 (1H, DD ), 3,50 (1H, DD), 3,9 (1H, Shir,), of 4.16 (1H, DD), 5,23 (1H, d), of 6.52 (1H, d), to 6.80 (1H, d), of 6.99 (1H, s,), and 7.1 to 7.4 (4H, m).

Example 11. CIS-4b,5,9 b,10-Tetrahydro-5,8-dimethindene[1,2-b]indole.

Solution 4b, 5,9 b, 10-tetrahydro-8-methylindene[1,2-b] indole (1.8 g, 8.1 mmol) in THF (20 ml) was cooled to -78oC and to it was added dropwise n-utility (5.6 ml, 1.6 M solution in hexane, 9.0 mmol). The solution temperature was allowed to rise to room temperature and was stirred for 30 minutes, the Reaction mixture was cooled to -78oC was added itmean (0.6 ml, 0.9 mmol). The reaction mixture was again allowed to warm to room temperature and then extinguished with a saturated solution of ammonium chloride (5 ml). After stirring the mixture overnight the organic layer was diluted with dichloromethane, separated, washed with brine and dried (MgSO4). After removal of the solvent in vacuo the residue was purified column chromatography, poluga substances. Yield: 1.0 g (53%). So pl. 54oC (from ethanol).1H NMR (CDCl3) : of 2.25 (3H, s,), to 2.94 (3H, s,), of 3.07 (1H, DD), to 3.41 (1H, DD), 4,11 (1H, m), 4,88 (1H, d), 6,30 (1H, d), to 6.88 (1H, d), of 6.96 (1H, d), and 7.1 to 7.4 (4H, m ).

Example 12. CIS-4b,5,9 b,10-Tetrahydro-8-isopropylidene[1,2-b]indole.

5,10-Dihydro-8-isopropylidene[1,2-b] indole (5,27 g of 21.3 mmol) was stirred at room temperature in glacial acetic acid (100 ml). Nitrobenzamide (5 g, 3 equivalents) was added in portions over 30 min, then was poured into ice water (150 ml). After stirring for 30 min the solution was neutralized aqueous sodium hydroxide, and the resultant solid substance was separated by filtration. This solid is abundantly washed with water until complete leaching of cyanide ion and then dried in a vacuum oven, getting mentioned in the title compound as a colourless solid. Yield: 3.25 g (61%), So pl. 104oC (from petroleum ether [60-80oC] ).1H NMR (CDCl3) : 1,19 (6N, d,), 2,80 (1H, septet,), 3,20 (1H, DD), of 3.48 (1H, DD ), 4,07 (1H, Shir,), is 4.15 (1H, DD), to 5.21 (1H, d), 6,53 (1H, d), 6,86 (1H, DD), 7,03 (1H, s,), and 7.1 to 7.4 (4H, m).

Example 13. CIS-4b,5,9 b,10-Tetrahydro-5-methyl-8-isopropylidene[1,2-b]indole.

A solution of CIS-4b, 5,9 b,10-tetrahydro-8-isopropylidene[1,2-b]indole (1.75 g, 7.0 mmol) was and the mixture was stirred for 2 h and added itmean (of 0.53 ml, 1.2 equivalent). The reaction mixture was stirred over night and then extinguished with a saturated solution of ammonium chloride. The organic phase was separated, the aqueous was extracted with diethyl ether. The combined organic phases were dried (Na2SO4) and the solvent was removed in vacuum, obtaining mentioned in the title compound in the form of a colorless gum, which was purified by reconcretion. Yield: 1 g (54%), So Kip. 200oC at 0.4 mm Hg1H NMR (CDCl3) : 1,22 (6N, d,), of 2.81 (1H, septet,), to 2.94 (3H, s, ), to 3.09 (1H, DD), of 3.43 (1H, DD), is 4.15 (1H, DDD,), the 4.90 (1H, d), 6,32 (1H, d), 6,93 (1H, DD), 7,02 (1H, Shir,) and 7.1 and 7.5 (4H, m).

Example 14. CIS-4b,5,9 b,10-Tetrahydro-2-methoxy-1,3-dimethylbenzene[1,2-b] indole.

5,10-Dihydro-2-methoxy-1,3-dimethylbenzene[1,2-b] indole (1 g, of 3.80 mmol) was stirred at room temperature in glacial acetic acid (15 ml). Nitrobenzamide (0.75 g, 3 equivalents) was added in portions over 15 min and the reaction mixture was stirred for a further 2 hours the Reaction mixture was poured into ice water (30 ml) and stirred for 30 minutes the Solution was neutralized aqueous sodium hydroxide and was extracted with diethyl ether. The organic extracts were abundantly washed with water to leaching of cyanide ion. The solvent was removed in vacuum, the Noah solid. Yield: 0.8 g (79%). So pl. 117oC (from EtOAc/petroleum ether [60-80oC]). Elemental analysis: Found: C 81,6, H 7,3, N, 5,8, Calc. for C18H19NO C 81,5, H 7,2, N 5,9,1H NMR (CDCl3) : of 2.15 (3H, s, in ), 2.25 (3H, s,), of 3.07 (1H, DD), to 3.36 (1H, DD), to 3.64 (3H, s,), 4,1 (1H, Shir, ), 4,19 (1H, DDD,), 5,20 (1H, d), 6,60 (1H, d), 6,74 (1H, DDD,), 6,97 (1H, s,), of 7.00 (1H, DDD,), 7,17 (1H, d,).

Example 15. CIS-4b,5,9 b,10-Tetrahydro-4b,6,8,9 b-tetramethylbenzene[1,2-b] indole.

A mixture of 5.1 g (0.03 mol) of 2,4-dimethylpentanenitrile, of 5.4 g (0.03 mol) of 2-methyl-1-indanone in 100 ml of ethanol (99.5% pure) and 2.5 ml conc. hydrochloric acid was boiled under reflux for 2 hours the mixture was filtered, the filtrate was evaporated and the residue was divided between ether and water. The organic phase is washed with aqueous sodium carbonate, dried (MgSO4), filtered and evaporated. The residue was chromatographically using high-performance chromatography on 60 silicon dioxide. After washing away non-polar impurities with a mixture of dichloromethane/isooctane (1/1) mixture of methanol/ethyl acetate/isooctane (1/4/5) washed 5 g crude 9b,10-dihydro-6,8,9[-trimethyl-b1,2-a] indole. Without further purification the product was dissolved in 100 ml of dry tetrahydrofuran. In an argon atmosphere at a temperature of from -65 to -55oC was added 50 ml of a 1.6 M solution meilleur ammonium chloride. The mixture was extracted with ether and the combined organic phase was evaporated, obtaining 5 g of a green oil. Chromatography on 60 silica using 7.5% ethyl acetate in isooctane gave 1 g specified in the connection header.1H NMR (CDCl3) : of 1.37 (3H, s) to 1.48 (3H, s) 2,07 (3H, s), measuring 2.20 (3H, s), 3.00 and-to 3.35 (2H, AB-system, J 15 Hz), 3,9 (1H, CL,), 6,60 (1H, s,), to 6.88 (1H, s), 7,08-7,28 (4H, m).

Example 16. CIS-5a,5,6,10 b-Tetrahydropyrimido[2,1-b]indole.

To a solution of 0.6 g (0,00289 mol) 5a,5,6,10 b-tetrahydroindene[2,1-b]indole, 0.9 g, (0,00723 mol) K2CO3and 1.03 g (0,00723 mol) under the conditions in 10 ml of acetonitrile was stirred overnight at room temperature. The resulting mixture was filtered and evaporated. The obtained residue was dissolved in ether and then washed twice with water. Drying (Na2SO4) and evaporation gave 0.25 g (39%) specified in the connection header.1H NMR (CDCl3) : 2,78 (3H, s), and 3.2 (2H, d), a 4.3 (1H, m), of 4.66 (1H, d), 6,37 (1H, d), of 6.68 (1H, t), 7,06 (1H, t), 7,13-to 7.18 (2H, m), 7,22-7,26 (1H, m), 7.3 to 7,37 (2H, m).

Example 17. CIS-4b,5,9 b,10-Tetrahydro-8-methoxy-6-methylindene[1,2-b]indole.

To a solution of 5.0 g (at 0.020 mol) of 5,10-dihydro-methoxy-6-methylindene[1,2-b] indole in 50 ml of tetrahydrofuran was added 8.1 g (0,080 mol) of morpholinopropan and dropwise 6.3 ml conc. of hydrochloric acid. Lyali addition of 6.3 ml conc. hydrochloric acid and the mixture was stirred over night. Then there was added 25 ml of water and the mixture was evaporated. The residue is suspended in 200 ml of water and 5 ml conc. hydrochloric acid, and the mixture was heated on a water bath to dissolve most of the solid material. The solution was filtered hot, the filtrate is cooled and podslushivaet by addition of 10 M sodium hydroxide solution. Filtration and washing with water gave 1,93 g (38.4 per cent) specified in the connection header. 1H NMR (CDCl3) : of 2.08 (3H, s), 3.15 and is 3.25 (1H, DD), 3,42-3,55 (1H, DD), and 3.7 (3H, s), 4,1-4,22 (1H, t), 5,22-55,28 (1H, d), 6.42 per-6,46 (1H, d), 6,6 - of 6.65 (1H, d), 7,14-of 7.25 (1H, m), 7.3 to 7.4 (1H, m).

Example 18. CIS-4b,5,9 b,10-Tetrahydro-8-methoxy-7,9-dimethindene[1,2-b] indole.

To a solution of 0.8 g (0.3 mmol) of 5,10-dihydro--methoxy-7,9-dimethindene[1,2-b]indole and to 1.21 g of morpholinopropan in 4 ml of dioxane was added dropwise 1 ml conc. of hydrochloric acid. The mixture was boiled under reflux for 30 min, then cooled, after which was added 3 ml of 6M hydrochloric acid. The resulting mixture was then boiled for 15 minutes After cooling, the solution was podslushivaet aqueous solution of sodium hydroxide and was extracted three times with ether. Drying (MgSO4) and evaporation gave the crude product, which was recrystallized by dissolving in e is the head of the connection.1H NMR (CDCl3) : of 2.08 (3H, s), 3,15-3,25 (IR, DD), 3,42-3,55 (IR, DD), and 3.7 (3H, s), 4,1-4,22 (IR, t), 5,22-55,28 (IR, d), 6.42 per-6,46 (IR, e), 6,6-6,65 (IR, e), 7,14-7,25 (IR, m), 7.3 to 7.4 (IR, m).

Example 19. CIS-4b,5,9 b,10-Tetrahydro-6-isopropylidene[1,2-b]indole.

To a solution of 4.95 g (at 0.020 mol) of 5,10-dihydro-6-isopropylidene[1,2-b]indole and 8.08 g (0,080 mol) of morpholinopropan in 25 ml of dioxane was added dropwise 7 ml of conc. of hydrochloric acid. The mixture was boiled under reflux for 30 min, then was cooled, adding 20 ml of 6 M hydrochloric acid. The resulting mixture was boiled for 15 minutes After cooling, the solution was podslushivaet by adding aqueous sodium hydroxide and was extracted three times with ether. Drying (MgSO4) and evaporation gave the crude product, which was purified by column chromatography on silica using a mixture of methylene chloride and light petroleum ether (20/80) as eluent. Thus received of 3.53 g (71%) specified in the connection header.1H NMR (CDCl3) : to 1.19 (3H, d), of 1.29 (3H, d), 2,84 (1H, DK) 3,26 (1H, DD), of 3.56 (1H, DD), 4,24 (1H, TD), 5,31 (1H, d), 6,79 (1H, DD), 6,97 (1H, d), 7,05-to 7.09 (1H, m), 7,28-7,21 (3H, m), of 7.36-7,40 (1H, m).

Example 20. CIS-4b,5,9 b,10-Tetrahydro-4b-methylindene[1,2-b]indole.

In a flame dried flask under inert atmosphere download is given to -78oC and to it was added dropwise a solution of n-utility (3,45 ml of 1.6 M solution in hexane, 1,1 EC). The light yellow solution was allowed to warm to room temperature and through him propulsively dry gaseous carbon dioxide until then, until the solution became colorless. The solvent and excess of carbon dioxide was carefully removed under reduced pressure of the vacuum pump and re-entered the atmosphere of dry nitrogen. The colorless solid is re-dissolved in dry tetrahydrofuran (30 ml) was cooled to -78oC and was added 1.1 equivalent of n-utillity. The reaction mixture was stirred at -78oC for 1.5 h and then extinguished by iodomethane (0.35 ml, 1,2 EQ.). After reaching the reaction mixture to room temperature the solvents were removed as before and added a 2M solution of HCl (20 ml). After cessation of gas (approximately 20 min) the solution was neutralized with solid sodium carbonate. The organic product was extracted with ethyl acetate, the extract was washed with brine and dried (Na2SO4). After removal of solvent the product was purified by high performance chromatography [Rf= 0,4 (the 10% EtOAc/60-80oC petroleum ether)], elwira 5% ethyl acetate in petroleum ether 60-80oC è0 (1H, DDD), 6,53 (1H, d, J=7,7 Hz), 4.2V (1H; Shir), 3,37 (1H, DM, J=8,2 Hz), 3,48 (1H, DD, J=16,3, 7,2 Hz), 3,14 (1H, DD, J=16,3, 2.0 Hz), to 1.61 (3H, s).

Example 21. CIS-4b,5,9 b,10-Tetrahydro-4b-methyl-8-isopropylidene[1,2-b] indole.

In an inert atmosphere in a flame dried flask was loaded 4b,5,9 b,10-tetrahydro-8-isopropylidene[1,2-b]indole (1,49 g, 5,98 mmol) and dry tetrahydrofuran (THF, 20 ml). The solution was cooled to -78oC and to it was added dropwise a solution of n-utility in hexane (4.0 ml, 1.6 M solution). The solution was heated to room temperature and through him propulsively dry gaseous CO2to the disappearance of the color of the anion. The solvent and excess CO2was carefully removed under vacuum pump, the obtained solid is re-dissolved in dry THF (20 ml) and cooled to -78oC. was Added an equivalent of n-utility and the reaction mixture was stirred at -20oC for 30 minutes was Added itmean (0.4 ml, 1 EQ.), the mixture was heated to room temperature and was stirred for 3 hours the Solvent was removed under a water-jet pump, and was added 2N HCl (20 ml). After 20 min the solution was made basic with solid sodium carbonate and extracted with ethyl acetate. The organic extract was washed with brine, dried (Na2SO4) the e light yellow oil. Yield: 1.01 g, 64%. 1H NMR (CDCl3) : 7,30-to 7.15 (4H, m), 7,00 (1H, s), 6,85 (1H, d, J=7.9 Hz), of 6.49 (1H, d, J=7.9 Hz), 4,0 (1H, Shir), to 3.73 (1H, DM, J=8.1 Hz), 3,49 (1H, DD, J=16,1, 8,2 Hz), and 3.16 (1H, d, J=16.1 Hz), and 2.79 (1H, septet, J=6.8 Hz), to 1.61 (3H, s), 1,19 (6N, d, J=6,8 Hz).

Example 22. CIS-4b,5,9 b,10-Tetrahydro-2-hydroxy-1,3-dimethylbenzene[1,2-b] indole.

In anhydrous conditions, 4b,5,9 b,10-tetrahydro-1-methoxy-1,3-dimethylbenzene[1,2-b] indole (76 mg, 0.29 mmol) was dissolved in dry dichloromethane (DHM, 1 ml) to which was added a small amount of ethanol. The solution was cooled to -78oC and the solution was added to tribromide boron in DHM (0.5 ml of 1M solution). The solution was slowly heated to room temperature, the reaction proceeded at 0oC. After 30 min at 10oC was carefully added water (1 ml) and the reaction mixture was stirred for 15 minutes the Main part of the solid material was fully extracted between DHM and saturated sodium bicarbonate solution. DHM layer was dried (Na2SO4) and filtered through a fresh layer of silicon dioxide, receiving a colorless solid. Yield: 73 mg, 100%, So pl. 178-180oC (Dec.).1H NMR (CDCl3) : 7,16 (1H, d, J=7,3 Hz), 6,99 (1H, DDM), 6,94 (1H, s), of 6.73 (1H, DDM, J=7,3, 1.1 Hz), 6,60 (1H, d, J=7,7 Hz), 5,20 (1H, d, J=8,4 Hz), 4,4 (2H, Shir), is 4.15 (1H, DDM), to 3.38 (1H, DD, J=16,1, 8,3 Hz), 3,09 (1 is-b]indole.

4b, 5,9 b,10-Tetrahydro-2-hydroxy-1,3-dimethylbenzene[1,2-b]indole (140 mg, of 0.53 mmol) was stirred in acetic anhydride (2 ml) for 5 minutes Then added water (5 ml) and stirring was continued for 30 minutes the Solution was neutralized with solid sodium bicarbonate and was extracted with dichloromethane. The organic product was dried (MgSO4), concentrated and the excess dichloromethane drove on a rotary evaporator in the form of an azeotrope with petroleum ether 60-80oC, receiving a colorless solid. Yield: 170 mg, 100%. So pl. 201oC (Dec. ).1H NMR (CDCl3) : (mixture of E/Z isomers). 8,10 (1/2 H, d, J=7.9 Hz), 8/4-7,0 (4 1/2H, m), 6,24 and 5.75 (1H, d, J=8,2 and 7.7 Hz), 4,23 and 4.13 (1H, DDD, J= 7,5 and 8.3 Hz), to 3.64 (3H, s), and 3.4 (1H, m), 3,13 (1H, 2 x DD, J=15,5 Hz), 2,59 and of 2.50 (3H, s), 2,53 and 2,22 (3H, C) of 2.16 and 2.14 (3H, s).

Example 24. CIS-5-Acetyl-4b,5,9 b,10-tetrahydro-2-hydroxy-1,3-dimethylbenzene [1,2-b]indole.

In anhydrous conditions, a solution of 5-acetyl-4b,5,9 b,10-tetrahydro-2-methoxy-3,3-dimethylindole[1,2-b]indole (109 mg, 0.35 mmol) in dichloromethane (1 ml) was cooled to -78oC and the solution was added to tribromide boron in dichloromethane (0.7 ml, 1M solution). The solution was allowed to warm to room temperature and was stirred for 90 min, then carefully added water (5 ml). After stirring for 10 SO4) and was filtered through a layer of fresh silicon dioxide, elwira 30% EtOAc in petroleum ether 60-80oC. Removal of solvent gave a colorless solid. Yield: 96 mg, 94%. So pl. 205oC (with decomp.).1H NMR (CDCl3) : A mixture of E/Z isomers). 8,06 (1/2 H, d, J=7,1 Hz), 8,05-7,00 (4 1/2H, m), 4,23 and 5.75 (1H, d, J=8.1 and 7.5 Hz), 4,6 (1H, Shir), 4,22-4,08 (1H,2 x DD), 3,45-3,26 (1H, m), 3.25 to 3,05 (1H, 2 x DD), 2,63 and 2.52 (3H, s), of 2.20 and 2.17 (3H, s), 2,13 and are 2.11 (3H, s).

Example 25. CIS-4b, 5,9 b,10-Tetrahydro-2-methoxy-1,3-dimethyl-8-isopropyl-indeno[1,2-b]indole.

5,10-Dihydro-2-methoxy-1,3-dimethyl-8-isopropylidene[1,2-b] indole (1.68 g, 5.5 mmol) was dissolved in triperoxonane acid (10 ml) and intensively stirred. Added triethylsilane (1 ml of 1.1 EQ) and stirring was continued for 4 h, the Reaction mixture was poured into water, stirred for 15 min and neutralized with 2 M NaOH. All organic products were extracted with ethyl acetate, washed with water and dried (Na2SO4). After removal of solvent, the solid is recrystallized from petroleum ether 60-80oC, receiving it in the form of white needle crystals. Yield: 1.18 g, 70%, So pl. 106oC,1H NMR (CDCl3) : 7,05 (1H, s), 6,97 (1H, s), to 6.88 (1H, DD, J=8.6 Hz), 6,55 (1H, d, J=8.1 Hz), 5,19 (1H, d, J=8,4 Hz), 4,18 (1H, DD), and 3.8 (1H, Shir), to 3.64 (3H, s) 3,36 26. CIS-4b,5,9 b,10-Tetrahydro-2-hydroxy-1,3-dimethyl-8 - isopropylidene[1,2-b]indole.

Solution 4b,5,9 b,10-tetrahydro-2-methoxy-1,3-dimethylbenzene-[1,2-b]indole (97 mg, 0.32 mmol) in dichloromethane (DHM, 1 ml) to which was added a little ethanol vapor was cooled to -78oC. was Added tribromide boron (0.4 ml 1M solution in DHM) and the reaction mixture was slowly heated to room temperature. Caution was added water (1 ml) and the reaction mixture was divided between DHM and sodium bicarbonate solution. The organic layer was dried (Na2SO4) and filtered through a fresh layer of silicon dioxide, elwira DHM. Removal of solvent gave a white solid. Yield: 88 mg, 94%. So pl. 165oC (with decomp. ).1H NMR (CDCl3):? 7.04 baby mortality (1H, s), to 6.95 (1H, s), 6.87 in (1H, s), 6,56 (1H, d, J= 8.1 Hz), 5,20 (1H, d, J=8.6 Hz), 4,16 (1H, DDM), 4,6-4,0 (2N, W), to 3.36 (1H, DD), 3,06 (1H, DD), of 2.81 (1H, septet, J=7.0 Hz), measuring 2.20 (3H, s), 2,12 (3H, C) 1,19 (6N, d, J=7.9 Hz).

Example 27. CIS-4b,5,9 b,10-Tetrahydro-2,8-dimethoxy-1,3-dimethylindole-[1,2-b]indole.

5,10-Dihydro-2,8-dimethoxy-1,3-dimethylbenzene[1,2-b] indole (1.04 g, 3,55 mmol) was dissolved in triperoxonane acid (5 ml) and vigorous stirring was added triethylsilane (0.6 ml). Stirring was continued for 4 h and was interrupted before completion due to discovery the content of inorganic fillers, the product was extracted with DHM, which was washed with sodium bicarbonate solution and filtered through patristically filter paper. The product and the source reagent was separated using column chromatography, elwira 20% EtOAc in petroleum ether 60-80oC, having a source of indole (0.06 g, 6%) and colourless solid. Output: 0,57 g, 58%, So pl. 149 stop just 50oC (from EtOAc/petroleum ether). 1H NMR (CDCl3) : of 6.99 (1H, s), 6,79 (1H, m), to 6.57 (2H, m), is 5.18 (1H, d, J=8.5 Hz), 4,18 (1H, DD (width)), 3,74 (3H, s) to 3.64 (3H, s) to 3.35 (1H, DD, J=8,4 Hz), 3,06 (1H, d(l) in), 2.25 (3H, s), of 2.15 (3H, s).

Example 28. CIS-5-Acetyl-4b,5,9 b,10-tetrahydro-4b,9b-dimethindene[1,2-b] indole.

4b, 5,9 b,10-Tetrahydro-4b,9b-dimethindene[1,2-b]indole (0.2 g, 0.85 mmol) was dissolved in acetic anhydride (1 ml) and the solution was stirred at room temperature for 16 hours the Reaction mixture was poured into saturated sodium bicarbonate solution and stirred for 0.5 hours Then the mixture was extracted with ether (3 x 15 ml) and the combined organic extracts were washed with brine, dried (Na2SO4) and was evaporated, having specified in the title compound in the form of oil. This oil was purified by high performance chromatography on silica, elwira 5-7% ethyl acetate in petroleum ether 60-80oC, and got the H, d, J= 15,9 Hz), 2,97 (1H, d, J=15,9 Hz), 2,42 (3H, s), 1.77 in (3H, s), 1,25 (3H, s).

Example 29. CIS-4b,5,9 b,10-Tetrahydro-4b,8,9 b-trimethylbenzene[1,2-b]indole.

To a solution of 9b,10-dihydro-8,9 b-dimethindene[1,2-b]indole (of 5.05 g of 0.022 mol) in dry tetrahydrofuran (100 ml) at -78oC in nitrogen atmosphere in a flame dried flask was added dropwise motility (1.4 M solution in diethyl ether, 23,2 ml, to 0.032 mol). The mixture was stirred at -78oC for 2 h and then at -15oC for another 1 h and Then was added a saturated solution of ammonium chloride (3 ml) and the mixture was allowed to warm to room temperature. The reaction mixture was divided between ether and a saturated solution of ammonium chloride, and the layers were separated. The aqueous phase was extracted with diethyl ether (2 x 25 ml) and the combined organic extracts were washed with brine, dried (Na2SO4) and was evaporated, obtaining mentioned in the title compound as a white solid. This substance was purified by high performance chromatography on silica, elwira 3-10% ethyl acetate in petroleum ether 60-80oC, having a colorless solid. Output: 2,73 g, 51%. So pl. 208-212oC.1H NMR (CDCl3) : 7,1-7,3 (4H, m) 6,94 (1H, m), 6,77 (1H, d, J= 7.8 Hz), 6,46 (1H, d, J=7.8 Hz), 3,35 (1H, d, J=15,9 Hz), 3,06 (1 [1,2-b]-indole.

To a solution of metallyte (1.4 M solution in diethyl ether, 14,5 ml, 12.4 mmol) in dry tetrahydrofuran (20 ml) at -78oC in nitrogen atmosphere in a flame dried flask was added dropwise over 1 h a solution of 9b,10-dihydro-9b-methyl-8-isopropylidene[1,2-b] indole (1,62 g of 6.20 mmol) in dry tetrahydrofuran (30 ml). After the addition the mixture was stirred at -78oC for 0.5 hours and Then was added a saturated solution of ammonium chloride (2 ml) and the mixture was allowed to warm to room temperature. The reaction mixture was divided between diethyl ether (50 ml) and a saturated solution of ammonium chloride (25 ml) and the layers were separated. The aqueous phase was extracted with diethyl ether (2 x 10 ml) and the combined organic extracts were washed with brine, dried (Na2SO4) and was evaporated. Thus obtained crude product was purified by high performance chromatography on silica, elwira 3-10% ethyl acetate in petroleum ether 60-80oC, having a light yellow resin. Output: 0,77 g, 45%,1H NMR (CDCl3) : 7,1-7,3 (4H, m), 6,98 (1H, d, J=1,8 Hz), PC 6.82 (1H, DD, J= 1,8 Hz and 7.9 Hz), 6,47 (1H, d, J=7.9 Hz), to 3.36 (1H, d, J=15,9 Hz), 3,06 (1H, d, J=15,9 Hz), 2,78 (1H, Sept., J=6,8 Hz) of 1.45 (3H, s) of 1.34 (3H, s), 1,18 (6N, DD, J=1.3 Hz and 6.9 Hz).

Example 31. CIS-5-Acetyl-4b, 5,9 b,10-tetrahydro-4b,8,9 b-Yali in acetic anhydride (1 ml) and stirred at room temperature for 16 hours The reaction mixture was poured into saturated sodium bicarbonate solution (25 ml) and stirred for 0.5 hours, the Mixture was extracted with ether (3 x 10 ml) and the combined organic extracts were washed with brine, dried (Na2SO4) and was evaporated. The crude product was purified by high performance chromatography on silica, elwira 4% ethyl acetate in petroleum ether 60-80oC, and received a light yellow resin. Yield: 0.15 g, 53%1H NMR (CDCl3) : to 7.84 (1H, s), 6.90 to-7.23 percent (6N, m), 3,26 (1H, d, J=15,9 Hz), 2,96 (1H, d, J=15,9 Hz), is 2.40 (3H, s), 2,31 (3H, s), 1.77 in (3H, s), 1,32 (3H, s).

Example 32. CIS-5-Acetyl-4b,5,9 b,10-tetrahydro-4b,9b-dimethyl-8-isopropylidene[1,2-b]indole.

4b, 5,9 b,10-Tetrahydro-4b,9b-dimethyl-8-isopropylidene[1,2-b]indole (0.24 g, 0.87 mmol) was dissolved in acetic anhydride (1 ml) and stirred at room temperature for 16 hours the Reaction mixture was poured into saturated sodium bicarbonate solution (25 ml) and was stirred for 0.5 hours, the Mixture was extracted with ether (3 x 25 ml). The combined organic extracts were washed with brine, dried (Na2SO4) and was evaporated. The crude product was purified by high performance chromatography on silica, elwira 4% ethyl acetate in petroleum ether 60-80oC, and got the), is 2.88 (1H, Sept., J=6.8 Hz), is 2.40 (3H, s), 1.77 in (3H, s) of 1.33 (3H, s), 1,23 (6N, DD, J=0,73 Hz and 6.8 Hz).

Example 33. CIS-4b,5,9 b-10-Tetrahydro-5-ethylidene[1,2-b]indole.

5,10-Dihydroindeno[1,2-b] indole (60,0 g, 0.29 mol) was intensively stirred in glacial acetic acid (1000 ml) and thereto portions over 40 min was added nitrobenzamide (79 g, 1.25 mmol). After 3 h stirring, the reaction mixture was poured into ice water (2000 ml) and the resulting gelatinase solid substance was separated and stirred with a mixture of ethyl acetate (75 ml) and water (100 ml). The remaining colorless solid, as it was found, is unreacted starting material (19,0 g). The original filtrate was extracted with ethyl acetate (2 x 75 ml) and the combined organic phase was dried and evaporated. The residue is then partially dissolved in a mixture of 60-80oC petroleum ether (20 ml) and ethyl acetate (40 ml). The remaining solid was removed and showed that this mixture of starting material (2.5 g). The filtrate was extracted with 2M hydrochloric acid (8 x 25 ml) and the combined acidic extracts were washed with ethyl acetate (2 x 15 ml) before treatment 0,89 ammonia. The liberated oil was extracted with ethyl acetate (6 x 25 ml) and the combined organic layers were then dried and evaporated, get the Hz), of 3.05 (1H, DD, J=16.5 and 5.0 Hz), 3,38 (2N, K, J= 7,0 Hz), 3,40 (1H, DD, J=16.5 and 9.0 Hz), 4,12 (1H, DDD, J=9,0, 5.0 and 5.0 Hz), 5,11 (1H, d, J=9.0 Hz), 6,33 (1H, d, J=7,0 Hz), to 6.57 (1H, dt, J=7.5 and a 1.01 Hz), 7,02 (1H, t, J=8.0 Hz), was 7.08 (1H, d, J=8.0 Hz), 7,14-7,20 (3H, m), 7,34-7,40 (1H, m).

Example 34. CIS-4b,5,9 b,10-Tetrahydro-2-(N,N-diethylamino)-indeno[1,2-b] indole.

5,10-Dihydro-2-(N,N-diethylamino)-indeno[1,2-b]indole (180 mg, of 0.65 mmol) was dissolved in triperoxonane acid (3 ml) containing triethylsilane (0.5 ml) and the solution was stirred at room temperature for 3 hours Then it was treated with water (15 ml) and 0,89 ammonia (5 ml) and stirred for 0.5 hours, the Mixture was extracted with dichloromethane (3 x 5 ml), the combined extracts were filtered through a paper for phase separation and evaporated, receiving light yellow oil (280 mg). The oil was chromatographically on column (silica gel, 7.5% of EtOAc in 60-80oWith petroleum ether) to give specified in the title compound in the form of colorless needle-like crystals. Yield: 65 mg, 35%. So pl. 116-118oC. This product was recrystallized from a mixture of diethyl ether - petroleum ether 60-80oC, having long colorless needle crystals. So pl. 118oC:1H NMR (CDCl3) : 1,08 (6N, t, J=7.0 Hz), 3,10 (1H, DD, J= 16.0 and 2.0 Hz) at 3.25 (4H, K, J=7,0 Hz), 3,42 (1H, DD, J=16.0 and 8.5 Hz), 3,55 (1H, Shir. C) 4,1 kg), 7,06-7,13 (2H, m).

Example 35. CIS-(E)- and (Z)-4b,5,9 b,10-Tetrahydro-5-acetyl-8-(N,N-diethylamino)-indeno[1,2-b]indole.

(E)- and (Z)-4b, 5,9 b, 10-Tetrahydro-5-acetyl-8-aminoindane-[1,2-b]indole (1.0 g), sodium carbonate (1 g) and ethyliodide (2.0 ml) was boiled under reflux in a mixture of tetrahydrofuran (80 ml) and water (15 ml) with stirring for 24 h were Then added ethyliodide (0.5 ml) and heating was continued for another 3 hours, the Solvent is evaporated and to the residue was added dichloromethane. A solid substance was separated by filtration and thoroughly washed with diethyl ether. The filtrate and washing solutions were combined and evaporated to a volume of approximately 15 ml cooling stood specified in the title compounds as pale yellow prismatic crystals. Yield: 0.75 g, 62%. So pl. 176-178oC:1H NMR (CDCl3) : 1,10 (6N, t, J=7.0 Hz), 1,13 (6N, t, J=7.0 Hz), 2,43 (3H, s) to 2.54 (3H, s), 3,21 (1H, d, J=16 Hz), 3,29 (10H, m) 4,06 (1H, DD, J= J=8 Hz), 4,16 (1H, DD, J=7.5 Hz), to 5.56 (1H, d, J=2.0 Hz), 5,72 (1H, d, J= 7.5 Hz), 6,27 (1H, d, J=8 Hz), 6,47 (2H, DDD, J=7,5, J=2.0 Hz), 6,63 (1H, d, J=2 Hz), make 6.90 (1H, d J=9 Hz), 7,15-7.23 percent (6N, m), 7,41 (1H, m), 7,60 (1H, m), 7,89 (1H, d J=9 Hz).

Example 36. CIS-4b,5,9 b,10-Tetrahydro-5-ethyl-8-(N,N-diethylamino)-indeno[1,2-b]indole.

CIS-(E)- and (Z)-4b,5,9 b,10-Tetrahydro-5-acetyl-8-(N,N-diethylamino)-indeno[1,2-b] indole (0,32 reaktsionnuyu the mixture is then boiled under reflux for 3 h, then the excess reagent was destroyed by addition of 30% ammonitrate sodium. The organic solvent is then decantation and the residue was extracted with tetrahydrofuran (3 x 10 ml). The solvent and the extracts were combined, dried and evaporated, receiving oil which was applied to silica (1 g) and brought to the top of the column with silica (5 g), after which he suirable 10% ethyl acetate in 60-80oC petroleum ether. Color column was dark blue, but is listed in the title compound was isolated as a colourless oil. Yield: 0.2 g, 65%. The connection is unstable and the air turns blue and then dark red.1H NMR (CDCl3) : 1,09 (6N, t, J=7,0 Hz) of 1.27 (3H, t, J= 7.0 Hz), 3,1-3,3 (5H, m), 3,3-3,5 (3H, m), 4,18 (1H, Shir. C) 5,07 (1H, Shir. C) 6,40 (1H, d, J=7,0 Hz), 6,74 (1H, s), 7,22 (3H, s), the 7.43 (1H, m).

Example 37. CIS-4b,5,9 b,10-Tetrahydro-8-tert-butylidene[1,2-b]indole.

The solution 5,10-dihydro-8-tertbutylbenzene[1,2-b]indole (or 0.57 g, 2.2 mmol) in triperoxonane acid (5 ml) was intensively stirred and to it one of these portions was added triethylsilane (0.7 ml, 2 EQ.). The reaction mixture was stirred overnight, poured into water and neutralized by adding sodium hydroxide. The product was extracted with diethyl ether (2 x 5 ml), combined is about washed with cold petroleum ether (60-80oC) and then recrystallized from petroleum ether, receiving in the form of a colorless solid. Output: to 0.47 g, 81%, So pl. 103-105oC:1H NMR (CDCl3) : 7,4-6,9 (6N, m), to 6.58 (1H, d, J=8 Hz), a 5.25 (1H, d, J=8.5 Hz), is 4.15 (2H, Shir.m), 3,5 (1H, DD, J=16.0 and 9 Hz), 3,2 (1H, d, J=16 Hz), 1,2 (N, C).

Example 38. CIS-4b,5,9 b,10-Tetrahydro-5-methyl-8-tert-butylidene [1,2-b] indole.

In a flame dried flask was loaded 4b,5,9 b,10-tetrahydro-8-tert-butylidene[1,2-b] indole (309 mg, 1,17 mm) and tetrahydrofuran (2.5 ml). The solution was cooled to -78oC and to it was added dropwise a solution of n-utility (0.75 ml, 1.6 M solution in hexane, 1,1 EC.). The reaction mixture was stirred at -78oC for 1 h and then added itmean (0.1 ml, a 1.3 EQ.). After slow heating of the reaction mixture to room temperature was introduced a saturated solution of ammonium chloride and the organic product was extracted with diethyl ether. The organic phase was washed with brine and dried (MgSO4). Evaporation of the solvent gave a light brown oil, which solidified upon cooling in the form of a beige solid. Output: 311 mg, 96%, So pl. 74oC:1H NMR (CDCl3) : 7,5-7,0 (6N,m), 6,32 (1H, d, J=8,3 Hz), 4,91 (1H, d, J=8,8 Hz), 4,16 (1H, DDD, J=9,0, of 8.8 and 5.3 Hz), 3,44 (1H, DD, J=16.3 and 9.1 Hz), 3,10 (1H, DD, J=16.3 and 5.3 of the/P> In a flame dried and purged with nitrogen, the flask was loaded 4b,5,9 b,10-tetrahydro-8-tert-butylidene[1,2-b] indole (240 mg, of 0.91 mmol) and freshly tetrahydrofuran (3 ml). Thus obtained solution was cooled to -78oC and to it was added dropwise n-utility (0,60 ml of 1.6 M solution in hexane, 1,1 EC. ). The light yellow solution was allowed to warm to room temperature, and after the solution propulsively dry gaseous carbon dioxide until then, until it became colorless. The solvent was carefully removed under reduced pressure and introduced an atmosphere of dry nitrogen. The colorless residue was re-dissolved in dry tetrahydrofuran (3 ml), the solution was cooled to -78oC and introduced 1.1 equivalent of n-utillity. The reaction mixture was stirred at -78oC for 2 h and then were treated with iodomethane (0.06 ml, 1,1 EC. ). After slow heating of the reaction mixture to room temperature, the solvent was removed and was added 2M hydrochloric acid (20 ml). After cessation of gas evolution (after about 20 min the solution was neutralized with solid sodium carbonate. The organic product was extracted with dichloromethane (3 x 5 ml), the combined extracts were washed with brine and dried (Na2SO4). After UDA is -80oC petroleum ether)] , elwira 10% EtOAc in 60-80oC petroleum ether. Thus obtained light yellow oil, which solidified at -20oC in the form of a pasty solid. Output: 0,86 mg, 34% of T. pl. 82-84oC:1H NMR (CDCl3) : 7,4-7,0 (6N, m) of 6.49 (1H, d, J=9.0 Hz), 4,15 (1H, Shir. m), 3,71 (1H, Shir, m), 3,51 (1H, DD, J=16,0, and 9.0 Hz), 3,17 (1H, DD, J=16.0 and 5 Hz) to 1.61 (3H, s), 1.27mm (N, C).

Example 40. CIS-4b,5,9 b,10-Tetrahydro-8-Florentino[1,2-b]indole.

The solution 5,10-dihydro-8-Florentino[1,2-b] indole (0.8 g, 3.6 mmol) in triperoxonane acid (5 ml) was intensively stirred and to it one of these portions was added triethylsilane (0,86 ml of 1.5 EQ.). The reaction mixture was stirred for 4 h and the excess triperoxonane acid was removed in vacuum. The solid residue was added water (10 ml) and neutralized by adding sodium hydroxide. The product was extracted with diethyl ether 2 x 5 ml), which was washed with water, dried and evaporated, getting a white solid. It was recrystallized from a mixture of ethyl acetate and petroleum ether (60-80oC) receiving in the form of a colorless solid. Output: 0,53 g, 81%. So pl. 92-94oC.1H NMR (CDCl3) : 7,34 (1H, m), and 7.8 to 7.2 (3H, m), 6.87 in (1H, m), 6,69 (1H, m ) of 6.52 (1H, DD, J=8.4 and 4.4 Hz), a 5.25 (1H, d, J=8,8 Hz), 4,16 (1H, DDM, J= 8.8 and 8.3 in the Deno[1,2-b]indole.

A solution of CIS-4b,5,9 b,10-tetrahydroindene[1,2-b]indole (1.0 g, 4.8 mmol) in concentrated sulfuric acid (20 ml) was intensively stirred for 45 min, then was cooled to 0oC and was treated with potassium nitrate (0.7 g, 6.9 mm) in small portions during 15 minutes to a Cherry-red solution was stirred at 0oC for 15 min and then poured into ice. The resulting yellow solid was collected by filtration and washed first with water and then hot 25% solution of ethanol in water (30 ml). The filtrate from the last wash was allowed to cool, and then specified in the title compound was allocated in the form of dark yellow plate crystals. Yield: 0.45 g, 31.5 per cent So pl. 174-176oC.1H NMR (CDCl3) : 3,30 (1H, DD, J=17.5 and 1.0 Hz), the 3.65 (1H, DD, J=17.5 and 8.5 Hz), 4,20 (1H, Shir.C) to 4.33 (1H, t, J=8.5 Hz), 5,41 (1H,d, J=8.5 Hz), 7,22 (1H,DD, J=8.0 and 1.0 Hz), 7,28 (1H, d, J=2.0 Hz), 7,38 (1H,d, J= 8.5 Hz), to 7.50 (1H, DD, J=8.0 and 2.0 Hz), 8,17 (1H, DD, J=8.5 and 2.0 Hz), 8,40 (1H,d, J=2.0 Hz).

Example 42. CIS-4b,5,9 b,10-Tetrahydro-5-acetyl-3,7-dinitrobenzene[1,2-b] indole.

CIS-4b, 5,9 b, 10-Tetrahydro-4,7-dinitrobenzene[1,2-b] indole (0.40 g, 1.35mm) and acetic anhydride (1.5 ml) was heated at 90oC for 1 h, cooled and poured into ice-cold water (7 ml) and the mixture was stirred for 30 minutes Released otadnoe in the title compound was separated from the cold solution in the form of prismatic crystals. Output: 0,42 g, 92%, So pl. 264-266oC.

Example 43. CIS-(E) and (Z)-4b,5,9 b,10-Tetrahydro-5-acetyl-3,7-diaminobenzene[1,2-b]indole.

CIS-4b,5,9 b,10-Tetrahydro-5-acetyl-3,7-dinitrobenzene[1,2-b]indole (0.4 g, 1.2 mm) was stirred in a solution of glacial acetic acid (30 ml) and water (5 ml). To this mixture was added trichloride titanium (3 ml of 3% solution in water of 24% hydrochloric acid) for 5 minutes After a further 2 h the mixture became colorless, and added another portion of trichloride titanium containing reagent (0.5 ml). Unreacted starting material was filtered (0,13 g) and the filtrate was poured upon the ground ice. the pH of the thus obtained solution was brought to 6 (15 ml, 0.89 ammonia), and the product was extracted with ethyl acetate (8 x 50 ml). The extraction process was extremely slow because of the formation of emulsions and was completed within 3 days. The extracts were combined and evaporated, having a greenish solid, which when crushed with diethyl ether gave colorless microscopic prismatic crystals. Output: 0,13 g, 58%, So pl. 254-256oC.

Example 44. CIS-4b, 5,9 b,10-Tetrahydro-5-acetyl-3,7-di(-N,N-diethylamino)-indeno[1,2-b]indole.

CIS-4b, 5,9 b, 10-Tetrahydro-5-acetyl-3,7-diaminobenzene[1,2-b]indole (0,13 g) was dissolved in Tetra is linecom within 24 hours Then typed more ethyliodide (0.8 ml) and heating was continued for 4 h, the Solvents and excess reagent was removed and the residue was extracted with diethyl ether (6 x 10 ml). The combined extracts was evaporated, getting brown with a maul (0.33 g) which was purified column chromatography on silica (4 g), elwira 20% ethyl acetate in 60-80 petroleum ether. This gave specified in the title compound in the form of colorless prismatic crystals. Output: 0,023 g, 12.5%, and So pl. 137-138.1H NMR (CDCl3) : 4 x [1,12 (6N, t, J=7.0 Hz)] 2,50 and 2,65 2 x [3H, s)], was 3.05 (1H, d, J=16.5 Hz), 3,10 (1H, d, J=16.0 Hz), 3,26 and 3.30 4 x [(4N, K, J=7.0 Hz)], 3,98 (1H, DD, J=7.5 and 7.5 Hz), 4,07 (1H, DD, J=7.5 and 7.0 Hz), 5,70 (1H, d, J=7,5), 6,23 (1H, d, J=7,0 Hz), 6,32-6,40 (2H, m), 6,59 (2H, DDD, J= 8.0 a, 8,0 1,5 Hz), of 6.96 (2H, d, J=1.0 Hz), 6,95 -7,10 (5H,m), to 7.61 (1H, d, J=1.5 Hz).

Example 45. CIS-5,5 a,6,10 b-Tetrahydro-9-methoxyimino[2,1-b]indole.

5,6-Dihydro-9-methoxyimino[2,1-b] indole (0.56 g) in suspension in glacial acetic acid (25 ml) in the 16oC were treated with nitrobenzimidazole (1.0 g) in small portions over 6 hours the resulting solution was stirred for 1 h and then poured into a mixture of ice water (100 ml). The solution was separated from a small amount of retinoid material, and the filtrate was treated caresto assembled and led from ethanol in the form of needle crystals. Yield: 0.31 g, 55% of T. pl. 129-130oC. 1H NMR (CDCl3) : a 3.06 (1H, gg, J=16.5 and 1.5 Hz), 3,2-3,8 (Shir. C), and 3.31 (1H, DD, J=16.5 and 6.0 Hz), 3,76 (3H, s), 4,71 (1H, d, J=8.0 Hz), 4,80 (1H, DDD, J=8,0, 6.0 and 2.0 Hz), and 6.5 (1H, d, J=8.5 Hz), to 6.58 (1H, DD, J= 8.5 and 2.5 Hz), of 6.99 (1H, d, J=2.5 Hz), 7,15-7,24 (3H, m), 7,33 and 7.36 (1H, m).

Example 46. CIS-5,5 a, 6,10 b-Tetrahydro-9-isopropylidene[2,1-b] indole and CIS-5,5 a,6,10 b-tetrahydro-6-ethyl-9-isopropylidene[2,1-b]indole.

To a suspension of 5,6-dihydro-9-isopropylidene[2,1-b] indole (2.3 g, 9.3 mmol) in glacial acetic acid (30 ml) was added nitrobenzamide (2 g) in small portions over 30 minutes and the Mixture was stirred for 3 h and the resulting solution was poured into a mixture of ice water (50 ml) and was stirred for 1 h Clear solution was carefully neutralized with sodium hydroxide, it was formed a white precipitate. This solution was extracted with diethyl ether (3 x 10 ml), the combined extracts were abundantly washed with water, dried (Na2SO4) and was evaporated. Analysis of the residue by TLC showed the formation of two products, which was separated by column chromatography, elwira 10% ethyl acetate in petroleum ether 60-80oC and receiving first a small amount of CIS-5,5 a,6,10 b-tetrahydro-6-ethyl-9-isopropylidene[2,1-b] indole (0.07 g, 3%), and then okologie by distillation.1H NMR (CDCl3) : of 7.4 and 7.1 (5H,m), 6.87 in (1H, DD, J=8.1 and 1.8 Hz), 6,50 (1H, d,J=8.1 Hz), to 4.81 (1H, DDD, J=8,1, 6,2 and 2.0 Hz), to 4.73 (1H, d, J=8.1 Hz), 3,32 (1H, DD, J=16,6 and 6.2 Hz), is 3.08 (1H, DD, J=16,6 and 2.0 Hz), and 2.83 (1H, septet, J= 6.9 Hz), 1,23 (6N, d, J=6,9 Hz).

Example 47. CIS-5,5 a,6,10 b-Tetrahydro-9-Florentino[2,1-b]indole.

5,6-Dihydro-9-Florentino[2,1-b]indole (0.55 g, 2.5 mm) in glacial acetic acid (25 ml) was stirred and treated with nitrobenzimidazole (2.1 g, 36.5mm) - small portions during 10 h, keeping the temperature below 18oC. the Amount of reducing agent is a critical value because adding large quantities of the formed mixture. The reaction mixture was then added to water with ice (100 ml) and the resulting yellow oil was separated from the aqueous phase. the pH of the aqueous phase was brought to 6 by addition of sodium carbonate (30 g), and a colorless oil was extracted with diethyl ether (4 x 20 ml). The combined extracts were dried and evaporated, obtaining oil, which was extracted with hot 60-80oC petroleum ether (6 x 10 ml), the residue triturated with ethanol (1 ml). This treatment caused the crystallization of the compound in the form of colorless prismatic crystals, which are recrystallized from ethanol, having specified in the header connection. Yield: 60 mg, 11%, So the(1H, DDD = 8,0 6,0 and 2.0 Hz), to 6.43 (1H, d, J=8.5 and 4.0 Hz), 6,70 (1H, DDD, J=8.5 a, 8.5 and 2.5 Hz), 7,07 (1H, DD, J=8.5 and 2.5 Hz), 7,16-of 7.25 (3H, m), 7,33 (1H, m).

Example 48. CIS-9-tert-butyl-5,5 a,6,10 b-Tetrahydroindene[2,1-b]indole.

9-Tert-butyl-5,6-dihydroindeno[2,1-b] indole (0.16 g, 0.6 mm) in glacial acetic acid (25 ml) was stirred and treated with nitrobenzimidazole (0.7 g, 11 mm) in small portions over 3 h, keeping the temperature below 18oC. the Reaction mixture was then added to water with ice (80 ml) and the resulting yellow oil was separated from the aqueous phase. the pH of the aqueous phase was brought to 6 by addition of sodium carbonate (25 g), and a colorless oil was extracted with diethyl ether (6 x 10 ml). The combined extracts were dried and evaporated, obtaining oil, which was chromatographically on the silicon dioxide, elwira 5% ethyl acetate in 60-80oC petroleum ether. Thus received is listed in the title compound in the form of colorless prismatic crystals. Yield: 0.11 g, 7%. So pl. 92oC.1H NMR (CDCl3) : 1,30 (N, C) 3,05 (1H, d, J=16.5 Hz), or 3.28 (1H, DD, J=16.5 and 6.0 Hz), with 3.79 (1H, s), 4,70 (1H, d, J=8.0 Hz), and 4.75 (1H, DDD, J=8,0, 6.0 and 2.0 Hz), 6.48 in (1H, d, J=8.0 Hz), 7,03 (1H, DD, J=8.0 and 2.0 Hz), 7,14-7,24 (3H, m), 7,34 (1H, m) 7,40 (1H, d, J=2.0 Hz).

Example 49. 9b,10-Dihydro-9b-methylindene[1,2-b]indole.

In vysushennom trichloride phosphorus (3.4 ml of 2M solution in DHM). The solution was boiled under reflux for 2 h, cooled and poured into a saturated solution of sodium bicarbonate. After stirring for 1 h, the organic product was extracted with additional DHM. The main components were extracted back 2M hydrochloric acid. This aqueous solution was again doing the main and re-extracted DHM. Evaporation of the solvent vacuum and column chromatography of the residue (20% EtOAc/petroleum ether [60-80oC]) gave the transparent resin (Rf[10% EtOAc/petroleum ether] 0,1), which was purified further by reconcretion, getting mentioned in the title compound in the form of a resin. Yield: 0.4 g (30%). So Kip.170oC (0.2 mm Hg).1H NMR (CDCl3) : of 1.39 (3H, s) 2,84 (1H, d ), 3,11 (1H, d), 6,4, 8,4 (8H, m).

Example 50. CIS-9b,10-Dihydro-8,9 b-dimethindene[1,2-b]indole.

To a solution of 4-methylphenylacetonitrile (9,73 g, 0.06 mmol) in absolute ethanol (240 ml) was added dropwise 2-methyl-1-indanone (8,14 g 0,056 mmol) and then concentrated hydrochloric acid (3 ml). The mixture was boiled for 2 h, the solvent was removed, and the residue was divided between diethyl ether and water and the layers separated. The aqueous phase was extracted with diethyl ether (3 x 50 ml). The combined organic phases Preveli. Thus obtained crude product was purified high-performance chromatography on silica gel, elwira 7-12% ethyl acetate in petroleum ether and receiving solid (of 5.05 g, 39%).1H NMR (CDCl3) : 7,87 (1H, m), 7,51 (1H, d, J=7.9 Hz), 7,39 (3H, m), 7,25 (1H, s), to 7.15 (1H, d, J=8.0 Hz), of 3.07 (1H, d, J=14,7 Hz), of 2.81 (1H, d, J=14,7 Hz) to 2.41 (3H, s), 7,37 (3H, s).

Example 51. 9b,10-Dihydro-9b-methyl-8-isopropylidene[1,2-b]indole.

To a solution of 4-isopropylphenylacetonitrile (6.50 g, 0.035 mmol) in absolute ethanol 9140 ml) was added dropwise 2-methyl-1-indanone (4.6 g, to 0.032 mmol) and then concentrated hydrochloric acid (2.5 ml). The mixture was boiled for 2 h, and the ethanol evaporated. The residue was divided between diethyl ether (100 ml) and water (100 ml) and the layers were separated. The aqueous phase was extracted with diethyl ether (2 x 30 ml), the organic extracts were washed sequentially with saturated sodium bicarbonate solution and brine and then dried (Na2SO4). Removal of solvent gave specified in the title compound, which was purified high-performance chromatography on silica gel, elwira 10% ethyl acetate in 60-80oC petroleum ether and receiving a yellow resin: (1,62 g, 25%).1H NMR (CDCl3) : 7,88 (1H,m), 7,55 (1H,d, J=8.1 Hz), 7,41 (3H, m), 7,30 (1H, d, J=1,8 Hz),>Source materials derived DGII and ISO-DGII are illustrated by a running example in the accompanying application.

Example 52. CIS-(E)- and (Z)-5-Acetyl-8-amino-4b,5,9 b,10-tetrahydroindene[1,2-b]indole.

(E)- and (Z)-5-Acetyl-8-nitro-4b, 5,9 b, 10-tetrahydroindene-[1,2-b]indole (4,2 g) in glacial acetic acid (250 ml) and water (25 ml) was stirred and treated with 30% aqueous trichloride titanium (42 ml) within 5 min after 15 min the reaction mixture was poured into ice water (800 ml) and the pH was brought to 4.5 with ammonium hydroxide. The product as quickly as possible was extracted with dichloromethane (6 x 75 ml). The combined extracts were dried and evaporated, receiving solid, which is triturated with diethyl ether, getting listed in the title compounds as colorless solids. Yield: 2.9 g, 77%. So pl. 196-198oC;1H NMR (CDCl3) : to 2.42 (3H, s) to 2.55 (3H), AND 3.16 (1H, d, J=16 Hz), up 3.22 (1H, d, J=16hz), 3,4 (2H, m), the 3.65 (4H, exchanged with D2O) to 4.01 (1H, DD, J=8.0 Hz), 4,13 (1H, DD, J=7.5 Hz), 5,72 (1H, d ), of 6.26 (1H, d, J=8.0 Hz), 6,46 (1H, d, J=8.5 Hz), to 6.57 (1H, s), only 6.64 (1H, ), PC 6.82 (1H, d, J=8.5 Hz), 7,16-7,25 (6N, m), 7,38 (1H, d, J=7.5 Hz), to 7.64 (1H, d, J=7.5 Hz), the 7.85 (1H, d, J=8,5 Hz). Specified in the title compound can be obtained with a similar yield by catalytic hydrogenation of mixed isomeric nitro.

Example 53. CIS-(E)- and (Z)-5-Acetyl-8-(N-acetylamino)-4b,5,9 b,10-tetrahydroindene[1,2-b]indole.

A mixture of CIS-(E)- and (Z)-5-acetyl-8-amino-4b,5,9 b,10-tetrahydroindene[1,2-b] indole from example 52 was azetilirovanie using conventional methods, getting listed in the connection header. [Found: C,74,1; H,5,8; N9,0; C19H18N2O2requires: C,74,5; H,5,9; N 9,2%].

New examples.

Example 54. CIS-4b,5,9 b,10-tetrahydro-4,6-dimethyl-8-methoxyimino [1,2-b] indole.

1) 4-Hydrazino-3-methylaminopropane

33 g (to 0.19 mol) of 4-methoxy-2-methylenechloride suspended in 100 ml (6 M) of hydrochloric acid in an argon atmosphere. The mixture was cooled to 5oC was added a solution of 13.1 g (to 0.19 mol) NaNO2in 35 ml of water is added dropwise with such speed that the temperature remained below 5oC. After addition the solution was stirred for 30 min at 5oC. of 101.7 g (of 0.58 mol) of Na2S2O4was dissolved in 500 ml of water in 5oC, the solution was poured into the reaction mixture and was stirred for 30 minutes was Added 250 ml of diethyl ether, and podslushivaet with NaOH (10 M) to pH 9. The phases were separated and the aqueous phase was extracted with diethyl ether. The combined organic phases are washed with NaCl (aq.) and dried over Na2SO4. EPE is jireh, and hydrochloric acid salt of hydrazine precipitated. The crystals were separated on a filter and washed with diethyl ether and chloroform. Allocated to 29.5 g (82%) of product.

2) 5,10-Dihydro-4,6-dimethyl-8-methoxyimino [1,2-b]indole.

Into the flask was loaded with 130 ml of ethanol saturated solution of HCl (gas) in 130 ml of ether, 5.8 g (31 mmol) of 4-hydrazino-3-methylenechloride and 4.8 g (31 mmol) of 7-methyl-1-indanone. The solution was stirred at room temperature overnight. A number of 7-methyl-1-indanone still remained in the reaction mixture. Added an excess of 4-hydrazino-3-methylenechloride (0.6 g) and the solution was stirred over night. The solvent was removed and the crude product was dissolved in ether, washed twice with NaOH (1M) and water. The organic phase was dried over Na2SO4, was filtered and was evaporated. The remaining oil was chromatographically and suirable dichloromethane. Earmarked 1.3 g (16%) of product.

3) CIS-4b,5,9 b,10-tetrahydro-4,6-dimethyl-8-methoxyimino-[1,2-b]indole.

In a round bottom flask was loaded 16 ml of dioxane, 1,3 g (4.9 mmol) of 5,10-dihydro-4,6-dimethyl-8-methoxyimino [1,2-b] indole and 1.98 g (a 19.6 mmol) of morpholinopropan. With stirring, to the solution was added dropwise 4 ml conc. of hydrochloric acid. The reaction mixture Ki is down to room temperature was added 50 ml of water. The mixture was podslushivaet with NaOH (aq.) to pH 9. The product was extracted with dichloromethane 2 times. The organic phase was dried over Na2SO4and the solvent was removed. The product was chromatographically dichloromethane. The isolated product was dissolved in acetonitrile, was added a saturated solution of HCl (gas) in ether and the residue is hydrochloric acid salt was removed by filtration. Allocated 1.2 g (82.2 per cent) of the product.1H NMR (CDCl3) : of 2.33 (3H,s), 2,48 (3H, s), 2,95 (1H, DD), of 3.56 (1H, DD), 377 (3H, s), of 4.44 (1H, DDD), 5,71 (1H, d), is 6.78 (1H, s), 6,93 (1H, s), 7,11-7,17 (2H, m), 7,30 (1H, d).

Example 55. CIS-5,5 a,6,10 b-tetrahydro-7-methyl-9-methoxyimino[2,1-b]indole.

1) 4-Hydrazino-3-methylanisole.

With stirring to a cooled suspension of 33.0 g (to 0.19 mol) of 2-methyl-4-methoxyacetanilide 100 ml of 6N hydrochloric acid was added dropwise in an argon atmosphere a solution of 13.1 g (to 0.19 mol) of sodium nitrate dissolved in 35 ml of water. The rate of addition was maintained such that the temperature did not exceed 5oC. After addition the mixture was stirred for another 30 min at the same temperature. The reaction mixture was then added with stirring under argon to a cooled (+5oC) the solution of 101.7 g (of 0.58 mol) of Na2SO4dissolved in 500 ml of water. PEFC is to pH with 10N NaOH solution. The organic phase was separated and washed with sodium chloride solution. After drying (Na2SO4), treatment with activated charcoal and filtration, the product was besieged in the form of the hydrochloride by addition of HCl (gas) in ether (to pH 3). Filtration and washing with ether, and chloroform gave 29,6 g (69%) of product.

2) 5,10-dihydro-7-methyl-9-methoxyimino[2,1-b]indole.

A mixture of 1.9 g (0.01 mol) of 4-hydrazino-3-methylenechloride and 1.3 g (0.01 mol) of 1-indanone in 25 ml of acetic acid was heated under argon for 6 hours After dilution with water the mixture was extracted 3 times with methylene chloride. The combined organic phases are washed twice with a solution of NaOH (1M), dried (Na2SO4), was treated with activated charcoal and evaporated to give crude product. Purification on silica using methylene chloride as eluent gave 0,85 g (34%) of product. So pl. 208oC.

3) CIS-5,5 a,6,10 b-tetrahydro-7-methyl-9-methoxyimino [2,1-b]indole.

To a stirred suspension of 0.74 g (0,00296 mol) 5,10-dihydro-7-methyl-9-methoxyimino[2,1-b] indole in 25 ml of acetic acid was added 0,93 g (0,0148 mol) NaCNBH3- portions over 5 minutes and the Mixture was stirred for 3 h at room temperature, then was diluted with water and whether the ether. The combined organic phases are washed twice with an aqueous solution of NaCl and dried (Na2SO4). After evaporation the residue was purified chromatography on silica using methylene chloride as eluent. This gave 0,61 g (24%) of the expected product, So pl. 104oC.1H NMR (CDCl3) : 2,2 (3H, s), of 3.0-3.4 (2H, DD), 3,4-3,5 (1H, Shir. with in), 3.75 (3H, s), 4,65-4,80 (2H, m), 6,4-7,4 (6N, m) - ibid 6,45 (1H, DD), to 6.75 (1H, DD).

4) Racemic mixture obtained in stage 3) was divided and the resulting enantiomers had the following physicochemical properties:

(-) CIS-5,5 a,6,10 b-tetrahydro-7-methyl-9-methoxyimino[2,1-b]indole

[[]D]=14,5o(C=1,CH2Cl2)

So pl. 93,5oC

(+) CIS-5,5 a,6,10 b-tetrahydro-7-methyl-9-methoxyimino[2,1-b]indole

[[]D]=+14,5o(C=1,CH2Cl2)

So pl. 93,5oC

Example 56. CIS-4b, 5,9 b,10-tetrahydro-8-methoxy-4b,6,9 b-trimethylbenzene [1,2-b]indole.

1) 2-Methyl-4-methoxyphenylhydrazine 2-methyl-1-indanone.

A mixture of 14.9 g (0.08 mol) of 4-hydrazino-3-methylanisole (obtained as described in example 55 (1) and 20 g (0.25 mol) of sodium acetate in 60 ml of water were thoroughly stirred and then filtered. To the stirred filtrate was added 9.3 g (0.06 mol) of 2-methyl-1-indanone in 10 ml of ethanol, ulali and recrystallized from ethanol, receiving 5.0 g (30%) of the expected product.

2) 9b, 10-dihydro-8-methoxy-6,9 b-dimethindene[1,2-b]indole. To a stirred solution of hydrazine obtained above in 100 ml of ethanol was added 35oC for 15 min, 75 ml of saturated HCl in ether. The mixture was heated at 35-45oC for 10 min and then the mixture was allowed to cool. After evaporation of the solvent the residue was dissolved in methylene chloride, washed with diluted aqueous sodium chloride solution, dried (Na2SO4) and was evaporated, obtaining 1.7 g (35%) of crude product as a brown oil. It was used directly in the next stage without further purification.

3) CIS-4b, 5,9 b, 10-tetrahydro-8-methoxy-4b, 6,9 b-trimethylbenzene[1,2-b] indole.

1.7 g (0,006 mol) of the crude product obtained above was dissolved in 20 ml of dry tetrahydrofuran and cooled to -78oC under argon. To this solution under stirring was added 10 ml metallyte (1.6 M in ether, after which the mixture was allowed to warm to room temperature (3 h). Quenching was performed by addition of a mixture of ether and a saturated solution of ammonium chloride. The organic phase was separated, washed with water, dried (Na2SO4) and was evaporated. The residue was purified chromatographically on silica, use the m gave 0.4 g (24%) of product as colorless crystals.1H NMR (CDCl3) : of 1.35 (3H, s), 1,5 (3H, s), and 2.1 (3H, s), is 3.08 (1H, d), to 3.38 (1H,d), and 3.7 (3H,s), 6,44 (1H,d), 7,1-7,28 (3H,m), 7,35 (1H,d).

Pharmacological properties.

Indenolol described in the invention are hydrophobic and stable structures, which form cations, stable cation radicals and radicals during the oxidation process. They are potential antioxidants that determined by the inhibition caused by Fe2+-ascorbate of peroxidizable lipids in vitro with the value of the IC50less than 10 nm. Compounds of formulas (IA) and (IB) effectively prevent the oxidation of lipoproteins in human plasma in the presence of smooth muscle cells of the rabbit or peritoneal macrophages mouse. They also prevent ischemic/reperfusion injury of isolated pehotnogo rat heart, and protect against caused by carbon tetrachloride, acetamidophenol, methylmethanesulfonate, menadione, tert-butylhydroperoxide and N-methyl-N1-nitro-N-nitrosoguanidine damage the liver of mice or isolated rat hepatocytes.

These properties suggest that the structure of formulas (IA) and (IB) are potentially applicable for the prevention or treatment of ischemic or reperfusion diseases, osobennosti Alzheimer's disease, tumors and toxicity of anticancer drugs, immunosuppressive funds, and inflammatory processes, including allergic/inflammatory condition type of bronchial asthma and rheumatoid arthritis. Other potential applications are hemaprodhite from the toxicity of chemicals or radiation damage. Indeoendence connections are not activated in an appreciable degree under UV irradiation, which makes them candidates for use in means for skin care. Another interesting and important feature indeoendence compounds is their ability to stabilize membranes.

Pharmacological tests.

The most important feature of the compounds of the invention is its effectiveness as traps free radicals or oxidants. Used test system for measuring the concentration of the compounds of formulas (IA) and (IB) required to inhibit peroxidizable lipids by 50% (IC50). Test peroxidizable lipids described below and the data are presented in table. 1. Other tests, described below, is a sample of the weakness of the red blood cells used to measure stabilization meridina (MNNG) in rat hepatocytes (table. 3). MNNG is a strong cytotoxic agent, mechanism of action which may include the destabilization of the membrane with the participation of radicals.

1. Ascorbate/Fe2+- dependent peroxidizable lipids. If peroxidative lipid system iron/ascorbate, and 6.25 ml of 0.1 M buffer solution of potassium phosphate (KPi), pH of 7.4) was added to 12.5 mg of dried phospholipids from soy beans. After blowing with argon for 2 min, the suspension was sealed five layers of film Parafilm and were treated by ultrasound until then, until the suspension became transparent. The final reaction mixture consisted of 200 μg/ml phospholipid, 10 μm FeNH4(SO4)2or Fe(NH4)2(SO4)2and 100 μm ascorbic acid in 0.1 M KPi (pH 7,4), as well as the tested antioxidant in acetone or DMSO. Medium volume never exceeded 1% of the total. The reaction was initiated by addition of ascorbic acid and iron. The reaction was continued at room temperature in a shaking water bath for 30 min and then terminated by adding 10 μm 0.5 M of bottled hydroxytoluene in DMSO. The above procedure and the subsequent determination of reacting with 2-thiobarbituric acid material is described in: Shertzer. the s peroxidizable lipids.

Stabilization of membranes of red blood cells.

The influence of indenolol on membrane stabilization was investigated using samples from the weakness of the red cells. Rats were anestesiologi using 65 mg pentobarbital per 1 kg of body weight by injection. Blood samples were taken using treated heparin syringes from the left ventricle and 20-tickrate diluted buffer solution containing 140 mm NaCl, 10 mm sodium citrate and 5 mm glucose (pH 7,4), at 0oC. the Diluted blood was kept on ice. A 0.75 ml aliquot of blood was placed in a 4 ml cuvette containing 10 μl of DMSO or 10 μl of antioxidant dissolved in DMSO. After 1 min of gentle stirring in the cuvette were injected with 0.75 ml of 0.9% NaCl or H2O by actively dripping from the pipette, and the absorbance at 656 we recorded with a spectrophotometer Beckman DV-70. Adding water in the absence of a stabilizing agent, the optical density was decreased in 15 seconds to 0.8. Adding NaCl instead of H2O let not time-dependent optical density of 2.2. In the presence of increasing concentrations of stabilizing chemicals observed after addition of water the decrease in optical density was diminished. The percentage protection osmolite obtained from the equation [[(2,2-0,8) is traci chemicals. The percentage of protection is then plotted on the graph based on several concentrations of chemicals that were processed. The protective value of the index of red blood cells (33AND-KKK) is the slope of the linear regression of this relationship, expressed as a percentage of protection against osmolite on micron protective agent. Table. 2 shows the values 33AND-KKK for different indenolol and-tocopherol.

3. Protection against the cytotoxic effects MNNG in hepatocytes

Protecting effects of indenolol caused from MNNG cytotoxicity was tested using rat hepatocytes. Hepatocytes were prepared from male rats, Sprague-douli by processing the collagenase as originally described Zaltana and Stratmann (Zahlten R. N. , F. W. Stratman, Arch. Biochem. Biophys 163,600 (1988)), as modified by Reitmann and others (Reitman F. A., Shertzer, H. G. , Berger, M. L., Biochem. Pharmacol. 37,3183 (1988)). To improve the viability of the cells was centrifuged through 0,508 g/ml Percoll (Pharmacia AB, Uppsala, Sweden) in 137 mm NaCl, and 8.1 mm Na2HPO4and 1.5 mm KH2PO4(pH of 7.4). Estimated protecting agents were added to the cells in the form of solutions in DMSO and the final concentration of DMSO never exceeded 5 μl per ml of cell suspension. MNNG was added to a concentration of 0.5 mm in the form of plants is a activity was defined as the percentage of cells who did not let 0,2% tripney blue. Protecting influence of indenolol and-tocopherylacetate from cytotoxicity shown in the table. 3. Values are concentrations of compounds required to increase at 1 h time needed for the callee MNNG the death of 50% of viable cells.

1. Tetrahydroisoquinoline the compounds of formula IA

< / BR>
or formula IB

< / BR>
in which R represents hydrogen, alkyl group or COR15;

R1, R2, R11and R12independently selected from hydrogen or lower alkyl groups;

R3, R4, R5and R6independently selected from hydrogen, hydroxy, halogen, lower alkyl groups or lower alkoxygroup, mono - or denissa alkylamino, NH2or NR13COR14;

R7R10independently selected from hydrogen, hydroxy, lower alkyl groups, lower alkoxygroup, mono - or denissa alkylamino, NH2or NR13COR14;

R13R15independently selected from hydrogen or lower alkyl groups

provided that when R is stands in the formula IA, then at matalom and R11is ethyl in formula IA, then at least one of the radicals R1R10or R12is not hydrogen,

or the enantiomers or salts.

2. Connection on p. 1, in which at least one of the substituents R3, R5, R7, R9, R11and R12represents a lower alkyl group, preferably methyl, ethyl or isopropyl.

3. Connection under item 1 or 2, in which at least one of the substituents R5and R8is mono - or denissa alkylaminocarbonyl, preferably acylamino or diethylaminopropyl.

4. Connection under item 1 or 2, in which at least one of the substituents R5and R8is hydroxyl or lower alkoxygroup, preferably methoxy.

5. The compound according to any one of the preceding paragraphs, in which R, R1, R2, R4, R6and R10are hydrogen.

6. Connection on p. 1, which is CIS-4b,5,9 b,10-tetrahydroindene[1,2-b] indole; CIS-4b,5,9 b,10-tetrahydro-6,8-dimethindene[1,2-b] indole; CIS-4b,5,9 b,10-tetrahydro-5,8-dimethindene[1,2-b]indole; CIS-4b,5,9 b, 10-tetrahydro-8-methylindene[1,2-b] indole; CIS-4b, 5,9 b, 10-tetrahydro-the toxi-5-methylindene[1,2-b] indole; CIS-4b, 5,9 b, 10-tetrahydro-8-methoxyimino[1,2-b] indole; CIS-4b, 5,9 b,10-tetrahydro-10,10-dimethindene[1,2-b]indole; CIS-4b,5,9 b,10-tetrahydro-9b methylindene[1,2-b] indole; CIS-4b,5,9 b,10-tetrahydro-4b,9b-dimethindene[1,2-b] indole; CIS-4b, 5,9 b,10-tetrahydro-4b,5,9 b-trimethylbenzene[1,2-b]indole; CIS-4b,5,9 b,10-tetrahydro-2-methoxy-1,3-dimethylbenzene[1,2-b] indole; CIS-4b, 5,9 b, 10-tetrahydro-2-methoxy-1,3-dimethyl-8-isopropylidene[1,2-b] indole; CIS-4b,5,9 b,10-tetrahydro-4b-methylindene[1,2-b]indole; CIS-4b,5,9 b,10-tetrahydro-2-hydroxy-1,3-dimethyl-8-isopropylidene[1, 2-b]indole; CIS-4b, 5,9 b,10-tetrahydro-2-hydroxy-1,3-dimethylbenzene[1,2-b]indole; CIS-4b, 5,9 b,10-tetrahydro-4b,8,9 b-trimethylbenzene[1,2-b]indole; CIS-4b,5,9 b,10-tetrahydro-8-isopropyl-4b, 9b-dimethindene[1,2-b]indole; CIS-4b,5,9 b,10-tetrahydro-8-isopropyl-4b-methylindene[1,2-b] indole; CIS-4b, 5,9 b,10-tetrahydro-2,8 dimethoxy-1,3-dimethylbenzene[1,2-b] indole; CIS-4b, 5,9 b, 10-tetrahydro-4b, 5,8,9 b-tetramethylbenzene[1,2-b] indole; CIS-4b,5,9 b,10-tetrahydro-8-tert.butylidene[1,2-b] indole; CIS-4b,5,9 b,10-tetrahydro-8-methoxy-7,9-dimethindene[1,2-b] indole; CIS-4b,5,9 b,10-tetrahydro-8-methoxy-6-methylindene[1,2-b] indole; CIS-4b,5,9 b,10-tetrahydro-8 diethylamino-5-ethylidene[1,2-b]indole; CIS-4b, 5,9 b,10-tetrahydro-2-diethylaminopentane[1,2-b]indole; CIS-4b,5,9 b,10-tetrahydro-8-tert. butyl-4b-methylindene[1,2-b] indole; CIS-4b,5,9 b,10-tetrahydro-8-Florentino[1 the hydro-9-isopropylidene[2,1-b]indole.

7. Connection on p. 1 representing CIS-4b,5,9 b,10-tetrahydro-4,6-dimethyl-8-methoxyimino[1,2-b] indole; CIS-5,5 a,6,10 b-tetrahydro-7-methyl-9-methoxyimino[2,1-b] indole or CIS-4b,5,9 b,10-tetrahydro-8-methoxy-4b,6,9 b-trimethylbenzene[1,2-b]indole.

8. Connection on p. 1, representing the (-)CIS-5,5 a,6,10 b-tetrahydro-7-methyl-9-methoxyimino[2,1-b]indole.

9. Connection on p. 1, representing the (+)CIS-5,5 a,6,10 b-tetrahydro-7-methyl-9-methoxyimino[2,1-b]indole.

10. Connection on p. 1, which is CIS-4b,5,9 b,10-tetrahydro-8-methoxy-6-methylindene[1,2-b]indole, or its enantiomer, or salt.

11. Connection on p. 1, which is CIS-5,5 a,6,10 b-tetrahydro-7-methyl-9-methoxyimino[2,1-b]indole, or its enantiomer, or salt.

12. Tetrahydroisoquinoline the compounds of formula IA

< / BR>
or formula IB

< / BR>
in which R is hydrogen, an alkyl group or COR15;

R>1, R2, R11and R12independently selected from hydrogen or lower alkyl groups;

R3R6independently selected from hydrogen, hydroxy, halogen, lower alkyl groups, lower alkoxygroup, mono - or denissa alkylamino, NH2or NR13COR14;

R7R1< denissa alkylamino, NH2or NR13COR14;

R13R15independently selected from hydrogen or lower alkyl groups,

provided that, when R represents a COR15then at least one of the substituents R3R10is hydroxyl or mono - or denissa alkylaminocarbonyl,

or its enantiomers, or a pharmaceutically acceptable salt, a potent antioxidant.

13. Pharmaceutical composition having antioxidant activity, including an active ingredient and a carrier or excipient, characterized in that the active ingredient is a compound as defined in any of paragraphs.1

11, or its enantiomer, or pharmaceutically acceptable salt in an effective amount.

14. The method of producing tetrahydroindazole (THII) of General formula IA under item 1

< / BR>
in which R, R1R12have the values listed in paragraph 1,

characterized in that the phenylhydrazine of the formula II

< / BR>
subjected to interaction with 2-substituted 1-indanone of formula III

< / BR>
obtaining indolenine formula IV

< / BR>
which restores the connection formulas V

< / BR>
in which R1
R11have the meanings given in paragraph 1, or restore the corresponding nitro-derivatives of 5-acyl-THII with subsequent N-alkylation of the amino group and optionally acidic hydrolysis of acetyl groups from obtaining THII, in which R3R6and/or R7R10represent mono - or denissow alkylamino, and R, R1, R2, R11and R12have the meanings defined for the formula IA, or a corresponding alkoxybenzenes THII subject ethereal dialkylamino obtaining THII, in which R3R6and/or R7R10represent hydroxy and R, R1, R2, R11and R12have the meanings defined for the formula IA, or an appropriate 4b-unsubstituted THII derived are metallation and subsequent alkylation of R12-halide or R12-sulfate and hydrolysis to obtain THII, in which R12represents a lower alkyl group and R, R1- R11have the meanings defined for formula IA.

15. The way p is P>2have the meanings given in paragraph 1,

characterized in that the phenylhydrazine of the formula II

< / BR>
subjected to interaction with indan-2-one of formula XII

< / BR>
obtaining indolenine formula VIII

< / BR>
which restores the compound of formula IX

< / BR>
in which R1R11in formulas II, XII, VIII and IX have the meanings defined for formula IB, and, if necessary, alkylate R-halide or R-sulfate, where R represents alkyl group, or restore the corresponding 6-acyl-ISO-THII obtaining 6-alkyl-ISO-THII, in which R1R11have the meanings given in paragraph 1, or restore the corresponding nitro-derivatives of 6-acyl-ISO-THII with subsequent N-alkylation of the amino group and optionally acidic hydrolysis of acetyl groups from obtaining ISO-THII, in which R3R6and/or R7R10represent mono - or denissow alkylamino and R, R1, R2, R11and R12have the meanings defined for formula IB, or a corresponding alkoxybenzenes ISO-THII subject ethereal dialkylamino with obtaining ISO-THII, in which R3R6and/or R7R10represent hydroxy eastwoodiae 5a-unsubstituted ISO-THII derived are metallation and subsequent alkylation of R12-halide or R12-sulfate and hydrolysis to obtain ISO-THII, in which R12represents a lower alkyl group and R, R1R11have the meanings defined for formula IB.

16. Anti-oxidant composition comprising a compound susceptible to oxidation, and the compound of formula IA or IB under item 1, or its enantiomer, or salt.

17. The composition according to p. 16, characterized in that the compound of formula IA or IB is a compound according to any one of paragraphs.1 9.

18. The composition according to p. 16, includes connection, susceptible to oxidation, and CIS-4b,5,9 b,10-Tetra-hydro-8-methoxy-6-methylindene[1,2-b]indole, or its enantiomer, or salt.

19. The composition according to p. 16, includes connection, susceptible to oxidation, and CIS-5,5 a, 6,10 b-tetrahydro-7-methyl-9-methoxyimino[2,1-b]indole, or its enantiomer, or salt.

20. Method of stabilizing compounds, susceptible to oxylene, including an introduction to contact receptive connection with the compound of the formula IA or IB, possibly in the form of a composition defined in the PP.16 19.

 

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< / BR>
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FIELD: medicine.

SUBSTANCE: method involves introducing 0.1-0.3 ml of photosensitizing gel preliminarily activated with laser radiation, after having removed neovascular membrane. The photosensitizing gel is based on a viscoelastic of hyaluronic acid containing khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-2% by mass. The photosensitizing gel is in vitro activated with laser radiation having wavelength of 661-666 nm during 3-10 min with total radiation dose being equal to 100-600 J/cm2. The gel is introduced immediately after being activated. To compress the retina, vitreous cavity is filled with perfluororganic compound or air to be further substituted with silicon oil. The operation is ended with placing sutures on sclerotomy and conjunctiva areas. Compounds like chealon, viscoate or hyatulon are used as viscoelastic based on hyaluronic acid. Perfluormetylcyclohexylperidin, perfluortributylamine or perfluorpolyester or like are used as the perfluororganic compound for filling vitreous cavity.

EFFECT: excluded recurrences of surgically removed neovascular membrane and development of proliferative retinopathy and retina detachment; retained vision function.

3 cl, 5 dwg

FIELD: medicine.

SUBSTANCE: method involves making incision in conjunctiva and Tenon's capsule of 3-4 mm in size in choroid hemangioma projection to sclera 3-4 mm far from limb. Tunnel is built between sclera and Tenon's capsule to extrasclerally introduce flexible polymer magnetolaser implant through the tunnel to the place, the choroid hemangioma is localized, after performing transscleral diaphanoscopic adjustment of choroid hemangioma localization and size, under visual control using guidance beam. The implant has permanent ring-shaped magnet in the center of which a short focus scattering lens of laser radiator is fixed. The lens is connected to light guide in soft flexible envelope. The permanent implant magnet is axially magnetized and produces permanent magnetic field of 2-3 mTesla units intensity. It is arranged with its north pole turned towards the choroid hemangioma so that extrascleral implant laser radiator disposition. The other end of the implant is sutured to sclera 5-6 mm far from the limb with two interrupted sutures through prefabricated openings. The implant is covered with conjunctiva and relaxation sutures are placed over it. Light guide outlet is attached to temple using any known method. 0.1-1% khlorin solution is injected in intravenous bolus dose of 0.8-1.1 mg/kg as photosensitizer and visual control of choroid hemangioma cells fluorescence and fluorescent diagnosis methods are applied. After saturating choroid hemangioma with the photosensitizer to maximum level, transscleral choroid hemangioma laser radiation treatment is carried out via laser light guide and implant lens using divergent laser radiation at wavelength of 661-666 nm with total radiation dose being equal to 30-120 J/cm2. The flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, samarium-iron-nitrogen or neodymium-iron-boron system material. The photosensitizer is repeatedly intravenously introduced at the same dose in 2-3 days after the first laser radiation treatment. Visual intraocular neoplasm cells fluorescence control is carried out using fluorescent diagnosis techniques. Maximum level of saturation with the photosensitizer being achieved in the intraocular neoplasm, repeated laser irradiation of the choroid hemangioma is carried out with radiation dose of 30-60 J/cm2.

EFFECT: enhanced effectiveness of treatment.

4 cl

FIELD: medicine.

SUBSTANCE: method involves creating tunnel between sclera and Tenon's capsule in intraocular neoplasm projection. Intraocular neoplasm localization and size is adjusted by applying transscleral diaphanoscopic examination method. 0.1-0.3 ml of photosensitizing gel based on viscoelastic of hyaluronic acid, selected from group containing chealon, viscoate or hyatulon, is transsclerally introduced into intraocular neoplasm structure using special purpose needle in dosed manner. The photosensitizing gel contains khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-1% by mass. Flexible polymer magnetolaser implant is extrasclerally introduced into the built tunnel in intraocular neoplasm projection zone under visual control using guidance beam. The implant has permanent ring-shaped magnet axially magnetized and producing permanent magnetic field of 3-4 mTesla units intensity, in the center of which a short focus scattering lens of laser radiator is fixed. The lens is connected to light guide in soft flexible envelope. The implant is arranged with its north pole turned towards the intraocular neoplasm so that implant laser radiator lens is extrasclerally arranged in intraocular neoplasm projection zone. The implant light guide is sutured to sclera 5-6 mm far from the limb with single interrupted suture. The implant is covered with conjunctiva and relaxation sutures are placed over it. Light guide outlet is attached to temple using any known method. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, transscleral intraocular neoplasm laser radiation treatment is carried out via laser light guide and implant lens using divergent laser radiation at wavelength of 661-666 nm. The treatment course being over, the flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, neodymium-iron-boron or samarium-iron-nitrogen. 0.1-1% khlorin solution as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is additionally intravenously introduced in 2-3 days at a dose of 0.8-1.1 mg/kg and repeated laser irradiation of the intraocular neoplasm is carried out with radiation dose of 30-45 J/cm2 15-20 min later during 30-90 s.

EFFECT: complete destruction of neoplasm; excluded its further growth.

4 cl

FIELD: medicine.

SUBSTANCE: method involves applying transscleral diaphanoscopic examination method for adjusting intraocular neoplasm localization and size. Rectangular scleral pocket is built 2/3 times as large as sclera thickness which base is turned from the limb. Several electrodes manufactured from a metal of platinum group are introduced into intraocular neoplasm structure via the built scleral pocket. Next to it, intraocular neoplasm electrochemical destruction is carried out in changing electrodes polarity with current intensity of 100 mA during 1-10 min, and the electrodes are removed. Superficial scleral flap is returned to its place and fixed with interrupted sutures. 0.1-2% aqueous solution of khlorin as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is intravenously introduced at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, transpupillary laser radiation of 661-666 nm large wavelength is applied at a dose of 30-120 J/cm2. the operation is ended with placing sutures on conjunctiva. Platinum, iridium or rhodium are used as the metals of platinum group. The number of electrodes is equal to 4-8. 0.1-1% khlorin solution, selected from group containing photolon, radachlorine or photoditazine, is additionally repeatedly intravenously introduced in 2-3 days at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, repeated laser irradiation of the intraocular neoplasm is carried out with radiation dose of 30-45 J/cm2.

EFFECT: complete destruction of neoplasm; excluded tumor recurrence; reduced risk of tumor cells dissemination.

3 cl, 3 dwg

FIELD: medicine.

SUBSTANCE: method involves intravenously administering 0.1-1% aqueous solution of khlorin, selected from group containing photolon, radachlorine or photoditazine at a dose of 0.2-0.5 mg/kg or 0.2-1% aqueous solution of porphyrin like photogem at a dose of 0.2-1 mg/kg. Laser irradiation of blood is carried out 5-15 min later after beginning photosensitizer injection into cubital vein of one arm via laser light guide set in advance in the cubital vein of the other arm during 10-40 min at wavelength of 661-666 nm and power of 20-50 mW one session per day during 3-10 days with the aqueous solution of khlorin used as the photosensitizer, or laser irradiation of blood with wavelength equal to 630-633 nm during 10-45 min with power of 20-50 mW one session per day with the aqueous solution of porphyrin used as the photosensitizer. Repeated intravenous administration of photosensitizer is carried out 1-3 months later combined with repeated laser irradiation of blood.

EFFECT: reduced risk of tumor cells dissemination and metastasis development.

2 cl

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacology, pharmacy.

SUBSTANCE: invention relates to a medicinal agent used for prophylaxis and treatment of diseases and disorders associated with dysfunction of benzodiazepine receptors. This medicinal agent comprises compound of the formula (I)

. Compound of the formula (I) elicits high cardioprotective, neurotrophic, renoprotective activity and enhanced bioavailability.

EFFECT: valuable medicinal properties of compounds.

5 cl, 1 tbl, 1 ex

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