Method for indolo-pyrrolo-carbazole derivative production

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to method for production of indolo-pyrrolo-carbazole derivative according to formula (I) , or its pharmaceutically acceptable salt, that have antitumour activity. Invention also relates to method for production of indole compound according to formula (XII) , or its pharmaceutically acceptable salt, where R1 is protective hydroxy-group, distinguished by conducting interreaction between compound with formula (XIII) , or its pharmaceutically acceptable salt, where R1 is definitely above, Ra and Rb are either separately C1-C7-alkyl, or together form C3-C6-alkylene group, and hydrogen gas at 1 to 5 atmospheres, in presence of hydrogenation catalyst (applied as novel catalyst as well), which consist of rhodium compound, metal compound, and optionally amine, in inert solvent at room temperature; the rhodium compound being 1 to 10% rhodium on carbon, aluminium oxide, calcium carbonate, or barium sulphate, and metal compound being nickel (II), iron (II), iron (III), cobalt (II), or cobalt (III). Method is also submitted for production of bis-indole compound by formula (VIII) , or its pharmaceutically acceptable salt, where R1 is protective hydroxy-group, Y is hydrogen, C1-C7-alkyl, phenyl, benzyloxymethyl, or C7-C12-aralkyl, consisting in reaction of indole compound by formula (XII), or its pharmaceutically acceptable salt, where R1 is protective hydroxy-group, with ethylmagnesium chloride, or butylmagnesium chloride, or magnesium compound by formula (X) RdMgRd, where Rd is butyl, in inert solvent, followed by conducting interreaction between product obtained and maleimide compound by formula (IX) , where X is halogen, and Y as above, in inert solvent.

EFFECT: improved method for indolo-pyrrolo-carbazole production.

15 cl, 68 ex, 12 tbl

 

The present invention is applicable in medicine. More specifically, the present invention relates to an efficient process for the preparation on an industrial scale compounds applicable in medicine.

Received in accordance with the method of the present invention derived introperative represented by the formula (I):

has antitumor activity, and the connection has been clinically tested (Mitsuru Ohkubo et al., Bioorganic & Medicinal Chemistry Letters, vol. 9, pages 3307-3312, 1999).

Methods for obtaining compounds of the present invention have been disclosed in WO 95/30682 and WO 01/62769.

In addition, Organic Synthesis Collective Volumes, vol. 7, page 34 disclosed is a method of obtaining derived introperative represented by the formula (XII):

in which R1represents hydroxyamino group.

In addition, known (U.S. patent No. 5105012) hydrogenation reaction using compounds of rhodium, in which to restore the nitro derivative of nitrobenzene in an acidic solvent such as acetic acid, as the catalyst used a large number of iron powder.

In addition, in WO 95-30682 disclosed a method of obtaining a bis-indole compounds represented by formula (VIII):

in which R11-C7is an alkyl group, phenyl group, benzoyloxymethyl or aracelio group.

The present invention relates to the elimination of the undesirable aspects of conventional methods of production represented by the formula (I) derived introperative applicable as a drug. In other words, the present invention relates to a method for, that does not include a stage with a low product yield and in accordance with which is not applied to a reagent, the production of which is associated with a high risk and which causes serious environmental pollution.

In a known method of obtaining indole compounds (Organic synthesis Collective volumes, vol. 7, page 34) the stage of restoration carried out using hydrazine in the presence of a catalyst of Raney Nickel. However, this method is undesirable for industrial production, as the hydrazine has a high danger of explosion. In addition, due to the fact that a large number of catalyst of Raney Nickel, there is a serious pollution generated during the production of liquid waste, indicating the undesirability of the use of this method in large-scale industrial production.

Besides, in the known methods of obtaining bis-indole compounds is the evysokaya, but because these processes are economically inefficient.

On the other hand, is known (U.S. patent No. 5105012) hydrogenation reaction using compounds of rhodium, in which to restore the nitro derivative of nitrobenzene in an acidic medium such as acetic acid, as the catalyst used a large number of iron powder. In this case, due to the fact that the hydrogenation reaction is carried out in acidic conditions, this method is not applicable to unstable in acidic conditions substances.

The authors of the present invention conducted a thorough study of the method of obtaining the derived introperative formula (I) and found the following (i-v):

(i) a new way of deriving introperative formula (I), which is not observed serious pollution generated during the production of liquid waste, which is extremely cost-effective and which can be safely and high reproducibility as an industrial method of production;

(ii) secure a new method of obtaining the derivative of the indole of formula (XII);

(iii) new and economically better way to obtain the derived bis-indole of the formula (VIII);

(iv) a new catalyst for the hydrogenation, which is safe, not syvaet serious pollution of the treated liquid waste and can be used not only in the acid, but in other conditions, and

(v) the method of obtaining the compound (VII), in which the regulation stages is easy, and the formation of hydrogen cyanide as a by-product in the reaction circuit loop with the use of 1,2-dichloro-5,6-dicyano-1,4-benzoquinone can be prevented.

The authors of the present invention have conducted further studies and has led to the present invention.

Namely, the present invention relates to a new method of deriving introperative formula (I), to a new method of obtaining the derivative of indole, to a new method of deriving bis-indole and to a new catalyst for the hydrogenation, which includes the following(1)-(24).

(1) a Method of obtaining derived introperative represented by formula (I), which comprises the following stages:

(i): stage of the interaction between the compounds of formula (XIII)

in which R1represents hydroxyamino group, and each Raand Rbindependently represents a C1-C7is an alkyl group, or Raand Rbcan be joined together with formation of C3-C6-alkalinous group, or its salt with gaseous hydrogen in the presence of compounds of rhodium and compounds of metalobtaining indole compounds form is s (XII):

in which R1defined earlier in this document, or its salt;

(ii): the implementation phase interaction of the obtained indole compounds of formula (XII) or its salt with manichaica formula (XI):

in which Rcrepresents a C1-C7is an alkyl group, phenyl group, vinyl group or allyl group; or a magnesium compound of the formula (X):

in which Rdrepresents a C1-C7is an alkyl group or phenyl group, or its salt, or a mixture of minikleid (XI) and compounds of magnesium (X), with the subsequent implementation of the interaction of the obtained product with maleimide compound of formula (IX):

in which X represents a halogen atom, and Y represents a hydrogen atom, a C1-C7is an alkyl group, phenyl group, benzyloxyethyl group or a C7-C12-aracelio group, to obtain the bis-indole compounds of the formula (VIII):

in which values for each R1and Y are defined above, or its salt;

(iii): the implementation phase response of the circuit in the resulting bis-indole compound (VIII) or its salt to obtain compound f is rmula (VII):

in which values for each R1and Y are defined above, or its salt;

(iv): stage combination of the obtained compound (VII) or its salt with an activated derivative of glucose of the formula (VI):

in which each R2, R3, R4and R5represents hydroxyamino group, and X1represents a halogen atom, to obtain the compounds of formula (V):

in which values for each R1, R2, R3, R4, R5and Y are defined above, or its salt;

(v): the stage of processing of the obtained compound (V) or its salts base with obtaining the compounds of formula (IV):

in which values for each R1, R2, R3, R4and R5defined above, or its salt;

(vi): the stage of interaction of the compound (IV) or its salt with the compound of the formula (III):

in which each R6and R7represents hydroxyamino group, and Xarepresents a molecule of acid, to obtain the compounds of formula (II):

in which values for each R1, R2, R3, R4, R5, R6and R7defined above, or its salt; and/p>

(vii): the stage of removing the protective group from the resulting compound (II) or its salt with obtaining derived introperative formula (I):

or its salt;

(2) the method in accordance with the above paragraph (1), in which the connection rhodium is a rhodium/carbon, rhodium/aluminium oxide, rhodium/calcium carbonate or rhodium/barium sulfate;

(3) the method according to the above item (1), in which the metal connectionis a combination of Nickel(II), the compound iron(II), the compound iron(III), a compound of cobalt(II) or a compound of cobalt(III);

(4) the method according to the above item (3), in which the connection of Nickel(II), the compound iron(II), the compound iron(III), a compound of cobalt(II) or a compound of cobalt(III) represent NiBr2, Ni(NO3)2, Ni(OCOCH3)2, FeBr3, FeCl2, FeSO4, FeCl3,FeCl3-SiO2, Fe(OCOCH3)2, fumarate, Fe(II), CoBr2, CoCl2,

(5) the method according to the above item (1), in which each R1, R2, R3, R4, R5, R6and R7represents a benzyl group;

(6) the method according to the above item (1), W is minikleid formula (XI) represents ethylaniline, isopropylacrylamide or n-butylaniline;

(7) the method according to the above item (1), in which the magnesium compound of the formula (X) is a di(n-butyl)magnesium, di(sec-butyl)magnesium, (n-butyl)(sec-butyl)magnesium, dimethylamine or diethylamine;

(8) the method according to the above item (1), in which maleimide compound of formula (IX) represents maleimide compound represented by formula (IX-a):

in which Y represents a hydrogen atom, a C1-C7is an alkyl group, phenyl group, benzyloxyethyl group or aracelio group;

(9) the method according to the above item (1)in which Y represents a methyl group;

(10) the method according to the above item (1)in which Xarepresents oxalic acid;

(11) the method according to the above item (1), in which the combination is carried out in the presence of a phase transfer catalyst such as Aliquat 336;

(12) the method of obtaining indole compounds or salts thereof, which includes obtaining indole compounds represented by formula (XII):

in which R1represents hydroxyamino group, or its salt by implementing entries batch which I join, represented by the formula (XIII):

in which the value of R1defined above, and each Raand Rbindependently represents a C1-C7is an alkyl group, or Raand Rbcan be joined together with formation of C3-C6-alkalinous group with gaseous hydrogen in the presence of compounds of rhodium and compounds of metal;

(13) the method according to the above item (12), which includes the interaction of the compounds represented by formula (XIII):

in which R1represents hydroxyamino group, and each Raand Rbindependently represents a C1-C7is an alkyl group, or Raand Rbcan be joined together with formation of C3-C6-alkalinous group, or its salt with gaseous hydrogen in the presence of compounds of rhodium and compounds of metal, and the processing of the crude product by silica gel;

(14) a method of obtaining a bis-indole compounds or salts thereof, which includes the implementation of the interaction of indole compounds of formula (XII):

in which R1represents hydroxyamino group, or its salt with manichaica formula (XI):

in which Rcrepresents a C1-C7is an alkyl group, phenyl group, vinyl group or allyl group; or a magnesium compound of the formula (X):

in which Rdrepresents a C1-C7is an alkyl group or phenyl group, or its salt, or a mixture of minikleid formula (XI) and compounds of magnesium formula (X), in an inert solvent, with subsequent implementation of the interaction of the obtained product with maleimide compound of formula (IX):

in which X represents a halogen atom, and Y represents a hydrogen atom, a C1-C7is an alkyl group, phenyl group, benzyloxyethyl group or a C7-C12-aracelio group, preferably in an inert solvent to obtain bis-indole compounds of the formula (VIII):

in which values for each R1and Y are defined above, or its salt;

(15) the method according to the above item (14), in which maleimide compound of formula (IX) represents maleimide compound represented by formula (IX-a):

in which Y represents a hydrogen atom, a C1-C7is an alkyl group, phenyl group, benzyloxy is tilen group or a C 7-C12-aracelio group;

(16) a method of obtaining a compound represented by the formula (VII):

in which R1represents hydroxyamino group, and Y represents a hydrogen atom, a C1-C7is an alkyl group, phenyl group, benzyloxyethyl group or a C7-C12-aracelio group, or its salt, which includes the processing of bis-indole compounds represented by formula (VIII):

in which values for each R1and Y are defined above, or its salt, with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a non-polar solvent in the reaction circuit;

(17) the method according to the above item (16), in which the nonpolar solvent is a benzene, toluene, xylene (ortho-, meta - or para-), ethylbenzene or 1,2,4-trimethylbenzene;

(18) used in the reaction of hydrogenation catalyst contains a compound of rhodium and a compound of the metal;

(19) the catalyst according to the above item (18) further comprises amine;

(20) the catalyst according to the above item (18) or (19), in which the connection rhodium is a rhodium/carbon, rhodium/aluminium oxide, rhodium/calcium carbonate or rhodium/barium sulfate;

(21) the catalyst in accordance with preveden the m above paragraph (18) or (19), in which the metal connectionis a combination of Nickel(II), the compound iron(II), the compound iron(III), a compound of cobalt(II) or a compound of cobalt(III);

(22) the catalyst according to the above item (19), in which the amine is a secondary amine or tertiary amine;

(23) the catalyst according to the above item (19)where Amin is pyrrolidine, piperidine, dimethylamine, diethylamine, Diisopropylamine, dibutylamine, trimethylamine, triethylamine or tributylamine; and

(24) the catalyst according to the above item (21), in which the connection of Nickel(II), the compound iron(II), the compound iron(III), a compound of cobalt(II) or a compound of cobalt(III) represent NiBr2, Ni(NO3)2, Ni(OCOCH3)2, FeBr3, FeCl2, FeSO4, FeCl3,FeCl3-SiO2, Fe(OCOCH3)2, fumarate, Fe(II), CoBr2, CoCl2,

.

The method in accordance with the invention it has become possible to obtain a connection that can safely, easily and effectively used in medicine as anti-cancer agents.

The BEST OPTION of carrying out the INVENTION

The present invention will be illustrated below in more detail. PR is continued to be just, will explain the terms used in the description of the present invention.

Examples of "C1-C7is an alkyl group" include an unbranched or branched alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and heptyl, among which preferred is methyl, ethyl, propyl, isopropyl or butyl, and more preferred is methyl, ethyl, propyl, butyl or heptyl.

Examples of "C3-C6-alkalinous group" include unbranched alkylenes group, such as trimethylene, tetramethylene, pentamethylene and hexamethylene, among which preferred is tetramethylene or pentamethylene.

Examples of "C7-C12-aranceles group" include C7-C12-aracelio group, such as benzyl, 1-naphthylmethyl and 2-naphthylmethyl, among which preferred is benzyl.

Examples of the "acid molecule" include proton acid, such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, methylsulfonate acid, para-toluensulfonate acid, oxalic acid, propionic acid, formic acid and benzoic acid, among which preferred is oxalic acid.

Examples of "hydroxyamine group" include groups, sushisushi the hydroxy-group, such as benzyl, Tomilina, para-nitrobenzyl, para-methoxybenzyl and benzyloxyethyl group, among which preferred is a benzyl group.

The term "compound of rhodium" refers to containing the atom of rhodium catalyst, usually a rhodium catalyst on a carrier, and its preferred examples include rhodium/carbon, rhodium/aluminium oxide, rhodium/calcium carbonate or rhodium/barium sulfate.

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

The term "compound of the metal" does not include the connection of rhodium and refers to the catalyst, which together with the connection of rhodium promotes the reaction of recovery, and its examples include a compound of Nickel(II), the compound iron(II), the compound iron(III), a compound of cobalt(II) and the compound of cobalt(III), preferably NiBr2, Ni(NO3)2, Ni(OCOCH3)2, FeBr3, FeCl2, FeSO4, FeCl3, FeCl3-SiO2, Fe(OCOCH3)2, fumarate, Fe(II), CoBr2, CoCl2,

.

The term "phase transfer catalyst" refers to a catalyst that facilitates the interaction between hydrophobic (oleophilic) organic compound and a hydrophilic organic compound in the two-phase system consisting of a fat phase and aqueous phase, and its examples include connection is ormula (XIV):

in which each Raindependently represents hydrogen, benzyl or C1-C18-hydrocarbon; M represents a nitrogen atom or a phosphorus atom; and A represents a hydroxy-group, fluorine atom, bromine atom, chlorine atom, iodine atom, cyano, HSO4CH3SO3or PhCH2COO, and Tris(2-(2-methoxyethoxy)ethyl)amine, and its preferred examples include tricaprylmethyl ammonium chloride, Tris(2-(2-methoxyethoxy)ethyl)amine, benzyltriethylammonium and hydrosulphate of tributylamine. Specific examples of the compounds of formula (XIV) include tricaprylmethyl ammonium chloride, and the like.

The term "salt" generally refers to an additive salt of the acid, and preferred is a pharmaceutically acceptable salt. Examples of the acid additive salt of the acid include inorganic acid such as hydrochloric acid and sulfuric acid, and organic acid such as acetic acid and oxalic acid.

Examples of "Amina" include primary amine, secondary amine and tertiary amine, and more specifically include amine, such as pyrrolidine, piperidine, dimethylamine, diethylamine, Diisopropylamine, dibutylamine, trimethylamine, triethylamine and tributylamine, preferably secondary amine or tertiary amine, and more preferably pyrrolidine.

The term "processing forces what Kagel" refers to the process of filtration of the crude product, dissolved in the solvent, filled through a silica gel column or through the filter, the surface of which is coated with silica gel.

The preferred method of receiving according to the present invention will be illustrated below in detail.

Stage receiving indole compounds of formula (XII):

in which R1represents hydroxyamino group, through the implementation of the interaction of the compound (XIII):

in which the value of R1defined above, and each Raand Rbindependently represents a C1-C7is an alkyl group, or Raand Rbcan be joined together with formation of C3-C6-alkalinous group with gaseous hydrogen in the presence of compounds of rhodium and compounds of metal, carry out so that the compound (XIII) interacts with gaseous hydrogen at a pressure of 1-5 atmospheres. in the presence of about 0.5 mol.% up to 30 mol.% compounds of rhodium and from about 1 mol.% to 100 mol.% compounds of the metal with respect to 1 pray compound (XIII)in an inert solvent at a temperature of from about -20°C to 80°C for about 1 to 120 hours.

Examples of the inert solvent which can be used in the above stage, include tetrahydrofuran, diethyl-the new ether, tert-butyl methyl ether, diisopropyl ether, disutility ether, methanol, ethanol, isopropanol, propanol, acetone, ethyl acetate, isopropylacetate and cyclopentylmethyl ether, or a mixture of these solvents, among which preferred is tetrahydrofuran, cyclopentylmethyl ether or tert-butyl methyl ether.

The compound of rhodium, which can be applied at the above stage, may be any compound containing in the molecule at least one atom of rhodium, and its preferable examples include containing 1-10% rhodium rhodium/carbon containing 1-10% rhodium rhodium/aluminium oxide containing 1-10% rhodium rhodium/calcium carbonate or containing 1-10% rhodium rhodium/barium sulfate), and more preferably represents a rhodium/carbon.

Examples of compounds of the metal, which can be applied at the above stage, include the connection of Nickel(II), the compound iron(II), the compound iron(III), a compound of cobalt(II) and the compound of cobalt(III), preferably NiBr2, Ni(NO3)2, Ni(OCOCH3)2, FeBr3, FeCl2, FeSO4, FeCl3, FeCl3-SiO2, Fe(OCOCH3)2, fumarate, Fe(II), CoBr2, CoI2, CoCl2,

Used at this stage, the initial connection may be by the researchers in accordance with the method, described, for example, in Organic Synthesis Collective Volumes, vol. 7, page 34, or in accordance with a similar method.

In the above stage, the interaction is preferably carried out in the presence of amine in addition to the compound of rhodium and the metal connection. Additional amine in the presence of a chemical reaction can increase the speed and yield of the reaction. With the use of amine can be dramatically increased the reaction rate. The amine comprises a primary amine, secondary amine or tertiary amine, and more specifically includes amine, such as pyrrolidine, piperidine, dimethylamine, diethylamine, Diisopropylamine, dibutylamine, trimethylamine, triethylamine and tributylamine, preferably secondary amine or tertiary amine, and more preferably pyrrolidine.

The amine is usually used in amounts of from about 0.01 to 10 equivalents relative to the exposed hydrogenation of the material (for example, the compound (XIII)). Moreover, in the case of selection of a suitable reagent, generating amine in the reaction solution at a constant hydrogenation in accordance with the reaction of the present invention, the additional addition of amine to the reaction solution is not required.

To obtained at this stage of the reaction solution (suspension) add aqueous ammonia solution and saturated saline solution, preferably their suspension, peremeci which indicate the mixture for approximately one hour and filtered to separate the solids, and then the residue is washed with a solvent, such as benzene, toluene or xylene. The filtrate and wash liquid combine, then sequentially washed with aqueous citric acid solution, 5% aqueous sodium bicarbonate and saturated brine, and then evaporated in vacuum to dryness. After dissolving the compounds of the formula (XII) or its salt in a solvent such as benzene, toluene or xylene, and the like, the solution is applied on a column Packed with silica gel with the same as the compound (XII) by weight, or filter, whose surface is covered with the aforementioned silica gel, and exposed to the pressure of the inert gas, such as nitrogen. Formed at the stage of reaction impurities such as colored substances can be effectively removed by purification on silica gel. The degree of purity of the compound (XII) increase by the purification method of the present invention, and therefore the chemical reaction and treatment in the subsequent stages can be effective from the point of view of industrial production methods without the use of a special method.

Then at the stage of obtaining bis-indole compounds of the formula (VIII):

in which values for each R1and Y are defined above, or its salt, the interaction obtained above indole joint is of the formula (XII):

in which the values for R1defined above, or its salt, with manichaica formula (XI):

in which Rcrepresents a C1-C7is an alkyl group, phenyl group, vinyl group or allyl group; with a compound of magnesium formula (X):

in which Rdrepresents a C1-C7is an alkyl group or phenyl group, or its salt, or a mixture of minikleid formula (XI) and compounds of magnesium formula (X)in the above-mentioned inert solvent, with subsequent implementation of the interaction of the obtained product with maleimide compound of formula (IX):

in which X represents a halogen atom, and Y represents a hydrogen atom, a C1-C7is an alkyl group, phenyl group, benzyloxyethyl group or a C7-C12-aracelio group, in the above-mentioned inert solvent preferably is carried out in accordance with the following methods 1), 2) or 3).

1) At a temperature of from about 30°C to 120°C for about 0.5 to 24 hours in an inert solvent interact approximately from 2 to 4 mol of indole compounds (XII) and from about 2 to 4 mol magni is chloride (XI) with respect to 1 pray maleimide compounds (IX).

2) At a temperature of from about 30°C to 120°C for about 0.5 to 24 hours in an inert solvent interact approximately from 2 to 4 mol of indole compounds (XII) and from about 2 to 4 mol of the magnesium compounds (X) with respect to 1 pray maleimide compounds (IX).

3) At a temperature of from about 30°C to 120°C for about 0.5 to 24 hours in an inert solvent interact approximately from 2 to 4 mol of indole compounds (XII) and from about 0.8 to 4 mol mixtures containing Manihari (XI) and the magnesium compound (X)with respect to 1 pray maleimide compounds (IX).

Preferred examples used in the methods 1), 2) and 3) of the solvent include toluene, and a mixture of toluene and tetrahydrofuran.

The examples used in the above stage of minikleid formula (XI) include alkylacrylate, such as methylaniline, ethylaniline, n-propylaniline, isopropylaniline, n-butylaniline, second-butylaniline, isobutylamine, tert-butylmagnesium, n-pentylaniline, n-hexylaniline, phenylaniline, vinylmania and allylanisole, or their mixture.

The examples used in the previous stage of the magnesium compounds of the formula (X) include dimethylamine, diethyl who Agni, di(n-propyl)magnesium, Diisopropylamine, di(n-butyl)magnesium, di(sec-butyl)magnesium, diisobutylamine, di(tert-butyl)magnesium, di(n-pentyl)magnesium, di(n-hexyl)magnesium, (n-butyl)(sec-butyl)magnesium, (methyl)(sec-butyl)magnesium, (ethyl)(sec-butyl)magnesium, (methyl)(n-butyl)magnesium, (ethyl)(n-butyl)magnesium, (methyl)(tert-butyl)magnesium, (ethyl)(tert-butyl)magnesium, (n-propyl)(n-butyl)magnesium, (n-propyl)(sec-butyl)magnesium, (n-propyl)(isopropyl)magnesium, (n-butyl)(isopropyl)magnesium, (sec-butyl)(isopropyl)magnesium, (isobutyl)(isopropyl)magnesium, (n-propyl)(isobutyl)magnesium and diphenylamine, or mix.

Then, at the stage of obtaining the compounds of formula (VII):

in which values for each R1and Y are defined above, or its salt, the reaction of the circuit obtained above bis-indole compounds represented by formula (VIII):

in which values for each R1and Y are defined above, or its salt, preferably is carried out in accordance with the following methods 1) and 2).

1) Compound of formula (VIII) or its salt is treated in an inert solvent at a temperature of from about 20°C to 200°C for about from 1 minute to 5 days, for example, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), palladium reagent, such as PdCl2and Pd(OAc)2or copper reagent is m, such as CuCl2in the amount of from about 1 to 10 molar equivalents relative to 1 mol of compound (VIII) or its salt.

The solvent which can be used in stage 1), may be any well-known inert solvent, and its examples include polar solvents, such as tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N-organic and N,N-dimethylacetamide, and non-polar solvent, such as benzene, toluene, xylene (ortho-, meta - or para-), ethylbenzene, and 1,2,4-trimethylbenzene. In the case of the use of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone using polar solvent during a chemical reaction or produces hydrogen cyanide, while when using a non-polar solvent, the formation of hydrogen cyanide suppressed, which is favourable for speed control.

2) the Compound of formula (VIII) or its salt is treated in an inert solvent with a reagent consisting of about 0.01 to 1.0 equivalent deposited on carbon, alumina, calcium carbonate, barium sulfate or silica gel catalyst containing a metal of variable valence (e.g., palladium, platinum and so on), relative to 1 mol of compound (VIII) at a temperature of from about 20°C to 200°C for about from 1 minute to 5 days, if d is the pressure from 1 to 5 ATM. oxidant selected from the group consisting of oxygen, air, ethylene and acetylene.

Examples of the inert solvent which can be used in stage 2)include toluene, tetrahydrofuran, methanol, ethanol, dimethylformamide, dimethylsulfoxide, N-organic and dimethylacetamide.

Then, at the stage of obtaining the compounds of formula (V):

in which values for each R1and Y are defined above, and each R2, R3, R4and R5represents hydroxyamino group, or its salt, a combination of the above compounds of formula (VII)

in which values for each R1and Y are defined above, or its salt, or its salt, with an activated derivative of glucose of the formula (VI):

in which values for each R2, R3, R4and R5defined above, and X1represents a halogen atom, preferably containing base in an aqueous solvent and a phase transfer catalyst in an inert organic solvent, can be carried out as follows.

The activated derivative of glucose (VI):

in which each R2, R3, R4and R5is a guy who resizewindow group, and X1represents a halogen atom, can be obtained by interaction derived glucose (VIa):

in which each R2, R3, R4and R5represents hydroxyamino group, for example, galogenangidridy, sulphonylchloride or idefinition at a temperature of from about -50°C to 200°C, preferably from approximately -10°C to 30°C, preferably in an inert solvent.

Examples of gelegenheid applied on the above-mentioned stage, include SOCl2, POCl3, SOBr3, POBr3, PBr3and oxalicacid, among which preferred is SOCl2or oxalicacid, and more preferable - SOCl2.

Examples of the inert solvent used in the above stage, include hydrocarbons, such as toluene, xylene, heptane and hexane; a nitrile such as acetonitrile; and a simple ester such as tert-butyl methyl ether and tetrahydrofuran; halogenated hydrocarbons such as methylene chloride, carbon tetrachloride, chloroform, triptorelin and dichlorobenzene; and a ketone such as methylisobutyl ketone and acetone, among which preferred is tert-butylmethylamine simple ether or tetrahydrofuran, and more preferred is tert-butylmethylamine p is hostoi ether.

As for the derivative of glucose (VIa), may be used commercially available products.

The result of the above activated derivative of glucose of the formula (VI) combine with the compound of the formula (VII):

in which values for each R1and Y are defined above, or its salt, using a system containing base in an aqueous solvent and a phase transfer catalyst in an inert organic solvent, typically at a temperature of from -50°C to 200°C, preferably from 0°C to 40°C.

Example an aqueous solvent used in the above stage, is water.

Examples of the base used in the above stage, include hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide, among which preferred is sodium hydroxide or potassium hydroxide. The concentration used of the base is from about 5 wt.% to 95 wt.%, preferably from about 45 wt.% up to 50 wt.%.

Examples of the inert solvent used in the above stage, include hydrocarbons, such as toluene, xylene, heptane and hexane; a nitrile such as acetonitrile; and a simple ester such as tert-butyl methyl ether and tetrahydrofuran; halogenated hydrocarbon, such the AK methylene chloride, carbon tetrachloride, chloroform, triptorelin and dichlorobenzene; a ketone, such as methylisobutyl ketone and acetone; and non-ionic solvent, such as N,N-dimethylformamide and 1-methyl-2-pyrrolidinone, among which preferred is tert-butyl methyl ether, methylene chloride or triptorelin.

Examples of the phase transfer catalyst used in the above stage, include a compound of formula (XIV):

in which each Raindependently represents hydrogen, benzyl or C1-C18-hydrocarbon; M represents a nitrogen atom or a phosphorus atom; and A represents a hydroxy-group, fluorine atom, bromine atom, chlorine atom, iodine atom, cyano, HSO4CH3SO3or PhCH2COO, and Tris(2-(2-methoxyethoxy)ethyl)amine, and its preferred examples include tricaprylmethyl ammonium chloride, Tris(2-(2-methoxyethoxy)ethyl)amine, benzyltriethylammonium and hydrosulphate of tributylamine.

The next stage of processing, the above compounds of formula (V):

in which values for each R1, R2, R3, R4, R5and Y are defined above, or its salt, a base, preferably in an inert solvent to obtain the compound represented by formula (IV):

in which values for each R1, R2, R3, R4and R5defined above, or its salt, usually performed with the use of the base number from about 50 to 100 mol, preferably approximately from 50 to 70 mol, relative to 1 mol of compound (V) or its salt, preferably in an inert solvent which does not adversely effect the chemical reaction.

Examples of the above-mentioned inert solvent include alcohols such as methanol, ethanol, isopropanol, tert-butanol, dimethylsulfoxide, and mixed of these solvents, among which preferred is methanol, ethanol or isopropanol.

Examples of the above-mentioned grounds include a base, such as sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, tert-piperonyl sodium tert-piperonyl potassium, among which preferred is sodium hydroxide, potassium hydroxide or sodium methoxide.

The reaction temperature is usually from room temperature to about 60°C, preferably from about 30°C to 50°C, and the duration of the chemical reaction is usually from about 1 hour to 1 day, preferably from about 3 hours to 10 hours.

Next, the stage of obtaining the compounds of formula (II):

in which values for each R1, R2, R3, R4and R5defined above, and each R6and R7represents hydroxyamino group, or its salt, by communicating the result of the above compounds of formula (IV):

in which values for each R1, R2, R3, R4and R5defined above, or its salt with the compound of the formula (III):

in which values for each R6and R7defined above, and Xarepresents a molecule of the acid is usually carried out using compound (III) in an amount of from about 1 mol to 3.0 mol, preferably approximately 1.0 to 1.5 mol, relative to 1 mol of the compounds of formula (IV)or its salt, in an inert solvent which does not adversely affect a chemical reaction.

The above-mentioned stage can be performed in the presence of an acid acceptor, or both acceptor acid and desiccant.

The amount used of the acid acceptor is from about 0.1 to 100 mol, preferably approximately from 0.1 to 2 mol, relative to 1 mol of the compounds of formula (IV) or its salt. The number of used desiccant is approximately from 0.1 to 100 mol, more predpochtitel is about approximately from 0.1 to 2 mol, relative to 1 mol of the compounds of formula (IV) or its salt.

Examples of the above-mentioned inert solvent include N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dimethylsulfoxide and N-organic, and a mixture thereof, among which preferred is N,N-dimethylformamide, N,N-dimethylacetamide or N-organic.

The reaction temperature is usually from room temperature to around 90°C, preferably from 30°C to 70°C, and the duration of the chemical reaction is usually from about 1 hour to 1 day, preferably from about 1 hour to 3 hours.

Examples of the acid acceptor include ethyldimethylamine, triethylamine, isopropylethylene, diisopropylethylamine, tributylamine, pyridine, 2,6-lutidine, 2,6-tert-butylpyridinium, 2,4,6-kallidin, 1,8-diazabicyclo[5.4.0]non-5-ene (DBU), 1,5-diazabicyclo[4.3.0]undec-7-ene (DBN), Diisopropylamine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane (DABCO) and N-methylmorpholin, among which more preferred are lower bonds alkylamines, such as triethylamine, diisopropylethylamine, tributylamine or Diisopropylamine and more preferred is triethylamine.

Examples of desiccants include magnesium sulfate, sodium sulfate, molecular sieve, HC(O-ISO-Pr)3, HC(O-Et)3The NS(O-CH3)3and (CH3)2(Och3)2among the more preferred is magnesium sulfate the sodium sulfate or molecular sieve, and more preferred is magnesium sulfate.

Further, at the stage of obtaining indiaparenting derivative of the formula (I):

or its salt by removing the protective group from compounds of formula (II):

in which values for each R1, R2, R3, R4, R5, R6and R7defined above, or its salt, in the case of the reaction by catalytic reduction, the catalyst includes, for example, palladium-on-coal and Raney Nickel. Such catalysts can be a well-known catalysts.

When the catalytic reduction of the preferred hydrogen pressure is generally from normal pressure to 3 ATM., and the specific ratio of the amount used of the catalyst to the weight of the starting compound (II) is usually from about 1/100 to 1, preferably from about 1/100 to 1/10.

The examples used in the reaction solvent include the solvents are mixed from alcohol solvents such as methanol, ethanol, isopropanol, butanol and tetrahydrofuran, among which preferred is a mixed solvent comprising isopropanol and tetrahydrofuran (50:50).

The reaction temperature is usually from -30 C to 60°C, preferably from 0°C to 50°C, and the duration of the chemical reaction is usually from about instant reaction to about 7 days, preferably from instant reaction to approximately 24 hours.

The method of purification of the compounds of formula (I) or its salt can be carried out as follows.

The resulting reaction solution is filtered and adjust the pH of the filtrate to a value of from about 1.5 to about 6.5, more preferably about 2.5.

To bring the concentration of the compounds of formula (I) in the solution to a value of approximately 10 ml/g to approximately 20 ml/g, preferably from about 12 ml/g to approximately 18 ml/g, more preferably to about 15 ml/g to the resulting solution was added approximately 10% to approximately 30%, preferably from about 15% to about 25%, more preferably about 20% aqueous solution of alcohol.

Thus obtained solution is heated to a temperature of from about 50°C to about 100°C, preferably about 70°C.

To the solution add ethanol in the amount equal to two-thirds of the volume of the solution.

The resulting solution was maintained at a temperature of from about 50°C to 100° C, preferably at about 70°C, and filtered, collecting the precipitated crystals.

In the above filtering process, the water content in the slurry of crystals is brought to a value from approximately 1 to approximately 10 wt./vol.%.

The example used in the above stage of alcohol includes C1-C5-aliphatic alcohol, preferably methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, Isobutanol, pentanol, isopentanol, and more preferably isopropanol.

The examples used to adjust the pH of the bases include triethylamine, diisopropylethylamine, tributylamine, pyridine, 2,6-lutidine, 2,4,6-kallidin, 1,8-diazabicyclo[5.4.0]non-5-ene (DBU), 1,5-diazabicyclo[4.3.0]undec-7-ene (DBN), Diisopropylamine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane (DABCO) or N-methylmorpholine, among which more preferred are lower bonds alkylamines, such as triethylamine, diisopropylethylamine, tributylamine or Diisopropylamine, and more preferred is triethylamine.

The compounds obtained in each of the above stages can be cleaned and, if necessary, selected individually or in combination by means known per se in the art methods such as column chromatography on silica gel or absorbent resin, liquid chromatograph is I, thin-layer chromatography, solvent extraction and recrystallization/pereosazhdeniya.

The present invention also relates to the hydrogenation catalyst containing the above-mentioned compound of rhodium and the above-mentioned compound of the metal.

This catalyst is used to restore the connection and contains the above-mentioned compound of rhodium and a compound of the metal. In accordance with the present invention, it is assumed joint presence of compounds of rhodium and metal or their mixture. Therefore, in addition to compounds of rhodium and compounds of metal in the catalyst according to the present invention can contain, for example, a solvent. The reaction of recovery, which uses the catalyst according to the present invention should not be limited to response and recovery in the above stage (1), although the recovery of the nitro groups to amino groups and recovery alkenyl groups or etkinlik groups to the corresponding alkyl group is preferred. The catalyst according to the present invention has a selective effect in the case of its application for recovery of nitro groups to amino groups and to restore alkenyl groups or etkinlik groups to the corresponding alkyl group, which is very advantageous for industrial applications. As the application is as mentioned selective action can be shown that a noticeable fact, when the restoration of the nitro groups to amino groups and at restoration alkenyl groups or etkinlik groups to the corresponding alkyl groups, even if subjected to restore the material containing, in addition to the nitro group, alkenylphenol or alkenylphenol groups, other functional groups, such as benzyloxy, carbonyl group, for example an aldehyde or ketone, or halogen, and restoration other than nitro, alkenyl or quinil functional groups essentially does not occurorsuppressed, or the restoration of the nitro groups to amino groups and recovery alkenyl groups or etkinlik groups to the corresponding alkyl groups is predominant compared with other recovery other than nitro, alkenyl or quinil, functional groups. Moreover, it also shows the ability of the catalyst of the present invention to accelerate the restoration of nitro groups to amino groups and recovery alkenyl groups or etkinlik groups to the corresponding alkyl group. Specifically, in the case of catalytic reduction using rhodium catalyst and catalyst containing the compound metal salt iron salt of Nickel or cobalt salt, restoration of functional groups, such as benzylamine groups who, the aryl halides, aldehydes or ketones, essentially noorsuppressed, and therefore it becomes possible selective recovery of nitro groups to amino groups and recovery alkenyl groups or etkinlik groups to the corresponding alkyl group. Therefore, in the case of the use of the catalyst according to the present invention in the reaction of recovery do not need to be used in the traditional reaction recoverycomplex stages, including the protection of functional groups by protective groups, the subsequent recovery process and removing the protective groups.

In the present invention it is preferable that in addition to the above-mentioned compounds of rhodium and the above-mentioned metal catalyst contained Amin, as mentioned above. When using catalyst containing amine of the present invention, in contrast to a catalyst not containing amine, the reaction rate increases sharply, the rate of recovery of easily recoverable groups such as benzylamine group decreases, and may be achieved by the selective recovery of the nitrogroup, alkenyl or quinil, thereby improving the product yield recovery.

EXAMPLES

The present invention is described in detail by way of examples and comparative examples, but is not limited, and the I.

Example 1

(Bn is a benzyl group (hereinafter in the text); Rh/C powdered rhodium/carbon powder; Ac is acetyl group)

3-Benzyloxy-6-(2-pyrrolidinyl)nitrobenzene (1) (5,00 g of 15.4 mmol), powdered 5% rhodium/carbon powder (952 mg, 0,462 mmol), iron acetate (II) (536 mg, is 3.08 mmol) and tetrahydrofuran (50 ml) were placed in a nitrogen atmosphere in a three-neck flask with a capacity of 100 ml equipped with a magnetic stirrer and thermometer. The resulting suspension was stirred at 22°C-25°C for 24 hours in an atmosphere of hydrogen and then stirred overnight under nitrogen atmosphere. To the suspension was added 28% aqueous ammonia (50 g) and 5% brine (20 ml) and the mixture was stirred for one hour, then filtered to separate the solids. The residue was washed with toluene (100 ml), and combined the previous filtrate and wash liquid. The solution is successively washed with 10% aqueous citric acid (50 g), 5% aqueous sodium bicarbonate (50 g) and 20% brine (50 g) and evaporated in vacuo to dryness. The residue was dissolved in toluene (approximately 100 ml) and filtered coated silica gel (5 g) filter. The silica gel was washed with toluene and the resulting colourless solution (152,15 g) were analyzed by high-performance liquid chromatography, which testified to the fact that wychodzenia compound (2) was 91% (party of 3.15 g).

1H-NMR (500 MHz, DMSO-d6,h/m): 10,90 (users, 1H), 7,49 (d, J=7.5 Hz, 1H), 7,44 (d, J=8.6 Hz, 1H), 7,40 (DD, J=7,5, 7.5 Hz, 1H), 7,33 (DD, J=7,5, 7.5 Hz, 1H), 7,21 (userid, J=2,4, 2,4 Hz, 1H), 7,01 (osirm, 1H), 6,77 (DD, J=1,8, 8.6 Hz, 1H), 6,36 (osirm, 1H), 5,12 (s, 2H).

13C-NMR (126 MHz, DMSO-d6,h/million): 154,7, 138,0, 136,8, 128,7, 128,0, 127,9, 124,4, 122,5, 120,9, 110,1, 101,3, 96,3, 69,9.

Examples 2-18

To perform an operation similar to that shown in example 1, using rhodium/carbon powder (Rh/C) and are presented in the following table supplements instead of acetate of iron(II).

Table 1
Example No.The number of Rh/CSupplements

(used amount)
The duration of the reaction (h)Output connections (2)
25 mol.%NiBr2(10 mol.%)3579%
45 mol.%Ni(OAc)2(20 mol.%)2087%
53 mol.%Ni(NO3)2(20 mol.%)2490%
63 mol.%Ni(acac)2(20 mol.%)2786%
85 mol.%FeCl3(III)(1 mol.%) 1185%
95 mol.%FeCl3(III)/SiO2< / br>
(10 mol.%)
1887%
105 mol.%FeBr3(III)(20 mol.%)1678%
135 mol.%Fe(III)(acac)3(20 mol.%)1677%
143 mol.%FeCl2(II)(20 mol.%)2192%
155 mol.%Fe(II)fumarate (20 mol.%)1694%
165 mol.%Fe(II)(acac)2(20 mol.%)1686%
175 mol.%Fe(II)SO4(20 mol.%)1696%
183 mol.%With(ASAS)3(III)(20 mol.%)1294%
Example comparison 13 mol.%No4262%

In this table "acac" means a group represented by the following formula, and Ac means acetyl.

Example 19

[Et means ethyl and Me means methyl (here and later in this document)]

6-Benzyloxyindole (2) (200 g, 8,96 mmol), tetrahydrofuran (2,70 ml) and toluene (15.2 ml) was placed in a nitrogen atmosphere in a three-neck flask with a capacity of 50 ml, equipped with a magnetic stir bar, refrigerator, Dimroth and thermometer. The mixture was heated to 33°C, was added 2,00M ethylaniline/diethyl ether (4,48 ml, 8,96 mmol) for 7 minutes, the mixture was heated to 55°C-60°C and stirred at 55°C-60°C for one hour. N-Methyl-1,2-dichloromaleimide (730 mg, 4,06 mmol) was dissolved in toluene (4.4 ml)was added over 10 minutes a solution to the mixture and washed with toluene (1 ml) container of N-methyl-1,2-dichloromaleimide. After adding wash liquid and the mixture was stirred at 55°C-60°C for 20 minutes. The reaction mixture was additionally heated to 100°C-108°C, stirred at 100°C-108°C for 12 hours and left to cool to room temperature and mixed during the night. The reaction mixture was heated to 80°C and added to a mixture of toluene (15.2 ml) and 13% aqueous ammonium chloride (17 ml). The resulting mixture was cooled to room temperature to obtain a suspension, which was filtered to obtain a red solid. The solid is then washed with toluene (20 ml), toluene/water (mixing ratio 1:1, 20 ml) and methanol (20 ml×2). The solid was dried in vacuum overnight at room temperature with obtaining CE is avago bis-indole (3) opening 84% (party 1,89 g).

1H-NMR (500 MHz, DMSO-d6,h/m): 11,50 (s, 2H), 7,63 (d, J=2.3 Hz, 2H), 7,42 (d, J=7,3 Hz, 2H), 7,37 (DD, J=7,3, 7,3 Hz, 2H), 7,30 (DD, J=7,3, 7,3 Hz, 2H), 6,97 (d, J=2.1 Hz, 2H), 6,72 (d, J=8,8 Hz, 2H), 6,41 (DD, J=2,1, 8,8 Hz, 2H,), 5,04 (s, 4H), 3,03 (s, 3H).

13C-NMR (126 MHz, DMSO-d6,h/million): 172,2, 155,0, 137,7, 137,1, 128,7, 128,5, 128,1, 128,0, 127,1, 122,0, 120,1, 110,4, 106,1, 96,3, 69,7, 24,3.

Designed TPL˜240°C (decomposition).

Example 20

* a mixture of di(n-butyl)magnesium, di(sec-butyl)magnesium, and (n-butyl)(sec-butyl)magnesium

6-Benzyloxyindole (2) (2.00 g, 8,96 mmol), tetrahydrofuran (2,64 ml) and toluene (15.2 ml) was placed in a nitrogen atmosphere in a three-neck flask with a capacity of 50 ml, equipped with a magnetic stir bar, refrigerator, Dimroth and thermometer. The mixture was heated to 38°C, was added within 10 minutes 0,90M dibutylaniline/heptane (4,96 ml, 4,47 mmol)and heptane contained a mixture of di(n-butyl)magnesium, di(sec-butyl)magnesium, and (n-butyl)(sec-butyl)magnesium, and stirred the mixture at 55°C-60°C for one hour. N-Methyl-1,2-dichloromaleimide (730 mg, 4,06 mmol) was dissolved in toluene (4.4 ml)was added over 10 minutes a solution to the above mixture and was washed with toluene (1 ml) container of N-methyl-1,2-dichloromaleimide. After adding wash liquid mixture was heated to 55°C-60°C, stirred at 55°C-60°C obtaining t is ejogo substances, which was dissolved to a homogeneous state by adding tetrahydrofuran (1.5 ml). The solution was stirred at 55°C-60°C for 30 minutes, then was heated to 98°C-100°C, stirred at 98°C-100°C for 12 hours and left to cool to room temperature and mixed during the night. After heating the reaction mixture to 90°C to the reaction mixture was added 13% aqueous ammonium chloride (17 ml) and cooled the mixture to room temperature to obtain a suspension, which was filtered to obtain a red solid, which was sequentially washed with toluene (20 ml), toluene/water (mixing ratio 1:1, 20 ml) and methanol (20 ml×2). The solid was dried in vacuum overnight at room temperature to obtain the desired bis-indole (3) with the release of 82% (party 1.85 g).

1H-NMR (500 MHz, DMSO-d6,h/m): 11,50 (s, 2H), 7,63 (d, J=2.3 Hz, 2H), 7,42 (d, J=7,3 Hz, 2H), 7,37 (DD, J=7,3, 7,3 Hz, 2H), 7,30 (DD, J=7,3, 7,3 Hz, 2H), 6,97 (d, J=2.1 Hz, 2H), 6,72 (d, J=8,8 Hz, 2H), 6,41 (DD, J=2,1, 8,8 Hz, 2H,), 5,04 (s, 4H), 3,03 (s, 3H).

13C-NMR (126 MHz, DMSO-d6,h/million): 172,2, 155,0, 137,7, 137,1, 128,7, 128,5, 128,1, 128,0, 127,1, 122,0, 120,1, 110,4, 106,1, 96,3, 69,7, 24,3.

Designed TPL˜240°C (decomposition).

Example 2 comparison

[Bn is benzyl; Me - methyl]

6-Benzyloxyindole (2) (2.00 g 8,96 mmol), tetrahydrofuran (2,64 ml) and toluene (15.2 ml) was placed in a nitrogen atmosphere in a three-neck flask with a capacity of 50 ml, equipped with a magnetic stir bar, refrigerator, Dimroth and thermometer. The mixture was heated to 38°C, was added for 7 minutes 2,82M ethylmagnesium/diethyl ether (3.12 ml, 8,82 mmol), was heated to 55°C-60°C and stirred at 55°C-60°C for one hour. N-Methyl-1,2-dichloromaleimide (730 mg, 4,06 mmol) was dissolved in toluene (4.4 ml)was added over 7 minutes the solution to the above mixture and was washed with toluene (1 ml) container of N-methyl-1,2-dichloromaleimide. After adding wash liquid and the mixture was stirred at 55°C-60°C for 30 minutes, then was heated to 100°C-107°C, stirred at 100°C-107°C for 12 hours and left to cool to room temperature and mixed during the night. After heating the reaction mixture up to 80°C to the reaction mixture were added toluene (15.2 ml) and 13% aqueous ammonium chloride (17 ml) and cooled the mixture to room temperature to obtain a suspension. The suspension was filtered to obtain a red solid, which was sequentially washed with toluene (20 ml), toluene/water (1:1, 20 ml) and methanol (20 ml×2). The solid was dried in vacuum overnight at room temperature to obtain the desired bis-indole (3) yield 70% (party 1.73 g).

1 H-NMR (500 MHz, DMSO-d6,h/m): 11,50 (s, 2H), 7,63 (d, J=2.3 Hz, 2H), 7,42 (d, J=7,3 Hz, 2H), 7,37 (DD, J=7,3, 7,3 Hz, 2H), 7,30 (DD, J=7,3, 7,3 Hz, 2H), 6,97 (d, J=2.1 Hz, 2H), 6,72 (d, J=8,8 Hz, 2H), 6,41 (DD, J=2,1, 8,8 Hz, 2H,), 5,04 (s, 4H), 3,03 (s, 3H).

13C-NMR (126 MHz, DMSO-d6,h/million): 172,2, 155,0, 137,7, 137,1, 128,7, 128,5, 128,1, 128,0, 127,1, 122,0, 120,1, 110,4, 106,1, 96,3, 69,7, 24,3.

Designed TPL˜240°C (decomposition).

Example 21

Bis-indole compound (3) (3.00 g, 5,42 mmol) and toluene (75,3 ml) were placed in a nitrogen atmosphere in a three-neck flask with a capacity of 300 ml, equipped with a magnetic stir bar, refrigerator, Dimroth and thermometer, and the mixture was heated to 110°C. To the resulting mixture for 15 minutes at 107°C-110°C solution was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1,37 g, 6,03 mmol) in toluene (48,0 ml). After washing containing DDQ capacity toluene (12 ml) to the reaction mixture was also added to the wash liquid. The mixture was stirred at 108°C-110°C for one hour and subjected to analysis by the method of high performance liquid chromatography, which indicated the disappearance of starting material. The reaction solution was cooled to 71°C and for 3 hours at 60°C-71°C was added methanol (134 ml) [phase measurement A]. The mixture was cooled to room temperature and was stirred techeneenii [phase measurement B]. The reaction solution was filtered and washed with methanol (15 ml×2) to obtain brown solid (2876 mg), which was suspended in N,N-dimethylformamide (54 ml). The suspension was heated and stirred at 95°C-105°C for one hour, cooled to room temperature and was stirred overnight. The reaction solution was filtered and washed with methanol (15 ml×2) to obtain yellow solid (3018 mg), which was suspended in dimethyl sulfoxide (28,3 ml). The suspension was heated to 60°C-70°C to dissolve the solid obtained above substances. Consistently added methanol (13.3 ml) and a small amount of the above compound in the form of the seed crystal and the mixture was stirred for one hour to cure the slurry. After adding methanol (42,4 ml) for 2 hours the mixture was cooled to room temperature and then was stirred overnight. The reaction mixture was filtered, washed with methanol (15 ml×2), dried in vacuum at 60°C overnight to obtain the desired indolocarbazole derivative (4) in the form of yellow crystals with a yield of 87% (party 2589 mg).

1H-NMR (500 MHz, DMSO-d6,h/million): of 11.26 (s, 2H), 8,69 (d, J=8.7 Hz, 2H), 7,54 (d, J=7,3 Hz, 2H), 7,43 (DD, J=7,3, 7,3 Hz, 2H), 7,37 (DD, J=7,3, 7,3 Hz, 2H), 7,27 (d, J=2.1 Hz, 2H), 6,72 (d, J=8,8 Hz, 2H), of 6.96 (DD, J=2,1, ,7 Hz, 2H), with 5.22 (s, 4H), 2,96 (s, 3H).

Designed TPL˜342°C (decomposition).

Conditions for HPLC analysis: the separation column YMC AM-303 250×4.6 mm; temperature measurement - 40°C; detection at a wavelength of 220 nm; the amount of applied sample 10 µl; mobile phase: MeCN/0.1% of phosphoric acid=(t=0, 65:35; t=20, 90:30); flow rate 1 ml/min

Example 22

Toluene (75,3 ml) and bis-indole compound (3) (3.00 g, 5,42 mmol) were placed in a nitrogen atmosphere in a three-neck flask with a capacity of 300 ml, equipped with a magnetic stir bar, refrigerator, Dimroth and thermometer, and the mixture was heated to 70°C. To the resulting mixture for one hour the solution was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1.29 g, 5,69 mmol) in N,N-dimethylformamide (24,0 ml). After washing containing DDQ capacity N,N-dimethylformamide (6.0 ml) to the reaction mixture was also added to the wash liquid. The mixture was stirred at 70°C for one hour [a measurement stage C] and were analyzed by the method of high performance liquid chromatography, which indicated the disappearance of starting material. After adding methanol (134 ml) for 2 hours, the reaction solution was stirred at 70°C for one hour, cooled to 25°C and was further stirred at the same temperature throughout the night. The reaction is mesh was filtered and washed with methanol (15 ml× 2) to give yellow solid, which was dried in vacuum overnight at 25°C obtaining the target indolocarbazole derivative (4) in the form of a crude yellow crystals (the party is 3.08 g).

Example 23

Toluene (28.6 kg) and bis-indole compound (3) (1,50 kg, a 2.71 mol) were placed in a nitrogen atmosphere in the reaction vessel with a capacity of 80 l and washed the inner wall of the vessel toluene (3,9 kg). After adding wash liquid obtained suspension was heated to 110°C and was added to the mixture over 1 hour a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.65 kg, of 2.86 mol) in toluene (20,8 l). After washing containing DDQ capacity toluene (5.2 kg) to the reaction solution were also added to the wash liquid. The mixture was stirred at 110°C for one hour and subjected to analysis by the method of high performance liquid chromatography, which indicated the disappearance of starting material. The mixture was cooled to 25°C for half an hour [stage dimension D] and stirred at the same temperature for one hour. The reaction mixture was filtered and washed with toluene (13 kg) to obtain a brown solid (2,07 kg), which was dried in vacuum at 60°C during the night. The solid is suspended in N,N-dimethylformamide (25,4 kg) and stirred su is pensio at 100° C-105°C for one hour. The suspension was cooled to 25°C for one hour and was stirred over night [the measurement stage E]. The reaction solution was filtered, washed with N,N-dimethylformamide (9,8 kg) and methanol (8.2 kg) and dried at 60°C overnight to obtain yellow solid (1,51 kg). The yellow solid is suspended in dimethyl sulfoxide (16.7 kg). The suspension was heated to 60°C to dissolve the solid obtained above substances. To the suspension was sequentially added methanol (5.6 kg) and the seed crystal (8.0 g) target indolocarbazole derivative (4). The suspension was stirred at 60°C-65°C for one hour to aging of the crystal. Then, after adding methanol (18,0 kg) for 2 hours, the mixture was stirred at the same temperature for one hour, cooled to 25°C and was stirred overnight. The reaction mixture was filtered, washed with methanol (12 kg)was dried in vacuum at 60°C overnight to obtain the desired indolocarbazole derivative (4) in the form of yellow crystals (1.29 kg, yield 86%). Presented in parentheses, the term "measurement stage" means the stage at which a measurement was performed hydrogen cyanide, and the results of measurement of hydrogen cyanide are presented in the following test examples.

The NMR spectrum and IR spectrum of the target compound (4) is this example is consistent with those of the target compound of example 21.

Test examples

Table 2

Measurement of hydrogen cyanide
Example No.The measurement stageThe content of cyanide ion (ppm) (ppm)
21A50
21In100
2280
23D, ENot found

Method of measurement:

During processing produced from the reaction vessel, nitrogen gas was introduced in 0.05 n sodium hydroxide solution (1 g of bis-indole compounds (3) used 7 ml of 0.05 n sodium hydroxide solution). With regard to the resulting solution of sodium hydroxide, cyanide ion was measured using ion-indicator paper (CN-) manufactured by ADVANTEC.

Example 24

Bis-indole compound (3) (500 mg, of 0.903 mmol), powdered 5% palladium/carbon powder (384 mg, 0,181 mmol) and toluene (22 ml) was placed on the air in baklazhanovyuyu flask with a capacity of 50 ml, equipped with a magnetic stirrer. The mixture was heated in an oil bath at 105°C, stirred at the same temperature for 4 hours, cooled and evaporated to dryness. After adding to the residue dimetilan the oxide (40 ml), the insoluble materials were removed by filtration. The filtrate was subjected to analysis by the method of high performance liquid chromatography, who testified about how to obtain the target compound (4) in the form of a solution in dimethyl sulfoxide to yield 66% (330 mg).

The NMR spectrum and IR spectrum of the target compound (4) in this example is consistent with those of the target compound of example 21.

Example 25

2,3,4,6-O-Tetrabenzyl-D-glucopyranose (5) (100,00 g, 185 mmol) was dissolved in 23°C in N,N-dimethylformaldehyde (360 ml). The solution was cooled to 9°C for 15 minutes was added thionyl chloride (16.2 ml, 222 mmol), then the temperature was increased to 20°C. the resulting solution was heated to 30°C and kept for one hour. The solution was cooled to -10°C and was added 10 wt.% a solution of potassium hydroxide (approximately 150 ml), keeping the temperature below 0°C. the Solution was heated up to 22°C and separated into an organic layer and an aqueous layer. The aqueous layer was extracted with tert-butylmethylamine ether (300 ml×1). Previously obtained organic layer and tert-butylmethylamine extract were combined and sequentially washed with a solution saturated brine (150 ml×1) and water (200 ml×1). The solution was concentrated in vacuum to a volume of 350 ml, containing 1-chloro-2,3,4,6-tetrabenzyl-1-deoxy-D-glucopyranose (6). The crude concentrate of cases the sludge as the source material for the needs of example 26.

Example 26

Obtained in example 21 indolocarbazole derivative (4) (72,00 g, 131 mmol) was dissolved in tert-butylmethylether ether (600 ml). The solution was stirred at 23°C within 10 minutes and to this solution was added a solution (350 ml)containing 1-chloro-2,3,4,6-tetrabenzyl-1-deoxy-D-glucopyranose (6)obtained in example 25. The solution was stirred for 10 minutes and added to 45 wt.% a solution of potassium hydroxide (300 ml). The solution was stirred for 10 minutes and gradually over a period of 22 minutes was added 40 wt.% Aliquat (registered trademark) 336 (product name) in tert-butylmethylether ether (obtained by dissolving Aliquat 336 (72 g) in tert-butylmethylether ether (110 g)). The mixture was stirred at 23°C for 6 hours and added to her water (350 ml). The mixture was stirred for 5 minutes and separated into an organic layer and an aqueous layer. The aqueous layer was extracted with tert-butylmethylamine ether (300 ml×1). Tert-butylmethylamine layer and the organic layer was combined, washed with 10 wt.% aqueous citric acid (300 ml×1), and then water (300 ml×1). The organic solution was stirred at 22°C overnight for precipitation of crystals of the target indolocarbazoles connection (7). The resulting suspension was concentrated at atmospheric pressure to a volume of approximately 625 ml and Oh what was Adali to 23° C. To the suspension gradually over one hour was added methanol (225 ml), cooled suspension -5°C and was stirred for 45 minutes with obtaining crystals. The crystals were collected by filtration, washed with cold methanol/tert-butylmethylamine ether (1:1) (400 ml×2) and dried in vacuum at 25°C to 40°C.

The analysis of the obtained crystals by the method of high performance liquid chromatography showed that the content of the target indolocarbazole compound (7) was 99%.

Used in this example Aliquat (registered trademark) 336 production Aldrich Chemical Co., Inc. represents tricaprylmethyl ammonium chloride.

Example 27

Ethanol (36 ml) was added in chetyrehosnuju flask with a capacity of 300 ml, equipped with a stirrer and thermometer, was added thereto under stirring 12,13-dihydro-2,10-dimensions-13-(β-D-2,3,4,6-Tetra-O-benzylphenol)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-6-methyl-5,7(6H)-dione (8) (670 mg, of 0.62 mmol). The mixture was stirred at room temperature for one hour and at the same temperature for 20 minutes was added dropwise 5 N. aqueous potassium hydroxide (8 ml). The mixture was stirred at the temperature of the mixture 60°C for 4 hours and at room temperature overnight to obtain a brown solution to which was added toluene (20 ml) After adding dropwise at the same temperature for 30 minutes to 1.0 N. hydrochloric acid (62 ml) to adjust pH to 2.6 was obtained yellow solution. To it was added tetrahydrofuran (10 ml) and the mixture was stirred for 6 hours. The aqueous layer (lower layer) was separated and then washed the organic layer with purified water (10 ml×2) and saturated saline (10 ml), dried over anhydrous sodium sulfate (5 g) and filtered. The filtrate was concentrated in vacuum to obtain 12,13-dihydro-2,10-dimensions-13-(β-D-2,3,4,6-Tetra-O-benzylphenol)-5H-indolo[2,3-a]carbazole-5,6-dicarboxylic anhydride (0,63 g) as an oily yellow residue with the release of 85%.

1H-NMR (270 MHz, CDCl3),(h/m): 10,79 (1H, s), 9,04 (1H, d, J=9,2 Hz), of 8.95 (1H, d, J=9.6 Hz), 7,26 (32H, m), 6,17 (2H, d, J=7,3 Hz), to 5.85 (1H, d, J=8,2 Hz), 4,89 (10H, m), 4,32 (1H, t, J=8,9 Hz), 3.96 points (6H, m), 3,13 (1H, d, J=10,2 Hz).

Example 28

The mixture obtained in example 27 12,13-dihydro-2,10-dimensions-13-(β-D-2,3,4,6-Tetra-O-benzylphenol)-5H-indolo[2,3-a]carbazole-5,6-dicarboxylic anhydride (9) (1.50 g, of 1.41 mmol), hemoccult N-(1-benzoyloxymethyl-2-benzyloxyethyl)hydrazine (10) (609 mg, of 1.84 mmol) and N,N-dimethylacetamide (14 ml) was subjected to degassing and was replaced by a nitrogen atmosphere. The mixture was heated to 62°C and dropwise added triethylamine (0.26 per ml, of 1.84 mmol). After stirring at the same temperature for 3 hours Rea is operating and the mixture was cooled to room temperature and added to it the tert-butyl ether (10 ml) and water (7 ml). The organic layer was separated, washed with water, dried over sodium sulfate and filtered. The solvent was removed by evaporation under vacuum to obtain the target compound (11).

1H-NMR (270 MHz, CDCl3,h/m): 10,63 (1H, users), 9,24 (1H, userd, J=9.6 Hz), 9,16 (1H, userd, J=9.6 Hz), 7,50-6,84 (42H, m), of 6.20 (2H, userd, J=7,6 Hz), of 5.84 (1H, d, J=8.6 Hz), 5,33 (1H, userd, J=3.0 Hz), to 5.21 (1H, d, J=and 12.2 Hz), 5,19 (1H, d, J=to 11.9 Hz), 5,16 (1H, d, J=and 12.2 Hz), to 5.08 (1H, d, J=11,9 Hz), to 5.08 (1H, d, J=10,9 Hz), 4,96 (1H, d, J=10,9 Hz), 4,89 (1H, d, J=10,9 Hz), is 4.85 (1H, d, J=10,9 Hz), 4.72 in (1H, d, J=12.9 Hz), and 4.68 (1H, d, J=12.9 Hz), 4,62-4,48 (4H, m)to 4.33 (1H, DD, J=a 9.6, 9.6 Hz), 4,06-of 3.77 (7H, m), and 3.72 (4H, d, J=5.6 Hz), 3.04 from (1H, d, J=9.9 Hz).

1H-NMR (68 MHz, CDCl3,h/million): 168,8, 168,7, 159,4, 159,3, 143,2, 142,9, 138,0, 137,9, 137,6, 136,9, 136,8, 136,6, 136,0, 130,2, 128,7, 128,6, 128,5, 128,4, 128,3, 128,2, 128,2, 128,1, 128,0, 127,9, 127,8, 127,7, 127,6, 127,5, 127,4, 127,3, 126,9, 126,6, 119,4, 119,1, 118,0, 116,9, 116,7, 116,1, 110,4, 96,7, 96,3, 85,8, 84,7, 80,9, 77,4, 77,2, 76,0, 75,9, 75,4, 74,9, 73,9, 73,3, 73,2, 70,7, 70,4, 69,9, 69,8, 66,7, 58,7, 49,4, 30,9, 27,0.

Example 29

The mixture obtained in example 27 12,13-dihydro-2,10-dimensions-13-(β-D-2,3,4,6-Tetra-O-benzylphenol)-5H-indolo[2,3-a]carbazole-5,6-dicarboxylic anhydride (9) (1.30 grams, of 1.23 mmol), monoacetate N-(1-benzoyloxymethyl-2-benzyloxyethyl)hydrazine (599 mg, of 1.59 mmol) and N,N-dimethylacetamide (12.3 ml) was subjected to degassing. The mixture was heated to 45°C in nitrogen atmosphere and to ply was added triethylamine (34,1 μl, 0.25 mmol). The reaction mixture was stirred at the same temperature for 16 hours and cooled to room temperature. After adding methyl tert-butylether (25 ml) and water (6,1 ml) the organic layer was separated, washed with water (5.2 ml×4), dried over sodium sulfate and filtered. The filtrate was subjected to analysis by the method of high performance liquid chromatography, who testified about how to obtain the target compound (11) (1.50 g) in the form of a solution with a yield of 92%.

Since the NMR spectrum and IR spectrum obtained in this example, the target compound (11) is consistent with those of the target compound of example 28, compound (11) was characterized as 12,13-dihydro-2,10-dimensions-6-N-(1-benzoyloxymethyl-2-benzyloxyaniline)13-(β-D-2,3,4,6-Tetra-O-benzylphenol)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-6-methyl-5,7(6H)-dione.

Example 30

The mixture obtained in example 27 12,13-dihydro-2,10-dimensions-13-(β-D-2,3,4,6-Tetra-O-benzylphenol)-5H-indolo[2,3-a]carbazole-5,6-dicarboxylic anhydride (9) (1.30 grams, of 1.23 mmol), monoacetate N-(1-benzoyloxymethyl-2-benzyloxyethyl)hydrazine (599 mg, of 1.59 mmol), miniswhite (1.48 g, 12.3 mmol) and N,N-dimethylacetamide (12.3 ml) was subjected to degassing. The mixture was heated to 45°C in nitrogen atmosphere and dropwise added triethylamine (446 μl, 3,20 mmol). The reaction is ionic mixture was stirred at the same temperature for 10 hours and cooled to room temperature. After adding methyl tert-butylether (25 ml) and water (6,1 ml) adjusting the pH of the aqueous layer to pH 3.5 by addition of 2n HCl (1,34 ml). The organic layer was separated, washed four times with water (5.2 ml), dried over sodium sulfate and filtered. The filtrate was subjected to analysis by the method of high performance liquid chromatography, who testified about how to obtain the target compound (11) (1.50 g) in the form of a solution with a yield of 92%.

Since the NMR spectrum and IR spectrum obtained in this example, the target compound (11) is consistent with those of the target compound of example 28, compound (11) was characterized as 12,13-dihydro-2,10-dimensions-6-N-(1-benzoyloxymethyl-2-benzyloxyaniline)-13-(β-D-2,3,4,6-Tetra-O-benzylphenol)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione.

Example 31

10% palladium/carbon (50 wt./wt.%, 112 g) were placed in the apparatus for hydrogenation and added to it 12-β-D-(2,3,4,6-Tetra-O-benzylphenol)-12,13-dihydro-2,10-dimensions-6-[[(2-benzyloxy-1-(benzoyloxymethyl)ethyl)amino]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (11) in tetrahydrofuran (175 g/l, 6.4 l, 1,12 kg), isopropanol (7,9 l) and 3 N. HCl (224 ml). The mixture was first made when hydrogen pressure of 40 PA/inch2under vigorous stirring at 40°C for 4-14 hours up until theoretical uptake in Dorada was not 110%. The reaction solution was cooled to 25°C and filtered using Solka Floc (registered trademark) in order to collect solids, such as catalyst. These solids were washed with isopropanol/tetrahydrofuran (3:2) (3 l×1). The filtrate and wash liquid were combined, adjusting the pH of the solution to pH of 2.5 by the addition of 1M triethylamine/isopropanol (approximately 600 ml). After adding water (4.0 l) the solution was concentrated at atmospheric pressure to a volume of 7.5 l, then concentrated adding isopropanol/water (4:1) (6.5 liters) and finally concentrated to a water content of 20 wt./vol.%, additionally adding isopropanol (about 9 l) and maintaining the approximate volume of 7.5 liters of the Concentrate was kept at 70°C and added to it a suspension of seed crystals (5 g) in isopropanol (50 ml). The mixture was stirred at 70°C for one hour and 1.5 hours was added isopropanol (5.0 liter). The resulting mixture was stirred at 70°C for 9-24 hours for the deposition of crystals in the sediment. The resulting suspension was concentrated at atmospheric pressure by adding isopropanol (17 l) to achieve the concentrate water content of 3 wt./vol.%. The suspension is kept at 70°C for 3-6 hours, cooled to 22°C and kept at the same temperature for one hour. When spengiu was filtered with getting on the filter sediment, which is then washed with isopropanol (2.5 l) and methanol (1.5 l). The precipitate from the filter was dried in vacuum at 38°C for 6 hours to obtain orange crystals with a yield of 80% or higher (content: 99% or higher). Since the NMR spectrum and IR spectrum obtained in this example, the orange crystals were consistent with those for the compound of example 6 in WO 95/30682 obtained in this example, the target compound (13) was described as 12,13-dihydro-2,10-dihydroxy-6-N-(1-hydroxymethyl-2-hydroxyethylamino)-13-(β-D-glyukopiranozil)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione.

The conditions of the analysis by the method of high performance liquid chromatography: the separation column YMC ODS-AQ (250×4.6 mm); flow rate of 1.5 ml/min; detection at a wavelength of 228 nm; mobile phase: A=0.1% of H3PO4/water, B=acetonitrile; the amount of applied sample 10 µl; temperature measurement - 25°C.

Example 32

3-Benzyloxy-6-(2-pyrrolidinyl)nitrobenzene (1,00 g is 3.08 ml), 5% rhodium/carbon powder (63.5 mg, 0,0309 mmol), iron acetate(II) (5.6 mg, 0,0309 mmol) as a metal link and tetrahydrofuran (20 ml) were placed in a nitrogen atmosphere in baklazhanovyuyu flask with a capacity of 30 ml, equipped with a magnetic stirrer, and then was replaced by a gaseous nitrogen gaseous hydrogen. Received suspense is stirred at room temperature for 41 hours in an atmosphere of hydrogen, then was replaced by a gaseous hydrogen gaseous nitrogen and was stirred overnight under nitrogen atmosphere. The reaction mixture was filtered to obtain a solid, which was washed with tetrahydrofuran. The filtrate and wash liquid were combined to obtain a brown solution (79,83 g). The solution was subjected to analysis by the method of high performance liquid chromatography, which testified to obtain the desired 6-benzyloxyindole (2c) (661 mg, yield 96%) and passing the resulting 6-hydroxyindole (3c) (2 mg, yield of 0.6%).

6-Benzyloxyindole:

1H-NMR (500 MHz, DMSO-d6,h/m): 10,90 (users, 1H), 7,49 (d, J=7.5 Hz, 1H), 7,44 (d, J=8.6 Hz, 1H), 7,40 (DD, J=7,5, 7.5 Hz, 1H), 7,33 (DD, J=7,5, 7.5 Hz, 1H), 7,21 (userid, J=2,4, 2,4 Hz, 1H), 7,01 (osirm, 1H), 6,77 (DD, J=1,8, 8.6 Hz, 1H), 6,36 (osirm, 1H), 5,12 (s, 2H).

13C-NMR (126 MHz, DMSO-d6,h/million): 154,7, 138,0, 136,8, 128,7, 128,0, 127,9, 124,4, 122,5, 120,9, 110,1, 101,3, 96,3, 69,9.

6-Hydroxyindole:

1H-NMR (500 MHz, DMSO-d6,ppm): is 10.68 (users, 1H), 8,88 (users, 1H), 7,33 (d, J=8,4 Hz, 1H), 7,12 (m, 1H), 6,79 (m, 1H), 6,56 (DD, J=8,4, 1.5 Hz, 1H), 6.30-in (m, 1H).

13C-NMR (126 MHz, DMSO-d6,h/million): 153,78, 137,90, 124,00, 121,90, 121,17, 110,37, 101,75, 97,36.

Examples 33-35

Following a methodology similar to that described in example 32, 2-(2-pyrrolidinyl)nitrobenzene was first made in risotti catalyst of the present invention, containing 5% rhodium/carbon powder and acetate of iron(II)nitrate, Nickel(II) or acetylacetonate cobalt(III) as the metal link. Indole was obtained with high yield, as shown below in table 3.

Table 3
Example No.5% Rh/C (the amount used)The compound of the metal (used amount)The duration of the reactionOutput (%)
331 mol.%Fe(OAc)2(1 mol.%)31 hours88
343 mol.%Ni(NO3)2·6H2O (20 mol.%)32 hours82
351 mol.%Co(acac)3(5 mol.%)38 PM85

Indole:

Product (2d) was characterized by comparing with the spectra of various commercially available products.

Examples 36-38

Following a methodology similar to that described in example 32, 3-benzyloxy-2-(2-pyrrolidinyl)nitrobenzene as the starting material was recovered in the presence of the catalyst of the present invention, containing 5% rhodium/carbon powder and acetate of iron(II)nitrate, Nickel(II) or acetylate eat cobalt(III) as the metal link.

The results are presented in the following table 4, and compared with example 3 comparison in the case of the use of reducing agents of the present invention 4-benzyloxyindole was obtained with a higher yield, and 4-hydroxyindole side formed with a smaller output.

Table 4
Example No.5% Rh/C (the amount used)The compound of the metal (used amount)The duration of the reactionOutput connections (A) (%)Output connections (B) (%)
361 mol.%Fe(OAc)2< / br>
(1 mol.%)
31 h835
373 mol.%Ni(NO3)2·6H2O

(20 mol.%)
32 h886
381 mol.%Co(acac)3< / br>
(5 mol.%)
38 h803
An example of comparison 33 mol.%No167 h4338

4-Benzyloxyindole:

1H-NMR (500 MHz, CDCl3,h/m): 8,12 (users, 1H), 7,49 (userd, J=7.5 Hz, 1H), 7,44 (ushort, J=7.5 Hz, 1H), 7,37(m, 1H), 7,14 (DD, J=8.0 a, and 7.8 Hz, 1H), 7,10 (m, 1H),? 7.04 baby mortality (d, J=8.0 Hz, 1H), 6,77 (m, 1H), only 6.64 (d, J=7.7 Hz, 1H), 5,28 (s, 2H).

13C-NMR (126 MHz, CDCl3,h/million): 152,88, 137,94, 137,66, 128,81, 128,05, 127,66, 123,00, 119,23, 105,02, 101,46, 100,40, 70,27.

4-Hydroxyindole:

1H-NMR (500 MHz, CDCl3,h/m): 8,19 (users, 1H), 7,13 (m, 1H), 7,06 (DD, J=8.0 a, 7,6 Hz, 1H), 7,01 (d, J=8.0 Hz, 1H), 6,62 (m, 1H), is 6.54 (d, J=7,6 Hz, 1H), 5,22 (users, 1H).

13C-NMR (126 MHz, CDCl3,h/million): 149,08, 137,86, 123,18, 123,03, 117,64, 104,37, 104,29, 98,91.

Examples 39-41

Following a methodology similar to that described in example 32, 4-benzyloxy-2-(2-pyrrolidinyl)nitrobenzene as the starting material was recovered in the presence of the catalyst of the present invention, containing 5% rhodium/carbon powder and acetate of iron(II)nitrate, Nickel(II) or acetylacetonate cobalt(III) as the metal link.

The results are presented in the following table 5, and compared with example 4 comparison in the case of the use of reducing agents of the present invention 5-benzyloxyindole was obtained with a higher yield and 5-hydroxyindole side formed with a smaller output.

Table 5
Example No.5% Rh/C (the amount used)

(mol.)
The compound of the metal (used amount)The duration of the reactionOutput connections (C) (%)Output connections (D) (%)
391 mol.%Fe(OAc)2< / br>
(1 mol.%)
9 h991
403 mol.%Ni(NO3)2·6H2O

(20 mol.%)
23 h930,4
411 mol.%Co(acac)3< / br>
(5 mol.%)
15 h963
Example 4 comparison3 mol.%No15 h8614

5-Benzyloxyindole:

1H-NMR (500 MHz, CDCl3,h/m): 7,92 (users, 1H), 7,44 (userd, J=7.5 Hz, 1H), was 7.36-7,26 (m, 2H), 7,17-to 7.15 (m, 2H), 7,03 (m, 1H), 6,92 (DD, J=8,8, 2.4 Hz, 1H), 6.42 per (m, 1H), is 5.06 (s, 2H).

13C-NMR (126 MHz, CDCl3,h/million): 153,64, 137,99, 131,45, 128,82, 128,53, 128,08, 127,89, 125,30, 113,29, 112,06, 104,32, 102,59, 71,26.

5-Hydroxyindole:

1H-NMR (500 MHz, DMSO-d6,h/m): 10,76 (users, 1H), 8,61 (users, 1H), 7,24 (m, 1H), 7,21 (d, J=8.6 Hz, 1H), 6.89 in (userd, J=2.0 Hz, 1H), 6,65 (DD, J=8,6, 2.0 Hz, 1H), 6,27 (m, 1H).

13C-NMR (126 MHz, DMSO-d6,h/million): 151,42, 131,38, 129,30, 126,37,112,50, 112,20, 104,76, 101,12.

Examples 42-44

Following a methodology similar to that described in example 32, 5-benzyloxy-2-(2-pyrrolidinyl)nitrobenzene as the starting material was recovered in the presence of the catalyst of the present invention, containing 5% rhodium/carbon powder and acetate of iron(II)nitrate, Nickel(II) or acetylacetonate cobalt(III) as the metal link.

The results are presented in the following table 6, and compared with a comparison example to 5 in the case of the use of reducing agents of the present invention 6-benzyloxyindole received with a higher output, and 6-hydroxyindole side formed with a smaller output.

Co(acac)3< / br>
(5 mol.%)
Table 6
Example No.5% Rh/C (the amount used)The compound of the metal (used amount)The duration of the reactionOutput connections (E) (%)Output connections (F) (%)
421 mol.%Fe(OAc)2< / br>
(1 mol.%)
9 h960,6
433 mol.%Ni(NO3)2·6H2About

(20 mol.%)
23 h901
441 mol.%15 h943
Example compare 53 mol.%No42 h5534

Example 45

Nitrobenzene (379 mg, is 3.08 mmol), benzylfentanyl ester (567 mg, is 3.08 mmol) as substrate, 5% rhodium/carbon powder (63.5 mg, 0,0309 mmol), iron acetate(II) (5.6 mg, 0,0309 mmol) as a metal link and tetrahydrofuran (20 ml) were placed in a nitrogen atmosphere in baklazhanovyuyu flask with a capacity of 30 ml, equipped with a magnetic stirrer. After substitution of gaseous nitrogen gaseous hydrogen obtained suspension was stirred at room temperature for 16 hours in an atmosphere of hydrogen, after replacement of the hydrogen with gaseous nitrogen, the resulting suspension was stirred overnight under nitrogen atmosphere. After removing the solids by filtration the residue was washed with tetrahydrofuran. The filtrate and wash liquid were combined to obtain a brown solution. The solution was subjected to analysis by the method of high performance liquid chromatography, which testified to the fact that aniline (A'), benzylfentanyl the air as an extracted substrate and phenol (B') as the recovered substrate was obtained with the yield of 86% (portion mg), with the recovery of 89% (portion 503 mg) and 1% (dose 4 mg), respectively.

Each component of the resulting solution was characterized by comparing with the spectra of various commercially available products.

Examples 46-48

Following a methodology similar to that described in example 45, the reduction was carried out using the catalyst of the present invention, containing 5% rhodium/carbon powder, acetate, iron(II)nitrate, Nickel(II) or acetylacetonate cobalt(III) as compounds of the metal, and antiferromag ester as substrate. The results are presented in the following table 7.

Aniline and restored the substrate (phenol) were characterized by comparing with the spectra of various commercially available products.

Table 7
Example No.5% Rh/C (the amount used)The compound of the metal (used amount)The duration of the reactionThe output of the compounds (A') (%)The output of the compounds (B')
463 mol.%Ni(NO3)2·6H2O (20 mol.%)16 h86%32%
471 mol.% Fe(OAc)2< / br>
(1 mol.%)
16 h86%1%
481 mol.%Co(acac)3< / br>
(5 mol.%)
16 h85%1%
An example of comparison 63 mol.%No16 h64%27%
Example 7 comparison1 mol.%No16 h62%15%

The output of the compounds (A') represents the output of aniline, and the output of the compounds (B') represents the output of the phenol.

Examples 49-51

Following a methodology similar to that described in example 45, the reduction was carried out using the catalyst of the present invention, containing 5% rhodium/carbon powder, acetate, iron(II)nitrate, Nickel(II) or acetylacetonate cobalt(III) as compounds of the metal, and chlorobenzene as the substrate. The results are presented below in table 8.

Aniline and restored the substrate (benzene) were characterized by comparing with the spectra of various commercially available products.

Table 8
Example No.5% Rh/C (used quantities is) The compound of the metal (used amount)The duration of the reactionThe connection output (C')Output connections (D')
493 mol.%Ni(NO3)2·6H2O

(20 mol.%)
16 h91%24%
501 mol.%Fe(OAc)2< / br>
(1 mol.%)
16 h90%4%
511 mol.%Co(acac)3< / br>
(5 mol.%)
16 h94%3%
Example 8 comparison3 mol.%No16 h10%78%
Example 9 comparison1 mol.%No16 h65%33%

The connection output (C') represents the output of aniline, the compound (D') represents the output of benzene.

Examples 52-54

Following a methodology similar to that described in example 45, the reduction was carried out using the catalyst of the present invention, containing 5% rhodium/carbon powder, acetate, iron(II)nitrate, Nickel(II) or acetylacetonate cobalt(III) as compounds of the metal, and benzaldehyde as substrate. Results PR is dstanley below in table 9.

Aniline and restored the substrate (benzyl alcohol) were characterized by comparing with the spectra of various commercially available products.

Table 9
Example No.5% Rh/C (the amount used)The compound of the metal (used amount)The duration of the reactionOutput connections (E')The connection output (F')
523 mol.%Ni(NO3)2·6H2O

(20 mol.%)
16 h83%16%
531 mol.%Fe(OAc)2< / br>
(1 mol.%)
16 h94%7%
541 mol.%Co(acac)3(5 mol.%)16 h81%8%
Example 10 comparison3 mol.%No16 h65%56%
Example 11 comparison1 mol.%No16 h92%29%

Output connections (E') represents the output of aniline, the compound (F') represents the output benzyl with the IRTA.

Example 55

Nitrobenzene (379 mg, is 3.08 mmol), benzylfentanyl ester (567 mg, is 3.08 mmol), pyrrolidine (0,257 ml, is 3.08 mmol), 5% rhodium/carbon powder (63.5 mg, 0,0309 mmol), iron acetate(II) (5.6 mg, 0,0309 mmol) as a metal link and tetrahydrofuran (20 ml) were placed in a nitrogen atmosphere in baklazhanovyuyu flask with a capacity of 30 ml, equipped with a magnetic stirrer. After substitution of gaseous nitrogen gaseous hydrogen obtained suspension was stirred at room temperature for 5 hours in an atmosphere of hydrogen and stirred overnight under nitrogen atmosphere. After removing the solids by filtration the residue was washed with tetrahydrofuran. The filtrate and wash liquid were combined to obtain a brown solution. The solution was subjected to analysis by the method of high performance liquid chromatography, which testified to the receipt of aniline with a yield of 88% (portion 252 mg) and a side of the formed phenol, obtained by recovering benzylaniline ether, with the release of 0.4% (dose 1 mg).

Examples 56-58

Following a methodology similar to that described in example 55, the reduction was carried out using the catalyst of the present invention, containing 5% rhodium/carbon powder, acetate, iron(II)nitrate, Nickel(II) or acetylacetonate cobalt(III) as with the organisations metal, and pyrrolidin as a base. The results are presented below in table 10.

Table 10
Example No.5% Rh/C (the amount used)The compound of the metal (used amount)The duration of the reactionOutput connections (G'): %Output connections (H'): %
563 mol.%Ni(NO3)2·6H2O

(20 mol.%) Pyrrolidin

(1 equiv.)
5 h908
571 mol.%Fe(OAc)2< / br>
(1 mol.%) Pyrrolidin

(1 equiv.)
5 h880,4
581 mol.%Co(acac)3< / br>
(5 mol.%) Pyrrolidin

(1 equiv.)
5 h946
Example 12 comparison3 mol.%The compound of the metal is not used

Pyrrolidin

(1 equiv.)
5 h8642
An example of comparison of 133 mol.%The compound of the metal is not used

Pyrrolidin

(1 equiv.)
2 hours9220
Example 14 comparison 1 mol.%The compound of the metal is not used

Pyrrolidin

(1 equiv.)
5 h9114

Output connections (G') represents the output of aniline, and the output connection (H') represents the output of the phenol. The abbreviation "EQ." means equivalent.

The above results confirmed that the selective catalytic reduction of functional groups can be improved by supplemental amine in the catalyst according to the present invention.

Example 59

3-Benzyloxyethanol (706 mg, is 3.08 mmol), pyrrolidine (0,257 ml, is 3.08 mmol), 5% rhodium/carbon powder (190 mg, 0,0924 mmol), uranyl nitrate Nickel(II) (179 mg, 0,616 mmol) and tetrahydrofuran (20 ml) were placed in a nitrogen atmosphere in baklazhanovyuyu flask with a capacity of 30 ml, equipped with a magnetic stirrer. After substitution of gaseous nitrogen gaseous hydrogen obtained suspension was stirred at room temperature for 2.5 hours in hydrogen atmosphere was replaced by an atmosphere of hydrogen atmosphere of nitrogen. The obtained solid substance was collected by filtration and washed with tetrahydrofuran. The filtrate and wash liquid were combined to obtain a brown solution. The solution was subjected to analysis by the method of high performance liquid chromatography to the who testified about receiving 3-benzyloxyaniline exit 92% (portion 565 mg) and 3-hydroxyanisole exit 1% (dose 3 mg).

Examples 60-66

Following a methodology similar to that described in example 59, the reduction was carried out with the use of acetate of iron(II)nitrate, Nickel(II) or acetylacetonate cobalt(III) as the metal link. The results are presented below in table 11.

Table 11
Example No.5% Rh/C (the amount used)The compound of the metal (used amount)PyrrolidinThe duration of the reactionThe yield of compound (I')Output connections(J')
603 mol.%Ni(NO3)2·6H2O (20 mol.%)No15 h922
613 mol.%Ni(NO3)2·6H2O (20 mol.%)1 equiv.2.5 h921
623 mol.%Ni(NO3)2·6H2O (20 mol.%)3 equiv.2.5 h950,5
631 mol.%Fe(OAc)2< / br>
(1 mol.%)
No33 h920,8
1 mol.%Fe(OAc)2< / br>
(1 mol.%)
1 equiv.2.5 h980,5
651 mol.%Co(acac)3< / br>
(5 mol.%)
No33 h890,6
661 mol.%Co(acac)3< / br>
(5 mol.%)
1 equiv.4 h917
Example comparison-tion

15
3 mol.%NoNo15 h7611
Example comparison-tion

16
3 mol.%No1 equiv.2.5 h7915
Example comparison-tion

17
3 mol.%No3 equiv.2.5 h8614

The yield of compound (I') represents the output (%) 3-benzyloxyaniline; output connection (J') represents the output of the 3-hydroxyanisole.

The results of examples 60-66 confirmed that the addition of amine, such as pyrrolidine to catalytic reduction system of the present invention, containing a catalyst of rhodium on a carrier and iron salts, Nickel salts or cobalt salts in which the quality of the connection metal there has been a sharp increase in the reaction rate, reducing the likelihood of recovery is capable of such recovery of functional groups, such as benzylamine group, selective recovery of the nitro group, and the increase in output.

Examples 67-68

Following a methodology similar to that described in example 45, the reduction was carried out using the catalyst of the present invention, containing 5% rhodium/carbon powder and acetate of iron(II)nitrate, Nickel(II) or acetylacetonate cobalt(III) as compounds of the metal, and styrene (K') as a substrate. The results are presented in the following table 12.

Aniline and restored the substrate (ethylbenzene (L')) were characterized by comparing with the spectra of various commercially available products.

Table 12
Example No.5% Rh/C (the amount used)The compound of the metal (used amount)The duration of the reactionOutput connections (K'): %Output connections (L'): %
681 mol.%Fe(OAc)2< / br>
(1 mol.%)
16 h80%98%
691 mol. Co(acac)3< / br>
(5 mol.%)
16 h89%99%
Example comparison 183 mol.%No16 h31%93%
Example comparison 191 mol.%No16 h73%98%

Output connections (K') represents the output of aniline, and the output connection (L') represents the output of ethylbenzene.

In the obtained above results confirmed that in the case of catalytic reduction using a catalyst of the present invention the recovery of the nitro group and the vinyl group is no recovery benzylamino group, the substituents chlorine and aldehyde groups.

Therefore, in the case of catalytic reduction using a catalyst of the present invention, i.e. a catalyst containing a rhodium catalyst on a carrier and iron salts, Nickel salts or cobalt salts as metal joints, restoring nitro, alkenylphenol or alkenylphenol group can be selective without recovery of functional groups, such as benzylamine group, aryl halides, aldehydes, ketones, etc.

APPLICABILITY IN INDUSTRIAL CONDITIONS

<> The target compound (I) according to the present invention is applicable as a drug, and the present invention relates to advantageous on an industrial scale method of production of the specified connection. Additionally, the catalyst of the present invention can be used as a catalyst in various reactions of recovery, making it possible electoral recovery.

1. The method of obtaining represented by formula (I) derived introperative, comprising the following stages:

(i): the stage in which the compound of formula (XIII)

in which R1represents hydroxyamino group, and each of Raand Rbindependently represents a C1-C7is an alkyl group, or RaandRbcan be joined together to form with3-C6-alkalinous group, or its pharmaceutically acceptable salt, is subjected to the interaction with gaseous hydrogen at 1-5 ATM in the presence of compounds of rhodium, metal link and, optionally, amine, in an inert solvent at room temperature,

moreover, the connection of the rhodium constitutes 1-10% rhodium on charcoal, rhodium on alumina, rhodium on calcium carbonate or rhodium on barium sulphate, and

the compound of the metal which is a salt of Nickel (II), iron (II), iron (III), cobalt (II) or cobalt (III)

obtaining indole compounds of formula (XII):

in which R1defined above, or its pharmaceutically acceptable salt;

(ii): the stage of interaction of the obtained indole compounds of formula (XII) or its pharmaceutically acceptable salt manichaica formula (XI):

in which Rcrepresents ethyl or butyl; or a magnesium compound of the formula (X):

in which Rdrepresents butyl, in an inert solvent, and then adding to the resulting mixture maleimides the compounds of formula (IX):

in which X represents a halogen atom, and Y represents a hydrogen atom, a C1-C7is an alkyl group, phenyl group, benzyloxyethyl group or7-C12-aracelio group, to obtain the bis-indole compounds of the formula (VIII):

in which values for each R1and Y are defined above, or its pharmaceutically acceptable salt;

(iii): the implementation phase response of the circuit in the resulting bis-indole compound (VIII) or the th pharmaceutically acceptable salt of obtaining the compounds of formula (VII):

in which values for each R1and Y are defined above, or its pharmaceutically acceptable salt;

(iv): stage combination of the obtained compound (VII) or its pharmaceutically acceptable salt with an activated derivative of glucose of the formula (VI):

in which each of R2, R3, R4and R5represents hydroxyamino group, and X1represents a halogen atom, to obtain the compounds of formula (V):

in which values for each R1, R2, R3, R4, R5and Y are defined above, or its pharmaceutically acceptable salt;

(v): the stage of processing of the obtained compound (V) or its pharmaceutically acceptable salt with inorganic base in an inert solvent to obtain compounds of formula (IV):

in which values for each of R1, R2, R3, R4and R5defined above, or its pharmaceutically acceptable salt;

(vi): the stage of interaction of the compound (IV) or its pharmaceutically acceptable salt with the compound of the formula (III):

in which each of R6and R7the stand is made by hydroxyamino group, and Xandrepresents a molecule of acid, to obtain the compounds of formula (II):

in which values for each R1, R2, R3, R4, R5, R6and R7defined above, or its pharmaceutically acceptable salt; and

(vii): deletion period hydroxyamine groups from the resulting compound (II) or its pharmaceutically acceptable salt with obtaining derived introperative formula (I):

or its pharmaceutically acceptable salt.

2. The method according to claim 1, wherein the salt of Nickel (II)salt of iron (II)salt of iron (III)salt of cobalt (II) or a salt of cobalt (III) represent NiBr2, Ni(NO3)2, Ni(OCOCH3)2, FeBr3, FeCl2, FeSO4, FeCl3, FeCl3-SiO2, Fe(OCOCH3)2, fumarate, Fe(II), CoBr2, CoCl2,

,

,

or

.

3. The method according to claim 1, in which each of R1, R2, R3, R4, R5, R6and R7represents a benzyl group.

4. The method according to claim 1, in which the connection rhodium is a rhodium on charcoal, rhodium on alumina, rhodium on the carbonate is calcium or rhodium on barium sulphate.

5. The method according to claim 1, in which maleimide compound of formula (IX) represents maleimide compound represented by formula (IX-a):

in which Y represents a hydrogen atom, a C1-C7is an alkyl group, phenyl group, benzyloxyethyl group or a C7-C12-aracelio group.

6. The method according to claim 1, in which Y represents a metal group.

7. The method according to claim 1, wherein Xandrepresents oxalic acid.

8. The method of obtaining indole compounds represented by formula (XII):

in which R1represents hydroxyamino group, or its pharmaceutically acceptable salt, wherein interact compounds represented by the formula (XIII):

in which the value of R1defined above, and each of Raand Rbindependently represents a C1-C7is an alkyl group, or Raand Rbcan be joined together to form with3-C6-alkalinous group, or its pharmaceutically acceptable salt with gaseous hydrogen at 1-5 ATM in the presence of compounds of rhodium and compounds of metal and, optionally, amine, in an inert solvent Ave is room temperature,

moreover, the connection of the rhodium constitutes 1-10% rhodium on charcoal, rhodium on alumina, rhodium on calcium carbonate or rhodium on barium sulphate, and

the compound of the metal is a salt of Nickel (II)salt of iron (II)salt of iron (III)salt of cobalt (II) or a salt of cobalt (III).

9. The method according to claim 8, characterized in that it includes additional processing of the crude indole compounds or pharmaceutically acceptable salts of silica gel.

10. A method of obtaining a bis-indole compounds of the formula (VIII) or its pharmaceutically acceptable salt, which includes the implementation of the interaction of indole compounds of formula (XII):

in which R1represents hydroxyamino group, or its pharmaceutically acceptable salt manichaica formula (XI):

in which Rcrepresents ethyl or butyl, or with a magnesium compound of the formula (X):

in which Rdrepresents butyl, in an inert solvent, with subsequent implementation of the interaction of the obtained product with maleimide compound of formula (IX)

in which X represents a halogen atom, and Y before the hat is a hydrogen atom, With1-C7is an alkyl group, phenyl group, benzyloxyethyl group or7-C12-aracelio group, in an inert solvent to obtain bis-indole compounds of the formula (VIII):

in which values for each R1and Y are defined above, or its pharmaceutically acceptable salt.

11. The method according to claim 10, in which maleimide compound of formula (IX) represents maleimide compound represented by formula (IX-a)

in which Y represents a hydrogen atom, a C1-C7is an alkyl group, phenyl group, benzyloxyethyl group or7-C12-aracelio group.

12. The hydrogenation catalyst, in which the compound of rhodium, metal connection and Amin are together or in a mixture,

where the compound of rhodium represents 1-10% rhodium on charcoal, rhodium on alumina, rhodium on calcium carbonate or rhodium on barium sulphate, and

the compound of the metal is a salt of Nickel (II)salt of iron (II)salt of iron (III)salt of cobalt (II) or a salt of cobalt (III).

13. The catalyst according to item 12, in which the amine is a secondary amine or tertiary amine.

14. The catalyst according to item 12, in which the amine is pyrrolidine, piperidine, dimethylamine,diethylamine, Diisopropylamine, dibutylamine, trimethylamine, triethylamine or tributylamine.

15. The catalyst according to item 12, which is a salt of Nickel (II)salt of iron (II)salt of iron (III)salt of cobalt (II) or a salt of cobalt (III) represent NiBr2, Ni(NO3)2, Ni(OCOCH3)2, FeBr3, FeCl2, FeSO4, FeCl3, FeCl3-SiO2, Fe(OCOCH3)2, fumarate, Fe (II), CoBr2, CoCl2,

,

,

or

.



 

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< / BR>
in which R1and R2each independently H, lower alkyl, lower alkenyl, phenyl, phenylalkyl, pyridyl or imidazolyl, and each of the groups lower alkyl, lower alkenyl, phenyl, phenylalkyl is optional from 1 to 5 substituents selected from carboxy, carbamoyl, cyano and hydroxy-group; or the group-Y - R2where Y is a carbonyl, thiocarbonyl or sulfonyl, and R3- H, lower alkyl, trifluoromethyl, phenyl, lower alkoxy, hydrazino, amino, phenylamino, carbarnoyl or Peregrina group, the lower alkyl or phenyl group are optionally 1 to 4 substituents such as hydroxy-group adjacent to the hydroxy-group-protected alkalinous group, carboxy or cyano, or R1and R2taken together with the nitrogen atom to which they are attached, form a piperazinilnom or pyrrolidinyloxy the group may hydroxylamino lower alkyl group, G - pentasa or hexana group, X1and X2independently H or halogen, OH, lower alkoxy - or benzyloxy

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29 cl, 10 tbl, 10 ex

FIELD: chemistry.

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30 cl, 40 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns (a) new compounds of the formula I: , where M is a macrolipid subunit (macrolipid group) obtained from a macrolipid inclined to accumulation in inflamed cells, S is a steroid subunit (steroid group) obtained from a steroid medicine with anti-inflammatory effect, and L is a linker molecule connecting M and S; (b) their pharmacologically acceptable salts, prodrugs and solvates; (c) methods and mediators for their obtaining; and (d) methods of their application in treatment of human and animal inflammation diseases and conditions. The claimed compounds are inhibiting many cytokines and immune mediators participating in immune reactions that cause inflammation, allergy or alloimmunity, including IL (interleukin)-1, 2, 4, 5, 6, 10, 12, GMCSF (Granulocyte Macrophage Colony Stimulating Factor), ICAM (Intercellular Adhesion Molecule) and TNF (tumour necrosis factor) - α without limitation. At that, antiinflammation steroids have immediate anti-inflammatory effect due to the link to glycocorticosteroid receptor.

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30 cl, 40 ex, 4 dwg

FIELD: chemistry.

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7 cl, 5 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention concerns polymorphs of 1-pyrrol-substituted 2-indolinone compound (2-pyrrolidine-1-ylethyl)amide 5-(5-fluor-2-oxo-1,2-dihydroindole-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrol-3-carboxylic acid, namely polymorphic form of the formula I: in the form of polymorphic form II mainly free of polymorph I characterised by PXRD powder radiogram with characteristic peaks expressed in degrees (±0.1) of double angle 7.1, 13.9, 16.0, 20.9 and 24.7, obtained with the use of CuKα1 radiation (wavelength = 1.5406 A), and polymorphic compound form of the formula I in the form of polymorphic form I mainly free of polymorph II characterised by PXRD powder radiogram with characteristic peaks expressed in degrees (±0.1) of double angle 5.0, 16.7, 18.9, 24.8 and 27.3 obtained with the use of CuKα1 radiation (wavelength = 1.5406 A). The invention also concerns pharmaceutical composition capable of catalytic proteinkynase activity and based on these forms, method of catalytic proteinkynase activity modeling and treatment method for patients with proteinkynase-induced diseases.

EFFECT: improved efficiency of preparations.

26 cl, 3 dwg, 4 tbl

FIELD: medicine; pharmacology.

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EFFECT: derivatives possess useful biological properties.

56 cl, 115 ex

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