Derivatives of 5-arylindole and their use as agonists of serotonin (5-ht1)

 

(57) Abstract:

The invention relates to new derivatives of 5-arylindole formula I, where R1matter referred to in the description, A, B, C, and D each represent a carbon or one of them represents a nitrogen; R2, R3, R4, R5each independently represents hydrogen, C1- C6-alkyl, phenyl, halogen, cyano,- (CH2)mNR14R15, -(CH2)mOR9, -(CH2)mNR14COR9, -(CH2)mNR14CONHR9, -CO2R9; R6represents hydrogen, -OR10; R7, R8, R14, R15each independently represents hydrogen, C1- C6-alkyl, (CH2)xOR11; R9represents hydrogen, C1- C6-alkyl, phenyl; R10is1- C10-alkyl; R11is1- C6-alkyl; n = 0,1 or 2; m = 0, 1, 2 or 3; x = 2 or 3; the dotted line indicates the optional single bond or their pharmaceutically acceptable salts. Describes a pharmaceutical composition based on compounds of formula I that bind receptors NT-1A and MT-1 in the treatment of conditions selected from hypertension, depression, migraine, and also a way of linking R is in to receive them, containing their pharmaceutical compositions and to their use in medicine. Active compounds of the present invention is suitable for treatment of migraine and other disorders.

U.S. patents 4839377 and 4855314 and European patent application 313397 refer to 5-substituted 3-aminoalkylindoles. Indicates that these compounds are suitable for treatment of migraine.

Patent application UK 040279 relates to 3-aminoalkyl-1H-indol-5-thioamides and carboxamides. Indicated that these compounds can be used for the treatment of hypertension, diseases of Raymond and migraines.

European patent application N 303506 relates to 3-poly: hydropyridine-5-substituted-1H-indoles. Indicated that these compounds have activity as 5-HT1receptor agonist and vasoconstrictor agents, and can also be used to treat migraine headaches.

European patent publication N 354777 relates to derivatives of N-piperidinyl : indolyl - ethyl-alkanesulfonyl. Indicated that these compounds have activity as 5-HT1-receptor agonist and vasoconstrictor agents, and can be used to treat headaches.

European patent publication N 438230 Rel the activity as a 5-HT1-like receptor agonists, and can be used to treat migraine and other disorders, which shows selective agonists of these receptors.

European patent publication of application N 313397 relates to derivatives of 5-heterocyclic indole. Indicated that these compounds possess exceptional properties for the treatment and prevention of migraines, "histamine" headaches and headaches associated with vascular disorders. Indicated that these compounds have the exclusive 5-HT1-like receptor agonism.

International patent application WO - 91-18897 relates to derivatives of 5-heterocyclic indole. Specify tatke that these compounds possess exceptional properties for the treatment and prevention of migraine, "histamine" headaches and headaches associated with vascular disorders. It was also mentioned that these compounds possess exclusive "5-HT1-like receptor agonism.

European patent application publication 457701 refers to a derivative arylacetamide as having a high affinity for the 5-HT1Dserotonin receptors. Indicated that these compounds are suitable for treatment zabolevaniya applications N 497512 A2 belongs to the class of imidazole derivatives, triazole and tetrazole, which are selective with respect to 5-HT1-like receptors. Indicated that these compounds are suitable for the treatment of migraine and associated disorders.

In "New Trends in Benzodiazepin Research in Drugs of Today, vol. 24, 649-663 /1987/ discusses the use of ligands of benzodiazepine receptors for the treatment of States of anxiety and other disorders.

European patent application EP-499527-A1 relates to new derivatives-carboline, which have affinity for the benzodiazepine receptors, and which can be used for the treatment of degenerative disorders of the Central nervous system such as Alzheimer's disease.

Summary of the invention

The present invention relates to compounds of the formula:

< / BR>
where R1is:

< / BR>
< / BR>
n is 0, 1 or 2;

A, B, C and D each independently represents a nitrogen or carbon;

each of R2, R3, R4and R5independently represents hydrogen, C1-C6alkyl, aryl, C1-C3alkylaryl, halogen (for example, fluorine, chlorine, bromine or iodine/, cyano, nitro, -/CH2/mNR14R15, - /CH2/mOR9, -SR9, -SO2NR14R15N/CH2/mNR14/mNR14CONHR9, -CONR14R15or-CO2R9;

R2and R3, R3and R4or R4and R5taken together, can represent five-semiline alkyl ring, a six-membered aryl ring, a five-semiline heteroalkyl ring containing 1 heteroatom selected from N, O or S, or a five or six-membered heteroaryl ring containing 1 or 2 heteroatoms selected from N, O or S; R6represents hydrogen, -OR10or-NHCOR10;

each of R7, R8, R14and R15each independently represents hydrogen, C1-C6alkyl, -/CH2/xOR11C1-C3alkylaryl, aryl;

R7and R8or R14and R15taken together form a three to six-membered ring; R9represents hydrogen, C1-C6alkyl, C1-C3alkylaryl or aryl;

R10represents hydrogen, C1-C6alkyl or C1-C3alkylaryl;

R11represents hydrogen, C1-C6alkyl or C1-C3alkylaryl;

m is 0, 1, 2 or 3;

x represents 2 or 3;

the dotted line represents an optional double bond, and the above aryl groups and aryl-related phenyl may be substituted one to three C1-C4by alkyl, halogen (for example, fluorine, chlorine, bromine or iodine/, hydroxy, cyano, carboxamido, nitro or C1-C4alkoxy; and their pharmaceutically acceptable salts.

These compounds are effective agonists of 5-HT1receptors and agonists and antagonists benzodiazepine receptors, and can be used in the treatment of migraine and other disorders.

Compounds of the present invention include optical isomers of formula I /i.e., R and S stereoisomers at any chiral site/ and their racemic, diastereoisomeric or epimeria mixture. If R6represents hydrogen, epimere with absolute R configuration at the chiral carbon is designated by an asterisk in formula I, preferred. If R6is-OR10or NHCOR10and n is 0 or 1, the preferred epimere with absolute S configuration at the chiral carbon is designated by an asterisk in formula I. If R6is-OR10or-NHCOR10and n = 2, the preferred epimere with absolute R configuration at the chiral carbon is designated by an asterisk in formula I. If R6is-OR10or-NHCOR10and n = 0, the preferred CIS-epimer is and n = 1, the preferred CIS-epimer //2S, 4R/ absolute configuration at the pyrolidine ring/. If R6is-OR10or-NHCOR10and n = 2, the preferred CIS-epimer //2R, 5R/ absolute configuration in piperidinium ring/.

If there are no other indications, alkyl and alkeneamine groups specified here, as well as alkyl fragments of the other groups listed here /for example, CNS/, can be linear or branched, and may be cyclic /for example, cyclopropyl, cyclopentyl or cyclohexyl/ or can be linear or branched and contain cyclic fragments.

Preferred compounds of the invention are the compounds of formula I in which R1is

< / BR>
or

< / BR>
n = 1;

A, B and C each represents carbon;

R6represents hydrogen or-OCH3;

R7represents hydrogen, C1-C3alkyl or-CH2CH2OCH3.

Of the above compounds, the most preferred R enantiomers with chiral carbon) are marked with an asterisk in formula I. among these compounds, particularly preferred CIS-epimer.

Most preferred is BR>
5-methoxycarbonyl-1-/3-/N-/2-methoxyethyl/pyrrolidin-2R - ylmethyl/indol-5-yl/-1H-benzimidazole;

5-cyano-1-/3-/4R-ethoxypyrrolidine-2R-ylmethyl/indol-5-yl/-1H - benzimidazole;

5-cyano-1-/3-/N-/2-methoxyethyl/-4R-ethoxypyrrolidine-2R - ylmethyl/indol-5-yl/-2H-benzimidazole;

5-hydroxymethyl-1-/3-/N-/2-methoxyethyl/pyrrolidin-2R-ylmethyl/- indol-5-yl/-1H-benzimidazole;

5-cyano-1-/3-/pyrrolidin-2R-ylmethyl/indol-5-yl/-1H-benzimidazole 1-/3-/N-cyclopropylmethyl/pyrrolidin-2R-ylmethyl/indol - 5-yl/-3H-imidazol[4,5-b] pyridine;

1-/3-/pyrrolidin-2R-ylmethyl/indol-5-yl/-3H-imidazo[4,5-b] pyridine 5-cyano-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5 - yl/-1H-benzimidazole;

5-cyano-1-/3-/N-cyclopropylmethyl/pyrrolidin-2R-ylmethyl/ indol-5-yl/-1H-benzimidazole;

1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-1H - benzimidazole; 5-methyl-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/- 1H-benzimidazole;

1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-3H-imidazo- [4,5-b]pyridine;

6-methoxy-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-3H - imidazo[4,5-b]pyridine;

1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-5-trifluoromethyl - 1H-benzimidazole;

1-/3-/2-N,N-dimethylaminoethyl/indol-5-yl/-3H-imidazo[4,5-b]- pyridine;

1-/3-/2-amino-ethyl/indol-5-yl/-3H-imidazo[4,5-b]pyridine;

1-/3-/N-methylpyrrolidine-2R-Gasol;

1-/3-/piperid-4-yl/indol-5-yl/-3H-imidazo[4,5-b]pyridine;

1-/3-/N-methylpyrrolidine-3-yl/indol-5-yl/-3H-imidazo [4,5-b]-pyridine;

5-chloro-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-1H - benzimidazole;

6-chloro-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-1H - benzimidazole;

7-chloro-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/- 1H-benzimidazole;

5-aminomethyl-1-/3-/N-/2-methoxyethyl/pyrrolidin-2R-ylmethyl/- indol-5-yl/-1H-benzimidazole;

5-acetamidomethyl-1-/3-/N-/2-methoxyethyl/pyrrolidin-2R - ylmethyl/indol-5-yl/-1H-benzimidazole;

5-cyano-1-/3-/piperid-4-yl/indol-5-yl/-1H-benzimidazole;

5-cyano-1-/3-/1,2,5,6-tetrahydropyridine-4-yl/indol-5-yl/-1H - benzimidazole;

N-phenyl-N'-/3-/N-/2-methoxyethyl/pyrrolidin-2R-ylmethyl/indol - 5-yl/-1H-benzo[b]imidazolidinedione;

5-cyano-1-/3-/N-methylpyrrolidine-3-yl/indol-5-yl/-1H - benzimidazole; 5-benzoylamino-1-/3-/N-/2-methoxyethyl/ pyrrolidin-2R-ylmethyl/indol-5-yl/-1H-benzimidazole;

5-aminomethyl-1-/3-N-methylpyrrolidine-2R-ylmethyl/indol - 5-yl/-1H-benzimidazole;

5-cyano-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-1H - pyrido[4,5-b] imidazole; and

4-methyl-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-1H - pyrido[4,5-b] imidazole.

The present invent relates also to the compound of the formula

< / BR>
where R12UB>2
, R3, R4and R5each independently represents hydrogen, C1-C6alkyl, aryl, C1-C3alkylaryl, halogen (for example, fluorine, chlorine, bromine or iodine/, cyano, nitro, -/CH2/mNR14R15, -/CH2/mOR9, -SR9, -SO2NR14R15, -/CH2/mNR14SO2R15,

-/CH2/mNR14CO2R9, -/CH2/mNR14R15or-CO2R9;

R2and R3, R3and R4or R4and R5taken together, form a five-semiline alkyl ring,

six-membered aryl ring, a five-semiline heteroalkyl ring containing 1 heteroatom selected from N, O or S, or a five or six-membered heteroaryl ring containing 1 or 2 heteroatoms selected from N, O or S;

R6represents hydrogen, -OR10or-NHCOR10; R7, R14and R15each independent represents hydrogen, C1-C6alkyl, -/CH2/xOR11C1-C3alkylaryl or aryl;

R14and R15taken together, may form a three to six-membered ring;

R9represents hydrogen, C1-C6alkyl, C1-C3alkylaryl or as the UB> represents hydrogen, C1-C6alkyl or C1-C3alkylaryl;

R13is-COR16, -CO2R16or-CH2Ph;

R16represents C1-C6alkyl, C1-C3alkylaryl or aryl;

m = 0, 1, 2 or 3;

x represents 2 or 3;

the dotted line represents an optional double bond; above aryl groups and aryl fragments above alcylaryl groups are independently phenyl, and substituted phenyl, and specified substituted phenyl may be substituted one to three C1-C4by alkyl, halogen (for example, fluorine, chlorine, bromine or iodine/, hydroxy, cyano, carboxamido, nitro and C1-C4alkoxy.

These compounds can be used as an intermediate in the formation of compounds of formula I.

The present invention relates also to pharmaceutical compositions for the treatment of conditions such as hypertension, depression, anxiety, disturbance of appetite, obesity, substance abuse, covering headaches, migraine, pain and chronic proximally hemicrania and headache associated with vascular disorders, containing such amount of the compounds of formula I or its farmerfriendly media.

The present invention relates also to a method of treatment of conditions such as hypertension, depression, anxiety, appetite disorder, obesity, substance abuse, covering headaches, migraine, pain and chronic proximally hemicrania and headache associated with vascular disorders, which includes an introduction to the mammal /for example the/ required for such treatment amount of compound of formula I, or its pharmaceutically acceptable salt, is effective in treating such condition.

The present invention relates also to a method of treatment of disorders caused by the deficiency of serotonergic neurotransmission /for example, depression, anxiety, disturbance of appetite, obesity, substance abuse, covering headaches, migraines, pain and chronic proximale of hemicrania and headache associated with vascular disorders/, including the introduction of a mammal (for example, the person in need of such treatment, such amount of the compounds of formula 1 or its pharmaceutically acceptable salt which is effective in the treatment of this condition.

The compounds of formula I can be obtained in accordance with the following reaction scheme (see conc>is indicated for the formula I of the signs, with the compound of formula V, where a, b, C, D, R2, R3, R4and R5are indicated for the formula I values, and where Z represents a suitable tsepliaeva group, such as F, Cl, Br, J, -SCH3, -SO2CH3, -SO2CH3, -SPh, - or-SO2Ph /Ph = phenyl, acid, neutral or alkaline conditions in an inert solvent. Preferred alkaline conditions. Suitable bases include sodium carbonate, sodium carbonate, trialkylamine /including, for example, triethylamine, sodium and sodium hydride. The preferred base is triethylamine. Suitable solvents include C1-C4alcohols, dioxane, diethyl ether, tetrahydrofuran, acetonitrile, N,N-dimethylformamide and N-methyl - pyrrolidin. The preferred solvent is ethanol. The reaction is usually conducted at temperatures from about 25oC to about 154oC, preferably from about 70oC to about 80oC.

The compounds of formula II can be obtained by recovery of the compounds of formula III, where A, B, C, D, R1, R2, R3, R4and R5are indicated for the formula I values, in an inert solvent. Such recovery can carry out is use transition metals, used as the hydrogen source. Suitable transition metals include palladium on charcoal, palladium hydroxide on coal and platinum oxide. Preferred palladium on coal. Suitable sources of hydrogen include hydrogen gas, ammonothermal and formic acid. As a source of hydrogen, it is preferable to use hydrogen gas at a pressure of from about 1 to about 3 atmospheres. The preferred pressure is the pressure of hydrogen gas in three atmospheres. Suitable solvents include C1-C4alcohols, acetonitrile, N,N-dimethylformamide and N-methylpyrrolidone. The preferred solvent is ethanol. Other metal reducing agents include FeSO4, Zn /metal/ aqueous hydrochloric acid, and Sn /metal/ aqueous hydrochloric acid. Of these groups preferred FeSO4. Suitable solvents include aqueous ammonium hydroxide /in a mixture of ethanol and concentrated aqueous hydrochloric acid. The preferred solvent is aqueous ammonium hydroxide /in a mixture of ethanol/. All these reduction reactions are typically conducted at temperatures from about 25oC to about 100oC, preferably from about 25oC to obnovleniya, without additional purification.

The compounds of formula I get in the reaction of compound (II), where A, B, C, D, R1, R2, R3, R4and R5are specified for formula I, with the synthon of formic acid in a neutral or acidic conditions in an inert solvent. Suitable synthons of formic acid include dimethylformamidine, triethylorthoformate, triethylorthoformate, ethoxymethylenemalononitrile and diethylethylenediamine. The preferred formic acid synthon is ethoxymethylenemalononitrile. For ethoxymethylenemalononitrile preferable to use neutral terms. Suitable acid catalysts which can be used with the above formic acid synthons include para-toluensulfonate, hydrochloric acid, formic acid or acetic acid. Suitable solvents include C1-C4alcohols) dioxane, diethyl ether, tetrahydrofuran, acetonitrile, N,N-dimethylformamide and N-methylpyrrolidone. The preferred solvent is 2-propanol. The reaction is usually conducted at temperatures from about 25oC to about 154oC, preferably at a temperature of from about 75oC to about 85oC.

The compounds of formula VIII can be obtained by the interaction of the compounds of formula VII, where R12has the formula IV, with a compound of formula V, where A, B, C, D, R2R3, R4and R5are indicated for the formula I of the signs and where ZG is such a suitable tsepliaeva group, such as F, Cl, Br, J, -SCH3, -SO2CH3, -SPh-or-SO2Ph, acid neutral go alkaline conditions in an inert solvent. Preferred alkaline conditions. Suitable bases include sodium bicarbonate, sodium carbonate, trialkylamine /for example, triethylamine, sodium and sodium hydride. The preferred base is triethylamine. Suitable solvents include C1-C1alcohols, dioxane, diethyl ether, tetrahydrofuran, acetonitrile, N,N-dimethylformamide and N-methylmorpholin. The preferred solvent is ethanol. The reaction is usually conducted at temperatures from about 26 to about 154oC, preferably from about 70oC to about 80oC.

The compounds of formula IX can be obtained by recovery of the compounds of formula VIII, where A, B, C, D, R1, R2, R3, R4and R5have the above for formula IV values, in an inert dissolve ivalsa agents. If you restore using the transition metal used as the hydrogen source. Suitable transition metals include platinum on charcoal, palladium hydroxide on coal and platinum oxide. Preferred palladium on coal. Suitable sources of hydrogen include hydrogen gas, ammonothermal and formic acid. As a source of hydrogen using gaseous hydrogen under a pressure of from about one to three atmospheres. The preferred pressure of hydrogen gas is the pressure of three atmospheres. Suitable solvents include C1-C4alcohols, acetonitrile, N,N-dimethylformamide and N-methylpyrrolidone. The preferred solvent is ethanol. Other metal reducing agents include FeSO4, Zn /metal/ aqueous hydrochloric acid, and Sn /metal/ aqueous hydrochloric acid. Preferred of these groups is FeSO4. Suitable solvents include aqueous ammonium hydroxide / in a mixture of ethanol/ water and concentrated hydrochloric acid. Preferred aqueous ammonium hydroxide /in a mixture of ethanol/. All of the above reactions recovery is usually carried out at a temperature from about 25oC to about 100oC, preferably from weakly recovery without additional purification.

The compounds of formula IV is obtained for the reaction of compounds of formula IX, where A, B, C, D, R2, R3, R4, R5and R12are specified in the formula IV, with the synthon of formic acid in a neutral or acidic conditions in an inert solvent. Suitable synthons of formic acid include dimethylformamidine, trimethylgermyl, triethylorthoformate, ethoxymethylenemalononitrile and diethylethylenediamine. The preferred formic acid synthon is tocommemorate. Although the preferred neutral conditions suitable acid catalysts include paratoluenesulfonyl, hydrochloric acid, formic acid or acetic acid. Suitable solvents include C1-C4alcohols, dioxane, diethyl ether, tetrahydrofuran, acetonitrile, N,N-dimethylformamide and N-methylpyrrolidone. 2-propanol is the preferred solvent. The reaction is usually conducted at temperatures from about 25oC to about 154oC, preferably at a temperature of from about 75oC to about 85oC.

The compounds of formula IA, where R7represents hydrogen, can be obtained by removing the protection of the basic nitrogen in the compounds of formula IV, where B,oritel. The nature of such removal of the protective groups, depends on the nature of R13. If R13represents-CH2Ph or-CO2CH2Ph, such removal can be accomplished by catalytic hydrogenation using a hydrogen source and a catalyst is a transition metal in an inert solvent. Suitable transition metals include palladium on charcoal, palladium hydroxide on coal and platinum oxide. Preferred palladium on coal. Suitable sources of hydrogen include hydrogen gas, ammonothermal and formic acid. The preferred hydrogen source is gaseous hydrogen under a pressure of from one to about three atmospheres, preferably a pressure of about three atmospheres. Suitable solvents include C1-C4alcohols, acetonitrile, N,N-dimethylformamide and N-methylpyrrolidone. The preferred solvent is ethanol. The reaction is usually conducted at temperatures from about 25oC to about 100oC, preferably from about 25oC to about 50oC. If R13is-COR16or-CO2R16where R16has the formula IV values, remove protection, you can make alkaline or acid hydrolysis. Suitable bases vkluci and sulfuric acid. Suitable solvents include water and C1-C3the alcohols. The reaction is usually conducted at temperatures from about 25oC to about 100oC, preferably from about 70oC to about 80oC.

The compounds of formula IB, where R7is not hydrogen, can be obtained by alkylation of compounds of formula IA, where R7represents hydrogen, and A, B, C, D, R1, R2, R3, R4and R5are indicated for the formula I, the values alkylating agent of formula R7-G, where G is a suitable tsepliaeva group, and a base in an inert solvent. Suitable alkylating agents include the halides /chlorides, bromides, or iodides/ alkylsulfate, alkylsilane, alkylacrylate, ,- unsaturated ketones, a ,- unsaturated esters, a ,- unsaturated aldehydes, unsaturated amides and unsaturated NITRILES. Preferred alkylhalides /iodides/. Suitable bases include sodium bicarbonate, sodium carbonate, trialkylamine /for example, triethylamine, sodium and sodium hydride. The preferred base is triethylamine. Suitable solvents include methylene chloride, chloroform, carbon tetrachloride, acetonitrile, tetrahydrofuran, diethyl ether, dioxane, N, ut at a temperature of from about 0oC to about 150oC, preferably from about 25oC to about 65oC.

The compounds of formula I in which R3represents-CH3NH2can be obtained by restoring the compound of formula I, where R3represents-CN, in an inert solvent. Suitable conditions for recovery include sociallyengaged and Raney Nickel with hydrogen. Preferred reducing conditions are Raney Nickel with hydrogen, preferably at a pressure of three atmospheres of hydrogen. Suitable inert solvents include diethyl ether, tetrahydrofuran, C1-C3alcohols and N,N-dimethylformamide. The preferred solvent is ethanol. The reaction is conducted at temperatures from about 0oC to about 100oC, preferably about 25oC.

The compounds of formula I in which R3represents-Ch2NH/C=O/R9and R9has the values specified for formula I, can be obtained by acylation of compounds of formula I, where R3represents-CH2NH2with an active derivative of ester of carboxylic acid of the formula R9CO2H, where R9has the previously indicated meanings, in an inert solvent, usually in prisutstvie-nitrophenolate esters. Preferred active ester derivatives are the acid chlorides. Suitable bases include trialkylamines, sodium carbonate and sodium bicarbonate. The preferred base is triethylamine. Suitable inert solvents include diethyl ether, tetrahydrofuran, 1,4-dioxane, methylene chloride, 1,2-dichloroethane, C1-C3alcohols and N,N-dimethylformamide. The preferred inert solvent is ethanol. The reaction is conducted at temperatures from about 0oC to about 100oC, preferably at a temperature of about 25oC.

The compounds of formula I in which R3represents-CH2NH/C=O/OTHER9and R9is indicated for the formula I, the values can be obtained by the interaction of the compounds of formula I, where R3represents-CH2NH2with an isocyanate of the formula O= C=NR9where R9has the previously indicated meanings, in an inert solvent, usually in the presence of a base. Suitable bases include trialkylamines, sodium carbonate and sodium bicarbonate. The preferred base is triethylamine. Suitable inert solvents include diethyl ether, tetrahydrofuran, 1,4-dioxane, methylene chloride, 1,2-dichloroethane, C1-C at a temperature of from about 0oC to about 100oC, preferably about 25oC.

The compounds of formula V are either commercially available, or you can get them known in the art methods.

The compounds of formula VI and VII can be obtained in accordance with the following reaction scheme (see below).

The compounds of formula XI, where R18represents-N/R20/2, -NHCOR20or 2,5-dimethyl-1H-pyrrole, and R20represents benzyl or substituted benzyl, produced by alkylation or acylation of compounds of formula X, where R17represents-NH2, benzyl or substituted by benzylmalonate /preferably, benzylbromide/, benzoyl or substituted by benzoylchloride /preferably a benzoyl chloride/ in the presence of a base in an inert solvent, or by condensation with 1,4-dicarbonyl compounds in dehydrating conditions in an inert solvent. For the reaction of alkylation of suitable bases include sodium bicarbonate, sodium carbonate, sodium hydride and trialkylamine. The preferred base is triethylamine. Suitable solvents include dimethylformamide, ethers, /including tetrahydrofuran/, and C1-C3the alcohols. Preferred is Colo 100oC, preferably at a temperature of about 25oC. For dehydrative condensation preferred 1,4-dicarbonyl compound is acetonylacetone. Suitable solvents include benzene, toluene and xylenes. The preferred solvent is toluene. The dehydration can be carried out using molecular sieves, drying agents or trap Dean-stark. The preferred trap Dean-stark. The reaction is usually conducted at temperatures from about 70oC to about 150oC, preferably at a temperature of from about 70oC to about 80oC.

The compounds of formula XII, where R19is:

< / BR>
or

< / BR>
R6and R7are indicated for the formula I value, and R13has the formula IV values can be obtained by the interaction of the compounds of formula XI, where R18represents-N/R20/2, -N/R20/2, -NHCOR20or 2,5-dimethyl-1H-pyrrole, and R20represents benzyl or substituted benzyl, with a suitable electrophilic compound, acid, alkaline or neutral conditions. Suitable electrophilic compounds include N-protected acid chlorides Proline, N-protected-4-piperidone, oxalicacid or maleimid the Oia with a secondary amine of the formula HNR7R8where R7and R8are indicated for the formula I signs. Suitable acids include mineral acids, acetic acid or formic acid. Suitable bases include Grignard reagents, including etimani-bromide, primary, secondary or tertiary amines, metallic sodium or potassium, or sodium hydride. Suitable solvents include ethers, /including tetrahydrofuran and diethyl ether, benzene, toluene, acetic acid, formic acid or C1-C4the alcohols. The reaction is usually conducted at temperatures from about 0oC to 150oC, preferably in the range of from about 0oC to about 120oC. for example, if the electrophilic compound is an N-protected Proline acid chloride, the preferred solvent is benzene, the reaction preferably leads in basic conditions using ethylmagnesium as the preferred base, and the reaction is conducted at a temperature of, preferably, about 0oC; in the case of electrophilic compound is N-protected-4-piperidone, the preferred solvent is methanol, the reaction of lead, preferably in basic conditions using sodium methoxide as if the electrophilic compound is oxalicacid, the preferred solvent is ether, the reaction is preferably carried out in basic conditions using HNR7R8as the preferred base, and the reaction is carried out at a temperature, preferably about 0oC, and in that case, if preferred electrophilic compound is maleimid, the preferred solvent is acetic acid, the reaction, preferably, lead to acidic conditions using acetic acid as the preferred acid, and the reaction is conducted at a temperature of about 101oC.

The compounds of formula XII, where R1is indicated for the formula I, value, and formula XIV, where R12have the above for formula IV values can be obtained due to the recovery of the compounds of formula XII, where R19is:

< / BR>
< / BR>
R6and R7are indicated for the formula I, the values of R13has the formula IV values, a R18has the formula XI values, in an inert solvent. Suitable reducing agents include sociallyengaged, litebrite and DIBORANE. Sociallyengaged preferred to obtain the compounds of formula XIII. Litebrite preferred for receiving the series of esters. Tetrahydrofuran is the preferred solvent. The reaction is usually conducted at temperatures from about 25oC to about 100oC, preferably at a temperature of about 65oC.

The compounds of formula VII, where R12has the formula IV values can be obtained by removing protection from C5-indole nitrogen of compounds of formula XIV, where R12has the formula IV values, a R18has the formula XI values, using as catalyst a transition metal and a source of hydrogen, or polyhydroxylated hydroxyamine. Suitable solvents include C1-C4alcohols, ethyl acetate, acetone and dimethylformamide. The preferred solvent is ethanol. Suitable catalysts are transition metals include palladium on charcoal, palladium hydroxide on charcoal, and platinum oxide. The preferred catalyst is palladium hydroxide on coal. Suitable sources of hydrogen include hydrogen gas, ammonothermal and formic acid. Preferred hydrogen gas, typically at a pressure of from about 1 to about 3 atmospheres, preferably at a pressure of 3 atmospheres. The reaction is usually conducted at temperatures from about 25oC to about 100oC to about 80oC.

The compounds of formula VI can be obtained by removing protection from C5-indole nitrogen of compounds of formula XIII, where R1is indicated for the formula I value, and R18has the formula XI values using the catalyst is a transition metal and a source of hydrogen or polyhydroxylated hydroxylamine. Suitable solvents include C1-C4alcohols, ethyl acetate, acetone and dimethylformamide. The preferred solvent is ethanol. Suitable catalysts are transition metals include palladium on charcoal, palladium hydroxide on coal and platinum oxide. The preferred catalyst is palladium hydroxide on coal. Suitable sources of hydrogen include hydrogen gas, ammonothermal and formic acid. Preferred hydrogen gas, typically at a pressure of from about 1 to about 3 atmospheres, preferably at a pressure of 3 atmospheres. The reaction is usually conducted at temperatures from about 25oC to about 100oC, preferably about 40oC. If the removal of protection of the indole nitrogen use polyhydroxylated hydrox the RA from the 70oC to about 80oC.

The compounds of formula X, where R17represents-NH2or NO2either commercially available, or you can get them known in the art methods.

The compounds of formula I, basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable /practice/ first allocate the compound of formula I from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert the compound in free base by treatment with an alkaline reagent, and then turn it a loose basis in pharmaceutically acceptable salt accession acid. Salt accession acids the major compounds of the present invention can easily be obtained by processing the primary connection is almost equivalent to the number of selected organic or mineral acid in an aqueous solvent or in a suitable organic solvent, such as methanol or ethanol. After careful evaporation of the solvent receive the target solid salt.

Acid to the present invention, are those acids which form non-toxic salts accession acids, i.e. salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saharat, benzoate, methanesulfonate, pamoat /ie 1,1'-methylene-bis-/2 hydroxy-3 - aftout//.

The compounds of formula I, which are also inherently acidic, for example, those in which R2contains carboxylate, can form basic salts with various pharmacologically acceptable cations. Examples of such salts include salts of alkali metals or alkaline earth metals, and, in particular, salts of nutria and potassium. These salts get in the usual ways. Chemical bases which are used as reagents for producing pharmaceutically acceptable basic salts of the present invention are those bases which form non-toxic basic salts described acidic compounds of formula I. Such non-toxic basic salts include salts derived from such pharmacologically acceptable cat is e connection aqueous solution, containing the target pharmacologically acceptable cations, and then viparita the resulting solution to dryness, preferably under reduced pressure. Alternatively, you can get them, shifting slightly alkaline solutions of the acidic compounds and alkoxides slot alkali metals together, and then viparita the resulting solution to dryness specified earlier by the way. In any case, the use, preferably, stoichiometric amounts of reactants in order to ensure the completeness of the reaction with the maximum yield of the desired final product.

The compounds of formula I and their pharmaceutically acceptable salts /hereinafter referred to as the active compounds of the invention/ have psychotherapeutic activities and are strong agonists serotonin /5-HT1/ and agonists and antagonists of benzodiazepines and can be used in the treatment of depression, anxiety, disturbances of appetite, obesity, substance abuse, covering headaches, migraines, chronic proximale of hemicrania and headache associated with vascular disorders, pain, and other disorders associated with deficiency of serotonergic neurotransmission. These compounds can also be used as the center of enemy as caused agents by testing the extent to which they imitate sumatriptan when Contracting isolated from dogs strips of the subcutaneous veins of the legs /P. P. A. Humphrey et al., Br. J. Pharmacol., 94, 1128 /1988//. This effect can be blocked by methiothepin known antagonist of serotonin. It is known that sumatriptan can be used in the treatment of migraines and it leads to a selective increase resistance carotid vessels have shot dogs. It was suggested /W. Fenwick et al., Br. J. Pharmacol., 96, 83 /1989// that this is the basis of its effectiveness.

Active compounds of the present invention can also be evaluated by the reaction extravasation of plasma protein inside the brain of Guinea pigs, followed by the electrical stimulation of the trigeminal ganglion by way Markowitz et al. , J. Neuro Sci., 7/12/, 4129-4136 /1967/. In this analysis determines the degree of imitation sumatriptan both from the point of view of strength and efficiency.

The activity of the agonist of serotonin 5-HTIAdetermine the in vitro receptor binding analysis as described for 5-HTIAreceptor, using as a source of receptors in the cerebral cortex of rats and /3H/-8-IT-D as radioligand /D. Hoyer et al., Eur. J. Pharm., vol. 118, 13/1985// and as described for 5-HT1Dreceptor, COI is eroutka, J. Neuroscience, vol. 7, 894 /1987//. The affinity for benzodiazepine receptors determined in vitro in the receptor binding analysis, using as a source of receptors in the cerebellum of Guinea pigs and3H flunitrazepam as radioligand /P. Supavilai and M. Karobath Eur., J. Pharm., vol. 70, 183 /1981//.

Compositions of the present invention can be obtained in the usual way, using one or more of pharmaceutically acceptable carriers. Thus, the active compounds of the present invention can be prepared for oral, buccal, through the nose, parenteral (for example, intravenous, intramuscular or subcutaneous/ or rectal administration, or in a form suitable for administration via inhalation or insufflation.

For oral administration the pharmaceutical compositions may take the form of, for example, tablets or capsules, obtained in the usual way, with such pharmaceutically acceptable excipients, as binding agents (for example, prezentatsionnym corn starch, polyvinylpyrrolidone or hypromellose/; fillers (for example, lactose, microcrystalline cellulose or calcium phosphate/; sliding /for example, magnesium stearate, talc or the surrounding agents /for example, nutritionrelated/. Tablets may be coated by methods known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for dissolving in water or other suitable solvent before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspendresume agents /for example, syrup, methyl cellulose or hydrogenated edible fats/; emulsifying agents such as lecithin or acacia/; nonaqueous media /for example, almond small, complex oily esters or ethyl alcohol/; and preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid/.

For buccal injection composition can be in the form of tablets or lozenges prepared in the usual way.

Active compounds of the present invention can be prepared for parenteral administration by injection, including using conventional catheterization or by injections. Compositions for injection may be presented in unit dozorova the future such forms, as suspensions, solutions or emulsions in oil or water carriers, and may contain such agents, compositions, as suspendida, stabilizing and/or dispersing agents. In another embodiment, the active ingredient may be in powder form for mixing with a suitable carrier, sterile water, not containing pyralene before applying.

Active compounds of the present invention can be prepared in the form of rectal compositions such as suppositories or held enemas, containing, for example, such conventional bases for suppositories as cocoa butter or other glycerides.

For insertion through the nose or by inhalation, the active compounds of the present invention is usually supplied in the form of a solution or suspension in containers under pressure, which the patient inhales or injects, or in the form of aerosol sprays in containers under pressure or spray, using a suitable propellant, e.g. DICHLORODIFLUOROMETHANE, trichloromethane, diclorhidrato ethane, carbon dioxide or other suitable gases. In the case of aerosols under pressure single dose can determine if to provide a valve for receiving a measured quantity. To the cartridges /manufactured for example, from gelatin) for use in inhalers or sprays may contain a mixture of powders of the compounds of the present invention and a suitable base, such as lactose or starch.

The proposed dose of the active compounds of the present invention for oral, parenteral or buccal introducing adults to treat conditions listed previously /for example, migraine headaches/ is from 0.1 to 200 mg of active ingredient in a unit dose, which you can enter, for example, from 1 to 4 times a day.

Aerosol composition for the treatment of the previously mentioned States /for example, migraines/ adult prepared so that each dimensional dose or "spray" of aerosol contains 20 μg to 1000 μg of the compound of the present invention. Full daily dose with an aerosol reaches values in the range from 100 μg to 10 mg you can Enter several times a day, for example, 2, 3, 4, or 8 times, using each time 1, 2 or 3 doses.

The following limitiruyuschie examples illustrate the formation of compounds of the present invention. Commercial reagents are used without additional purification. So melting is given without amendment. Data of NMR are given in parts per million /ml and the temperature, using the line of the sodium D /589 nm/. Unless otherwise noted, all mass spectra obtained under conditions of electron impact /E1, 70 eV/. Chromatographic data obtained through column chromatography with silica gel 32 - 63 microns and under nitrogen pressure /flash - chromatography/. Room temperature is 20 - 25oC.

Example 1

Synthesis of 1-indolyl-1H-benzimidazole and 1-indolyl-3H-imidazo- [4,5-b]pyridines

A mixture of 5-/2-nitroaniline/-1H-indole /2.00 mmole/ and Pd) coal /20 weight. %/ in absolute ethanol is shaken in hydrogen atmosphere /3 ATM/ at room temperature for 8 hours. The reaction mixture is filtered through CeliteRand the resulting filtrate is evaporated under reduced pressure to obtain crude 5-/2-aminoaniline/-1H-indole, which was used without further purification. In another embodiment, a mixture of 5-/2-nitroaniline/-1H-indole /2.00 mmole/ and FeSO4/5.5 g, 20 mmol, 10 EQ./ in a mixture of ammonium hydroxide/water/ethanol /1:5:3, respectively, the total volume of 27 ml/ was stirred at room temperature for 24 hours. The reaction mixture is filtered through Celite, and the ethanol is removed from the filtrate viparita it under reduced pressure. The remaining aqueous mixture is extracted with metilen pressure to obtain crude 5-/2-aminoaniline/-1H-indole, used directly.

Then 5-/2-aminoaniline/-1H-indole and either dimethylformamidine /10 ml/ triethylorthoformate /formic acid /5 ml/5 ml/ or ethoxymethylenemalononitrile /0,49 g, 4,01 mmole 2.0 EQ/. in 10 ml of propanol is heated at the boil under reflux in nitrogen atmosphere for 1 to 24 hours, depending on the substrate. If you use dimethylformamidine, the solvent of the reaction changed to toluene after 1 hour, add a catalytic amount of 5 mg /paratoluenesulfonyl acid and the reaction solution heated to boiling under reflux in nitrogen atmosphere for 12 - 24 hours depending on the substrate. Then the resulting reaction solution is evaporated under reduced pressure, and the residue is treated through column chromatography using silica gel and about 50 g/ and the appropriate solvent system to obtain the corresponding 1-indolyl-1H-benzimidazole or 1-indolyl-3H - imidazo[4,5-b]pyridine.

The same way we obtain the following compounds.

A. 5-cyano-1-/3-/N-/2-methoxyethyl/pyrrolidin-2R-ylmethyl/indol - 5-yl/-1H-benzimidazole

5-/4-cyano-2-nitrophenylamino/-3-/N-/2-methoxyethyl/pyrrolidin - 2H-ylmethyl/1H and animalanimal in propanol) and the reaction mixture for cyclization heated for 2 hours. After chromatographic processing 18: 1: 1 /ethyl acetate/methanol/triethylamine/ receive specified in the title link /83%/ in the form of a white foam: 13C NMR /CD3OD/ : : 146,4, 142,4, 137,3, 136,4, 128,2, 126,6, 126,3, 125,0, 124,1, 119,0; 117,7, 114,9, 113,3, 112,2, 112,1, 105,6, 70,9, 65,6, 57,5, 54,4, 53,6, 30,2, 29,1 21,4; ()25= +33o/methylene chloride, C = 1/. Mass spectrum high resolution: calculated for C24H25N5O 399,2054 found 399,2050.

Elemental analysis for C24H25N5O 1,2 H2O:

Calculated: C 68,45 H 6,56 N 16,63

Found: C 68,21 H 6,18 N 16,82

Century 5-methoxycarbonyl-1-/3-/N-/2-methoxyethyl/-pyrrolidin-2R - ylmethyl/indol-5-yl/-1H-benzimidazole

5-/4-methoxycarbonyl-2-nitrophenylamino/-3-(N-(2-methoxyethyl) pyrrolidin-2R-ylmethyl)-1H-indole use. Restore catalytic hydrogenation, cyclization reaction using ethoxymethylenemalononitrile in propanol) and the reaction mixture cyclization heated in turning 14 hours. After chromatographic processing 38:1:1/ethyl acetate/methanol/triethylamine get mentioned in the title link /75%/ foam pale yellow color.13C NMR /CD3OD/ : : 167,4, 145,5, 142,3, 137,7, 136,3, 128,1, 126,8, 124,9, 124,7, 124,6, 121,2, 117,7, 114,7, 113,0, 112,2, 110,5, 70,6, 65,8, 57,5, 54,4, 53,5, 51,2, 30,1, 28,9, 21,4; ()25= +63o/meilinger what about 432,2167.

C. 1-/3-/N-benzyloxycarbonyl-4R-ethoxypyrrolidine-2R - ylmethyl/-indol-5-yl/-5-cyano-1H-benzimidazole

Use 3-/N-benzyloxycarbonyl-4R-ethoxypyrrolidine-2R - ylmethyl/-5-/4-cyano-2-nitrophenylamino/-1H-indole. Restore FeSO47H2O, in the reaction of cyclization use ethoxymethylenemalononitrile in propanol, the reaction mixture cyclization heated for 2 hours. After chromatographic treatment using a gradient of ethyl acetate in hexano /1:2 to 1:1 to 1.0, respectively/ receive specified in the title connection /47%/ in the form of a pale yellow foam. Rf= 0.15 in a mixture of ethyl acetate/hexane /1:1/.

D. 5-cyano-1-/3-/N-tert.-butoxycarbonylamino-2R - ylmethyl/-indol-5-yl/-1H-benzimidazole

Use 3-/N-/tert. -butoxycarbonyl/pyrrolidin-2R ylmethyl/-5-/4-cyano-2-nitrophenylamino/-1H-indole. Restore catalytic hydrogenation, cyclization reaction using dimethylformamidine, the reaction mixture cyclization heated for 24 hours. After chromatographic processing 25% hexane in the air get mentioned in the title link /71% in the form of a white solid, melting with decomposition 215,0oC; ()25= + 71o/methylene chloride, C = 1/; SVR: calculated for CO20,7 C6H14/hexane/: 0,25 H2O:

Calculated: C 71,74 H 7,50 N 13,71

Found: C 72,10 H 7,10 N 13,60

That is, 1-/3-/N-cyclopropylmethanol-2R-ylmethyl/indol - 5-yl/-3H-imidazo[4,5-b]pyridine

Use 3-/N-cyclopropylmethanol-2R-ylmethyl/-5-/3 - nitrapyrin-2-ylamino/-1H-indole. Restore catalytic hydrogenation, cyclization reaction using triethylorthoformate /formic acid, the reaction mixture cyclization reaction heated for 2.6 hours. In the chromatographic processing a mixture of 9:1:0,1 /methylene chloride : methanol : hydroxylamine/ receive specified in the title compound as a pale yellow foam: Rf= 0.55 in a mixture of methylene chloride/methanol/hydroxylamine /9:1:0,1/; 1H NMR /CDCl3/ : 8,44 /DD, J = 1,5 and 4.7 Hz, 1H/, 8,39 /Shir. with, NH/, 8,33 /C, 1H/, 8,16 /DD, J = 1.5 and 8.1 Hz/1H/, 7,80 /d, J = 1.9 Hz, 1H/, 7,50-7,42 /m, 2N/, 7,30 /DD, J = 4.7 and 8.0 Hz, 1H/, 7,12 /d, J = 2.1 Hz, 1H/, 3,43-3,35 /m 1H/, 3,22-3,12 /m 1H/, 2,94 /DD, J = 6,1 and 12.3 Hz/, 1H/, 2,69-2,61 /m, 2N/, 2,22-2,16 /m 1H/, 1,98 /DD, J = 7,2 and 18.3 Hz, 1H/, 1,81-1,51 /3M, 6N/, 0,99-0,888 /m 1H/, 0,58-0,43 /m, 2N/;13C NMR /CDCl3/ : 147,8, 144,3, 135,7, 128,4, 128,2, 127,0, 123,9, 118,8, 118,6, 115,3, 114,9, 112,0, 64,8, 59,9, 54,9, 30,9, 30,3, 22,2, 15,1. 10,1.

F. 5-cyano-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-1H - benzimidazole

Using 5-/4-cyano-2-nitrophenylazo use ethoxymethylenemalononitrile in propanol, the reaction mixture cyclization reaction heated for 14 hours. In the chromatographic treatment with a mixture of ethyl acetate/methanol/triethylamine /18:1:1/ get mentioned in the title link /85%/ in the form of off-white foam:13C NMR /DMSO-d6/ : : 146,9. 143,1, 137,1, 135,6, 128,1, 126,5, 126,3, 125,4, 124,4, 124,9, 119,8, 117,6, 114,8, 113,1, 112,5, 112,1, 104,4, 66,1, 57,0, 40,5, 30,8, 29,1, 21,7.

Elemental analysis for C22H21N5:

Calculated: C 74,34, H 5,96 N 19,70

Found: C 74,18 H 5,61 N 19,84

The mass spectrum of high resolution FAB*designed 355,1999 found 355, 1889 ()25= +111o/methylene chloride, with = 1.

G. 1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-1H - benzimidazole

Use 3-/N-methylpyrrolidine-2R-ylmethyl/-5-/2 - nitrophenylamino/-1H-indole. Restore catalytic hydrogenation, cyclization reaction using triethylorthoformate/formic acid, the reaction mixture is heated for 12 hours. In the chromatographic treatment with a mixture of methylene chloride/methanol/ammonium hydroxide /9:1:0,1/ receive specified in the title link /43%/ in the form of a pale yellow foam:13C NMR /CDCl3/ : : 143,7, 143,2, 135,9, 134,9, 128,5, 128,0, 124,6, 123,5, 122,6, 120,2, 118,6, 115,1, 114,2, 112,4, 110,8, 66,7, 57,5, 40,9, 31,5, 29,9, 21,9 ()25= +59o/methylenchlorid.

*Hereinafter FAB reduction for fast atom bombardment

H. 4-methyl-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indole-5/Il/- 3H-imidazo[4,5-b]pyridine

Using 5-/4-methyl-3-nitrapyrin-2-ylamino/-3-/N - methylpyrrolidine-2R-ylmethyl/-1H-indole. Restore catalytic hydrogenation, cyclization reaction using triethylorthoformate/formic acid, the reaction mixture is heated for 12 hours. In the chromatographic treatment with a mixture of methylene chloride/methanol/ammonium hydroxide /12:1:0,04/ receive specified in the title link /29%/ in the form of a pale yellow foam:13C NMR /CDCl3/ : 147.2, 144,6, 143,3, 139,8, 135,9, 135,4, 128,2, 126,8, 124,2, 119,6, 118,6, 115,2, 114,1, 112,1, 66,5, 57,4, 40,8, 31,5, 29,8, 21,8, 16,4()25= 55o/methylene chloride, s = 1, 2/. The mass spectrum of high resolution FAB /C21H23N5H/ 346,2034 found 346,2039.

1. 1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-3H - imidazo[4,5-b]pyridine

Use 3-/N-methylpyrrolidine-2R-ylmethyl/-5-/3-nitrapyrin-2-ylamino/-1H-indole. Restore catalytic hydrogenation, cyclization reaction, a mixture of triethylorthoformate/ formic acid, the reaction mixture is heated for 1.5 hours. In the chromatographic processing the mixture methylthio the R /CDCl3/ 147,7, 144,8, 144,3, 135,8, 135,7, 128,3, 128,2, 127,0, 124,1, 118,8, 118,6, 115,3, 114,4, 112,1, 66,6, 57,5, 40,8, 31,4, 29,7, 21,8 ()25= +40o/methylene chloride, c = 1,8/. The mass spectrum of high resolution calculated for C20H21N5331,1799 found 331,1786.

J. 6-methoxy-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5 - yl/-3H-imidazo[4,5-b]pyridine

Using 5-/6-methoxy-3-nitrapyrin-2-ylamino/-3-N - methylpyrrolidine-2R-emetel/-1H-indole. Restore catalytic hydrogenation, the reaction mixture cyclization reaction is heated for 4 hours. After chromatographic purification of a mixture of methylene chloride/methanol/ammonium hydroxide /12:1 : 0,04/ get mentioned in the title of the link /38%/ in the form of a yellow-brown foam: Rf= 0,35 /mixture metavolcanic/methanol/ammonium hydroxide /6:1:0,1/;13C NMR /CDCl3/ 161,7, 144,3, 141,2, 135,4, 130,8, 130,4, 128,0, 127,5, 124,1, 117,9, 114,2, 111,9, 106,7, 66,8, 57,5, 53,7, 40,8, 31,4, 30,0, 21,8. The mass spectrum of high resolution calculated for C20H21N5: 361,1905. Found 361,1881.

K. 1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-5 - trifluoromethyl-1H-benzimidazole

Use 3-/N-methylpyrrolidine-2R-ylmethyl/-5-/4 - trifluoromethyl-2-nitrophenylamino/-1H-indole. Restore catalytic hydrogenation, cyclization reaction using dimethylformamid telengard/methanol/ammonium hydroxide /18:1:0,1/ receive specified in the title link /49%/ in the form of a yellow foam:13C NMR /CDCl3/ : 145,0, 143,3, 136,8, 135,8, 128,5, 127,7, 124,8, 124,5, 120,3, 118,2, 115,3, 114,5, 112,4, 111,1, 66,7, 57,5, 40,8, 31,4, 29,6, 21,9 ()25= +64o/methylene chloride, with a = 1/ a; Mass spectrum high resolution calculated for C22H21F3N4: 398,1720 found: 398,1643. Elemental analysis for C22H21F3N40,1 H2O:

Calculated: C 66,02 H 5,34 N 13,99

Found: C 65,97 H 5,27 N 13,61

Z 1-/3-/2-N,N-dimethylaminoethyl/indol-5-yl/-3H-imidazo[4,5 - b]-pyridine

Use 3-/2-N, N-dimethylaminoethyl/-5-/3-nitrapyrin-2 - ylamino/-1H-indole. Restore catalytic hydrogenation. In the reaction of cyclization use dimethylformamidine, the reaction mixture cyclization reaction heated for 2.5 hours. In the chromatographic treatment with a mixture of methylene chloride/methanol/ammonium hydroxide /9: 1:0,1/ receive specified in the title link /63%/ in the form of a white foam:

1H NMR /CDCl3/ : becomes 9.97 /Shir. with, NH/, 8,44 /DD, J = 1,4 and 4.7 Hz/ 1H/, 8,35 /C, 1H/, 8,15 /DD, J = 1.4 and 8.1 Hz, 1H/, 7,76 /Shir. with/, 1H/, 7,35-7,25 /m, 3H/, 6,98 /d, J = 2.0 Hz, 1H/, 2,95-1,88 /m, 2N/, 2,66-2,60 /m, 2N/, 2,31 /s, 6N/; 13C NMR /CDCl3/ : 146,6, 144,8, 144,4, 135,9, 135,7, 128,2, 127,9, 126,8, 123,8, 118,6, 115,0, 114,4, 112,2 60,0, 45,3; 23,5: FAB Mass spectrum of the low resolution /m/Z/, the relative intensity /306 ///MH+, 19/, 155/67/, 135/32/, 119/100/ 103/4�pyrrolidin-2R-ylmethyl/-5-/4-phenyl - nitrophenylamino/-1H-indole. Restore catalytic hydrogenation, cyclization reaction, a mixture of triethylorthoformate/formic acid, the reaction mixture is heated for 3 hours. After chromatographic treatment with a mixture of methylene chloride/methanol/hydroxylamine /12:1:0,44/ receive specified in the title link /75%/ in the form of a yellow-brown foam.

13C NMR /CDCl3/ : 143,8, 141,8, 136,3, 135,7, 134,3, 128,8, 128,2, 127,5, 126,8, 124,2, 123,2, 122,1, 120,7, 118,8, 118,7, 115,2, 114,7, 112,3, 110,8, 66,5, 57,5, 40,9, 31,5, 29,8, 21,9. The mass spectrum of the low resolution /m/z/, the relative intensity /407 //MH/+, 100/, 391/9/, 350/7/, 336/14/, 323/29/, 310/7/, 298/37/; FAB Mass spectrum of high resolution calculated for C27H26N4H 407,2238 Found 407,2198.

N. 6,7-dichloro-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/- 1H-benzimidazole

Use a 5/5,6-dichloro-2-nitrophenylamino/-3-/N - methylpyrrolidine-2R-ylmethyl/-1H-indole. Restore catalytic hydrogenation, cyclization reaction, a mixture of triethylorthoformate/formic acid, the reaction is carried out at heating for 2.5 hours. After chromatographic treatment with a mixture of methylene chloride/methanol/ammonium hydroxide /12: 1:0,04/ receive specified in the title link /27%/ in the form of off-white foam:

13C NMR /CDCl+, 1/, 314 /4/, 216/2/, 84/100/, Mass spectrum high resolution: calculated for C21H20Cl2N4398,1066 found 398,1063.

O. 1-/3-/N-tert. -butoxycarbonylamino-4-yl/indol-5-yl/-3H - imidazo[4,5-b]pyridine

Use 3-/N-tert.-butoxycarbonylamino-4-yl/-5-/3 - nitrapyrin-2-ylamino/-1H-indole. Restore catalytic hydrogenation, cyclization reaction using dimethylformamidine, the reaction mixture is heated for 12 hours. After chromatographic processing 5% methanol in ethyl acetate followed by recrystallization from methylene chloride receive specified in the title link /39%/ in the form of a white solid: so pl. 212-218oC; Rf= 0,60 /5% methanol in ethyl acetate, FAB mass spectrum of the low resolution /m/z, relative intensity /418 / /MH+, 94/, 362/100/, 318/65/, 261/38/, 235/35/,

Elemental analysis for C24H27N5O2:

Calculated: C EUR 69.04 H 6,52 N 16,77

Found: C 68,72 H 6,90 N 16,59

P. 1-/3-/N-methylpyrrolidine-3-yl/indol-5-yl/-3H-imidazo [4,5-b]pyridine

Use 3-/N-methylpyrrolidine-3-yl/-5-/3/nitrapyrin-2 - ylamino/-1H-indole. Restore catalytic hydrogenation. In the reaction of cyclization use dimetil is ESU ethyl acetate/methanol/triethylamine /9: 1: 1/ get mentioned in the title link /24%/ in the form of a white solid; so melting 110,0-112,0oC;

13C NMR /CDCl3/ : 147,7, 144,8, 144,3, 136,2, 135,7, 128,3, 127,3, 126,8, 122,4, 119,0, 118,7, 115,6, 112,4, 62,3, 56,2, 42,2, 34,9, 32,1.

The mass spectrum of high resolution calculated for C19H19N5317,1643 found 317, 1665. Elemental analysis for C19H19N50.5 C4H8O4/ethyl acetate/:

Calculated: C 68,08 H 6,53 N 18,90

Found: C 67,93 H 6,51 N 19,17

Q. 1-/3-/N-/2,2,2-trichlorocyanuric/pyrrolidin-2R - ylmethyl/-indol-5-yl/-3H-imidazo[4,5-b]pyridine

Using 5-/3-nitrapyrin-2-ylamino/-3-/N-/2,2,2 - trichlorocyanuric/pyrrolidin-2R-ylmethyl/-1H-indole. Restore catalytic hydrogenation, cyclization reaction, a mixture of triethylorthoformate/formic acid, the reaction mixture was heated for 3.5 hours. After chromatographic treatment with 10% methanol in methylene chloride receive specified in the title connection /17%/ in the form of a yellow-brown foam: Rf= 0,50 /5% methanol in methylene chloride/.

R. 5-chloro-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-1H - benzimidazole

Using 5-chloro or 4-chloro-2-nitrophenyl/amino-3/N-methyl - pyrrolidin-2R-ylmethyl/-1H-indole. Restore catalytic hydrogenation, cyclization reaction, a mixture of triethylorthoformate/ the methylene chloride/methanol/ammonium hydroxide /12: 1:0,4 / receive specified in the title link /34%/ in the form of an off-white solid: Rf= 0,35 /methylene chloride/methanol/hydroxylamine 9:1:0,1/. FAB mass spectrum of high resolution calculated for [C21H21ClN4H]+365,1535 Found 365,1535 ()25= +61omethylene chloride, C = 0,29/.

S. 6-Chloro-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-1H - benzimidazole

Using 5-/5-chloro-2-nitrophenyl/amino-3-/N-methylpyrrolidine - 2R-ylmethyl/-1H-indole. Restore catalytic hydrogenation, cyclization reaction, a mixture of triethylorthoformate/formic acid, the reaction mixture is heated for 4.5 hours. After chromatographic treatment with a mixture of methylene chloride/methanol/ammonium hydroxide /12:1:0,4/ get mentioned in the title of the link /28%/ in the form of a pale yellow solid; Rf= 0,35 /methylene chloride/methanol/ammonium hydroxide 9: 1: 0,1/. FAB mass spectrum of high resolution calculated for [C21H21ClN4H]+365,1535 found 366,1513; ()25= +57o/methylene chloride, C = 0,27/.

T. 7-chloro-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-1H - benzoimidazol

Using 5-/6-chloro-2-nitrophenyl/amino-3-/N - methylpyrrolidine-2R-ylmethyl/-1H-indole. Restore catalytic hydrogenation. In the cyclization reaction, a mixture of triethylorthoformate/ Mouravi methylene chloride/methanol/ammonium hydroxide /12:1:0,4 / get mentioned in the title of the link /28%/ in the form of a light yellow solid: Rf= 0,35 /methylene chloride/methanol/ammonium hydroxide 9:1:0,1/; FAB mass spectrum of high resolution calculated for [C21H21ClN4H]+365,1535 found 365,1504 ()25= +45o/methylene chloride, C = 1,36/.

U. 5-cyano-1-/3-/N-tert.-butoxycarbonylamino-4-yl/-indol - 5-yl/-1H-benzimidazole

Using 5-/4-cyano-2-nitrophenyl/amino-3-/N-tert - butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-yl/-1H-indole. Restore catalytic hydrogenation. In the reaction of cyclization use ethoxymethylenemalononitrile, the reaction mixture is heated for 48 hours. In the chromatographic treatment with 10% ethyl acetate in methylene chloride receive specified in the title connection /10%/ in the form of a brown foam: Rf= 0,2 /10% ethyl acetate in methylene chloride/. The mass spectrum of high resolution, designed for a /C26H27N5O2/ 441,2167 Found 441,2169.

Y. 5-cyano-1-/3-/N-tert. -butoxycarbonyl-1,2,5,6 - tetrahydropyridine-4-yl/indol-5-yl/-1H-benzimidazole

Using 5-/4-cyano-2-nitrophenyl/amino-3-/N-tert. - butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-yl/-1H-indole. Restore water FeSO4in ethanol. In the reaction of cyclization use ethoxymethylenemalononitrile, the reaction mixture is heated for 56 hours. Obedinenie /10%/ in the form of a brown foam; Rf= 0.5 in 5% acetone in methylene chloride; Mass spectrum high resolution for C26H26N5O2Designed 439,2011 found 439,1999.

W. 5-cyano-1-/3-/N-methylpyrrolidine-3-yl/indol-5-yl/-1H - benzimidazole

Using 5-/4-cyano-2-nitrophenyl/amino-3-/N - methylpyrrolidine-3-yl/indol-5-yl/-1H-benzimidazole. Restore catalytic hydrogenation. In the reaction of cyclization use triethylorthoformate/formic acid, the reaction mixture is heated for 2 hours. In the chromatographic treatment with a mixture of methylene chloride/methanol/ hydroxylamine 9:1;0,5 /get mentioned in the title of the link /22%/ in the form of light yellow solids; Rf= 0,35 /methylene chloride/methanol/ammonium hydroxide 9:1:0,1/;13C NMR /CDCl3/ 145,7, 143,3, 137,5, 136,5, 127,5, 126,8, 126,7, 125,4, 123,0, 120,3, 119,9, 118,5, 115,8 112,7, 111,9, 105,7, 62,8, 56,3, 42,3, 35,0, 32,3. FAB mass spectrum of the low resolution /m/z, relative intensity /342/MH+/.

X. 5-cyano-1-/3-/-N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/- 1H-pyrido[4,5-b]imidazol

Using 5-/5-cyano-3-nitrapyrin-2-ID/amino-3-/N - methylpyrrolidine-2R-ylmethyl/-1H-indole. Restore catalytic hydrogenation. In the reaction of cyclization use triethylorthoformate/formic acid, reacts anal/ammonium hydroxide /12:1:0,4/ receive specified in the title link /50%/ in the form of a light yellow solid: Rf= 0,2 /methylene chloride/methanol/hydroxylamine 12:1:0,4/:

13C NMR /CDCl3/ : 149,3, 147,7, 147,0, 136,0, 134,8, 131,9, 128,4, 125,8, 124,4, 118,4, 117,7, 115,3, 114,6, 112,3, 104,1, 66,6, 57,5, 40,8, 31,4, 29,7, 21,9; the mass spectrum of high resolution calculated for C21H20N6356,1752 found 356,1784; ()25= +78o/methylene chloride, C = 0,48/. Elemental analysis for C21H20N60.5 H2O

Calculated: C 69,07 H 5,80 N 23,01

Found: C 69,11 of 5.82 H N 22,62

Y. 5-methyl-1-/3-/N-methylpyrrolidine-2R-ylmethyl/indol-5-yl/-1H - benzimidazole Using 5-/4-methyl-2-nitrophenyl/amino-3-/N-methylpyrrolidine-2R-ylmethyl/-1H-indole. Restore catalytic hydrogenation. In the reaction of cyclization use ethoxymethylenemalononitrile, the reaction mixture is heated for 24 hours. In the chromatographic treatment with a mixture of ethyl acetate/methanol/triethylamine /8: 1: 1/ get mentioned in the title of the link /21%/ in the form of a brown foam: Rf= 0,3 /ethyl acetate methanol/triethylamine 8:1:1/;

3C NMR /CDCl3/ : 143,1, 143,0, 136,1, 132,6, 132,4, 127,9, 127,6, 124,9, 124,8, 118,5, 117,8, 114,2, 112,4, 110,1, 67,3, 56,8, 39,4, 30,7, 28,3, 21,0, 20,1. The mass spectrum of the low resolution /m/z relative intensity /344 /M+, 38/, 334 /10/, 318 /100/, 289 /18/. The mass spectrum of high resolution calculated for C22Hperemeshivaemogo solution derived pyrrolidine /1.00 mmole/ triethylamine /0.126 g, 1.25 mmole/ or sodium carbonate /0,132 g, 1.25 mmole, 1.25 equiv./ either in anhydrous methylene chloride, anhydrous acetonitrile, dehydrated ethanol or ISO-propanol /10 ml at room temperature under nitrogen atmosphere was added dropwise alkylating agent /1.25 mmole, 1.25 equiv./. The resulting reaction solution was then stirred under nitrogen atmosphere at room temperature or heated at the boil under reflux for 1 to 20 hours, depending on the substrate. The reaction mixture is processed on a chromatographic column with silica gel and about 25 g/, elwira a mixture of methylene chloride : methanol : ammonium hydroxide /9:1:0.1 to/ to obtain the corresponding alkylated pyrrolidine. This way get:

A. 3-/N-cyclopropylmethanol-2R-ylmethyl/-5-/3 - nitrapyrin-2-yl-amino/-1H-indole

Use 3-/pyrrolidin-2R-ylmethyl/-5-/3-nitrapyrin-2 ylamino/-1H-indole and bromelicola as alkylating agent. As the base used triethylamine, the solvent is methylene chloride, the reaction solution is heated at the boil under reflux for 4 hours. In the chromatographic processing receive specified in the title link /34%/ as pany,9, 30,3, 22,2, and 10.0. FAB mass spectrum of the low resolution /m/z, relative intensity /392 /MH+, 33/, 374/3/, 307/3/, 267/7/, 220/7/, 154/10/, 124/100/; the mass spectrum of high resolution calculated for C22H25N5O2391,2011 found 391,1988.

Century 5-/2,5-dimethyl-1H-pyrrol-1-yl/-3-/N-/2-methoxyethyl/ pyrrolidin-2R-ylmethyl/-1H-indole

Using 5-/2,5-dimethyl-1H-pyrrol-1-yl/-3-/pyrrolidin-2R - ylmethyl/-1H-indole. As the alkylating agent used bromatology ether and sodium iodide. As the bases use sodium carbonate as solvent N, N-dimethylformamide, the reaction solution is heated at a temperature of 120oC for 2 hours. In the chromatographic processing receive specified in the title link /54%/ in the form of off-white foam: Rf= 0,75 in a mixture of methylene chloride/methanol/hydroxylamine /9:1:1/; the mass spectrum of the low resolution /m/z relative intensity/ 351/M+, 48/, 304/10/, 210/57/, 128/100/; the mass spectrum of high resolution calculated for C22H29N3O: 351,2313 found 351,2262.

C. 5-cyano-1-/3-/N-/2-methoxyethyl/-4R-ethoxypyrrolidine - 2R-ylmethyl/indol-5-yl/-1H-benzimidazole

Using 5-cyano-1-/3-(4R-ethoxypyrrolidine-2R-ylmethyl - indol-5-yl/-1H-benzimidazole. In kachestvenna sodium, and as solvent using N,N-dimethylformamide. The reaction solution is heated at 130oC for 2 hours. In the chromatographic processing receive specified in the title link /60%/ in the form of off-white foam: Rf= 0,60 /methylene chloride/methanol/ammonium hydroxide 9:1:1/;

13C NMR /CDCl3/ : 145,6, 143,3, 137,5, 135,8, 128,6, 127,2, 126,7, 125,6, 124,7, 119,8, 118,6, 115,5, 114,3, 112,5, 111,9, 105,8, 78,8, 71,6, 64,5, 60,0, 58,8, 56,5, 53,5, 37,9, 29,4; ()25= +61o/methanol, C = 0,53/. FAB Mass spectrum of high resolution, designed for a /C25H27N5O2H/ 430,2246 found 430,2222.

D. 5-cyano-1-/3-(N-cyclopropylmethyl)pyrrolidin-2R-ylmethyl/- indol-6-yl/-1H-benzimidazole

Using 5-cyano-1-/3-(pyrrolidin-2R-ylmethyl)indol-5-yl/- 1H-benzimidazole. As the alkylating agent used (methyl bromide)cyclopropane and iodide of sodium. As the base used sodium carbonate, the solvent is N,N-dimethylformamide, the reaction solution is heated to boiling under reflux for 2 hours. In the chromatographic processing receive specified in the title link /59%/ in the form of a pale yellow foam: Rf= 0,40 /methylene chloride/methanol/ammonium hydroxide /9:1:1/;

13C NMR /CDCl3/ : 146,4,ID, C = 0,5/; FAB mass spectrum of the low resolution /m/z, relative intensity /396 //MH+/, /100/, 309/21/, 273/9/; Field mass spectrum of high resolution calculated for [C25H25N5H] 396,2191 found 396,2191

Example 3

The General method of conversion of N-benzyloxycarbonylglycine in NH-pyrrolidine

A mixture of N-benzyloxycarbonylglycine /10.0 mmole/ and 20% palladium hydroxide on coal /1.0 g/ absolute ethanol /50 ml/ shaken in an atmosphere of nitrogen /3 ATM/ at room temperature in the course of time, depending on the substrate. The reaction mixture is filtered through Celite and the resulting filtrate is evaporated under reduced pressure. The remainder either used directly as the corresponding NH-pyrrolidine, or the residue is purified on a chromatographic column with silica gel and about 100 g/, elwira appropriate solvent system to obtain the target NH-pyrrolidine.

In this way we obtain the following connections:

A. 5-/2,5-dimethyl-1H-pyrrol-1-yl/-3- /pyrrolidin-2R-ylmethyl/-1H-indole

Using 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(N - benzyloxycarbonylamino-2R-ylmethyl)-1H-indole; the reaction time is 18 hours. The resulting filtrate is evaporated at lower and methylene chloride/methanol/ ammonium hydroxide /9:1:0,1/;

13C NMR /CDCl3/ 135,8, 130,6, 129,4, 128,5, 127,8, 127,0, 124,6, 122,0, 118,1, 112,7, 111,9, 105,2, 59,8, 45,7, 31,5, 30,6, 24,9, 23,3.

B. 5-cyano-1-/3-(4R-ethoxypyrrolidine-2R-ylmethyl)indol-5-yl /-1H-benzimidazole

Use 1-/3-(N-benzyloxycarbonyl-4R-ethoxypyrrolidine - 2R-ylmethyl)indol-5-yl/-5-cyano-1H-benzimidazole, and responses are within 24 hours. After chromatographic processing, elwira a mixture of methylene chloride/methanol/ammonium hydroxide /12: 1: 0,04/ receive specified in the title link /44%/ in the form of a pale yellow amorphous substance, Rf= 0,35 /methylene chloride/methanol/ammonium hydroxide 9:1:0,1/;

13C NMR /CDCl3/ 145,7, 143,3, 137,6, 136,1, 128,3, 127,0, 126,7, 125,4, 125,0, 119,8, 118,4, 115,3, 114,1, 112,6, 111,9, 105,7, 82,1, 59,1, 56,5, 52,4, 38,7, 31,6. The mass spectrum of high resolution designed for a /C22H21N5O H/ 372,1827 found 372,1825

Example 4

The General method of conversion of N-tert.-butoxycarbonylamino in NH-amine

To a stirred solution of N-tert.-butoxycarbonylamino /2.00 mmole/ in an appropriate anhydrous solvent /10 ml at 0oC was added dropwise a solution of hydrogen chloride in dioxane /4.0 M, 2 ml, 8.0 mmole, 4 equiv./. The resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 12 hours, the precipitated precipitated solid is t the following connections:

A. 5-cyano-1-/3-(pyrrolidin-2R-ylmethyl)indol-5-yl/-1H - benzimidazole

Using 5-cyano-1-/3-(N-tert. -butoxycarbonylamino - 2R-ylmethyl/indol-6-yl/-1H-benzimidazole, and the solvent used methylene chloride. After filtration receive specified in the title link /83%/ in the form of a solid white; So melting with decomposition 185oM is the mass spectrum of the low resolution /m/z relative intensity /341/M+, 4/, 339/60/, 272/73/, 70/100/; the mass spectrum of high resolution, designed for a /C21H19N5/ 341,1643 found 341,1649.

Century 1-/3-(piperid-4-yl)indol-8-yl/-3H-imidazo[4,5-b]pyridine

Use 1-/3-(N-tert.-butoxycarbonylamino-4-yl)indol - 5-yl/-3H-imidazo[4,5-b] pyridine, and the solvent used methylene chloride. After filtration receive specified in the title compound /100%/ in the form of a solid yellow color, So melting 260-268oC /with rapid evolution of gas/;

13C NMR /CD3OD/ 149,7, 145,6, 144,0, 138,5, 127,7, 126,0, 125,8, 125,6, 124,6, 123,9, 120,6, 119,7, 117,4, 113,7, 45,7, 32,6, 30,7; FAB mass spectrum /m/z, relative intensity /318 /M+, 22/, 277/12/, 261/4/, 235/5/, 185/100/.

C. 5-cyano-1-/3-(piperid-4-yl)indol-5-yl/-1H-benzimidazole

Using 5-cyano-1-/3-(N-tert.-butoxycarbonyl the training taught specified in the title link /64%/ in the form of a solid yellow; IR /KBr/ 2229 cm-1;13C NMR /CDOD/ : 137,4, 129,6, 126,6, 124,7, 123,6, 120,6, 119,2, 117,9, 116,4, 114,8, 112,8, 109,9, 44,6, 31,3, 29,4. Elemental analysis for C21H19N53HCl. 1,25 H2O. Calculated: C 53,29 H 5,22 N 14,80

Found: C 53,63 H 5,34 N 14,68

D. 5-cyano-1-/3-(1,2,5,6-tetrahydropyridine-4-yl)-indol-5-yl/-1H - benzimidazole

Using 5-cyano-1-/3-(N-tert.butoxycarbonyl-1,2,5,6 - tetrahydropyridine-4-yl)indol-5-yl/-1H-benzimidazole, and the solvent used methylene chloride. The result of the filter gain is specified in the title link /75%/ in the form of a solid yellow; So melting with decomposition 240oC; IR /KBr/ 2228 cm-1;13C NMR /CD3OD/ : 144,4, 137,9, 133,6, 131,1, 129,9, 126,0, 125,3, 125,2, 120,1, 118,4, 118,3, 117,6, 117,3, 116,1, 114,8, 113,2, 112,9, 110,4, 66,7, 42,0, 40,9.

Elemental analysis for C21H17N51,1 C4H8O2/dioxane/ 1,1 HCl:

Calculated: C 64,03 H 5,69 N 14,70

Found: C 64,20 H 5,54 N 14,47

Example 5

5-hydroxymethyl-1-/3-(N-(-methoxyethyl)pyrrolidin-2R-ylmethyl)- indol-5-yl/-1H-benzimidazole

To a stirred solution of sociallyengaged /of 0.081 g, 2.13 mmole, 3 EQ. / in anhydrous tetrahydrofuran /6 ml/ add a solution of 5-methoxycarbonyl-1-/3-(N-(2-methoxyethyl) pyrrolidin-2R - ylmethyl)indol-5-yl/-1H-benzimidazole /0.31 g, 0,72 MOV nitrogen atmosphere for 1 hour. Then add decahydrate sodium sulfate /5 g/ gently, then 0.1 ml of water and 10 ml of ethyl acetate. The resulting mixture was stirred at room temperature for 1 hour. The mixture is then filtered through Celite, and the filtrate is evaporated under reduced pressure to obtain the title compounds /0,19 g, 65%/ in the form of a pale brown foam; Rf= 0,40 /ethyl acetate/methanol/triethylamine 18:1:1/;

13C NMR /CD3OD/ : 143,6, 142,8, 136,4, 136,1, 133,8, 128,1, 127,3, 124,7, 123,0, 117,7, 117,4, 114,5, 113,1, 112,1, 110,4, 70,8, 65,6, 64,1, 57,5, 54,4, 53,5, 30,2, 29,1, 21,4; the mass spectrum of high resolution, designed for a /C24H28N4O2/ 404,2214 Found 404,2121.

Example 6

1-/3-(2-amino-ethyl)indol-5-yl/-3H-imidazo[4,5-b]pyridine

To a stirred mixture of sociallyengaged /0,22 g, 5,80 mmole, 5 EQ./ in 10 ml of anhydrous tetrahydrofuran add 5-/3- (2-nitroethanol)indol-5-yl/-1H-benzimidazole /0,35 g to 1.14 mmole/ quickly, but portions in solid form. The resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 12 hours. Then to the reaction mixture carefully add 10 g of decahydrate sodium sulfate, and then 0.5 ml of water and 25 ml of ethyl acetate. The reaction mixture is intensively stirred at room temperature is evaporated under reduced pressure. The residue is treated on a chromatographic column with silica gel /about 30 g/) and elute with a mixture of ethyl acetate/methanol/triethylamine/ ammonium hydroxide /8: 1: 1:0,1/ to obtain specified in the title compounds /41%/ in the form of a clear colorless oil: Rf= 0,10 /ethyl acetate/methanol/triethylamine/ammonium hydroxide 8:1:1:0,1 /. This oil is dissolved in a mixture of methanol/methylene chloride /0.5 mo/ 4 ml, respectively, and to this solution was added maleic acid /0,050 g, 0.43 mmole/. The obtained solid product was filtered to obtain the title compound in the form of its maleate salt /of 0.085 g/; So melting 195,0 - 196,0oC intensive gassing

1H NMR /DMSO-d6/ : 11,3 /Shir.with, NH/, 8,81 /C, 1H/, 8,42 /DD J = 1,40 4,7 Hz/, 1H/, by 8.22 /DD, J = 1.4 and 8.0 Hz, 1H/, 7,97 /d, J = 1.7 Hz, 1H/, 7,78 /Shir. with 2N/, to 7.61-7,52 /m, 2N/, 7,43 was 7.36 /m, 2N/, 6,04 /C, 2N/, 3,37 /Shir. with 2N/, 3,16-3,01 /m, 4H/. Elemental analysis for C16H15N5C4H4O4/maleic acid/ 0,1 H2O:

Calculated: C 60,78 H 4,89 N 17,72

Found: C 60,58 H 4,53 N 17,50

Example 7

1-/3-(pyrrolidin-2R-ylmethyl)indol-5-yl/-3H-imidazo[4,5-b] pyridine

A mixture of 1-/3-(N-2,2,2-trichlorocyanuric)pyrrolidin-2R - ylmethyl)indol-5-yl/-3H-imidazo[4,5-b] pyridine /0,090 g of 0.18 mmole/ zinc dust /0.45 g/ rastenii 12 hours. Then to the reaction mixture is added sodium carbonate /0,35 g/ and the resulting mixture was filtered through Celite, rinsing abundantly ethanol. The combined filtrates evaporated under reduced pressure, and the residue is treated on a chromatographic column with silica gel /about 1 g/ and elute with a mixture of methylene chloride/methanol/hydroxylamine /6:1:0.1 to obtain the title compounds /0,022 g, 40%/ in the form of an amorphous white solid:

1H NMR /CDCl3/ : 9,20 /Shir.with, NH/, 8,44 /DD, J = 1.4 and 4.8 Hz, 1H/, 8,31 /C, 1H/, 8,15 /DD, J = 1.4 and 8.1 Hz, 1H/, 7,80 /d, J = 1.7 Hz, 1H/, 7,44/d, J = 8.5 Hz, 1H/, 7,38 /DD, J = 1.9 and 8.6 Hz, 1H/, 7,29 /DD, J = 4.8 and 8.1 Hz, 1H/, 7,07 /C, 1H/, 3,38-3,30 /m 1H/, a 3.06-2,80 /m, 4H/, 2,48 /Shir. with, NH/, 1,95-1,64 /m, 3H/, 1,49-1,40 /m 1H/, the mass spectrum of the low resolution /m/z, relative intensity /317 /M+, 1/, 315/25/, 248 /100/, 129/39/, 70/80, the mass spectrum of high resolution designed for a /C19H19N5/ 317,1643 found 317,1659.

Example 8

A common way to obtain 5-(2-nitroaniline)-1H-indoles

A solution of 5-amino-1H-indole /2.00 mmole/, 2 nitroglicerina /3,00 mmole, 1.5 EQ/ and reason / when you need to 3.00 mmole/ in a suitable anhydrous solvent /10 ml/ depending on the substrate or heated by boiling under reflux in an atmosphere of nitrogen the leaders introduce pressure, the residue is treated on a chromatographic column with silica gel /about 50 g/, elwira with methylene chloride : methanol : ammonium hydroxide /9: 1:0,1/ or other appropriate solvent system to obtain 5-aryl-1H-indole derivative. In some cases, to obtain analytically pure samples of the corresponding 5-/2-nitroaniline/-1H-indoles after chromatographic processing carry out the recrystallization of the solid samples. In accordance with this method are the following connections:

A. 5-(4-cyano-2 nitrophenylamino)-3-(N-(2-methoxyethyl) pyrrolidin-2R-ylmethyl)-1H-indole

Using 5-amino-3-((2 methoxyethyl)pyrrolidin-2R - ylmethyl)-1H-indole and 4-chloro-3-nitrobenzonitrile. As grounds using triethylamine as solvent is absolute ethanol, the reaction mixture is refluxed for 2 hours. In the chromatographic treatment using as eluent a mixture of ethyl acetate/methanol/triethylamine /18:1:1/ get mentioned in the title link /74%/ foam red: Rf= 0,55 /ethyl Acetate/methanol/triethylamine 18:1:1/;

13C NMR /CD3OD/ : 148,8, 138,0, 137,1, 132,9, 132,7, 129,8, 129,6, 125,6, 121,0, 119,1, 118,3, 117,6, 114,2, 113,6, 99,4, 72,2, 67,2, 59,0, 55,9, 55,0, 31,6, 30,5, 22,9.


Found: C 64,33 H 5,94 N 16,19

Century 5-(4-methoxycarbonyl-2-nitrophenylamino)-3-(N-(2 - methoxyethyl)-pyrrolidin-2R-yl-methyl)-1H-indole

Using 5-amino-3-(1-(2-methoxyethyl)pyrrolidin-2R - ylmethyl-1H-indole and methyl-4-chloro-3-nitrobenzoate. As grounds using triethylamine as the solvent used absolute ethanol, the reaction mixture is refluxed for 2 hours. In the chromatographic treatment using a mixture of ethyl acetate/methanol/triethylamine/ /34:1: 1/ get mentioned in the title link /88%/ foam red: Rf= 0,60 /ethyl acetate/methanol/triethylamine 18:1:1/:

13C NMR /CD3OD/ : 165,5, 147,7, 135,5, 134,9, 131,1, 128,6, 128,5, 128,3, 124,1, 119,7, 117,3, 116,0, 115,6, 112,7, 112,1, 70,7, 65,8, 57,5, 54,4, 53,6, 51,2, 30,2, 29,1, 21,4. The mass spectrum of the high-resolution C24H27N4O5designed 452,2061 found 452,1965.

Elemental analysis for C24H27N4O5:

Calculated; (C 63,08 H 6,29 N OF 12.26

Found: C 63,12 H 6,38 N 12,16

C. 3-(N-benzyloxycarbonyl-4R-ethoxypyrrolidine-2R-ylmethyl- -5-(4-cyano-2-nitrophenylamino)-1H-indole

Using 5-amino-3-(N-benzyloxycarbonyl-4R-methoxy - pyrrolidin-2R-ylmethyl)-1H-indole and 4-chloro-3-nitrobenzonitrile. As the basis ATiM fridge for 3.5 hours. In the chromatographic treatment using ethyl acetate/hexane /1:3/ get the specified in the title link /70%/ foam red: Rf= 0,45 /ethyl acetate/hexane 1:1/.

D. 3-(N-tert. -butoxycarbonylamino-2R-ylmethyl/)-5-(4 - cyano-2-nitrophenylamino)-1H-indole

Using 5-amino-3-(N-tert. -butoxycarbonylamino - 2R-ylmethyl)-1H-indole and 4-chloro-3-nitrobenzonitrile. As grounds using triethylamine as the solvent used absolute ethanol, the reaction mixture is heated at the boil under reflux for 3 hours. As a result of processing on a chromatographic column, elwira a mixture of methylene chloride/methanol/ammonium hydroxide /18:1:0,1/ receive specified in the title link /82%/ foam red: So melting with decomposition of the 60oC; IR /KBr/ 2226, 1688, 1681, 1671, 1621 cm-1; Mass spectrum low resolution /m/z relative intensity / 461/ M+, 23/, 431/27/, 388/13/, 291/50/; 244/43/, 170/53/, 114/75/, 70/100/; the mass spectrum of high resolution, designed for a /C25H27N5O4/ 461,2065 found 461,2071.

E. (R)-5-(3-nitrapyrin-2-ylamino)-3-(pyrrolidin-2-ylmethyl)- 1H-indole

Using (R)-5-amino-3-(pyrrolidin-2-ylmethyl)indole and 2-chloro-3-NITR the one the reaction mixture is heated at boiling under reflux /116oC/ 2 hours. After chromatographic processing get mentioned in the title of the link /23%/ foam dark-red:

1H NMR /CDCl3/ : of 10.05 /W, s, 1H/, 9,23 /Shir, C., 1H/, 8,49 /DD, J = 1,8 and 8.3 Hz, 1H/, 8,39 /1.8 and 4.5 Hz, 1H/, 7,70 /d, J = 1.7 Hz, 1H/, 7,33-7,22 /m, 2N/, 6,98 /C, 1H/, 6.73 x /DD, J = 4,5 and 8.3 Hz, 1H/, 3,47-3,34 /m 1H/, 3,10-2,97 /m 1H/ 2,97-2,78 /m, 3H/, 1,99-1,64 /m, 3H/, 1,56-1,42 /m 1H/;

13C NMR /CDCl3/ : 155,7, 151,5, 135,5, 134,5, 129,2, 128,1, 127,8, 123,8, 119,4, 114,3, 113,0, 111,6, 59,5, 45,7, 31,3, 30,6, 24,7; FAB mass spectrum of the low resolution /m/z, relative intensity /338/6/ /MH+/, Z/12/, 155/49/, 135/38/, 119/100/.

Elemental analysis for C18H19N5O20,67 C2H4O2/acetic acid/:

Calculated: C 61,53 H 5,79 N 18,56

Found: C 61,57 H 5,74 N 18,82

F. 5-(4-cyano-2-nitrophenylamino)-3-(N-methylpyrrolidine-2 - ylmethyl)-1H-indole

Using (R)-5-amino-3-(N-methylpyrrolidine-2-ylmethyl)-1H - indole and 4-chloro-3-nitrobenzonitrile. As the base used triethylamine, and the solvent is absolute ethanol, the reaction mixture is heated at the boil under reflux for 4 hours. After chromatographic processing receive specified in the title with the / : 147,3, 137,1, 135,4, 132,0, 131,4, 128,6, 128,0, 125,3, 120,6, 117,9, 118,1, 116,3, 113,1, 111,9, 99,1, 68,1, 57,3, 40,6, 31,2, 28,1, 21,9. Elemental analysis for C21H21N5O20,05 CH2Cl2:

Calculated: C 66,59 H ceiling of 5.60 N 18,44

Found: C 66,56 H 5,26 N 18,42

G. 3-(N-methylpyrrolidine-2-ylmethyl)-5-(2 nitrophenylamino)-1H - indole

Using (R)-5-amino-3-(N-methylpyrrolidine-2-ylmethyl)-1H - indole and-nitrofurant. As the base used triethylamine, and the solvent used o-nitrofurant, the reaction mixture is refluxed for 24 hours. After chromatographic processing receive specified in the title link /48%/ in the form of an amorphous solid red:

1H NMR /CDCl3/ : 9,62 /Shir. with, NH/, 8,77 /Shir.with, NH/, 8,19 /DD, J = 8.7 and 1.5 Hz, 1H/, 7,47 /d, J = 1.6 Hz, 1H/, 7,38 /d, J = 8.5 Hz, 1H/, 7,29-of 7.23 /m 1H/, 7,09-7,00 /m, 3H/, 6,69-6,64 /m 1H/, 3,20-3,12 /m, 2N/, 2,63 /DD, J = 14.0 and 9.5 Hz, 1H/, 2,54-2,45 /s, 3H/, 2,25 /DD, J = 17.1 to and 9.2 Hz, 1H/, 1,91-1,54 /m, 4H/,

13C NMR /CDCl3/ : 145,4, 135,7, 134,8, 132,1, 130,1, 128,6, 126, 123,6, 120,7, 116,4, 116,1, 114,1, 112,2, 66,7, 57,5, 40,8, 31,5, 29,8, 21,9. FAB mass spectrum of high resolution designed for a /C20H22N4O2H/ 351,1823 found 351,1797.

N. 5-(4-methyl-3-nitrapyrin-2-ylamino)-3-(1-methylpyrrolidine-2 - ylmethyl)-1H-indole

Using (R)-5-amino-3 is, and as the solvent used absolute ethanol, the reaction mixture is refluxed for 24 hours. In the chromatographic processing receive specified in the title link /34%/ in the form of an amorphous solid product red:1H NMR /CDCl3/ : 9,26 /Shir. with, NH/, 8,79 /Shir. with, NH/, 8,10 /d, J = 4,8 Hz, 1H/, of 7.64 /d, J = 1.7 Hz, 1H/, 7,29 /d, J = 8.5 Hz, 1H/, 7,17 /DD, J = 8.5 and 1.9 Hz, 1H/, 6,97 /d, J = 2.2 Hz, 1H/, 6,56 /d, J = 4,8 Hz, 1H/, 3,25-3,16 /m, 2N/, 2,67 /DD, J = 13.2 and 9.4 Hz, 1H/, 2,64-2,56 /m 1H/, 2,56 /C, 3N/, 2,46 /C, 3N/, 2,30 /DD, J = 17.7 and and 9.4 Hz, 1H/, 1,90-1,60 /m, 4H/;

13C NMR /CDCl3/ : 152,2, 151,5, 146,6, 134,3, 131,0, 130,0, 127,9, 123,4, 119,4, 117,1, 114,0, 113,3, 111,3, 111,6, 67,0, 57,4, 40,7, 31,4, 29,5, 21,8, 21,7;

FAB mass spectrum of high resolution, designed for a /C20H23N5O2H/ 366,1932 found 366,1957.

1. (R)-3-(N-methylpyrrolidine-2-ylmethyl)-5-(3-nitrapyrin-2 - ylamino)-1H-indole

Using (R)-3-(N-methylpyrrolidine-2-ylmethyl)indole and 2-chloro-3-nitropyridine. As the base used triethylamine, and the solvent used acetonitrile. The reaction mixture is refluxed for 3.5 hours. After chromatographic processing receive specified in the title link /81%/ foam dark-red:1H NMR /CDCl3
13C NMR /CDCl3/ : 155,7, 151,5, 135,5, 134,3, 129,8, 128,2, 128,1, 123,1, 119,4, 114,3, 113,0, 111,4, 66,7, 57,5, 40,8, 31,5, 29,9, 21,9. Elemental analysis for C19H21N5O21/3H2O:

Calculated: C 63,85, H 6,11 N 19,59

Found: C 63,86 H 5,86 N 19,31

J. 5-(6-methoxy-3-nitrapyrin-2-ylamino)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole

Using (R)-5-amino-3-(N-methylpyrrolidine-2-ylmethyl)-1H - indole and 2-chloro-5-methoxy-3-nitropyridine. As the base used triethylamine, and the solvent used absolute ethanol, the reaction mixture is heated at the boil under reflux for 5.5 hours. In the chromatographic processing receive specified in the title link /54%/ in the form of amorphous material, red:

1H NMR /CDCl3/ : 8,80 /W, s, NH/, of 8.37 /d, J = 9.1 Hz, 1H/, a 7.85 /C, 1H/, 7,34-7,28 /m, 2H/, 7,03 /d, J = 2.0 Hz, 1H/, 6,14 /d, J = 9.1 Hz, 1H/, 3,85 /C, 3N/, 3,19-3,11 /m, 2N/, 2,61 /DD, J = 13.8 and 9.5 Hz, 1H/, 2,54 at 2.45 /m, 1H/, 2,45 /C, 3N/, 2,24 /DD, J = 17.1 to and 9.3 Hz, 1H/, 1,91-1,54 /m, 4H/;

13C NMR /CDCl3/ : 166,9, 151,3, 138,2, 134,0, 129,6, 127,8, 123,3, 122,0, 118,6, 114,1, 113,3, 111,1, 102,0, 66,5, 57,5, 54,7, 40,8, 31,6, 29,9, 21,9. The mass spectrum of high-resolution computed dimetyl-2 - nitrophenylamino)-1H-indole

Using (R)-5-amino-3-(N-methylpyrrolidine-2-ylmethyl)-1H - indole and 4-chloro-3-nitrobenzotrifluoride. As grounds using triethylamine as the solvent used absolute ethanol, the reaction mixture is refluxed for 4.5 hours. In the chromatographic processing get mentioned in the title of the link /38%/ foam red: Rf= 0,30 /methylene chloride/methanol/ammonium hydroxide 9:1: 0,1/.

13C NMR /CDCl3/ : 147,0, 139,7, 135,1, 131,6, 131,0, 129,2, 128,5, 124,7, 124,2, 120,7, 118,6, 116,8, 113,6, 112,6, 67,1, 57,4, 40,8, 31,3, 29,2, 21,9. FAB mass spectrum of the low-resolution 419 /MH+/. Elemental analysis calculated for C21H21F3N4O20,6 CH2Cl2:

Calculated: C 55,27 H 4,77 N 11,94

Found: C 55,44 H 4,58 N TO 11.52

L. 3-(2-dimethylaminoethyl)-6-(3-nitrapyrin-2-ylamino)-1H-indole

Using 5-amino-3-(2-dimethylaminoethyl)indole and 2-chloro-3 - nitropyridine. As grounds using triethylamine as the solvent used p-dioxane, the reaction mixture is refluxed for 3 hours. In the chromatographic processing receive specified in the title link /67%/ foam dark-red color; So melting 59,0-61,07,24 /m, 2N/, 6,97 /d, J = 2.1 Hz, 1H/, 6.73 x /DD, J = 8,3 and 4.4 Hz, 1H/, 2,97-2,91 /m, 2N/, 2,70-2,63 /m, 2N/, 2,36 /s, 6N/;

13C NMR /CDCl3/ : 155,7, 151,5, 135,5, 134,5, 129,4, 128,2, 127,9, 122,8, 119,3, 114,4, 114,3, 113,0, 111,5, 60,3, 45,4, 23,7. Elemental analysis for C17H19N5O21/3 H2O:

Calculated: C 61,62 H 5,98 N 21,13

Found: C 61,58 H 5,65 N 20,80

M 3-(N-methylpyrrolidine-2-ylmethyl)-5-(4-phenyl-2 - nitrophenylamino)-1H-indole

Using (R)-5-amino-3-(N-methylpyrrolidine-2-ylmethyl)-1H - indole and 4-bromo-3-nitrobiphenyl. As grounds using triethylamine as solvent using N,N-dimethylformamide, the reaction mixture is heated at 110oC for 12 hours. In the chromatographic processing receive specified in the title link /24%/ in the form of a solid amorphous material red color.

1H NMR /CDCl3/ : 9,63 /Shir. with, NH/, 8,97 /Shir. with, NH/, 8,42 /d J = 2.2 Hz, 1H/, 7,56-7,25 /m, N/, 7,08 /d, J = 9.0 Hz, 2H/, 3,50-3,32 /m, 2N/, 2,59-2,52 /m 1H/, 2,53 /C, 3N/, 2,05-1,71 /m, 4H/; 13C NMR /CDCl3/ : 144,4, 138,8, 134,9, 132,4, 131,1, 130,2, 129,7, 129,0, 127,3, 126,2, 124,7, 124,1, 120,8, 116,7, 115,9, 112,7, 112,0, 67,9, 57,4, 40,6, 31,2, 28,6, 21,9. FAB mass spectrum of high resolution, designed for a /C26H26N4O2H/ 427,2136 found 427,2099.

N. 5-(5,6-dichloro-2-nitrophenylamino)-3-(N-methylpyrrolidine-2 - ylmethyl)-1H-indole
o
C for 3 hours. In the chromatographic processing receive specified in the title link /60%/ in the form of a solid red, Rf= 0,4 /methylene chloride/methanol/ammonium hydroxide, (9:1:0,1).

1H NMR /CDCl3/ : 8,59 /Shir. with, NH/, at 8.36 /Shir. with, NH/, of 7.96 /d, J = 9.1 Hz, 1H/, OF 7.23 D, J = 8.6 Hz, 1H/, 7,09 /C, 1H/, 7,07 /d, J = 9.1 Hz, 1H/, 6,99 /d, J = 1.9 Hz, 1H/, for 6.81 /DD, J = 8.6 and 2.1 Hz, 1H/, 3,15-3,05 /m, 2N/, 2,54 /DD, 13,8 and 9.6 Hz, 1H/, 2,46-2,33 /m, 1H/, 2.40 a /C, 3N/, 2,22 /DD, J = 17.4 and 9.3 Hz, 1H/, 1,84 is 1.48 /m, 4H/; Field mass spectrum of high resolution, designed for a /C20H20Cl2N4O2H/ 419,1044 found 419,1046.

O. 3-(N-tert-butoxycarbonylamino-4-yl)-5-(3-nitrapyrin-2 ylamino)-1H-indole

Using 5-amino-3-(N-tert. -butoxycarbonylamino-4-yl)- 1H-indole and 2-chloro-3-nitropyridine. As grounds using triethylamine as the solvent used dioxane, the reaction mixture is heated at boiling under reflux /101oC/ within 6 hours. In the chromatographic treatment using ethyl acetate /30 - 40%/ hexano as eluent, get mentioned in the title link /70%/ foam dark-KRA is fair analysis for C23H27N5O41/4 C4H8O2/ethyl acetate/:

Calculated: C 62,73 H 6,36 N 15,24

Found: C 62,51 H between 6.08 N 15,21

P. (R,S)-3-(N-methylpyrrolidine-3-yl)-5-(3-nitrapyrin-2 ylamino)-1H-indole

Using (R, S)-3-(N-methylpyrrolidine-3-yl)indole and 2-chloro-3 - nitropyridine. As grounds using sodium acetate as solvent use acetic acid, the reaction mixture is refluxed for 4 hours. In the chromatographic processing receive specified in the title link /44%/ foam dark-red color; So melting 55,0-57,0oC

13With NMR /CDCl3/ : 155,7, 151,5, 135,5, 135,0, 129,0, 128,1, 127,1, 121,7, 119,3, 119,2, 114,7, 113,0, 111,6, 62,8, 56,2, 42,4, 35,1, 32,1. FAB mass spectrum of high resolution /m/z, relative intensity /306 /MH+, 100/, 155/38/. Elemental analysis for C18H19N5O20.5 C4H4O2/ethyl acetate/

Calculated: C 62,98 H between 6.08 N 18,36

Found: C 62,71 H 5,80 N 18,51

Q. 5-(3-nitrapyrin-2-yl)-1H-indole

Using 5-aminoindole and 2-chloro-3-nitropyridine. As grounds using triethylamine as the solvent used absolute ethanol, the reaction mixture was stirred at room temperature for 4 days.society orange; So melting point 162-163,5oC;

13C NMR /CDCl3/ : 155,6, 150,5, 135,5, 129,7, 127,9, 125,9, 127,6, 118,5, 115,0, 113,4, 111,2, 101,2, Elemental analysis for C13H10N4O2:

Calculated: C 61,41 H 3,96 N 22,04

Found: C 61,22 H 3,80 N 22,08

R. 5-(4-chloro-2-nitrophenyl)-amino-3-(N-methylpyrrolidine - 2R-ylmethyl)-1H-indole

Using (R)-5-amino-3-(N-methylpyrrolidine-2-ylmethyl)-1H - indole and 2,5-dichloronitrobenzene. As the Foundation of the use of sodium carbonate as a solvent using N, N-dimethylformamide, the reaction mixture is heated at 110oC for 5 hours. In the chromatographic treatment using methylene chloride/methanol/ammonium hydroxide as eluent /12: 1: 0,4, respectively/, get mentioned in the title of the link /35%/ in the form of a solid red: Rf= 0,5 /methylene chloride/methanol/ammonium hydroxide 9: 1:0,1/;1H NMR /CDCl3/ : 9,58 /C, 1H/, 8,21 /d, J = 2.5 Hz, 1H/, 8,14 /Shir. C., 1H/, 7,46 /d, J = CA. 2 Hz/, 7,40 /d, y = 8.5 Hz, 1H/, 7,21 /DD, J = 2.5 and 9.3 Hz, 1H/, 7,11 /d, J = CA. 2 Hz/, 7,05 /DD, J = 2.0 and 8.5 Hz, 1H/, 6,98 /d, J = 9,3 Hz, 1H/. 3,18-is 3.08 /m, 2N/, 2.57 m /DD, J = a 9.5 and 14.2 Hz, 1H/, is 2.50-2.40 a; a /m, 1H/, 2,28-2,17 /m 1H/, 2,44 /C, 3N/, 1,85-1,50 /m, 4H/,

S. 5-(5-chloro-2-nitrophenyl)amino-3-(N-methylpyrrolidine-2R - ylmethyl)-1H-indole

Using (R)-5-amino-3-(N-methylpyrrolidine use N, N-dimethylformamide, the reaction mixture is heated at 110oC for 5 hours. In the chromatographic processing, using as eluent methylene chloride/methanol/ammonium hydroxide /12,1,0,4/ receive specified in the title link /51%/ in the form of a solid red; Rf= 0.5 methylenchloride/ammonium hydroxide 9: 1: 0,1/; FAB mass spectrum of high resolution, designed for a /C20H21N4ClO2H/ 385,1434 found 385,1451.

So 5-(6-chloro-2-nitrophenyl)amino-3-(N-methylpyrrolidine-2R - ylmethyl)-1H-indole

Using (R)-5-amino-3-(N-methylpyrimidin-2-ylmethyl)-1H - indole and 2,3-dichloronitrobenzene. As the Foundation of the use of sodium carbonate as a solvent using N, N-dimethylformamide, the reaction mixture is heated at 110oC for 6 hours. In the chromatographic processing, using as eluent methylene chloride/methanol/ ammonium hydroxide /12: 1: 0,4/ receive specified in the title link /62%/ in the form of a solid red; Rf= 0,5 /methylene chloride/methanol ammonium hydroxide 9: 1: 0,1/.1H NMR /CDCl3/ : 8,33 /C, 1H/, 8,21 /Shir. s, 1H/, 7,99 /DD, J = 1.5 and 8.5 Hz, 1H/, 7,56 /DD, J = 1.6 and 7.8 Hz, 1H/, 7,25 /d, J = 8.5 Hz, 1H/, 7,08 /d, J= 1.8 Hz, 1H/, 7,05 /d, j 2.1 Hz, 1H/, 6,92 /DD>/P>U. 5-(4-cyano-2-nitrophenyl)amino-3-(N-tert. - butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-yl)-1H-indole

Using 5-amino-3-(N-tert. -butoxycarbonyl-1,2,5,6 - tetrahydropyridine-4-yl)-1H-indole and 4-chloro-3-nitrobenzonitrile. As grounds using triethylamine as the solvent used absolute ethanol, the reaction mixture is refluxed for 2 hours as a result of processing through column chromatography, using as eluent 1% methanol in methylene chloride, get mentioned in the title of the link /40%/ foam red; So melting with decomposition 85oC. Rf= 0,35 (1% methanol in methylene chloride/; Mass spectrum high resolution calculated for C25H25N5O4459,1909 found 459,1853.

V. 5-(4-cyano-2-nitrophenyl)amino-3-(N-methylpyrrolidine-3-yl)- 1H-indole

Using 5-amino-3-(N-methylpyrrolidine-3-yl)-1H-indole and 4-chloro-3-nitrobenzonitrile. As grounds using sodium acetate as solvent use acetic acid, the reaction mixture is refluxed for 5 hours. After processing through column chromatography receive specified in the title connection /16%/ in the form of a solid amorphous wisest,0, 135,8, 132,1, 131,4, 128,2, 127,8, 122,2, 120,4, 120,3, 118,2, 117,2, 112,7, 98,9, 62,7, 56,3, 42,4, 35,0, 32,3. The mass spectrum of high resolution calculated for [C20H19N5O2]: 361,1541 found 361,1500.

W. 5-(5-cyano-3-nitrapyrin-2-yl)amino-3-(N-methylpyrrolidine - 3-ylmethyl)-1H-indole

Using (R)-5-amino-3-(N-methylpyrrolidine-2-ylmethyl)-1H - indole and 2-chloro-5-cyano-3-nitropyridine. As grounds using triethylamine as the solvent used absolute ethanol, the reaction mixture is heated at the boil under reflux for 2 hours. In the chromatographic treatment using methylene chloride/methanol/ammonium hydroxide /9:1:0,1/ receive specified in the title link /53%/ foam red; Rf= 0,2 /20% methanol in methylene chloride;13C NMR /CD3OD/ : 158,3, 140,3, 136,5, 130,0, 128,4, 125,9, 122,2, 120,4, 115,2, 112,8, 111,1, 96,4, 70,1, 57,9, 40,4, 31,3, 28,2, 22,4. The mass spectrum of high resolution calculated for [C20H20N6O2] 376,1650 found 376,1653.

X. 5-(4-methyl-2-nitrophenyl)amino-3-(N-methylpyrrolidine-2R - ylmethyl)-1H-indole

Using (R)-5-amino-3-(N-methylpyrrolidine-2-ylmethyl)-1H - indole and 4-chloro-3-nitrotoluene. Do not use any of the bases. As the solvent used 4-chloro-3-nitro-toluene, neapolitanum as elution solvent a mixture of methylene chloride/methanol/ammonium hydroxide /18: 1: 0,1/, get listed in the title link /63%/ foam red; Rf= 0,6 /methylene chloride/methanol/ammonium hydroxide 18:1:0,1/;

13C NMR /CD3OD/ : 144,8, 138,2, 136,6, 132,9, 131,3, 129,6, 127,2, 126,3, 125,1, 121,2, 117,3, 116,8, 113,8, 113,3, 68,4, 58,3, 41,0, 32,3, 30,2, 22,4, 20,0.

Elemental analysis for C21H24N4O20.5 H2O:

Calculated: C 67,54 H 6,75 N 15,00

Found: C 67,58 H 6,90 N 14,66

Example 9

The General method of conversion of 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H - indoles and 5-amino-1H-indoles

A mixture of 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indole /10.00 mmole/ hydroxylaminopurine /6,95 g, 100 mmole, 10 EQ./ triethylamine /6,97 ml, 50 mmol, 5 EQ./ in 35 ml of 2-propanol and 5 ml of water is heated at the boil under reflux in nitrogen atmosphere for a period of time, which depends on the substrate. The resulting reaction mixture is cooled, add the sodium hydroxide /of 4.00 g, 100 mmol, 10 EQ./, and the resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 24 hours. Then the reaction mixture was filtered through Celite, and the filtrate is evaporated under reduced pressure. The residue is treated on a chromatographic column with silica gel and about 100 g/, elwira appropriate system RA
A. 5-amino-3-(N-(2-methoxyethyl)pyrrolidin-2R-ylmethyl)-1H-indole.

Using 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(N-(2 - methoxyethyl)-pyrrolidin-2R-ylmethyl)-1H-indole) and refluxed for 4.5 hours. In the chromatographic processing, using as eluent ethyl acetate/methanol/triethylamine /18: 1: 1/ get mentioned in the title link /71%/ foam brown; Rf= 0,70 /ethyl acetate/methanol/triethylamine /8: 1; 1/;13C NMR /CD3OD/ : 146,0, 138,0, 132,0, 128,2, 122,7, 112,8, 111,2, 104,4, 70,9, 65,9, 57,6, 54,6, 53,7, 30,2, 29,4, 21,4; FAB mass spectrum of high resolution calculated for [C16H22N3O H] 273,1661 found 273,1838.

Elemental analysis for C16H22N3O 0,9 H2O:

Calculated: C 66,59 of 6.31 H N 14,56

Found: C 06,59 H 8,15 N 14,34

Century 5-amino-3-(N-benzyloxycarbonyl-4R-ethoxypyrrolidine-2R - ylmethyl)-1H-indole

Using 5-(2,5-dimethyl-1H-yirol-1-yl)-3-(N - benzyloxycarbonyl-4R-ethoxypyrrolidine-2R-ylmethyl)-1H-indole, the reaction mixture is refluxed for 4 hours. In the chromatographic processing by elution with a mixture of ethyl acetate/methanol/triethylamine/18:1:1/ get mentioned in the title link /92%/ in the form of a transparent pale brown who pyrrolidin-2R-ylmethyl)- 1H-indole

Using 3-(N-tert.-butoxycarbonylamino-2R-ylmethyl)- 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indole, the reaction mixture is refluxed for 12 hours. In the chromatographic treatment with a mixture of ethyl acetate/hexane /1: 1/ get mentioned in the title link /78%/ foam pale brown; So melting with decomposition of the 50oC; Rf= 0,30 /ethyl acetate/hexane 1:1/, IR /KBr/ 1673, 1405 cm-1; Mass spectrum high resolution calculated for C18H25N3O2315,1949 found 315, 1914.

D. 5-amino-3-(N-methylpyrrolidine-2R-ylmethyl)-1H-indole

Using 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(N-methyl-pyrrolidin - 2R-ylmethyl)-1H-indole, the reaction mixture is refluxed for 4.5 hours. In the chromatographic processing, using as eluent a mixture of ethyl acetate/methanol/triethylamine /8:1:1/ get mentioned in the title link /83%/ in the form of a brown foam; Rf= 0,4 /ethyl acetate/methanol/triethylamine /8: 1: 1/; So melting 43 - 47oC;13C NMR /CDCl3/ : 138,9, 131,2, 128,5, 122,7, 112,8, 112,7, 111,7, 104,0, 66,7, 57,5, 40,7, 31,5, 29,8, 21,8. The mass spectrum of high resolution calculated for C14H19N3found 229,1560

Example 10

A common way of preures To stir the mixture of sociallyengaged /1,71 g, 45,1 mmole, 4.5 EQ. / in anhydrous tetrahydrofuran /40 ml/ at 0oC was added dropwise a solution of 3-(N-benzyloxycarbonylamino-2 - ylcarbonyl)-1H-indole /10.0 mmole/ in 20 ml of anhydrous tetrahydrofuran. The reaction mixture is refluxed under nitrogen atmosphere for 6 hours. The reaction mixture is cooled, very carefully, portions add decahydrate sodium sulfate /50 g/, then 1 ml of water and 100 ml of ethyl acetate. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 24 hours. The reaction mixture was filtered through Celite, the resulting filtrate is evaporated under reduced pressure. The residue is treated on a chromatographic column with silica gel and about 100 g/ elwira appropriate solvent system to obtain the target 3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole. In this way we obtain the following connections:

A. 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(N-methylpyrrolidine-2R - ylmethyl)-1H-indole

Using 5-(2,5-dimethyl-1H-pyrrol-1-yl) (3-N - benzyloxycarbonylamino-2R-ylcarbonyl)-1H-indole. After chromatography using as eluent ethyl acetate/methanol/triethylamine /8:1:1/ get mentioned in the title link /92%/ in the form of a white foam; So the UP> = +81o/methylene chloride, C = 1/. Elemental analysis for C20H25N30.5 H2O:

Calculated: C 75,92 H 8,28 N OF 13.27

Found: C 75,88 H 8,43 N 13,24

C. (R)-5-dibenzylamino-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole

Using 3-(N-benzyloxycarbonylamino-2R-ylcarbonyl)- 5-dibenzylamino-1H-indole. In the chromatographic processing, elwira a mixture of methylene chloride/methanol/ammonium hydroxide /9:1:0,1/ receive specified in the title link /89%/ foam pale green color:

1H NMR /CDCl3/ : 7,82 /Shir. S., NH/, 7,35-7,19 /m, 10H/, 7,20 /d, J = 8.6 Hz, 1H/, 6,95 / d, J = 2.1 Hz, 1H/, 6,85 /DD, J = 2.3 and 8.7 Hz, 1H/, 6,80 /d, J = 2.2 Hz, 1H/, 4,65 /s, 4H/, 3,25-3,02 /m, 2N/, 2,52 /DD, J = 9.5 and a 13.9 Hz, 1H/, 2,39-2,15 /m, 2N/, 2,30 /C, 3N/, 1,85-1,40 /m, 4H/;13C NMR /CDCl3/ 143,2, 139,7, 130,5, 128,5, 127,3, 126,8, 122,9, 112,5, 112,2, 111,8, 103,4, 67,0, 57,4, 56,4, 40,6, 31,4, 29,7, 21,9. FAB Mass spectrum of high resolution calculated for C28H31N3409,2520 found 409,2475.

Example 11

The General method of conversion of 3-(pyrrolidin-2-ylcarbonyl)-1H - indoles 3-(pyrrolidin-2-ylmethyl)-1H-indoles

To a stirred solution of literotica /0.33 g, 15.2 mmole, 3.0 EQ. / in 10 ml of anhydrous tetrahydrofuran under nitrogen atmosphere was added dropwise a solution of 3-pyrrolidin-2-ylcarbonyl)-1H-indole /10 ml/ 40 ml bezvodnoye period of time, which depends on the substrate. The reaction mixture is cooled, slowly and carefully add decahydrate of sodium sulfate and about 25 g/, then 1 ml of water and 50 ml of ethyl acetate. The resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. Then the reaction mixture was filtered through Celite, and the filtrate is evaporated under reduced pressure. The residue is treated on a chromatographic column with silica gel and about 200 g/, elwira appropriate solvent system to obtain 3-/pyrrolidin-2-ylmethyl/-1H-indole. In this way receive the following connections:

A. 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(N - benzyloxycarbonylamino-2R-ylmethyl)-1H-indole

Using 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(N - benzyloxycarbonylamino-2R-ylcarbonyl)-1H-indole, the reaction mixture is refluxed for 1.5 hours. In the chromatographic processing by elution with a mixture of ethyl acetate/hexane /1:3/ get the specified in the title link /59%/ in the form of a colorless mixture of oil and foam. Rf= 0.45 in the air. IR /KBr/ 3340-3300, 1686, 1680, 1451, 1415 cm-1; Field of the mass spectrum of the low resolution /m/z relative intensity/: 488/M+, 100/, 294/14/, 224/32/; FAB mass spelements analysis for C27H29N3O20,75 H2O:

Calculated: C 73,53 H 6,97 N AT 9.53

Found: C 73,49 H of 6.71 N 9,17

Century 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(N-benzyloxycarbonyl-4R - ethoxypyrrolidine-2R-ylmethyl)-1H-indole

3-(N-benzyloxycarbonyl-4-ethoxypyrrolidine-2R-ylcarbonyl)- 5-(2,5-dimethyl-1H-pyrrolyl)-1H-indole is used, the reaction mixture is refluxed for 12 hours. In the chromatographic processing, using as eluent 30% methylene chloride in hexano receive specified in the title link /57%/ in the form of a clear colorless oil that crystallized upon standing; Rf= 0,80 /methanol/ethyl acetate 1:9/; the Field of the mass spectrum of the low resolution /m/z, relative intensity /458 /MH+, 100/, 367/7/ 350/5/, 324/17/, 239/10/; FAB mass spectrum of high resolution calculated for [C28H31N3O3H] 458,2446 found 458,2468.

C. 3-(N-benzyloxycarbonylamino-2R-ylmethyl)-5 - dibenzylamino-1H-indole

Using 3-(N-benzyloxycarbonylamino-2R-ylcarbonyl)- 5-dibenzylamino-1H-indole) and the reaction mixture is refluxed for 4 hours. In the chromatographic processing, using as eluent ethyl acetate in hexano /1:3/ get the Naya intensity /530/ MH+, 87/, 529 /M+, 100/, 439/10/, 409/10/, 325/32/, 235/20/.

Example 12

General method for the preparation of 3-(N-benzyloxycarbonylamino-2 - ylcarbonyl)-1H-indoles.

To a stirred solution of N-benzyloxycarbonylamino /10 mmol/ in 25 ml of anhydrous methylene chloride with traces of N,N-dimethylformamide /0.1 ml/ add oxalicacid /1.31 ml, 15,02 mmole, 1.5 EQ/. The result of the reaction solution with intensive gas, which was stirred at room temperature under nitrogen atmosphere for 3 hours. Then the reaction solution is evaporated under reduced pressure, add 50 ml of anhydrous hexanol, and the resulting solution was again evaporated under reduced pressure to obtain N-benzyloxycarbonylamino acid chloride, which is dissolved in anhydrous benzene /25 ml/.

In parallel, a solution of ethylmagnesium /3.0 M in ether 6.8 ml, 20.4 mmole, 2.0 EQ. / added dropwise to a stirred solution of 3-unsubstituted-1H-indole /20,0 mmole, 2.0 EQ/ in 50 ml of benzene at 0oC in nitrogen atmosphere. The resulting reaction solution was stirred at 0oC in nitrogen atmosphere for 15 minutes. Then, under vigorous stirring was added dropwise previously obtained a solution of N-benzyloxycarbonylamino chlorine is 1 hour. Then add 75 ml of saturated sodium bicarbonate solution and this aqueous mixture is extracted three times with ethyl acetate portions 75 ml. Organic extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The remaining foam is recrystallized from a mixture of ethyl acetate in diethyl ether /total volume of 25 ml to obtain the corresponding 3-/N-benzyloxycarbonylamino-2-ylcarbonyl/-1H-indole. This way we obtain the following connections:

A. 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(N - benzyloxycarbonylamino-2R-ylcarbonyl)-1H-indole

Using (R)-N-benzyloxycarbonylamino and 5-(2,5-dimethyl - 1H-pyrrol-1-yl)-1H-indole. As a result of crystallization extraction of the residue from diethyl ether get mentioned in the title link /75%/ in the form of an off-white solid. So melting 155,0 - 157,0oC / intensive gassing/; ()25= +101o/methylene chloride, C = 1/. Elemental analysis for C27H27N3O3:

Calculated: C 73,45 H 6,16 N 9,52

Found: C 73,41 of 6.02 H N 9,52

Century 3-(N-benzyloxycarbonyl-4-ethoxypyrrolidine-2R-ylcarbonyl) -5-(2,5-dimethyl-1H-pyrrolyl)-1H-indole

Using (R)-CIS-N-benzyloxycarbonyl-4-methoxypropan /Krapcho, et. al, Med, Chem. 1148/1988// and 5-(2,5-is Il, get listed in the title compound 54% as off-white solids: T melting 189,0-191,0oC. Rf= 0.4 V mixture of ethyl acetate/hexane /2:1/; ()25= +89o/methylene chloride, with a = 1/ a; FAB mass spectrum of high resolution calculated for [C28H29N3O4H] 472,2238 found 472,2281.

Elemental analysis for C28H29N3O4:

Calculated: C 71,32 H 6,20 N 8,91

Found: C 71,56 H 6,28 N 8,92

C. 3-(N-benzyloxycarbonylamino-2R-ylcarbonyl)-5 - dibenzylamino-1H-indole

Using (R)-N-benzyloxycarbonylamino and 5 dibenzylamino - 1H-indole. As a result of crystallization of the extraction residue using diethyl ether, receive specified in the title link /24%/ in the form of a white solid substance; So the melting point 176-177,0oC. the mass spectrum of the low resolution /m/z, relative intensity /543/100; M+/, 453 /10/, 407/7/, 339/40/, 307/10/, 247/10/, 154/36/; ()25= +112oTHF, C = 1/.

Elemental analysis for C35H33N3O3:

Calculated: C 77,32 H 6,12 N 7,73

Found: C 77,35 H 6,30 N 7,66

Example 13

(R)-5-amino-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole

A mixture of (R)-5-dibenzylamino-3-(N-methylpyrrolidine-2-ylmethyl)- 1H-indole /1,08 g of 2.64 mmole/ and 20% hydroxide for 4 hours. The resulting mixture was filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure to obtain the title compounds /0,60 g, 2,62 mol, 99% of/ in the form of a white foam:1H NMR /DMSO-d6/ : 10,65 /Shir. with, NH/, 7,14 /d, J = 2.2 Hz, 1H/, 7,12 /d, J = 8.6 Hz, 1H/, 6,85 /d, J = 1.6 Hz, 1H/ 6,60 /DD, J = 2.0 and 8.6 Hz, 1H/, 3,63-2,63 /m, 7H/, 2,78 /C, 3N/, 2.06 to 1,67 /m, 4H/; ()25= +9o/MeOH, C = 1,0/. The mass spectrum of high resolution calculated for C14H19N322,1575 found 229,1593.

Example 14

5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indole

A mixture of 5-aminoindole /1,32 g, 10.0 mmole/, acetylacetone 4,0 ml, 34 mmole, 3.4 equiv./ and 25 ml of toluene is refluxed in a nitrogen atmosphere, using a trap Dean-stark within 24 hours. The reaction mixture is cooled, and then poured through silikagelya filter /about 200 g/, then rinsing it with 10% ether in hexano to obtain specified in the title compounds /1.52 g, 72%/ in the form of off-white solids, Rf= 0,75 in diethyl ether; 13C NMR /CDCl3/ : 135,0, 131,4, 129,5, 128,1, 125,6, 122,4, 120,3, 111,3, 105,0, 103,0, 13,2. Elemental analysis for C14H14N2:

Calculated: C 79,97 H of 6.71 N 13,52

Found: C 79,72 H 6,75 N 13,13

Example 15

5-dibenzylamino-1H-indole

To premesis the Oh temperature in a nitrogen atmosphere add benzylbromide /8,2 ml, 68.9 mmole, 3.0 EQ. / dropwise. The reaction mixture is refluxed under nitrogen atmosphere for 3 hours. The resulting reaction mixture is filtered, the resulting filtrate is evaporated under reduced pressure. After processing the obtained residue on chromatographic column with silica gel and about 200 g/, elwira a mixture of ethyl acetate/hexane /from 1:9 to 1:1, get mentioned in the title compound as off-white solids; So melting 124,0-126,0oC13C NMR /acetone-d6/ : 144,3, 140,8, 131,8, 129,9, 129,2, 128,3, 127,5, 125,5, 113,5, 112,4, 106,4, 101,9, 57,0; TCX /15% ethyl acetate in hexano/: Rf= 0,3

Example 16

5-amino-3-(N-methylpyrrolidine-3-yl)-1H-indole

A mixture of 5-benzylamino-3-(N-methylpyrrolidine-3-yl)-1H-indole /7,80 g, 25.5 mmole/ format ammonium /16,10 g, 255 mmol, 10 EQ./ and 10% Pd on coal /0,78 g/ 250 ml absolute ethanol is refluxed in nitrogen atmosphere for 1 hour. The reaction mixture was filtered, and the filtrate is evaporated under reduced pressure. The remaining oil is treated on a chromatographic column with silica gel and about 200 g/, elwira 0.3% triethylamine in methanol to obtain the title compounds /0,90 g, 16% of/ in the form of a pale yellow oil;1H NMR /, 2,67-2,50 /m, 2N/, 2.40 a /C, 3N/, 2,37-2,24 /m 1H/, 2,08-1,93 /m 1H/; FAB mass spectrum of the low resolution /m/z, relative intensity /216/MH+, 100/.

Example 17

5-benzylamino-3-(N-methylpyrrolidine-3-yl)-1H-indole

To a stirred solution of N-methyl-3-/5 - phenylcarbonylamino-3-yl/succinamide /18,31 g, 52,71 mmole/ in anhydrous tetrahydrofuran /270 ml/ at 0oC add sociallyengaged /20,01 g, 527 mmol, 10 EQ.) in solid form, portions over 45 minutes. The resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 24 hours. Then gently add decahydrate sodium sulfate /50 g/ to this reaction mixture, then add 5 ml of water and 100 ml of ethyl acetate. The resulting mixture was stirred at room temperature for one hour. The reaction mixture was filtered, and the filtrate is evaporated under reduced pressure. The remaining oil is treated on a chromatographic column with silica gel /about 500 g, elwira a mixture of ethyl acetate:methanol:triethylamine /9:0:1 to 8:1:1 to obtain the title compounds /of 7.90 g, 49%/ as blignault oil,13C NMR /acetone-d6/ : 142,9, 142,1, 132,3, 129,3, 128,6, 127,5, 121,9, 119,6, 112,8, 112,5, 102,0, 63,6, 57,1, 49,9, 42,6, 36,5, 33,0. FAB mass spectrum of the low resolution shall urbanregional-3-yl)succinamic

A solution of 5-phenylcarbonylamino-1H-indole /2.50 g, of 10.58 mmole,/ Chem. Abctracts, 10991g /1954// and N-methylmaleimide /2,94 g, 26,46 mmole, 2.5 EQ./ in 75 ml of glacial acetic acid is refluxed in nitrogen atmosphere for 24 hours. The resulting reaction solution is evaporated under reduced pressure and the remaining oil is dissolved in 50 ml of ethyl acetate. This solution was washed with saturated aqueous sodium bicarbonate /2 x 25 ml/ dried over magnesium sulfate and evaporated under reduced pressure. The remaining oil is treated on a chromatographic column of about 100 g /silica gel/, using as eluent a mixture of ethyl acetate/hexane/ 1:3 to 1: 1 to obtain the title compounds /1.06 g, 29% of/ in the form of a solid white color. So melting 226,5 - 227,5oC. FAB mass spectrum of the low resolution /m/z, relative intensity /348/ MH+, 100/, 332 /2/, 275/4/, 263/5/. Elemental analysis for C20H17N3O31/8 H2O:

Calculated: C 68,71 H equal to 4.97 N 12,02

Found: C 68,68 H 4,74 N 11,91

Example 19

5-amino-3-(2-dimethylaminoethyl)indole

A mixture of 3-(2-dimethylaminoethyl)-5-nitroindole /1.85 g, 7,93 mmole/ and 10% palladium on coal /0.40 g, 20 wt.%/ in 30 ml absolute ethanol is shaken in hydrogen atmosphere /uterovaginal ethanol. The combined filtrates evaporated under reduced pressure to obtain the title compounds /1,60 g, 7,87 mmole, 99% of/ in the form of a transparent, slightly darkish hygroscopic oil: IR /CHCl3/ 3480, 1610, 1585. 1640, 1335 cm-1:

1H NMR /CDCl3/ : 8,10 /Shir. m NH/, 7,12 /d, J = 8.5 Hz, 1H/, 6,91 /d, J = 2.3 Hz, 1H/, 6,88 /d, J = 2.2 Hz, 1H/, 6,64 /DD. J = 2.2 and 8.5 Hz, 1H/, 2,89-2,84 /m, 2N/, 2,64-2,58 /m, 2N/, 2,34 /s, 6N/;13C NMR /CDCl3/ : 139,1, 131,2, 128,3, 122,2, 113,1, 112,9, 111,7, 103,8, 60,3, 45,4, 23,7; the mass spectrum of the low resolution /m/z, relative intensity /203 /9, M+/, 158/2/, 145/6/, 83/66/, 58/100/. The mass spectrum of high resolution calculated for C12H17N3203,1424 found 203, 1418. Elemental analysis for C12H17N31/2 H2O:

Calculated: C 67,89 H 8,55 N 19,79

Found: C 67,71 H at 8.60 N 19,41

Example 20

3-/2-dimethylaminoethyl/-5-nitroindole

To a stirred solution of 5-nitroindole-3-N,N - dimethylglyoxime /are 5.36, to 20.52 mmole/ in 55 ml of anhydrous tetrahydrofuran added borane in tetrahydrofuran /1.0 M, 78.8 ml 78,8 mmole, 3.8 equiv./ slowly dropwise. The resulting reaction solution was stirred at room temperature under nitrogen atmosphere for 16 hours. Carefully added to the reaction solution, a saturated solution of bicarbonate soda is combined dried over magnesium sulfate, evaporated under reduced pressure to obtain 3-/2-dimethylaminoethyl/-5 - nitroindole boranova complex in the form of amorphous solids orange /6,9 g/.1H NMR /DMSO-d6/ : 11,7 /Shir. m, NH/, 8,58 /d, J = 2.2 Hz, 1H/, 8,00 /DD, J = 2.3 and 9.0 Hz, 1H/, 7,52 /d, J = 8,8 Hz, 1H/, 7,49 /W, s, 1H/, 3,23-3,17 /m, 2N/, 3,02-2,97 /m, 2N/, 2,63 /s, 6N/. This solid is placed in absolute ethanol /150 ml/ together with rezeptoren /6,9 g/ sodium carbonate /6,9 g/ and the mixture was refluxed under nitrogen atmosphere for 16 hours. The reaction mixture is filtered through celite and the resulting filtrate is evaporated under reduced pressure. The remaining oil is treated chromatography on silica gel /about 450 g/, elwira a mixture of methylene chloride/methanol/ammonium hydroxide /8:2:0,1/ to obtain specified in the title compounds /2.58 g, 11,06 mmole, 54% of/ in the form of a solid yellow; So melting 133,0, 135,0oC. IR /KBr/ 1625, 1575, 1550, 1520, 1480, 1470, 1460, 1445, 1380, 1370, 1330 cm-1;1H NMR /DMSO-d6/ : 11,55 /Shir. m, NH/, 8,48 /d, J = 2.2 Hz, 1H/, 7,94 /DD, J = 2.3 and 9.0 Hz, 1H/ 7,47 /d, J = 9.0 Hz, 1H/, 7,40 /Shir. s, 1H/, 2,88-2,83 /m, 2N/, 2,53-2,48 /m, 2N/, 2,19 /s, 6N/;13With NMR /DMSO-d6/ : 140,2, 139,3, 126,6, 126,5, 116,3, 116,0, 115,6, 111,7, 59,8, 45,1, 22,7; the mass spectrum of the low is high resolution, calculated for C12H15N3O2: 233,1166 found: 233,1155.

Elemental analysis for C12H15N3O2:

Calculated: C 61,79 H 6,48 N TO 18.01

Found: C 61,39 H 6,45 N 17,68

Example 21

5-nitroindole-3-N,N-dimethylglyoxime

To a stirred solution of 5-nitroindole /10,00 g, 61,7 mmole and phtalimide /4,00 g, 40 wt.%/ in anhydrous ether /250 ml/ add oxalicacid /17,0 ml, 0,194 mol, 3.1 EQ./ dropwise. The resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 72 hours. The resulting reaction mixture is cooled in an ice bath /0oC/, and carefully add the solution of ether /80 ml/ dimethylamine /80 ml condensed at -78oC/ under vigorous stirring. The resulting mixture was intensively stirred at room temperature for one hour. The ether from the reaction mixture is evaporated under reduced pressure and the residue is divided between water /500 ml/ methylene chloride /500 ml/. the pH of the aqueous layer set 3 using concentrated HCl. Methylenchloride layer removed and the aqueous layer was extracted three times with methylene chloride /portions of 500 ml/. Methylenechloride extracts are combined, dried over magnesium sulfate, evaporated under reduced pressure. the hladini get mentioned in the title compound /Rf= 0.15 in 10% acetone in methylene chloride, 5,74/, 22,0 mmole, 36% of/ in the form of a pale yellow solid. So melting 248,0-249oC. IR /KBr/ 1755, 1740, 1730, 1650, 1620, 1585, 1530 cm-1;1H NMR /DMSO-d6/ : 12,9 /Shir. c, NH/, 3,97 /d, J = 2.3 Hz, 1H/, 8,43 /C, 1H/, 8,18 /DD, J = 2.3 and 9.0 Hz, 1H/, 7,74 /d, J = 9.0 Hz, 1H/, 3,02 /C, 3N/, 2,95 /C, 3N/;13C NMR /DMSO-d6/ : 166,6, 143,2, 140,4, 140,2, 124,5, 118,9, 117,2, 114,2, 113,6, 36,8, 33,6. The mass spectrum of the low resolution /m/z, relative intensity /261 /24, M+/, 190/29/, 189/100/, 173/15/, 143/83/ 115/23/; the mass spectrum of high resolution calculated for C12H11N3O4: 261,0750 found 261,0746. Elemental analysis for C12H11N3O4:

Calculated: C 55,17 H 4,24 N 16,08

Found: C 55,15 H 3,96 N 15,96

Example 22.

5-amino-3-(N-tert.-butoxycarbonylamino-4-yl)-1H-indole.

A mixture of 3-(N-tert. -butoxycarbonyl-1,2,5,6-tetrahydropyran-4 - yl)-5-nitro-1H-indole /3,55 g, 10,34 mmole/ and 10% palladium on coal /0.55 g/ 60 ml absolute ethanol is shaken in hydrogen atmosphere /3 ATM/ for 7 hours at room temperature. The reaction mixture is filtered through diatomaceous earth and the resulting filtrate is evaporated under reduced pressure. The remaining solid part triturated with diethyl ether to obtain the the group 215oC.13With NMR /CDCl3/ : 155,0, 139,0, 131,3, 127,3, 120,4, 119,8, 112,9, 111,8, 104,1, 79,4, 44,5, 33,8, 32,7, 28,5. Elemental analysis for C18H25N3O21/2 H2O:

Calculated: C 67,57 H 8,03 N 13,13

Found: C 67,20 H 8,07 N 13,44.

Example 23

3-(N-tert. -butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-yl)-5 - nitro-1H-indole

To a stirred solution of the sodium /of 2.51 g, 105 mmol, 7 EQ. in 50 ml absolute methanol is added 5-nitroindole /2,43 g of 15.0 mmole/ and N-tert. -butoxycarbonyl-4-piperidone /8,96 g, 45 mmol, 3.0 equiv./. The resulting reaction solution is evaporated under reduced pressure and the residue is divided between a saturated solution of sodium bicarbonate /50 ml/ ethyl acetate /50 ml/. The organic layer removed and the aqueous layer was extracted with ethyl acetate /2 x 50 ml/. The organic extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. As a result of processing the extraction of the residue on a column of silica gel and about 100 g/ with elution by ethyl acetate hexano / gradient elution from 1:2 to 1:1 / get mentioned in the title link /72%/ in the form of a solid yellow color. So melting with decomposition 230oC;1H NMR /CDCl3/ : 9,24 /Shir. s, 1H/, 8,78 /d, J = 1.3 Hz, 1H/, 8,09 /DD, J = 1.4 and 9,4 entry analysis for C15H21N3O40,1 H2O

Calculated: C 62,62 to 6.19 H N 12,17

Found: C 62,71 H 6,09 N 11,81

Example 24

3-(N-tert-butoxycarbonylamino-2R-ylmethyl)-5-(2,5 - dimethyl-1H-pyrrol-1-yl)-1H-indole

A mixture of 3-(N-benzyloxycarbonyl-4-ethoxypyrrolidine-2R - ylcarbonyl)-5-(2,5-dimethyl-1H-pyrrolyl)-1H-indole /6,16 g, 14,41 mmole/ and 10% palladium on coal /of 3.32 g/ absolute ethanol /75 ml/ shaken in an atmosphere of hydrogen for 20 hours at room temperature. The reaction mixture is filtered through Celite, and the filtrate is evaporated under reduced pressure. The remaining foam was dissolved in anhydrous tetrahydrofuran /50 ml and added dropwise di-tert.-BUTYLCARBAMATE /3,45 g 15,88 mmole, 1.1 EQ./ to stir the solution at room temperature. This reaction solution was stirred at room temperature under nitrogen atmosphere for 30 minutes, then the solution is evaporated under reduced pressure. The residue is treated on a chromatographic column with silica gel and about 200 g/, elwira a mixture of ethyl acetate/hexane /1:2 to obtain the title compounds /91%/ in the form of a white solid; ()25= -1,3o/methylene chloride, with a = 1/ a; Mass spectrum high resolution calculated for C242:

Calculated: C 73,25 H 7,94 N IS 10.68

Found: C 73,28 H 7,76 N 10,51

Example 25

5-(3-formylindole-5-yl)-1H-benzimidazole

A mixture of 5-amino-3-(N-methylpyrrolidine-2R-ylmethyl)-1H-indole /5.50 g, 21,63 mmole/ and 10% palladium on coal /1,00 g/ 75 ml absolute ethanol is shaken in an atmosphere of hydrogen /3 ATM/ for 5 hours. The resulting mixture was filtered through Celite, the resulting filtrate is evaporated under reduced pressure. The rest /of 4.95 g/ dissolved in dimethylformamidine /25 ml and the resulting solution was refluxed under nitrogen atmosphere for 12 hours. Then the reaction solution is evaporated under reduced pressure, and the residue is placed in a solution of 75 ml/ 10% aqueous sodium hydroxide/ethanol /5: 1/. The resulting mixture was refluxed under nitrogen atmosphere for 3 hours. Then add concentrated hydrochloric acid to establish a pH of 3 and this aqueous mixture is extracted with ethyl acetate /3 x 75 ml/. The organic extracts are combined, dried over magnesium sulfate and concentrated to about 20 ml volume. The precipitated solid part was filtered to obtain the title compounds /1.54 g, 29% of/ in the form of a solid white color. So melting more than 280oC;1H NMR /DMSO-d6/ : Entry analysis for C14H10N40,26 H2O:

Calculated: C 67,54 H 3,97 N 21,00

Found: C 67,82 H 3,99 N 20,68

Example 26

5-/3-(2-nitroethanol)indol-5-yl/-1H-benzimidazole

A mixture of 5-/3-formylindole-5-yl/-1H-benzimidazole /0.40 g, 1,53 mmole) and ammonium acetate /50 mg/ solution of nitromethane /10 ml/, N,N-dimethylformamide /5 ml and dimethyl sulfoxide /1 ml/ refluxed in nitrogen atmosphere for 4 hours. The resulting reaction mixture is cooled to room temperature and filtered to obtain the title compounds /0.40 g, 86%/ in the form of a solid yellow color. So melting more than 280oC:13C NMR /DMSO-d6/ : 146,9, 145,3, 144,3, 137,4, 136,6, 135,5, 134,2, 132,1, 129,8, 127,8, 125,0, 119,9, 118,7, 115,9, 113,4, 108,7. Elemental analysis for C16H11N5O20,125 H2O:

Calculated: C 62,49 H 3,69 N 22,77

Found: 62,34 H 3,51 N 22,45

Example 27

5-(3-nitrapyrin-2-ylamino)-3-(N-(2,2,2 - trichlorocyanuric)-pyrrolidin-2R-ylmethyl)-1H-indole

To a stirred solution of (R)-5-(3-nitrapyrin-2-ylamino/-3- (pyrrolidin-2-ylmethyl/-1H-indole /0,42 g of 1.24 mmole) and pyridine /0,11 ml of 1.36 mmole, 1.1 EQ./ in anhydrous dichloroethane /6 ml at room temperature add 2,2,2-trihloretilamina /of 0.18 ml, 1.30 mmol, of 1.05 equiv./ Received reactionat to the obtained reaction mixture and the resulting mixture was washed with a saturated solution of sodium bicarbonate /20 ml/. The organic layer is dried over magnesium sulfate and evaporated under reduced pressure to obtain the title compounds /0,62 g, 100%/ in the form of an amorphous solid red. FAB mass spectrum of the low resolution /m/z, relative intensity /516 /MH+with two37Cl and one35Cl, 36/, 515/41/, 514//MH+one37Cl and two35Cl, 100/, 513/66/, 512//MH+with three35Cl/, 99/, 511/36/, 498/7/, 478/14/, 391/8/.

Example 28

5-aminomethyl-1-/3-(N-(2-methoxyethyl)pyrrolidin-2R - ylmethyl)-indol-5-yl/-1H-benzimidazole

To a stirred mixture of sociallyengaged /0,200 g, 5,27 mmole, 3.0 EQ. / in anhydrous tetrahydrofuran /9 ml/ add 5-cyano-1-/3-(N-(2-methoxyethyl)pyrrolidin-2R-ylmethyl)indol-5-yl/-1H - benzimidazole /0,700 g, 1.75 mmole/ and the resulting reaction mixture is refluxed under nitrogen atmosphere for 24 hours. Then gently add decahydrate of sodium sulfate and about 10 g/, then the water /2 ml/, and then ethyl acetate /20 ml/. The resulting mixture was stirred at room temperature for 1 hour. The mixture is filtered through Celite and the resulting filtrate is evaporated under reduced pressure. The residue is treated on a chromatographic column with silica gel /about 50 g/ elwira CME is ledno-yellow color. Rf= 0,15 /methylene chloride/ methanol/ammonium hydroxide 9:1; 0,1/13C NMR /CD3OD/ : 145,2, 144,3, 137,6, 137,2, 135,2, 129,6, 128,7, 126,2, 125,0, 119,3, 119,1, 115,9, 114,5, 113,5, 112,1, 72,3, 67,1, 58,9, 55,8, 55,0, 46,6, 31,6, 30,5, 22,9; ()25= +61o/methylene chloride, C = 1/.

Elemental analysis for C24H29N5O 0.25 ethyl acetate C4H8O20,8

Calculated: C 68,30, H 7,47 N 15,93

Found: C 67,97 H 7,19 N 15,95

Example 29

5-aminomethyl-1-/3-(N-methylpyrrolidine-2R-ylmethyl)indol-5-yl/- 12-benzimidazole

A mixture of Raney Nickel and about 0.25 g/ 5-cyano-1-/3-(N - methylpyrrolidine-2R-ylmethyl)indol-6-yl/-1H-benzimidazole /1,00 g of 2.81 mmole/ in absolute ethanol saturated with ammonia and shaken in an atmosphere of hydrogen /3 ATM/ for 5 hours. The resulting mixture was filtered through Celite, the resulting filtrate is evaporated under reduced pressure to obtain the title compounds /to 0.900 g, 89%/ in the form of off-white foam, Rf= 0,2 /ethyl acetate/methanol/triethylamine /6: 2: 2/;13WITH NMR (CD3OD) : 143,5, 142,9, 137,5, 136,1, 136,0, 133,5, 128,1, 127,4, 124,7, 123,4, 117,7, 117,5, 114,2, 113,0, 112,1, 110,5, 66,9, 56,9, 45,6; 39,6, 30,9, 28,8, 21,0. Elemental analysis for C22H25N51,5 H2O:

Calculated: C 68,36 H 7,30 N 18,12

Found: C 68,26 H 7,38 N 17,88

Example 30

A common way acylation of 5-aminoiminomethyl-1-/3-(N-(2 - methoxyethyl)pyrrolidin-2R-ylmethyl)indol-5-yl/-1H-benzimidazole /0,100 g 0.25 mmole/ triethylamine /0,04 ml, to 0.3 mol, 1.1 equiv./ in absolute ethanol /3 ml at room temperature was added dropwise a corresponding allerease agent /a 0.27 mmole, 1.1 EQ. /. The resulting reaction solution was stirred at room temperature under nitrogen atmosphere overnight, then evaporated under reduced pressure. The residue is treated on a chromatographic column with silica gel/about 10 g/, elwira appropriate solvent system to obtain the corresponding 5-acylaminoacyl-1-/3-(N-(2-methoxyethyl) pyrrolidin-2R-ylmethyl)indol-5-yl/-1H-benzimidazole. In this way receive the following connections:

A. 5-acetamidomethyl-1-/3-(N-(2-methoxyethyl)pyrrolidin-2R - ylmethyl)indol-5-yl/-1H-benzimidazole

As Alliluyeva agent use acetylchloride, the reaction residue is treated chromatographic, elwira 5% methanol in methylene chloride to obtain the title compounds /68%/ in the form of a pale brown solid: Rf= 0.35 in 10% methanol in methylene chloride. 13WITH NMR /CD3OD/ : 173,6, 142,5, 140,6, 138,5, 132,8, 132,4, 128,8, 128,3, 128,2, 126,6, 119,4, 117,0, 114,7, 114,5, 114,4, 111,7, 70,3, 68,2, 59,3, 56,3, 55,4, 43,9, 30,9, 27,8, 22,7. The mass spectrum of high resolution calculated for C26H31N5O2445,2480 found 445,2439, ()
As Alliluyeva agent use phenylisocyanate, the reaction residue is treated chromatographic, elwira a mixture of ethyl acetate/methanol/triethylamine /36:1:1 to obtain the title compounds /57%/ in the form of a white amorphous material; Rf= 0,3 /ethyl acetate/methanol/triethylamine /18:1:1/; FAB mass spectrum of high resolution calculated for [C31H34N6O2H] 523,2825 found 523,2866 ()25= 169o/methylene chloride, C = 1/.

C. 5-benzoylamino-1-/3-(N-(2-methoxyethyl)pyrrolidin-2R - ylmethyl)indol-5-yl/-1H-benzimidazole

As Alliluyeva agent use benzoyl chloride, and the reaction residue is treated chromatographic, elwira a mixture of ethyl acetate/methanol/triethylamine /18:1:1 to obtain the title compounds /20%/ in the form of a white amorphous material; Rf= 0,5 /ethyl acetate/methanol/triethylamine 16: 1:1/; FAB mass spectrum of high resolution calculated for [C31H33N5O2H] 508,2715 found 508,2722; ()25= +75o/methylene chloride, C = 1/.

Example 31

5-amino-3-(N-tert. butoxycarbonyl-1,2,5,6-tetrahydropyridine-4 - yl)-1H-indole

To a stirred solution of the sodium /2,61 g, 0,114 mol/ 50 ml absolute methanol is added 5 is actor refluxed in nitrogen atmosphere for 6 hours. Then the reaction solution is evaporated under reduced pressure and the residue is divided between ethyl acetate and saturated sodium bicarbonate solution /100 ml each/. The organic layer removed and the aqueous layer was extracted with ethyl acetate /2 x 100 ml. The organic extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue is treated on a chromatographic column with silica gel /150 g/, elwira diethyl ether to obtain the title compounds /4,10 g, 70%/ in the form of off-white foam. Rf= 0,1 /diethyl ether/1H NMR /CD3OD/ : 7,26 /d, J = 1.8 Hz, 1H/, 7,17 /C, 1N/ 7,16 /d, J = 6,8 Hz, 1H/, 6,70 /DD, J= 2.0 and 8.5 Hz, 1H/, 6,06 /Shir. m, 1H/, 4,88 / exchange H/, 4.09 to /Shire. m, 2N/, 3,65 /Shir. t, J = 5.7 Hz, 2H/, 2,52 /Shir. m, 2N/, 1,49 /s, N/

Example 32

6-hydroxy-5-nitronicotinic acid

A mixture of 6-hydroxynicotinic acid /16,60 g, 0,119 mol/ and fuming nitric acid /166 ml/ heated under 50oC for 4 hours. The resulting reaction solution was cooled to room temperature, and then carefully added to ice /300 g/. The resulting mixture was stored at 10oC overnight and then the solid precipitate is filtered and dried in vacuo to obtain the title compounds /5.50 g, or 0.027 mol, 23%/ as twards NMR /DMSO-d6/ : 164,1, 154,4, 138,5, 137,2, 107,9. The mass spectrum of high resolution calculated for C6H4N2O5184,0120 found 184,0134.

Elemental analysis for C6H4N2O5< / BR>
Calculated: C 39,14 H 2,19 N 15,21

Found: C 39,21 2,33 H N 15,56

Example 33

6-chloro-5-nitronicotinic

A mixture of 6-hydroxy-5-nitronicotinic acid /1,33 g, 7,22 mmole/ petaluridae phosphorus /1.5 g, 7,20 mmol, 1.0 EQ./ and phosphorus oxychloride /2,7 ml/ heated at 130oC in nitrogen atmosphere for 4 hours. The resulting solution was concentrated, viparita when lowering the pressure. The remaining oil /presumably 6-chloro-5 - nitronicotinic acid acid chloride/ dissolved in a solution of tetrahydrofuran and methylene chloride /1:1, 20 ml and the solution cooled to -78oC. was added dropwise a solution of ammonia in THF /2.7 M, 15 ml, 40 mmol, 5 EQ. / and the resulting reaction solution was left to warm to room temperature. Then add 50 ml of water, and the aqueous mixture extracted with methylene chloride /2 x 50 ml/. The obtained extracts are combined, dried over sodium sulfate and evaporated under reduced pressure to obtain the title compounds /0,72 g of 3.57 mmole, 49%/ in the form of a solid yellow color.1H NMR /CD36
H4ClN3O3designed 200,9942 found 200,9938. Elemental analysis for C6H4ClN3O3:

Calculated: C 35,75 H 2,00 N 20,85

Found: C 35,41 H 2,14 N 20,29

Example 34

2-chloro-5-cyano-3-nitropyridine

A mixture of 6-chloro-5-nitronicotinic /0,60 g, 2,98 mmole/ and phosphorus oxychloride /9 ml/ heated to boiling under reflux in nitrogen atmosphere for 3 hours. Then the reaction solution is evaporated under reduced pressure and the remaining oil is shared between saturated sodium bicarbonate solution and ethyl acetate /10 ml each/. The organic layer removed, dried over sodium sulfate, and evaporated under reduced pressure to obtain the title compounds /0,38 g 2,07 mmole, 69% of/ in the form of a solid yellow color.

1H NMR /CD3OD/ : 9,00 /d, J = 2.0 Hz, 1H/, 8,91 /d, J = 1,9 Hz, 1H/.13C NMR /CD3OD/ : 156,1, 147,7, 139,4, 115,3, 111,3; the mass spectrum of high resolution calculated for C6H2ClN3O2182,9837 found 182,9834. Elemental analysis for C6H2ClN3O20,08 C4H8O2/ethyl acetate/:

Calculated: C 39,82 H 1,40 N 22,05

Found: C 39,47 N 1,48 N 21,99

All compounds are non-lethal products.


R2, R3, R4, R5each independently represents hydrogen, C1-C6-alkyl, phenyl, halogen, cyano, -(CH2)mNR14R15, -(CH2)mOR9, -(CH2)mNR14R9, - (CH2)mNR14CONHR9, -CO2R9;

R6represents hydrogen, or SIG10;

R7, R8, R14, R15each independently represents hydrogen, C1-C6-alkyl, -(CH2)xOR SIG11;

R9represents hydrogen, C1-C6-alkyl, phenyl;

R10is1-C10-alkyl;

R11is1-C6-alkyl;

n = 0, 1, or 2;

m = 0, 1, 2 or 3;

x = 2 or 3;

the dotted line indicates the optional single bond,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, where R1represents a

< / BR>
or

< / BR>
3. Connection on p. 2, where R1represents a

< / BR>
4. Connection on p. 3, which is a CIS-epimer.

5. Connection on p. 4, where R6is1-C3-alkoxy.

6. Connection on p. 3, where R6represents hydrogen.

7. Connected is on p. 7, where R1is

< / BR>
9. Connection on p. 8, which is a CIS-epimer.

10. Connection on p. 9, where R6is1-C3alkoxy.

11. Connection on p. 8, where R6represents hydrogen.

12. Connection on p. 1, which is chosen from:

5-cyano-1-/3-(N-(2-methoxyethyl)pyrrolidin-2R-ylmethyl)indol-5-yl/-1H-benzimidazole,

1-/3-(2-N,N-dimethylaminoethyl)indol-5-yl/-3H-imidazo [4, 5-b]-pyridine,

1-/3-(2-amino-ethyl)indol-5-yl/-3H-imidazo [4, 5-b]pyridine,

1-/3-(N-methylpyrrolidine-2R-ylmethyl)indol-5-yl)/-5-phenyl-1H-benzimidazole,

6,7-dichloro-1-/3-(N-methylpyrrolidine-2R-ylmethyl)indol-5-yl/-1H-benzimidazole,

1-/3-(piperid-4-yl)indol-5-yl/-3H-imidazo [4, 5-b]pyridine,

5-chloro-1-/3-(N-methylpyrrolidine-2R-ylmethyl)indol-5-yl/-1H-benzimidazole,

6-chloro-1-/3-(N-methylpyrrolidine-2R-ylmethyl)indol-5-yl/-1H-benzimidazole,

5-aminomethyl-1-/3-(N-(2-methoxyethyl)pyrrolidin-2R-ylmethyl)-indol-5-yl/-1H-benzimidazole,

5-acetamidomethyl-1-/3-(N-(2-methoxyethyl)pyrrolidin-2R-ylmethyl)indol-5-yl/-1H-benzimidazole,

5-cyano-1-/3-(piperid-4-yl)indol-5-yl/-1H-benzimidazole,

5-cyano-1-/3-(1,2,5,6-tetrahydropyridine-4-yl/-1H-benzimida-5-cyano-1-/3-(N-methylpyrrolidine-3-yl)indol-5-yl/-1H-benzimidazole,

5-Ben is iparralde-2R-ylmethyl)indol-5-yl/-1H-benzimidazole,

5-cyano-1-/3-(N-methylpyrrolidine-2R-ylmethyl)indol-5-yl/-1H-pyrido [4, 5-b] imidazole, and

4-methyl-1-/3-(N-methylpyrrolidine-2R-ylmethyl)indol-5-yl/-1H-pyrido [4, 5-b]-imidazole.

13. Pharmaceutical composition that binds the receptors NT-1A and MT-1D in the treatment of conditions selected from hypertension, depression, anxiety, disturbance of appetite, obesity, substance abuse, cluster headache, migraine, pain, chronic of paroxysmal hemicrania and headache associated with vascular disorders, comprising an active substance and a pharmaceutically acceptable carrier, characterized in that the active substance it contains a connection on p. 1 in an effective amount.

14. Method binding receptors NT-1A and MT-1D in the treatment of conditions selected from hypertension, depression, anxiety, disturbance of appetite, obesity, substance abuse, cluster headache, migraine, pain, chronic of paroxysmal hemicrania and headache associated with vascular disorders by administration of a drug, characterized in that, as a medicinal substance use connection on p. 1 in an effective amount.

15. The compound of formula IV

< / BR>
where a, b, C, D - kdy independently represents hydrogen, WITH1-C6-alkyl, phenyl, halogen, cyano, -(CH2)mNR14CONHR9, -CO2R9,

R6represents hydrogen, or SIG10;

R7, R14, R15each independently represents hydrogen, C1-C6-alkyl, (CH2)xOR SIG11;

R9represents hydrogen, C1-C6-alkyl, phenyl;

R10is1-C6-alkyl;

R11is1-C6-alkyl;

R12represents a

< / BR>
< / BR>
or

< / BR>
R13- represents-CO2R16;

R16is1-C6-alkyl, C1-C3-alkylphenyl,

the dotted line represents an optional single bond.

16. Connection on p. 15, where R12represents a group of the formula

< / BR>
17. Connection on p. 16, which is CIS-epimer.

18. Connection on p. 17, where R6is1-C3alkoxy.

19. Connection on p. 16, where R6represents hydrogen.

 

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