The method of treatment status, which shows nci-like agonist, derived tetrahydrocarbazole, method thereof, pharmaceutical composition active agonist nti-like receptors

 

(57) Abstract:

The use of compounds of General formula I

< / BR>
in which R1represents hydrogen, halogen, trifluoromethyl, nitro, hydroxy, C1-6-alkoxy, aryl-C1-6-alkoxy, -CO2R4, -(CH2)nCN, (CH2)nCONR5R6, (CH2)nSO2NR5R6C1-6-alkanolamine(CH2)nor C1-6-alkylsulfonamides(CH2)n; R4represents hydrogen, C1-6is alkyl or aryl (C1-6; R5and R6each independently represent hydrogen or C1-6-alkyl, or R5and R6together with the nitrogen atom to which they are attached, form a ring; n is 0,1 or 2; R2and R3each independently represent hydrogen, C1-6-alkyl or benzyl or together with the nitrogen atom to which they are attached, form a ring pyrrolidino, piperidino or hexahydroazepin, or its physiologically acceptable salts for the treatment condition, which shows the 5-HT1-like agonist, such as migraine. Describes new compounds of formula I, methods for their preparation and pharmaceutical compositions containing them. 4 C. and 15 C.p. f-crystals, 2 tab.

Izobreteniya excessive expansion of the lumen of the vessels, in particular the treatment of migraine.

Migraine - non-fatal disease that affects one out of ten people; the main symptom is headache, other symptoms include vomiting, photophobia. Currently, the most widely used treatment is the purpose of ergotamine, digidroergotamina or methysergide, which are also used as preventive measure. These drugs, by the way, are agonists of 5-HT1-like receptor, but have a different effect; the treatment of them is associated with a number of adverse side effects. In addition, some patients experience "headaches while taking medicines that appear after stopping treatment product ergot, such as ergotamine, forcing them to repeat the treatment, and leads to addiction. Recently, for potential use in the treatment of migraine have been proposed various derivatives of tryptamine.

In view of the foregoing, there is a need to create a safe and effective medicines for the treatment of migraine.

In U.S. patent N 4257952, 4172834, 4062864 and 3059309 revealed a large class of tetrahydrocarbazole with the formula:

< / BR>
where N = B is, inter alia, -other' or-NR'r R", where the od;

Q1- inter alia, hydrogen, halogen, lower alkoxy, cyano, -CO2R1or-CONR2R3where R1can be hydrogen, lower alkyl or-CH2Ar and R2and R3is hydrogen, lower alkyl or together form a heterocyclic ring;

Q2- inter alia, hydrogen, aryl-(lower alkoxy), hydroxy, trihalomethyl, nitro or alkanolamine; and

Q3and Q4can each be, inter alia, hydrogen.

These compounds are known as having analgesic, psychotropic and antihistaminic activity.

Unexpectedly it was found that some tetrahydrocarbazole counteract and partially counteract a 5-oxitriptan-like receptors and may find application in the treatment of conditions in which it is shown that 5-HT1-like agonist or partial agonist, particularly conditions associated with headache, such as migraine, General headache and pain associated with changes in the blood vessels. In this description, the term "5-HT1-like agonist" includes a partial agonist at this receptor.

Therefore, the present invention provides the use of compounds of General formula I:

< / BR>
in which

THE1-6-alkoxy, -CO2R4, -/CH2/nCN, -/CH2/nCONR5R6, -/CH2/nSO2NR5R6C1-6-alkanolamine /CH2/nor C1-6-alkylsulfonamides /CH2/;

R4represents hydrogen, C1-6is alkyl or aryl (C1-6-alkyl;

R5and R6each independently represents hydrogen or C1-6-alkyl, or R5and R6together with the nitrogen atom to which they are attached, form a ring;

n represents 0, 1 or 2; and

R2and R3each independently represents hydrogen, C1-6-alkyl or benzyl or together with the nitrogen atom to which they are attached, form a ring pyrrolidino, piperidino or hexahydroazepin; and their physiologically acceptable salts in the manufacture of drugs to treat the condition, which shows the 5-HT1-like antagonist, in particular migraine and its prevention.

The invention also provides a method of treatment status, which shows the 5-HT1-like agonist, in particular migraine, which includes assignment to a subject in need, an effective amount of the compounds of formula (I) or its physiologically acceptable salt.

R/SUP>, -/CH2/nCONR5R6or/CH2/nSO2NR5R6and R2and R3each independently represent hydrogen or C1-6-alkyl.

It should be said that the compounds of formula I can contain one or more asymmetric centers; such compounds exist as optical isomers /enantiomers/. Thus, the invention includes all such enantiomers and mixtures, including racemic mixtures.

In the compounds of formula I, the halogen atom may be fluorine, chlorine, bromine or iodine. Alkyl group, or half may have a straight or branched chain. Suitable akrilovye groups include, for example, unsaturated monocyclic or bicyclic ring and partially saturated bicyclic ring with 1 to 12 carbon atoms, such as phenyl, naphthyl and tetrahydronaphthyl. If R5and R6together with the nitrogen atom form a ring, it is preferably a 5 - to 7-membered saturated heterocyclic ring which may contain another heteroatom selected from oxygen, sulfur or nitrogen. Suitable rings include pyrrolidine, piperidine, piperazine derivatives, morpholine.

In the above compounds, R1preferably represents halogen /nab, the H2/nSO2NR5R6or C1-6-alkanolamine. Most preferably, R1represents a group -/CH2/nCONR5R6in which n is 0, and R5and R6each independently represent hydrogen, methyl, ethyl or propyl. Preferably, R5and R6independently represented by hydrogen or methyl.

If R1represents-CO2R4, R4preferably represents C1-6-alkyl.

R2and R3each preferably represents hydrogen, methyl or ethyl. Most preferably NR2R3- -NH2.

For use in accordance with the present invention the compound of formula I is preferably a partial antagonist.

Suitable physiologically acceptable salts are obvious to those skilled in the art, and include, for example, salts of an acid of joining, such as those formed with inorganic acids such as hydrochloric, sulfuric or phosphoric acids and organic acids such as succinic, maleic, acetic or fumaric acid. Other physiologically unacceptable salts, e.g. oxalates, may espressomachine also included solvate and hydrates of compounds of formula IA.

< / BR>
in which R1is as defined above, with the proviso that R1is not hydrogen, hydroxy, methoxy or benzyloxy, and their salts.

This connection further includes the following specific compounds, which are also considered to be new:

3-amino-6-cyano-1,2,3,4-tetrahydrocarbazole hydrochloride,

/+/-3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride,

/-/-3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride,

3-amino-6-bromo-1,2,3,4-tetrahydrocarbazole hydrochloride,

3-amino-6-methyl-1,2,3,4-tetrahydrocarbazol oxalate,

3-amino-6-ethoxycarbonyl-1,2,3,4-tetrahydrocarbazol oxalate,

3-amino-6-/N-methyl, carboxamido/-1,2,3,4-tetrahydrocarbazol poloxamer,

3-amino-6-cyanomethyl-1,2,3,4-tetrahydrocarbazol oxalate,

3-amino-6-/N-methylsulfonylmethyl/-1,2,3,4-tetrahydrocarbazol oxalate,

3-amino-6-chloro-1,2,3,4-tetrahydrocarbazol oxalate,

3-amino-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazol oxalate,

3-amino-6-n-Butylochka-1,2,3,4-tetrahydrocarbazol oxalate,

3-amino-6-sulfonamide-1,2,3,4-tetrahydrocarbazol oxalate,

3-amino-6-nitro-1,2,3,4-tetrahydrocarbazol oxalate,

3-amino-6-/N, N-dimethylcarbamate/ -1,2,3,4-tetrahydrocarbazol poloxamer,

3-amino-6-/piperidine-1-ylcarbonyl/ -1,2,3,4-tetrahydrocarbazole hydrochloride,

3-amino-6-/pyrrolidin-1-ylcarbonyl/ -1,2,3,4-tetrahydrocarbazole hydrochloride,

3-amino-6-/N, N-diethylcarbamyl/ -1,2,3,4-tetrahydrocarbazole hydrochloride,

3-amino-6-acetamido/-1,2,3,4-tetrahydrocarbazol oxalate,

3-amino-6-methanesulfonamido-1,2,3,4-tetrahydrocarbazol oxalate,

3-amino-6-carboxymethyl-1,2,3,4-tetrahydrocarbazole hydrochloride,

3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazol oxalate,

3 ethylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazol oxalate,

3-n-propylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazol oxalate,

3-i-propylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazol oxalate,

3-dimethylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazol oxalate,

3 benzylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazol oxalate,

3-pyrrolidinyl-6-carboxamido-1,2,3,4-tetrahydrocarbazol oxalate, and

3-/N-/methyl/ethylamino/-6-carboxamido-1,2,3,4-tetrahydrocarbazol oxalate,

3-amino-6-/2-carboxamidates/ -1,2,3,4-tetrahydrocarbazol oxalate.

In another aspect the present invention provides a new compound of formula I, i.e., compound IA or any of the mentioned joint is anyone agent, in particular, 5-HT1agonist or partial agonist, for example, in the treatment of migraine.

The invention also provides a method of obtaining new compounds of formula I.

The compounds of formula I can be obtained by methods known in the technical field to obtain tetrahydrocarbazole, for example:

A) Reaction of compounds of formula II:

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in which R1is as defined above or its salt of the acid of accession with the compound of the formula III:

< / BR>
/in which R2and R3as identified above and/ or N-protected derivative; or

B) Reaction of the compound of formula IV:

< / BR>
/in which R1has the same meaning as defined for formula I and Z is a leaving group with a compound of the formula HNR2R3;

C) Reaction of the compound of formula V:

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with allermuir or sulfonylureas agent;

D) Converting one compound of formula I into another compound of formula I, for example

/i/ to obtain a compound of the formula I, in which R1is -/CH2/nCONH2or CO2R4spend the hydrolysis of compounds of formula I in which R1is -/CH2/nCN, or N-protected derivative;

/ie formula I, in which R1represents-CO2H, or N-protected derivative; or

/iii/ to obtain a compound of formula I in which one of R2and R3is hydrogen and the other is C1-6-alkyl, alkylate compound I in which R2and R3both hydrogens;

/iv/ to obtain a compound of the formula I, in which R1represents hydroxy, split connection, in which R1represents alkoxy or Alcoxy; if necessary with subsequent release from the protection of any protective nitrogen atoms and the formation of salt if desired.

Method (A), which is a form of synthesis, Fischer indole, can be carried out using methods well known in chemistry. Thus, the reaction can be done in a solvent such as alcohol, such as ethanol or butanol; or acetic acid, at a temperature in the range of 0 - 150oC.

The hydrazines of the formula II, which are typically used as the hydrochloride salt, the compounds are known and can be obtained by known methods.

Cyclohexanone of the formula III can be obtained by oxidation of the corresponding cyclic alcohol using an oxidizing agent such as pyridine chlorproma, pyridine dichromate, deeper is soedineniyah formula /IV/ maybe for example, a halogen atom or sulfonyloxy group, for example, p-toluensulfonate or methansulfonate. Process (B) can be done in an inert organic solvent such as an alcohol, e.g. methanol, or an ether, e.g. tetrahydrofuran, and at a temperature in the range of 0 - 150oC. the compounds of formula IV can be obtained by reaction of a hydrazine of the formula II with a suitable substituted compound of cyclohexanone. If the Z - acyloxy or sulfonyloxy, it can be obtained from compounds IV in which Z is hydroxy, using standard procedures. Suitable alleluya and sulfonylurea agents that can be used in method (C) include the chlorides of carboxylic and sulfonic acids (for example, acetylchloride or methansulfonate/, alkylester, activated esters and symmetrical or mixed anhydrides. The reaction can be carried out in an organic solvent, such as haloalkane /for example, dichloromethane/, amide /for example, N,N-dimethylformamide/; ether /for example, tetrahydrofuran/ or tertiary Amina, such as pyridine. In General also used the base, such as triethylamine, dimethylaminopyridine or a carbonate or bicarbonate of an alkali metal. The reaction is carried out at a temperature in the range of -10 is mentioned above.

Another compound V can be obtained by reduction of compound of formula I, in which R1- nitro, for example, by catalytic hydrogenation.

In chemistry it is well known that the hydrolysis of the nitrile initially gives amide, which you can then hydrolyze in acid. So the exact product method (Di) will depend on the reaction conditions selected for hydrolysis. To obtain a connection, in which R1is H2NCO-, hydrolysis is preferably carried out using hydrogen peroxide in the presence of alkali metal hydroxide, e.g. sodium hydroxide, in a solvent such as alcohol, methanol. Other suitable means of hydrolysis include acetic acid and BF3; or formic acid and Hydrobromic or hydrochloric acid. To obtain a connection, in which R1represents-COOH acid or base, it is possible to use catalytic hydrolysis.

Method (Dii) can be made by reaction of compounds of formula I in which R1- -CO2H, amidon HNR5R6in the presence of a coupling agent, for example, dicyclohexylcarbodiimide or N, N-carbonyldiimidazole. In another embodiment, the source material carboxylic acid can pilot chloride, acid anhydride or activated ester, which is then directly reacts with the amine HNR5R6. The carboxylic acid can also be activated on the spot treatment hexamethylphosphorotriamide.

The alkylation according to method (Diii) can be made by reaction of the amine of formula I with allermuir agent, for example, anhydride, such as acetic or propionic anhydride, to obtain an intermediate compound in which one of R2or R3is C/O/C1-6-alkyl, with the subsequent recovery of this intermediate compound to produce the desired product. Experts also other known reagents and conditions.

The splitting method (Div) you should do a restore using well known methods.

In many of these reactions it is necessary to protect the group - R2R3when one or both of the groups represent hydrogen. Suitable N-protective groups are well known in the field of engineering and include, for example, acyl groups such as acetyl, triptorelin, benzoyl, methoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl or phthaloyl; and kalkilya groups such as benzyl, diphenylmethyl or tripe Protective group should be easily removed at the end of the sequence reactions. N-protection can be removed by conventional means, for example palailogou group can be removed by reaction with hydrazine; acyl group such as benzoyl, can be split by hydrolysis, and aracelio group, such as benzyl, can be split by hydrogenolysis.

If the compound of formula I is obtained in the form of a mixture of enantiomers, they can be separated by conventional methods, for example, a reaction mixture with a suitable optically active acid, such as d-tartaric acid, l-malic acid, l-almond, l-Galanova or 2,3,4,6-di-O-isopropylidene-ketogulonic acid, to obtain two stereoisomeric salts, which can be divided, for example by crystallization.

Otherwise, a mixture of enantiomers can be separated by chromatography, for example on a chiral HPLC column.

As noted, the compounds of formula I are agonists and partial agonists for the receptors, such as 5-HT1and will find application in the treatment and/or prevention of migraine and other conditions associated with headaches.

For use in medicine, the compounds of the present invention are usually prescribed as a standard pharmaceutical composition. So next, the present invention provides pharmaceutical is Eski acceptable carrier.

Compounds of the present invention of formula I can be administered orally, parenterally and reception of the cheek, under the tongue, the nose, through the rectum, through the skin in the form of appropriate pharmaceutical compositions.

The compounds of formula I and their pharmaceutically acceptable salts which are active when oral administration may be in the form of liquids, for example syrups, suspensions or emulsions, or tablets, capsules and pellets.

The liquid dosage form may typically consist of a suspension or solution of the compound or its physiologically acceptable salt in a suitable liquid carrier, for example, an aqueous solvent /water, ethanol, glycerin/ or nonaqueous solvent, such as glycol or oil. The form may also contain suspendisse agent, preservative, flavoring or color agent.

Composition in the form of tablets can be prepared using any suitable pharmaceutical carrier used in the preparation of solid forms. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

Composition in the form of a capsule can be obtained using conventional procedures encapsulation. For example, pellets containing the gelatin capsule; the dispersion or suspension can be prepared using suitable pharmaceutical carriers, for example, aqueous resins, cellulose, silicates or oils and the filling of a dispersion or suspension in a soft gelatin capsule.

Conventional parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example, polyethylene glycol, polyvinyl-pyrrolidone, lecithin, peanut oil or sesame oil. In another case, the solution can be lyophilized and then restored with a suitable solvent before taking.

Compositions for nasal application can be in the form of aerosols, drops, gels and powders. The form of aerosols typically includes a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and is intended for single-use or reusable sterile form and sealed container, which can take the form of a cartridge or filled in a container with a sprayer. The sealed container may be a universal dispenser in the form of disposable inhaler or as an aerosol dispenser with m which includes aerosol dispenser, it contains propellant, which may be a compressed gas, air, or organic propellant, such as prorogation. Aerosol dosing form can also be a pump-spray.

Compositions intended for application in the cheek or under the tongue, include tablets, pellets and tablets in which the active ingredient is formed with a carrier, such as sugar and Arabian gum, tragakant or gelatin and glycerin.

Compositions for rectal usually in the form of beads containing the usual suppository Foundation - cocoa butter.

Compositions acceptable for transdermal application include liquid ointments, gels and patches.

The preferred dosage form is a unit dose /tablet, capsule or ampoule/.

Each unit dosage contains for oral administration of from 1 to 250 mg /day for parenteral and from 0.1 to 25 mg/ compounds of formula I or its physiologically acceptable salts calculated as the free base.

Physiologically acceptable compounds of the invention are usually assigned on a daily basis /adult patient/ with oral dose of between 1 and 500 mg, preferably between 10 and 400 mg, intravenous, ormolu I or its physiologically acceptable salts, calculated as the free base, the compound is from 1 to 4 times per day for a period of continuous therapy, for example, in the course of a week or more.

Biological data.

Testing of 5-HT1-like receptor.

Saphenous vein of the dog.

The helices saphenous vein of the dog was placed at 37oC in modified Krebs solution with the power of peace 10 MP. The solution also contained 1 mmol/l of each of ketanserin prazosin, atropine and mepyramine, 6 Ámol/l of cocaine and 200 Ámol/l ascorbate. Polygraph with force sensors was measured almost isomeric contraction. Tissue was twice subjected to the action of 5-oxitriptan /5-HT/ 2 Ámol/l followed by washing. Was determined by the curve of the cumulative effect of concentration, and then curve to 5-HT in the presence of the highest concentration of the test compounds. The reduction caused by the test compound was compared with reductions caused by 5-HT. Calculated activity of the test compounds as the ratio of maximum action caused by the connection over the action caused 2 Ámol/l 5-HT. From the appropriate curve was calculated EC50the test compounds is the Association equilibrium.

In this test the compounds of examples 2, 4, 5, 6, 9, 10, 11, 13, 17, 18, 21 and 24 had EC50in the range from 0.1 to 15 Ámol.

The main artery of the rabbit.

Methods.

The experiments were carried out on intracranial arteries rabbit, isolated basilar artery using the same method as described above /Person and Welly, 1989, Eur. J. Pharmacol. 174, 189-196/.

Briefly, rabbits were wordplays large dose anastrozole of the substance /pentobarbital sodium/.

The whole brain was rapidly removed and immersed in cold modified Krebs solution, and basilar artery were removed using preprofile magnifier. The Krebs solution had the following composition /mm /Na+/120/; K+/5/; Ca2+/2.25/; Mg2+/0.5/; Cl-/98.5/; SO42-/1/; add /0.04/, balanced 95% O2/5%/ CO2. The endothelium was removed with a soft touch to the cavity of the thin metal wire. The arteries were cut into ring segments /width 4 - 5 mm/ and plunged to record isometric tension in 50-ml tissue baths for with modified Krebs solution and adding /mm/ Na2+/20/; fumarata /10/; pyruvate /5/; L-glutamate /5/ and glucose /10/. Then the artery was placed in the power of peace 3-4 MP at 37oC and through races depolarizing KCl solution /90 mm/ and in the absence of relaxation, caused by acetylcholine, because the previous reduction of 5-HT /10 mm, in the presence of 200 mm ascorbate, cocaine 6 mm, indometacin 2.8 mm, ketanserin 1 mm and prazosin (1 mm cumulative curves were constructed concentration - impacts /2 nm - 60 mm/ 5-HT.

In this test the compounds of examples 2, 5, 6, 15, 17, 24, 25, 26, 28 and 29 had EC50within 0.04 to 15.

Example 1.

3-Amino-6-cyano-1,2,3,4-tetrahydrocarbazole hydrochloride.

A solution of 4-aminocyclohexanol hydrochloride /6.08 g, 0.04 M/ water /60 ml/ brought to pH 8 with an aqueous solution of sodium bicarbonate. Was added N-carbethoxy-phthalimid /0.76 g, 0.04 M/, and then tetrahydrofuran to obtain a homogeneous solution/. Clean the solution stirred at room temperature overnight. During this precipitated substance of white color. The tetrahydrofuran was removed under vacuum and the remaining aqueous solution was extracted with ethyl acetate to complete cleansing solution. The ethyl acetate extracts were combined, were washed with water, dried /MgSO4/ and concentrated to obtain 4-phthalimido of cyclohexanol in the form of a white substance /7,1 g/.

A solution of 4-phthalimido cyclohexanol /7,1 g 0,029 M/ V dichloromethane /250 ml/ processed pyridine Helen diethyl ether /50 ml/, and the mixture was filtered through diatomaceous earth. The filtrate was concentrated in vacuo, and the residue was purified column chromatography /SiO2; CHCl3/EtOAc to obtain 4-phthalimido cyclohexanone in the form of a solid substance white /6.4g/.

4-Cyanophenyl hydrazine hydrochloride /to 4.41 g, 0,026 M/ dissolved in acetic acid /100 ml and was added sodium acetate /2 g/. Was added 4-phthalimido cyclohexanone /6.4 g, 0.026 M/, and the mixture was heated with phlegmasia all night. The solvent was removed in vacuo, and the residue was pulverized with methanol to obtain 3-phthalimido-6-cyano-1,2,3,4-tetrahydrocarbazole in a solid beige /5.3g/.

Suspension of the specified product /1 g/ ethanol /40 ml/ was treated with hydrazine in water /10 ml/. The reaction mixture was stirred at room temperature overnight, during which time the reactants were dissolved. The solvent was removed in vacuo, and the residue was divided between aqueous potassium carbonate and ethyl acetate. The ethyl acetate solution was washed with water, dried and concentrated in vacuo to obtain 3-amino-6-cyano-1,2,3,4-tetrahydrocarbazole in a solid beige /500 mg/. This product was converted to the hydrochloride salt to obtain the desired compounds is, ,22 /1H, DD/, 3,68 /1H, m, 7,34 /1H, d/, 7,43 /1H, d/, of 7.82 /1H, s/.

Example 2.

3-Amino-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride.

The product of example 1 /400 mg/ dissolved in tetrahydrofuran, was added di-t-butyl dicarbonate /500 mg/. The mixture is stirred at room temperature overnight. The solvent was removed in vacuum and the residue was purified column chromatography /SiO2; CHCl3/EtOAc) to obtain 3-t-butyloxycarbonyl-6-cyano - 1,2,3,4-tetrahydrocarbazole /40 mg/.

A mixture of the above nitrile product /440 mg/, aqueous hydrogen peroxide /30%, 0.5 ml) and sodium hydroxide /water./ /20%, 0.5 ml/ methanol /25 ml/ stirred at room temperature overnight. Added metabisulfite sodium /100 mg/, and the solvent was removed in vacuum. The residue was dissolved in ethyl acetate, and the ethyl acetate layer was separated, dried and concentrated in vacuum to obtain a viscous solid, which was purified column chromatography /SiO2; CHCl3/EtOAc) to obtain 3-t-butyloxycarbonyl - 6-carboxamido-1,2,3,4-tetrahydrocarbazole matter white /400 mg, so pl. 270oC /colour / div./.

The above product (400 mg) 0,0012 M/ dissolved in dioxane /100 ml, and races through the ode was removed from the solution by passing through him N2and the solid product 3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride was collected by filtration, washed with diethyl ether and dried to obtain the desired compound in the form of a solid substance white /300 mg/. so pl. 270oC /colour / div./.

1H NMR [250 MHz, DMSO-d6] 1,96 /1H, m, 2,16 - 2,30 /1H, m, 2,74 /1H, DD/, 2,85 /2H, m, 3,12 /1H, DD/, one signal obscured H2O 3.6 7,08 /1H, Shir. with/, 7,27 /1H, d/, to 7.61 /1H, d/, 7,87 /1H, Shir.with/, 7,99 /1H/, 8,39 /3H, Shir.s/.

Example 3.

3-Amino-6-methoxy-1,2,3,4-tetrahydrocarbazole hydrochloride.

The reaction of 4-methoxyphenyl hydrazine hydrochloride /0.87 g, 5.0 mm/ s 4 phthalimido-cyclohexanone /1.22 g, 5.0 mm in ethanol /20 ml/ was heated with phlegmasia 2 h followed by cooling and removing the precipitated substance is filtered, which gave 3-phthalimido-6-methoxy-1,2,3,4-tetrahydrocarbazol /1,62 g/.

The specified product /1,57 g, 4.5 mm/ suspenderbelt in methanol /100 ml and was treated with hydrazine hydrate /23 ml/ s by stirring at room temperature. After 30 min the solvent was removed in vacuum and the residue was divided between the K2CO3/water./ and EtOAc. The last layer was separated, washed with water, dried /MgSO4/ and evaporated to dryness. This residue was dissolved in etano the g/, so pl. > 250oC.

1H NMR [250 MHz, DMSO-d6] 1,81 - 2,02 /1H, m, 2,10 - 2,28 /1H, m, 2,65 /1H, DD/, 2,82 /2H, m, 3,02 /1H, DD/, 1 signal darkened H2O 3.5, 3,74 /3H/, 6,66 /1H, d/, 6,84 /1H, d/, 7,14 /1H, d/, 8,16 /3H, Shir.s/.

Example 4.

3-Amino-6-bromo-1,2,3,4-tetrahydrocarbazole hydrochloride.

The reaction of 4-bromophenylacetate hydrochloride /4.0 g, 18,1 mm/ s 4 phthalimido cyclohexanone /4,39 g, 18,1 mm/ in irrigating n-butanol for 20 min followed by cooling, filtration and evaporation of the filtrate to dryness gave 3-phthalimido-6-bromo-1,2,3,4 - tetrahydrocarbazol in a solid orange /7,45 g/.

This product /0.33 g, or 0.83 mm/ suspenderbelt in ethanol /13 ml and was treated with hydrazine hydrate /3 ml/, then stirred at room temperature overnight. The solid precipitate was filtered off and the filtrate was evaporated to dryness and was divided between the K2CO3/water/ ethyl acetate. After separation of the organic layer, washing with water, drying /MgSO4/ and evaporation to dryness the residue was dissolved in MeOH and treated with HCl gas. The solvent was removed in vacuo and the residue crystallized from ethanol/ethyl acetate to yield the desired compound in the form of a cream solid color /0,11 H, DD/, 3,50 /1H, m, 7,12 /1H, d/, 7,24 /1H, d/, 7,55 /1H/, 8,15 /2H, Shir.with/, 11,12 /1H, s/.

Example 5.

3-Amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole.

4-Carboxamidotryptamine hydrochloride /2,87 g/ and 4-telemedicine /3.00 g/ mixed in acetic acid, and the mixture was heated with phlegmasia 2 hours After cooling, the mixture was kind of balanced out using an aqueous solution of potassium carbonate, and the resulting yellow solid was filtered, rinsed with water and dried. Purification of column chromatography gave 3-phthalimido-6-carboxamido-1,2,3,4-tetrahydrocarbazol /2.8 g/. (SiO2, CHCl3/CH3OH).

The specified product /1.0 g/ suspenderbelt in ethanol /10 ml and was added hydrazine hydrate /5 ml/. It turned out a clean solution, and the mixture was left to mix overnight to obtain a precipitate. The entire mixture was evaporated to dryness, washed with an aqueous solution of K2CO3and water. Was obtained in the form of a monohydrate desired compound 3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole, so pl. 146 - 148oC.

1H NMR [250 MHz, DMSO-d6] 1,49 - 1,77 /1H, m, 1,83 - 2,03 /1H, m, 2,17 - 2,40 /1H, m, 2,62 - 2,80 /1H, m, 2,90 /1H, DD/, 1 signal invisible because of the water on 3.1, 7,03 /1H, Shir.with/, 7,18 /1H, d/, 7,58 /1H, d/, 7,83 /1H, Shir.with/, 7,98 /1H, s/.

<.

//-3-t-Butyloxycarbonyl-6-carboxamido-1,2,3,4 - tetrahydrocarbazole was separated into its enantiomers using chiral HPLC: /chiracel OD 4.6 mm column by washing with hexane/ethanol 85:15/. /+/-Enantiomer was going first and had so pl. 150 - 152oC and []2D5= +70,1 /methanol, 0,41% weight/vol. /. /-/-Enantiomer had so pl. 150 - 152oC and []2D5= is 79.4 /in methanol, and 0.40 wt%/vol/. /+/-Enantiomer was converted into related aminogidrohlorid treatment with HCl gas in dioxane to obtain /+/-enantiomer of 3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride, T. pl. 248 - 251oC []2D5= +26,2 /in methanol, and 0.50 wt%/vol/. /-/-Enantiomer of 3-t-butyloxycarbonyl-6-carboxamido - 1,2,3,4-tetrahydrocarbazole was also transformed into /-/-enantiomer of 3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride, T. pl. 248 - 251oC []2D5= -28,6 /in methanol, and 0.50 wt%/vol/.

Method 2.

//-6-Carboxamido-3-amino-1,2,3,4-tetrahydrocarbazol was treated with one equivalent of 2,3,4,6-di-O-isopropyl-2-keto-L-gulonovoy acid in methanol, to obtain the salt /+/-enantiomer in 38% of the output relative to the racemate/ and 34% enantiomeric excess of /ei/. This material rcris is>98% of ei. This product was converted into hydrochloride salt first processing water R-rum of an alkali metal, and the precipitated free base was treated with 2 M of water. HCl in ethanol to obtain /+/-enantiomer of 3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride.

Example 7.

3-Amino-6-methyl-1,2,3,4-tetrahydrocarbazol oxalate.

The reaction of 4-telemedicineexchange /2.16 g/ 4-tuluallikaid hydrochloride /1,41 g/ and the subsequent removal of the protection of the product by the method described in example 3, gave the free base of the desired compound, which was converted to the oxalate salt /0,23 g/, so pl. 272 - 5oC.

Example 8.

3-Amino-6-etoxycarbonyl-1,2,3,4-tetrahydrocarbazol oxalate.

The reaction of 4-telemedicineexchange /0,37 g/ 4-ethoxycarbonylpyrimidine hydrochloride /0.33 g/, and the subsequent removal of the protection method described in example 3, gave the free base of the desired compound. It was converted to the oxalate salt /0.11 g/, so pl. 230 - 240oC, decomp.

Example 9.

3-Amino-6-/N-methyl-carboxamido/-1,2,3,4-tetrahydrocarbazol proxalt.

The reaction of 4-phthalimidohexyl /1.20 g/ 4-/N-methylcarbamate/-phenylhydrazine hydrochloride /1,00 g/, and was converted to salt polyacetate /0,22 g/, so pl. 227oC, decomp.

Example 10.

3-Amino-6-cyanomethyl-1,263,4-tetrahydrocarbazol oxalate.

The reaction of 4-telemedicineexchange /1,05 g/ 4-cyanoethylidene hydrochloride /0,79 g/, and the subsequent removal of the protection method described in example 3, gave the free base of the desired compound which was treated with oxalic acid to obtain a salt of oxalate /0,49 g/, so pl. 219 - 224oC, decomp.

Example 11.

3-Amino-6-/N-methylsulfonylmethyl/-1,26364-tetrahydrocarbazol oxalate.

The reaction of 4-telemedicineexchange /0,42 g/ 4-/N-methylsulfonylmethyl/ phenyl hydrazine hydrochloride /0,44 g/, and the subsequent removal of the protection method described in example 3, gave the free base of the desired compound. It was treated with oxalic acid to obtain a salt of oxalate /0.15 g/, so pl. 218 - 222oC, decomp.

Example 12.

3-Amino-6-chloro-1,2,364-tetrahydrocarbazol oxalate.

The reaction of 4-telemedicineexchange /6.7 g/ 4-course hydrazine hydrochloride /4,93 g/, and the subsequent removal of the protection method described in example 3, gave the free base of the desired compound which was treated with oxalic acid to obtain the salt oxal the Alat.

The reaction of 4-telemedicineexchange /1,14 g/ 4-trifluoromethyl phenyl hydrochloride /1.0 g/ and the subsequent removal of the protection method described in example 3, gave the free base of the desired compound /0.40 g/. It was treated with oxalic acid, so pl. 212 - 213oC.

Example 14.

3-Amino-6-n-Butylochka-1,2,3,4-tetrahydrocarbazol oxalate.

The reaction of 4-telemedicineexchange /1.12 g/, and the subsequent removal of the protection method described in example 3, gave the free base of the desired compound. It was treated with oxalic acid, and was obtained salt of oxalate /0,47 g/, so pl. 227 - 229oC.

Example 15.

3-Amino-6-sulfonamide-1,2,3,4-tetrahydrocarbazol oxalate.

The reaction of 4-telemedicineexchange /1,00 g/ 4-sulfonamide phenyl hydrazine hydrochloride /1,08 g/, and the subsequent removal of the protection method described in example 3, gave the free base of the desired compound. It was converted to the oxalate salt /0,090 g/, decomp. > 200oC.

Example 16.

3-Amino-6-nitro-1,2,364-tetrahydrocarbazol oxalate.

The reaction of 4-telemedicineexchange /1.28 g/ 4-nitrophenyl hydrazine hydrochloride /1,00 g/, and the subsequent removal of the protection method described in example 3, d is
C.

Example 17.

3-Amino-6-/N,N-dimethyl, carboxamido/-1,2,3,4-tetrahydrocarbazol proxalt.

3-Amino-6-etoxycarbonyl-1,2,3,4-tetrahydrocarbazol /260 mg, 1.0 mm/ suspenderbelt in dry THF /5 ml and was added di-tert-butyl dicarbonate /320 mg, 1.5 mm/. After 10 min the solution was clear. The mixture is stirred for 20 h, then the solvent was removed, and the residue was dissolved in ethyl acetate, was washed with an aqueous solution of sodium bicarbonate and dried /MgSO4/. After removal of the ethyl acetate the residue was pulverized with ether and hexane to obtain 3-t-butyloxycarbonyl-6-etoxycarbonyl-1,2,3,4-tetrahydrocarbazol /310 mg/.

The above product /556 mg, 1,55 mm/ suspenderbelt in ethanol /5 ml/ 2 M NaOH /3 ml was added to it. The mixture was heated with phlegmasia 1 h and evaporated to dryness. The residue was dissolved in water and was kind of balanced out with acetic acid, when precipitated 3-t-butyloxycarbonyl-6-carboxy-1,2,3,4-tetrahydrocarbazol in a solid white color /425 mg/. The solution of the above product (400 mg, 1.2 mm/ in dry THF /8 ml/ was processed HEXAMETHYL phosphorous triamide /198 mg, 1.2 mm) and cooled to -10oC.

Gaseous diethylamine was passed through the mixture 10 is Ř stirred at room temperature for 1 h, then VHI was removed in vacuum. The residue was separated between ethyl acetate and water and the organic layer was washed with a saturated solution of sodium bicarbonate, then brine and dried /MgSO4/. The solvent was removed in vacuo, and the residual oil was pulverized with ether and hexane, and the solid was recrystallizations from toluene to obtain 3-t-butyloxycarbonyl-6-/N,N-dimethyl, carboxamido/-1,2,3,4-tetrahydrocarbazol /198 mg/.

This product was dissolved in dioxane /5 ml/, and through it passed the HCl gas to precipitate an oil. The solvent was removed in vacuo, and the oil was dissolved in water and treated with a solution of K2CO3to bring the pH to 12. Then the free base of the amine was extracted with ethyl acetate, dried /MgSO4/ and evaporated to dryness. The resulting oil was dissolved in methanol and treated with oxalic acid to obtain the desired compound in the form of solid pale pink color /140 mg/ I. pl. = 190 - 195oC.

Example 18.

3-Amino-6-/piperidine-1-yl carbonyl/-1,2,3,4-tetrahydrocarbazole hydrochloride.

The reaction of 3-t-butyloxycarbonyl-6-carboxy-1,2,3,4 - tetrahydrocarbazole /175 mg/ piperidine and product unprotect JV is x2">

3-Amino-6-/pyrrolidin-1-yl carbonyl/-1,2,3,4-tetrahydrocarbazole hydrochloride.

The reaction of 3-t-butyloxycarbonyl-6-carboxy-1,2,3,4 - tetrahydrocarbazole /140 mg/ pyrrolidino, and the product is removed from protection followed as described for example 17 gave the desired compound, so pl. 201 - 212oC /81 mg/.

Example 20.

3-Amino-6-/N,N-diethyl-carboxamido/-1,2,3,4-tetrahydrocarbazole hydrochloride.

The reaction of 3-t-butyloxycarbonyl-6-carboxy-1,2,3,4 - tetrahydrocarbazole /105 mg/ diethylamine and removing protection product as described in example 17 gave the desired compound, so pl. 200 - 205oC /50 mg/.

Example 21.

3-Amino-6-acetamido/-1,2,3,4-tetrahydrocarbazol oxalate.

The reaction of 4-phthalimido cyclohexanone /1.2 g/ 4-acetamido-phenyl hydrazine hydrochloride /1.0 g/, and the subsequent removal of the protection of the product by the method of example 3 gave the free base of the desired compound /570 mg/. Part of this product /50 mg/ was treated with oxalic acid in methanol, to obtain a salt of oxalate, which melts at >170oC /38 mg/.

Example 22.

3-Amino-6-methanesulfonamido-1,2,3,4-tetrahydrocarbazol oxalate.

3 Phthalimido-6-nitro-1,2,3,4-tetrahydrocarbazol the lyst hydrogenation, and the mixture was gerasoulis at initial pressure in 39 f/d2/2.74 kg/cm2/ 4 h After filtering off insoluble materials, the filtrate was evaporated to dryness and extracted twice in 20% aqueous methanol, and the extracts were combined and reduced in volume to give 3-phthalimido-6-amino-1,2,3,4-tetrahydrocarbazol /0,31 g/.

The specified product /0.50 g/ dissolved in fresh distilled pyridine /30 ml, and was added methanesulfonamide /0.28 g/ 4-dimethylaminopyridine /46 mg/. The mixture was heated with stirring at 50oC 5 h, then evaporated to dryness. The residue was dissolved in chloroform, washed with water, brine and aqueous sodium bicarbonate, then dried /MgSO4/ and evaporated to dryness to obtain a pale yellow substance that was recrystallizations from aqueous ethanol to yield 3-phthalimido-6-methanesulfonamido-1,2,3,4 - tetrahydrocarbazole /0.27 g/.

The specified connection was suspendibility in ethanol /15 ml and was added hydrazine hydrate /2,72 g/. After 25 minutes of mixing at room temperature the mixture was evaporated to dryness, was divided between water and ethyl acetate, and the aqueous layer was re-extracted with ethyl acetate. Organic extracts of Segesta. It was dissolved in methanol and treated with oxalic acid /89 mg/. The addition of ether resulted in crystallization of the desired connection /50 mg/, so pl. 230 - 233oC.

Example 23.

3-Amino-6-carboxymethyl-1,2,3,4-tetrahydrocarbazole hydrochloride.

3-Amino-6-cyanomethyl-1,2,3,4-tetrahydrocarbazol /2.5 g/ and di-t-butyl dicarbonate /3,63 g/ stirred in THF /56 ml/ 2 h THF was evaporated, and the residue was divided between aqueous sodium bicarbonate solution and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate, and the combined organic extracts were washed with water, dried /MgSO4/ and evaporated to dryness to obtain a solid substance, which was pulverized with ether/hexane /20%/ for 3-t-butyloxycarbonyl-6 - cyanomethyl-1,2,3,4-tetrahydrocarbazole in the form of a pure white substance /3,44 g/.

Product /7,0 g/ dissolved in DMSO /70 ml) was added hydrogen peroxide /100., 3.5 ml/. After stirring 1 h was added peroxide /8,5/ ml, and the mixture is stirred 2 h at room temperature. Was added potassium carbonate /0.84 g/, and the mixture is stirred overnight and an additional 20 hours, the Reaction mixture was poured into water /500 ml, and the obtained solid white Hotfile the l-1,2,3,4 - tetrahydrocarbazol /5,42 g/.

The specified product /500 mg was dissolved in dry dioxane /30 ml) and HCl gas was passed through it for 20 minutes the resulting solution and otorisasi resin was evaporated to dryness and treated with an aqueous solution of potassium carbonate. This was extracted with ethyl acetate, and the extracts were combined, dried /MgSO4/ and evaporated to dryness. The residue was dissolved in methanol and treated with excess oxalic acid. Addition of ether gave the crystallization of the desired connection /250 mg/, so pl. 257 - 260oC.

Example 24.

3-Methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride.

4-Cyanophenyl hydrazine hydrochloride /20,2 g/ and 4-benzyloxyacetophenone /25,9 g/ dissolved in glacial acetic acid /400 ml, and the mixture was heated with phlegmasia 1,5 hours After cooling, the mixture was filtered, and the filtrate was evaporated to dryness, and was kind of balanced out with an aqueous solution of sodium bicarbonate, to obtain a solid residue, which was purified by chromatography /SiO2; hexane/ethyl acetate to yield 3-benzoyloxy-6-cyano-1,2,3,4-tetrahydrocarbazole /18.0 g/. This product /11.6 g/ suspenderbelt in ethanol /230/ ml and were treated with 2.5% aqueous solution of potassium hydroxide /120 ml) and was heated with phlegmasia 1 tsp of OHL who was Romualda water and dried, to obtain 3-hydroxy-6-cyano-1,2,3,4-tetrahydrocarbazol /6.6 g/.

The specified product /3.57 g/ dissolved in dry pyridine /35 ml, and the mixture is stirred at 100oC 2 h After cooling the solution was poured into water /500 ml/. Was extracted with ethyl acetate, and the latter extract was washed with 2 M HCl, dried /MgSO4/ and evaporated to dryness. Purification by chromatography /SiO2; hexane/ethyl acetate/ Dali 3-tosyloxy-6-cyano-1,2,3,4-tetrahydrocarbazol /0,53 g/.

This product /0.40 g/ dissolved in 33% methylamine in ethanol /25 ml and heated at 100oC in a sealed steel vessel 1,5 hours After cooling, the mixture was evaporated to dryness and purified by chromatography /SiO2; chloroform/methanol/ to get a 3-methylamino-6-cyano-1,2,3,4-tetrahydrocarbazol /0,13 g/.

The specified product /0.12 g/ dissolved in THF /10 ml and reacted with di-tert-butyl dicarbonate /0.36g/ THF /3 ml at room temperature overnight. The reaction mixture was evaporated to dryness, was divided between 2 M solution of sodium bicarbonate and ethyl acetate, and the organic layer was dried and evaporated to obtain the substance of white color. It was pulverized with ether/hexane to obtain 3-t-butyloxycarbonyl-methyl amino-6-cyano-1,2,3,aqueous sodium hydroxide /0,20/ ml and 30% hydrogen peroxide /0,20 ml/, and the mixture stirred at room temperature overnight. Was added sodium metabisulfite /38 mg/, and the solution was evaporated to dryness and chromatographically /SiO2; chloroform/10% NH4OH in methanol/ to get a 3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazol /0.12 g/. The specified connection /0.11 g/ dissolved in methanol /10 ml and processed 3 M hydrochloric acid at room temperature. The mixture was evaporated to dryness, azeotropically ethanol, to obtain a solid substance, which was recrystallizations from methanol/ether to obtain the desired connection, so pl. 327 - 328oC /80 mg/.

1H NMR [250 MHz, MeOH-d4] D. 1,98 - 2,20 /1H, m/, to 2.29 - 2.49 USD /1H, m, of 2,75 2,90 /5H, s+m/, 2,90 - 3,09 /2H, m, 3,52 at 3.69 /1H, m, 7,31 /1H, d/, 7,63 /1H, d/, 8,05 /1H, s/.

Example 25.

3 Ethylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazol oxalate.

1,4-Cyclohexanedione mono-2',2'-dimethyl trimethylene ketal /2,00 g/ was mixed with anhydrous ethylamine /10.0 g/ benzene /10.0 ml) and the mixture was cooled to 5oC. was added dropwise a solution of Titania tetrachloride /0.95 g/ benzene /10 ml, the mixture is then stirred at room temperature for 1 h the Mixture was filtered and evaporated to dryness to obtain an oil, cod was gerasoulis at 50 f/d2/3.5 kg/cm2/ pressure all night. The catalyst was filtered off and the ethanol was evaporated to obtain 4-ethylamino-cyclohexanone 2',2'-dimethyl trimethylene ketal in the form of oil /2.0 g/.

This connection /0,80 g/ dissolved in formic acid /20 ml, and the solution was heated to 90oC 1 h of Formic acid was evaporated, and the residue was divided between chloroform and 1M hydrochloric acid. The aqueous layer was evaporated to dryness to give 4-ethylaminoethanol /0.40 g/.

A mixture of the specified product /0.40 g/ and 4-carboxamidine hydrazine hydrochloride /0,60 g/ glacial acetic acid /20 ml/ was heated with phlegmasia 1 h Acid was evaporated in vacuo to an oil, which was purified by chromatography /SiO2; CHCl3/10% NH3in MeOH/ to get the oil /0.50 g/. Part of this product /150 mg/ dissolved in methanol and treated with oxalic acid. The solution was treated with ether to obtain the desired compound in the form of a crystalline solid, so pl. 165-170oC /100 mg/.

1H NMR [250 MHz, DMSO-d6] D. 1,25 /3H, t/, 1,81-2,05 /1H, m, 2,20 - 2,38 /1H, m, 2,61 - 2,79 /1H, m, 2,79 - 2,94 /2H, m, 2,98 of 3.28 /3H, DD+/, 3,41 - 3,60 /1H, m, 7,08 /1H, Shir.with/, 11,12 /1H, s/.

Example 26.

3-n-Propylamino cooling was added 1.5 M HCl in methanol /5.6 ml/. After 1 min was added 1,4-cyclohexanedione mono-2',2'-dimethyl trimethylene ketal /1.0 g/, and after another 10 min - cyanoborohydride sodium /0,23 g/. The mixture is stirred at room temperature for 3 days. The resulting mixture was filtered and the filtrate was evaporated and processed 1M HCl /10 ml/ cooling. The residue was evaporated to form a solution which was washed with ether, had reason to pH 12 with aqueous sodium hydroxide and was extracted with dichloromethane. This extract was washed with saturated aqueous sodium bicarbonate solution, dried /MgSO4/ and evaporated to dryness. Chromatography /SiO2; chloroform/methanol/ammonia/ gave 4-n-propylamino cyclohexanone 2',2'-dimethyl trimethylene ketal /0,72 g/.

This product /0,66 g/ hydrolizable to the ketone, which was reacted with 4-carboxamidine hydrazine hydrochloride was converted to the oxalate salt as described in example 25 to give the desired output connection /0,44 g/, so pl. >168oC, decomp.

Example 27.

3-i-Propylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazol oxalate.

The reaction Isopropylamine /9,54 g/ s 1,4-cyclohexanedione mono-2',2'-dimethyl trimethylene katalam /2.0 g/ in the manner described for example 25, gave 4-i-Propylamine is AMINOPHENYL hydrazine hydrochloride /0.45 g/, and the mixture was processed as described above to obtain the free base of the desired compound /0.34 g/. It was converted to the oxalate, so pl. >235oC, decomp.

Example 28.

3-Dimethylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazol oxalate.

Dimethylamine /10.0 g/ reacted with 1,4-cyclohexanedione mono-2',2'-dimethyl trimethylene katalam /2.0 g/ in the manner described for example 25 to obtain 4-dimethylamino-cyclohexanone-2',2'-dimethyl trimethylene ketal /0,72 g/. This product /0,72 g/ hydrolizable and reacted with 4-carboxamidine hydrazine hydrochloride /0,47 g/, and the product was converted to the oxalate salt as described above to obtain the desired connection /0.20 g/, so pl. 99 - 101oC.

1H NMR [250 MHz, DMSO-d6] D. 1,83 - 2,05 /1H, m, and 2.27 - 2.40 a /1H, m, 2,72 - 3,00 /9H, 2m+/, 2,37 - 3,22 /1H, DD/, 3,50 - 3,68 /1H, m, 7,05 /1H, Shir. with/, 7,27 /1H, d/, 7,60 /1H, d/, 7,81 /1H, Shir.with/, 8,00 /1H/, to 11.11 /1H, s/.

Example 29.

3 Benzylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazol oxalate.

The reaction benzylamine /0,59 g/ s 1,4-cyclohexanedione-mono-2',2'-dimethyl trimethyl-katalam /1.0 g/ and the subsequent restoration of the imine cyanoborohydride sodium in the manner described for example 26, gave 4-benzylamino-cyclohexane 2', 2'-dimethyl truck was treated with oxalic acid, to get the connection, so pl. >190oC, decomp. /0.11 g/.

Example 30.

3-Pyrrolidinyl-6-carboxamido-1,2,3,4-tetrahydrocarbazol oxalate.

The reaction pyrrolidine /15.6 g/ s 1,4-cyclohexanedione mono-2',2'-dimethyl trimethylene katalam /2.0 g/ in the manner described for example 26, gave 4-pyrrolidinyl-cyclohexanone-2',2'-dimethyl trimethylene ketal /1,74 g/. This product /1.70 g/ hydrolizable and reacted with 4-carboxamidine hydrazine hydrochloride /1.70 g/, and the product was treated with oxalic acid as described above to obtain the desired connection /32 mg/, so pl. >190oC, decomp.

Example 31.

3-/N-Methyl, ethylamino/-6-carboxamido-1,2,3,4-tetrahydrocarbazol oxalate.

The reaction of N-methyl-ethylamine /13,0 g/ s 1,4-cyclohexanedione mono-2',2'-dimethyl trimethylene katalam /2.0 g/ in the manner described for example 265, gave 4-/N-methyl, ethylamino/-cyclohexanone-2',2'-dimethyl trimethylene ketal /1,71 g/. This product /0,86 g/ hydrolizable and reacted with 4-carboxamidine hydrazine hydrochloride /0.52 g/ and processed as described above to obtain the desired connection /76 mg/, so pl. >130oC, decomp.

Example 32.

3-Amino-6-/2-carboxamidates/-1,2,3,4-tetrahydrocarbazol oxalate.

oC and stirring. The solvent was removed in vacuo, and the residue was dissolved in hot ethyl acetate, and the solution was shaken with 1M solution of sodium hydroxide. The resulting organic phase was dried, filtered and evaporated. Remained a residue, which was removals with ethyl acetate to obtain 4-nitro cinnamamide in the form of a crystalline substance /18,6 g/. This product /18,6 g/ suspenderbelt in ethanol /1 l/ and gidrirovaniya using Pd-C catalyst /6.6 g/ at a pressure of 50 lb/d2/3.5 kg/cm2/ for 1 h the mixture was filtered and evaporated to dryness to obtain 4-AMINOPHENYL propionamide /17.1 g/.

Was slowly added concentrated hydrochloric acid /4 ml/ product 4-AMINOPHENYL propionamide /0,80 g/, with maintaining the temperature below 5oC. To this slurry was added a solution of sodium nitrite in /0,37 g/ in water /2 ml for 15 min dropwise, followed by stirring for 15 minutes thus Obtained turbid solution portions were added to the cooled AC is the solution recovered in the volume until then, until the formed inorganic sediment. It was filtered, and the filtrate was evaporated to dryness. The residual resin was crystallized from acetic acid to obtain crude 4-hydrazinophenyl propionamide hydrochloride /1,05 g/.

A mixture of the above product /1,05 g/ and 4-telemedicineexchange /1.18 g/ acetic acid /40 ml/ was heated with phlegmasia 40 minutes the Solvent was removed in vacuo, and the residue was divided between aqueous potassium carbonate solution and ethyl acetate. The organic phase was dried /MgSO4/ and evaporated to dryness, and the residue was chromatographically /SiO2; CH2Cl2/MeOH to give 3-phthalimido-6-carboxymethyl-1,2,3,4-tetrahydrocarbazol /0,70 g/.

This product /0,70 g/ dissolved in methanol /50 ml, was treated with hydrazine hydrate /1.0 ml/ and was heated with phlegmasia 30 minutes the Mixture was evaporated to dryness, then was divided between ethyl acetate and aqueous potassium carbonate solution. The organic phase was dried /MgSO4/ and evaporated to dryness, and the residue was dissolved in ethanol and was treated with oxalic acid /83 mg/ ethanol. Turned out solid, which was recrystallizations from ethanol to obtain the desired connection /110 mg/, so PL is e of the formula I (in the example At the end of the description) is dissolved in citric acid, and the pH is slowly brought up to 3.2 solution of sodium hydroxide. Then the solution is supplemented to 100 ml with water, sterilized by filtration and sealed in ampoules of various sizes.

1. The method of treatment status, which shows the 5-HT1-like agonist, wherein appointed to a subject in need of such treatment, derived tetrahydrocarbazole General formula I

< / BR>
in which R1represents hydrogen, halogen, trifluoromethyl, nitro, hydroxy, C1-6-alkyl, C1-6-alkoxy, aryl-C1-6-alkoxy, -CO2R4, -(CH2)nCN, -(CH2)nCONR5R6, -(CH2)nSO2NR5R6C1-6-alkanolamine(CH2)nor C1-6alkylsulfonamides (CH2)n;

R4represents hydrogen, C1-6alkyl or aryl (C1-6alkyl; R5and R6each independently represents hydrogen or C1-6alkyl or

R5and R6together with the nitrogen atom to which they are attached, form a ring;

n represents 0, 1 or 2;

R2and R3each independently represents hydrogen, C1-6-alkyl or benzyl or together with the nitrogen atom to which they are attached, form a ring pyrrolidino, p/P> 2. The method of treatment under item 1, characterized in that the compound of the formula I R1represents halogen, CF3C1-6alkoxy, -(CH2)nCN, -(CH2)nCONR5R6, -(CH2)nSO2NR5R6or C1-6alkanolamine and R5and R6is as defined above.

3. The method of treatment under item 1 or 2, characterized in that the compound of the formula I R1is a group -(CH2)nCONR5R6in which n = 0 and R5and R6each independently represent hydrogen, methyl or ethyl.

4. The method according to PP.1 to 3, wherein R2and R3each independently represent hydrogen, methyl or ethyl.

5. The method of treatment according to PP.1 to 4, characterized in that the compounds of formula I using 3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole or its physiologically acceptable salt, MES or hydrate.

6. The method according to PP.1 to 5, characterized in that the use of physiologically acceptable salt of the compounds of formula I derived from hydrochloric, sulfuric, phosphoric, succinic, maleic, acetic or fumaric acid.

7. The method of treatment according to PP.1 - 6, characterized in that it is done with migraines.

8. MES or hydrate administered in dosed form at the rate of 0.1 - 500 mg per day.

9. The method according to any of paragraphs.1 to 8, characterized in that the compound of formula I or its physiologically acceptable salt prescribe oral, parenteral, buccal (cheek), sublingual, nasal (through the nose), rectal, or transdermal.

10. Derived tetrahydrocarbazole formula 1A

< / BR>
where R1represents nitro, CN, -CO2R4, -(CH2)nCONR5R6C1-6alkylsulfonamides (CH2)nor -(CH2)nSO2NR5R6where R4means aryl C1-6alkyl, R5and R6each independently represents hydrogen or C1-6-alkyl, or R5and R6together with the nitrogen atom to which they are connected, form a ring,

n = 0, 1, or 2,

or its physiologically acceptable salt, MES or hydrate of the compound.

11. Derived tetrahydrocarbazole formula 1A under item 10, where R1represents a group -(CH2)nCONR5R6where n is 0 and R5and R6each independently mean hydrogen, methyl, ethyl or propyl.

12. Connection on p. 10, chosen from:

(+)-3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole, 3-amino-6-cyano-1,2,3,4-tetrahydrocarbazole,

(-)-3-am/BR>3-amino-6-(N-methylsulfonylmethyl)-1,2,3,4-tetrahydrocarbazole,

3-amino-6-sulfonamide-1,2,3,4-tetrahydrocarbazole,

3-amino-6-nitro-1,2,3,4-tetrahydrocarbazole,

3-amino-6-(N,N-dimethylcarbamate)-1,2,3,4-tetrahydrocarbazole,

3-amino-6-(piperidine-1-yl-carbonyl)-1,2,3,4-tetrahydrocarbazole,

3-amino-6-(pyrrolidin-1-yl-carbonyl)-1,2,3,4-tetrahydrocarbazole,

3-amino-6-(N,N-diethylcarbamyl)-1,2,3,4-tetrahydrocarbazole,

3-amino-6-methanesulfonamido-1,2,3,4-tetrahydrocarbazole,

3-amino-6-carboxymethyl-1,2,3,4-tetrahydrocarbazole,

3-amino-6-(2-carboxymethyl)-1,2,3,4-tetrahydrocarbazole,

or a physiologically acceptable salt of the compound, its MES or its hydrate.

13. The compound of formula 1, described in paragraph 1, chosen from:

3 ethylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole,

3-n-propylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole,

3 isopropylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole,

3-dimethylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole,

3 benzylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole,

3-pyrrolidinyl-6-carboxamido-1,2,3,4-tetrahydrocarbazole,

3-(N-(methyl)ethylamino)-6-carboxamido-1,2,3,4-tetrahydrocarbazole,

or visionneur in paragraph 1, representing 3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole or its physiologically acceptable salt, MES or hydrate.

15. Connection PP.10 to 14, where the physiologically acceptable salt is formed from hydrochloric, sulfuric, phosphoric, succinic, maleic, acetic or fumaric acid.

16. The method of obtaining compounds of General formula IA according to p. 10, which consists in the fact that the compound of General formula II

< / BR>
in which R1matter specified in paragraph 10, or its additive salt of the acid, is subjected to the interaction with the compound of the formula III

< / BR>
in which R2and R3is hydrogen,

or N-protected derivative, followed, if necessary, converting the compounds of formula IA, where R1=(CH2)nCN, the hydrolysis of the compound of formula IA, where R1=(CH2)nCONH2or CO2R4or N-protected derivative, or converting the compounds of formula IA, where R1=CO2H, aminating the compound of formula IA, where R1=CONR5R6or N-protected derivative, the values of R4, R5, R6defined in paragraph 10, followed, if necessary, removing any group protecting the nitrogen atom is IA under item 10, namely, that carry out the reaction of the compound of formula IV

< / BR>
in which R1matter specified in paragraph 10,

Z is a leaving group,

with the compound of the formula

HNR2R3,

in which R2and R3is hydrogen,

followed, if necessary, converting the compounds of formula IA, where R1= -(CH2)nCN, the hydrolysis of the compound of formula IA, where R1=-(CH2)nCONH2or CO2R4or N-protected derivative, or converting the compounds of formula IA, where R1=-CO2H, aminating the compound of formula IA, where R1= -CONR5R6or N-protected derivative, the values of R4, R5and R6defined in paragraph 10, followed, if necessary, removing any group protecting the nitrogen atom and, if desired, the formation of salts of the compounds obtained.

18. The method of obtaining compounds of General formula IA according to p. 10, namely, that carry out the reaction of the compound of formula V

< / BR>
in which R2, R3is hydrogen,

with allermuir or sulfonylureas agent, followed, if necessary, converting the compounds of formula IA, where R1=-(CH2)nCN, guide the military derivative, or the transformation of compounds of formula IA, where R1=CO2H, aminating the compound of formula IA, where R1=-CONR5R6or N-protected derivative, the values of R4, R5and R6defined in paragraph 10, followed, if necessary, removing any group protecting the nitrogen atom, and optionally, the formation of salts of the compounds obtained.

19. The pharmaceutical composition active agonist NT1-like receptors, including an active ingredient and a carrier, wherein the active ingredient contains an effective amount of compounds of formula IA, as defined in any of paragraphs.10 to 15, or its physiologically acceptable salt.

 

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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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