Heteroaromatic or their pharmaceutically acceptable salts and pharmaceutical compositions on their basis

 

(57) Abstract:

Usage: in medicine as acetylcholinesterase inhibitors. The inventive products: heteroarenes formula (I), where a is benzene, R1- benzyl or alkyldiethanolamine, R2and R3is hydrogen, C1-C6-alkyl, phenyl, NR2, NH2or CH3C(O)-NH-group, X is nitrogen or CH, Y Is O, S or NR6, R6- N, (C1-C6)alkyl, NO2is phenyl, n is 1-4, q is 1 or 2, Z is oxygen. Reagent 1: compound of formula (II). Reagent 2: compound of formula (III). Reaction conditions: in the presence of base: 2 S. and 4 C.p. f-crystals, 2 PL.

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q

The invention relates to heteroelement formula I, below, and pharmaceutically acceptable salts of such compounds. The compounds of formula I are acetylcholinesterase inhibitors and are useful to enhance memory in patients suffering from dementia and Alzheimer's disease.

Alzheimer's disease is associated with degeneration of cholinergic neurons in the basal anterior segment of the brain that play a fundamental role in cognitive functions, including memory (Becker at al. Drug Development Research, 12, 163-195 1988).

As a result of this degeneration in pertransaction, the activity of acetylcholinesterase and the uptake of choline.

It is known that the acetylcholinesterase inhibitors are effective in enhancing cholinergic activity and is useful to improve memory in patients with Alzheimer's disease.

Inhibition of the enzyme acetylcholinesterase and connections increase the level neiroperedacha of acetylcholine in the brain and thus enhance memory.

Becker at al. supra, reports that corresponding changes following the inhibition of cholinesterase, match the predicted peak levels of acetylcholine in the brain.

They also discuss the effectiveness of three known inhibitors of acetylcholinesterase of physostigmine, metrifonate and tetrahydroaminoacridine.

Patent application US N 07/639614 January 10, 1991, and patent application U.S. N 07/676918 dated March 28, 1991, both are in common to the present application and to heteroarylboronic to acetylcholinesterase inhibitors.

The present invention relates to compounds of the formula:

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where one of R2, R3and a side chain containing a-Z, can be optionally joined to the carbon atom marked with an asterisk in the ring, rather than to the atom of ring A;

R1represents phenyl, phenyl-(C1-C6)alkyl, cinnamyl or heteroaromatic, where heteroaryl residue specified heteroaromatic selected from imidazole, thiazole, thieno, pyrido and isoxazole and where specified phenyl and the heteroaryl residue may be optionally substituted by one or two substituents, independently selected from (C1-C6)alkyl, (C1-C6)alkoxy and halogen;

R2and R3are independently selected from hydrogen, (C1-C6)alkoxy, (C1-C6)alkyl, optionally substituted from one to three fluorine atoms, benzyloxy, hydroxy, phenyl, benzyl, halogen, nitro, cyano, COOR4, CONHR4, NR4R5, NR4COR5or COpCH2-phenyl, where p is 0, 1 or 2;

or R2and R3are attached to adjacent carbon atoms and form together with the carbon to which they are attached, a 5-or 6-membered ring, where each atom of the ring is carbon, nitrogen or oxygen (for example, methylenedioxy, Ethylenedioxy or laktamovogo ring);

R4and R5are independently selected from hydrogen and (C1-C6)alkyl, or R4and R5if they ablauts the ring, containing from 4 to 8 atoms, in which one of the ring atoms is nitrogen and the others are carbon, oxygen or nitrogen, or R4and R5if they are part of the specified NR4COR5not necessarily form together with the nitrogen atom and the carbon to which they are attached, a 4 to 8-membered laktamovogo ring;

X represents nitrogen or CH;

Y represents oxygen, sulfur or NR6;

R6represents hydrogen, (C1-C6)alkyl, CO(C1-C6)alkyl or SO2- phenyl, where the phenyl residue specified SO2is phenyl optionally may be substituted by one to five substituents, optionally selected from (C1-C4)alkyl;

n is an integer from 1 to 4;

each q is independently 1 or 2 and

Z represents oxygen or sulfur;

provided that any CHqgroup, where q is 1, should join the one and only such other group CHqin which q is 1.

The present invention also relates to pharmaceutically acceptable additive salts of acid compounds of formula I.

Examples of such pharmaceutically acceptable additive salts of acids are salts of hydrochloric acid, p-toloo the Oh of the acid, oxalic acid, Hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, di-p-Dalwallinu acid and almond acid.

In addition, this invention relates to pharmaceutical compositions for the inhibition of acetylcholinesterase-containing compound of the formula I or its pharmaceutically acceptable salt accession acid and a pharmaceutically acceptable carrier.

The invention also relates to a method of inhibiting acetylcholinesterase in mammals comprising the administration to a mammal the compounds of formula I or its pharmaceutically acceptable salt accession acid in a quantity effective for the inhibition of acetylcholinesterase.

The invention also relates to a method to enhance memory or the treatment or prevention of Alzheimer's disease in mammals, which consists in the introduction to the mammal the compounds of formula I or its pharmaceutically acceptable salt accession acid in a quantity effective to enhance memory or the treatment or prevention of Alzheimer's disease.

The term "mlekopitayushchie" as it is used here, includes people.

The term "halogen", as he espasa compounds of the formula

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X represents CH, CCH3, CCH2CH3or N; Y is NH, NCH3NCH2CH3, S, O or NSO2C6H5; R2and R3represent substituents, independently selected from the group consisting of (C1-C4)alkyl, chlorine, fluorine, methoxy, or amino and R2and R3together with the carbon to which they are attached, form a-laktamovogo ring; and R1represents benzyl, methoxybenzyl, tormentil or a group of the formula:

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W represents hydrogen, (C1-C6)alkyl, phenyl or benzyl.

Specific preferred compounds of the invention are:

1-/2-methyl-1H-benzimidazole-5-yl/-3-/1-/phenylmethyl/-4-piperidinyl/-1-propanone;

1-/2-phenyl-1H-benzimidazole-5-yl/-3-/1-/phenylmethyl/-4-piperidinyl/-1-propanone;

1-/I-ethyl-2-methyl-1H-benzimidazole-5-yl/-3-/1-/phenylmethyl/-4-piperidinyl/-1-propanone;

1-/2-methyl-6-benzothiazolyl/-3-/1-/phenylmethyl /-4-piperidinyl/-1-propanone;

1-/2-methyl-6-benzothiazolyl/-3-/1-/2-methyl-4 - thiazolyl/methyl/-4-piperidinyl/-1-propanone;

1-/5-methyl-benzo[b]Tien-2-yl/3-/1-phenylmethyl/-4-piperidinyl/-1-propanone;

1-/6-methyl-benzo[b] Tien-2-yl/-3-/1-/phenylmethyl/-4-piperidinyl/-1-propanone;

1-/3,5-dimethyl-benzo[b] Tien-2-yl/-3-/1-/phenylmethane-2-yl/C-/1-/phenylmethyl/-4-piperidinyl/-1-propanone;

1-/1-phenylsulfonyl-6-methyl-indol-2-yl/-3-/1-/phenylmethyl/-4-piperidinyl/-1-propanone;

1-/6-methyl-indol-2-yl/-3-/1-/phenylmethyl/-4-piperidinyl/-1-propanone;

1-/1-phenylsulfonyl-5-amino-indol-2-yl/-3-/1-/phenylmethyl/-4-piperidinyl/-1-propanone;

1-/5-amino-indol-2-yl/-3-/1-/phenylmethyl/-4-piperidinyl/-1-propanone and

1-/5-acetylamino-indol-2-yl/-3-/1-/phenylmethyl/-4-piperidinyl/-1-propanone;

Examples of other compounds of the invention are:

1-/6-chinolin/-3-/1-/phenylmethyl/-4-piperidinyl /-1-propanone;

1-/5-indolyl/-3-/1-/phenylmethyl/-4 - piperidinyl/-1-propanone;

1-/5-bestanal/-3-/1-/phenylmethyl/-4 - piperidinyl/-1-propanone;

1-/6-chinadoll/-3-/1-/phenylmethyl/-4 - piperidinyl/-1-propanone;

1-/6-benzoxazolyl/-3-/1-/phenylmethyl/-4 - piperidinyl/-1-propanone;

1-/5-benzofuranyl/-3-/1-/phenylmethyl/-4 - piperidinyl/-1-propanone;

1-/5-methyl-benzimidazole-2-yl/-3-/1-/phenylmethyl/-4-piperidinyl/-1-propanone;

1-/6-methyl-benzimidazole-2-yl/-3-/1- /phenylmethyl/-4-piperidinyl/-1-propanone;

1-/5-chloro-benzo[b]Tien-2-yl/-3-/1- /phenylmethyl/-4-piperidinyl/-1-propanone;

1-/5-isoindol-2-yl/-3-/1-/phenylmethyl/-4-piperidinyl/-1-propanone;

1-/6-azabenzo[b]Tien-2-yl/-3-/1-/phenylmethyl/- 4-piperidinyl/-1-propanone;

1-/IH-2-oxo-pyrrolo- [2',3',5,6]benzo[b]thieno-2-yl/-3-/1-/phenyl is 1-/6-methoxy-indol-2-yl/-3-/1-/phenylmethyl/-4-piperidinyl/-1-propanone;

1-/6-methoxy-benzo[b]Tien-2-yl/-3-/1- /phenylmethyl/-4-piperidinyl/-1-propanone;

1-/6-acetylamino-benzo[b] Tien-2-yl/-3-/1- /phenylmethyl/-4-piperidinyl/-1-propanone and

1-/5-acetylamino-benzo[b] Tien-2-yl/-3-/1- /phenylmethyl/-4-piperidinyl/-1-propanone;

Formula I, above, includes connection, identical to those already described, but for the fact that one or more atoms of hydrogen, nitrogen or carbon are replaced by their isotopes (for example, isotopes of Tricia, carbon-14 and nitrogen-15).

Such compounds are useful for research and diagnostic purposes in pharmokinetics studies of metabolism and in experiments on the binding.

The compounds of formula I can be optically-active centers and therefore may exist in different isomeric forms. The invention includes all isomers of such compounds having formula I, including their mixtures.

Obtaining compounds having the formula I is illustrated by the following reaction schemes. Unless, otherwise stated, in the reaction schemes and the discussion following R1, R2, R3, R4, R5, R6, n, q, p, X, Y and Z and the structural formula I have the meanings as defined above.

Character * (i.e. zvezdov which it appears, indicates that the side chain containing the group, can be optionally joined to the carbon atom marked with an asterisk, rather than to the atom of ring A.

All articles, books, patents, and patent applications mentioned in the following discussion, are presented as links.

Diagram 1 5 presented at the end of the text.

Scheme 1 illustrates a method of obtaining compounds of formula I where Z is oxygen and the side chain containing , attached to the carbon atom marked with an asterisk in the ring (hereinafter it is referred to as the compound of the formula (I-A).

The source compounds having the formulas II and III are either commercially available or obtained by the methods described in the literature.

(See J. Med. Chem. 33,2777 /1990/; Tetrahedron Letters, 30, 6117, /1989/; Eur. J. Med. Chem. 25, 191 /1990/; Heteracycles, 29, 849 /1989/; J. Orq. Chem. 47,757 /1982/; J. Orq. Chem. 54, 4350 /1989/; Tetrahedron, 44, 3195 /1988/; Zur. J. Med. Chem. Chim. Ther. 21,233 /1986/; Chem. Ber. 88,34 /1954/; Tetrahedron, 28, 2553 /1972/; J. Chem. Soc. /S/ 1733 /1968/; United States Patent 4909694; J. Heterocyclic Chem. 25, 1271 /1988/; Bull. Chem. Soc. Jpn. 58,785 /1986/; J. Ind. Chem. Soc. 12, 561 /1975/; Synthetic Communications, 14, 947 (1984).

About the scheme 1, the compound of formula 11 communicates with the appropriate compound of formula II in the presence of a base, with the formation of setvariable at a temperature of from about -78oC to about 0oC. Appropriate solvents include tetrahydrofuran (THF), a simple ether, toluene, methylene chloride, benzene and dioxane.

Appropriate bases include lithium/bis/(trimethylsilyl)/amide, sitedisability, nutritionalvalue, athribis/(trimethylsilyl)/amide, n-utility, /n-BuLi/ with-utility /S-BuLi/ t-utility /t-BuLi/.

The compound of formula IV obtained in the previous stage, and then converted into the corresponding compound of formula I And its interaction with oxidizing agent.

Examples of oxidizing agents that can be used include manganese dioxide, chromium trioxide and dioxide selenium. The manganese dioxide is preferred.

Typically the oxidation is carried out in an inert reaction solvent at a temperature from about room temperature up to about 80oC, preferably from about 50oC to about 80oC.

Examples of appropriate solvents are methylene chloride, chloroform, ethyl acetate, benzene and toluene. The preferred solvent is methylene chloride or benzene.

Scheme 2 illustrates a method of obtaining compounds of formula I where Z is oxygen and n is 2, 3 or 4 (hereinafter referred to who will win at least one carbon-carbon double bond (hereinafter, it refers to compounds of formula I-V).

On the scheme 2, the starting compound having the formula V and VI, may be commercially available or obtained, as described in the literature (see J. Org. Chem. 54, 4350, /1989/; Tetrahedron, 44, 3195 /1988/; Chem. Pharm. Ball, 39, 181 /1991/; Chem. Ber. 119,2069 /1986/: J. Ind. Chem. Soc. 12,561 (1975).

As shown in scheme 2, the compound of formula V interacts with the aldehyde of the formula VI in the presence of a base with formation of the corresponding compounds of formula VII.

Appropriate bases for this reaction include sodium hydride, lithium/bis/(trimethylsilyl)/amide, piperidine, pyrrolidine, sitedisability, nutritionalvalue, n-utillity and s-utility.

The reaction is usually conducted in an inert reaction solvent such as THF, dimethylformamide (DMF), dioxane, toluene, methylene chloride or ether, preferably THF, ether or toluene.

The reaction temperature may be in the range from about -78oC to 40oC and is preferred from about -78oC to about 0oC.

If the reaction between the compounds of formulae V and VI is carried out in the presence of sodium or potassium (C1-C5)alkoxide, preferably using toluene, DMF, THF or methylene chloride as a solvent, (C1is respectfully from about 0oC to about room temperature.

Subjecting the compound of formula VII thus obtained, the reaction of elimination, receive a corresponding compound of formula IB.

Elimination is usually carried out by the interaction of the compounds of formula VII in the presence of a base, with a reagent capable of forming a group to delete in the interaction with the hydroxy group of the formula VII.

Appropriate reagents include acetic anhydride, R7S02Cl, R7COCl, R7OCOCl and R7NCO, where R7selected from (C1- C4)alkyl or phenyl, optionally substituted C1- C6)alkyl, (C1-C4)alkoxy or nitro.

Examples of appropriate bases are triethylamine, diisopropylethylamine, diazobicyclo (DBU) and diazabicyclo. The solvent may be any inert reaction solvent (e.g. methylene chloride, chloroform, THF or toluene).

The reaction temperature may be in the range from about 0oC to about 60oC and, preferably, from about 0oC to about room temperature.

In addition, the compounds of formula IB can be obtained by the interaction of soedineniya, as described in J. Arner. Chem. Soc. 90, 4744 /1968/.

Generally, this reaction is carried out in an inert solvent, such as THF, ether, benzene, toluene or dioxane, preferably THF, at a temperature from about room temperature up to the temperature phlegmy solvent, preferably, from about 50oC to about 80oC.

The corresponding compound of formula I-A' then obtained by hydrogenation of the compounds of formula I, obtained in the above stage.

In General, the hydrogenation is accompanied by the use of platinum dioxide or palladium on coal at a pressure of from about 0.2 kg/cm2up to about 0.35 kg/cm2.

Appropriate inert reaction solvents include THF, methanol, ethanol, ethyl acetate and mixtures thereof. Preferably the solvent is a mixture of ethanol and THF, or a mixture of ethanol and ethyl acetate.

The reaction temperature may be in the range from about 0oC to about 60oC. Preferably, the temperature is room temperature.

Obtaining compounds having formula I-C and I-D is illustrated in scheme 3. The compounds of formula I-C are those compounds of formula I, where a is benzo, Y represents NR6, R6represents hydrogen, X prockai (*) in the ring Century.

The compounds of formula I-D are those compounds of formula I, where a is benzo, Y represents NR6, R6represents the value, other than hydrogen, X is nitrogen, R3is hydrogen and R2attached to the carbon atom marked with an asterisk (*) in the ring Century.

About the scheme 3, the reaction of the compound of formula IX with an aldehyde of formula X to obtain the compounds of formula XI is carried out, using the method presented in scheme 2 and described above for the reaction stages Y _ YII _ I__ B _ I__A.

The resulting compound of formula XII is then subjected to cyclization in the presence of acid to obtain the corresponding compounds of formula I-C.

Examples of acids that can be used are acetic acid, a mixture of acetic acid and (C1-C4)alcohol, hydrochloric acid and ether saturated with hydrogen chloride.

This reaction is usually carried out at a temperature from about room temperature up to about 120oC. Temperatures from about 60oC to about 90oC are preferred.

The group R6can be attached to the compound of formula I-C to obtain the corresponding compounds having the formula I-D, interaction of the This reaction is usually carried out in an inert solvent in the presence of a base at a temperature from about -78oC to about temperature phlegmy solvent.

Appropriate bases include sodium hydride, sitedisability, t-utility, t-piperonyl potassium.

Appropriate solvents include THF methylene chloride, benzene, ether, toluene or dioxane. The reaction is preferably carried out in THF in the presence of sodium hydride at a temperature of from about 0oC to about 30oC.

Scheme 4 illustrates the formation of compounds of formula I, where Z is sulfur (hereinafter this relates to compounds of formula I-F), compounds of formula I-E.

This transformation is accompanied by the interaction of the compounds I-E with Lawesson reagent/2,4-bis/4-methoxyphenyl/-1,3-dithia-2,4-diphosphate-2,4-disulfide/ or pentasulfide phosphorus (P2S5). Typically this reaction is carried out in an inert reaction solvent such as THF, acetonitrile, chloroform or toluene at temperatures from about room temperature to about 120oC. Preferably the reaction is performed in THF or toluene at a temperature of from about 60oC to about 80oC.

The compounds of formula I, where R1is Deputy other than benzyl, can be obtained from corresponding compounds of formula I, where R1is.

First, the compound of formula I-G interacts with CHLOROFORMATES formula where R9is l3, -CH2CH3or-CH2WITH6H5. The preferred reagent is 1-chloroethylphosphonic (ether of Harborview acid).

This reaction, which gives the corresponding compound of formula XIV, is usually conducted in an inert reaction solvent such as methylene chloride, chloroform, dichloroethane, THF or toluene, preferably toluene, at a temperature of from about 60oC to about 100oC, preferably from about 80oC to about 85oC.

Heating the compounds of formula XIV, thus obtained, (C1-C4)alcohol, preferably methanol or ethanol, gives the corresponding compound of formula XV.

The reaction temperature may be in the range from about 80oC to about temperature phlegmy solvent and preferably about temperature phlegmy solvent.

The compound of formula XV obtained in the above stage, then alkylate and thus converted into the corresponding compound of formula I by its interaction with the compound of the formula R1L, where L is the deleted group, in the presence of the triflate (OTf). Appropriate bases include pyridine, triethylamine, dimethylaminopyridine and potassium carbonate. The triethylamine is preferred.

Typically, the alkylation is carried out in an inert reaction solvent such as methylene chloride or DMF, at a temperature of from about 0oC to about 100oC, preferably from about room temperature to about 60oC.

In each of the above reaction pressure is not critical. A suitable pressure is in the region of about 0.5 to 3 ATM, and normal pressure (usually about 1 ATM) is preferred for convenience.

For these reactions, where the preferred temperature vary by reacting compounds not set the preferred temperature.

For such reactions the preferred temperature for these reagents can be determined by monitoring the reaction using thin layer chromatography.

Compounds of the invention can be administered to the patient in a variety of ways, for example, orally in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of a solution.

Connection izobreteniya salts accession acids.

Daily dose of the compounds of the invention typically is in the range from about 1 to 300 mg/day for an adult and can be administered in one single dose or multiple doses.

For parenteral administration, when the compounds of the invention is administered in the form of a solution or suspension, they are usually present at a concentration of at least 1 wt. and preferably between 4-70 wt. (on the total weight of the solution) of the unit). Parenteral dose is usually between about 5 to 100 mg of active compound/s/.

Compounds of the present invention can be administered orally with an inert diluent or edible carrier, or they may be enclosed in gelatin capsules or formed into tablets.

These preparations should contain at least 0.5% of active compound/s/, but the concentration may vary depending on individual forms and can be from 4 to 70 wt. (on the total weight of the preparation). Oral dose typically contains between 1.0 mg and 300 mg of active compound.

The activity of the compounds of the present invention as inhibitors of acetylcholinesterase can be defined a number of standard biological or pharmacological tests.

One such procedure for the 8 /1961/.

The present invention is illustrated by the following examples. It is clear, however, that the invention is not limited to the specific details of these examples.

The melting temperature is not fixed. Proton nuclear magnetic resonance spectrum (IH-NMR) and13nuclear magnetic resonance (13NMR) were measured for solutions in deuterium chloroform (CDCl3) and peak positions are expressed in parts per million (ppm) using as a standard tetramethylsilane (TMS).

Forms peaks are defined as follows: s-singlet; d, doublet; m is a triplet; sq Quartet, m-multiplet; W wide (see tab.1).

Example 1. 1-/2-/5-methyl-benzothiazol/-3-/1- /phenylmethyl/-4-piperidinyl/-2-propen-1-ol.

A solution of 5-methyl-benzothiophene (356 mg, 2.4 mmol) in 10 ml dry tetrahydrofuran (THF) is treated with n-butyllithium /n-BuLi/ if -10oC and the mixture is stirred at room temperature for 30 minutes

To the reaction mixture add a solution of 3-/4- /N-benzylpiperidine/propenas /550 mg, 2.4 mmol/ 5 ml dry THF at room temperature.

After stirring for 30 min the mixture was quenched with water and extracted with chloroform. The organic layer is dried and concentrated to obtained the 7 /d, 1H/, 5,6-5,8 /m, 2N/, 7,0-7,7 /m, N/, M. D.

The connections defined in the names of examples 2-4 were obtained in a manner analogous to that described in example 1.

Example 2. 1-/2-/6-methylbenzothiazol//-3-/1-/phenylmethyl/-4-piperidinyl/-2-propen-1-ol.

1H-NMR (CDCl3): d 1,3-2,0 /m, 7H/ 2.4GHz /C, 3N/, 2,8-2,95 /m, 2N/, 3,45 /C, 2N/, 5,35 /l, 1H/, 5,6-5,8 /m, 2N/, 7,0-7,6 /m, N/, M. D.

Example 3. 1-/2-/2,5-dimethyl-benzothiazol//-3- /1-/phenylmethyl/-4-piperidinyl-2-propen-1-ol.

1H-NMR (CDCl3): d 1,35-2,0 /m, 7H/, 2,3 /s, 3H/, 2,5 /C, 3N/, 2,8-2,9 /m, 2N/, 3,5 /C, 2N/, 3,7-3,8 /m, IN/, 5,5-5,9 /m, 3H/, 7,0-7,8 /m, 8H/, M. D.

Example 4. 1-/2-benzothiazyl/-3-/1-/phenylmethyl /-4-piperidinyl/-2-propen-1-ol.

1H-NMR (CDCl3): d 1,3-2,0 /m, 7H/, 2,7-2,9 /m, 2N/, 3,45 /C, 2N/, 5,4 /l, 1H/, 5,6-5,8 /m, 2N/, 7,1 /C, 1H/, 7,2-7,3 /m, 7H/, 7,65 /DD, 1H/, 7,72 /DD, 1H/ memorial plaques

Example 5. 5-methyl-benzothieno-2-yl-2-/1- /phenylmethyl/4-piperidinyl/vinyl ketone.

A solution of the crude 1-/2-/5-methyl - benzothiazol//-3-/1-/phenylmethyl/-4-piperidinyl/-2 - propen-1-ol /750 mg of 2.16 mmol from example 1, in 30 ml of benzene is treated with manganese dioxide /1.8 g, of 20.7 mg/ DL, and the resulting suspension is heated to boiling under reflux for 2 h

The mixture is cooled to room temperature and filtered through the Dogo product.

1H-NMR (CDCl3): 1,4-1,9 /m, 4H/, 2,0 /dt, 2H/, 2,15-2,3 /m 1H/, 2,4 /C, 3N/, 2,8-3,0 /m, 2N/, 3,5 /C, 2N/, 6,8 /a 0.4 N/ a, 6,85 /s, 0.6 N/, 7,0-7,18 /m 1H/, 7,2-7,9 /m, N/, M. D.

Named examples 6 and 7 compounds were obtained in a manner analogous to the method described in example 5.

Example 6. 2,5-dimethyl-benzothieno-2-yl-2-/1-/phenylmethyl/4-piperidinyl/vinyl ketone.

1H-NMR (CDCl3): d 1,5-2,0 /m, 4H/, 2,1 /dt, 2H/, 2,2-2,4 /m 1H/, 2,56 /C, 3N/, 2,8 /C, 3N/, 2,9-3,05 /m, 2N/, 3,56 /C, 2N/, 6,72 /s, 0,4 H/ 6,8 /s, 0,6 H/ 7,06 /d, or 0.6 H/ 7,1 /d, 4H/, 7,3-7,8 /m, 8H/, M. D.

Example 7. Bestien-2-yl-2-/1-/phenylmethyl/4 - piperidinyl/vinyl ketone.

1H-NMR (CDCl3): d 1,4-1,9 /m, 4H/, 1,95-2,1 /dt, 2H/, 2,2-2,35 /m 1H/, 2,8-3,0 /m, 2N/, 3,54 /C, 2N/, 6,86 /s, 0,4 H/ 6,9 /s, 0,6 H/ 7,1 /d, or 0.6 H/ 7,15 /d, 0,4 H/, 7,2-8,0 /m, 10H/, M. D.

Example 8. 1-/5-methyl-benzo[b]Tien-2-yl/-3-/1- /phenylmethyl/-4-piperidinyl-1-propanone.

A solution of the crude 5-methyl-benzothieno-2-yl-2-/1-/phenylmethyl/-4-piperidinyl/vinylketones from example 5 /600 mg, 1.6 mmol/ ethanol /20 ml) and ethyl acetate /40 ml/ treated with platinum oxide /Pt0260mg/ and hydronaut at a pressure of 3.5 kg/cm2within 2 hours

(Thin layer chromatography indicates that the reaction is not completed). Add an additional 45 mg PtO2and the mixture hydronaut dafia, using chloroform with 2% methanol in chloroform as additionally separated by obtaining 232 mg specified in the connection name.

1H-NMR (CDCl3): 1,2-2,1 /m, N/, 2,52 /3H/, 2,9-3,0 /m, 2N/, 3,05 /t, 2N/, 3,52 /C, 2N/, 7,2-7,4 /m, 6N/, 7,7 /C, 1H/, 7,75 /l, 1H/, 7,9 /C, 1N/ m D.

Named examples 9-11 compounds were obtained in a manner analogous to that described in example 8.

Example 9. 1-/5-methyl-benzo[b] Tien-2-yl-3-/1- /phenylmethyl/-4-piperidinyl-1-propanone.

1H-NMR (CDCl3): d 1,2-2,05 /m, N/, 2,5 /C, 3N/, 2,7-2,8 /m, 2N/, 3,0 /t, 2N/, 3,5 /C, 2N/, 7,2-7,4 /m, 6N/, 7,65 /C, 1H/, 7,8 /l, 1H/, 7,9 /C, 1N/ m D.

Example 10. 1-/3,5-diethyl-benzo[b]Tien-2-yl/- 3-/1-/phenylmethyl/-4-piperidinyl-1-propanone.

1H-NMR (CDCl3): d 1,2-2,0 /m, N/, 2,5 /C, 3N/, 2,75 /C, 3N/, 2,8-3,0 /m, 4H/, 3,5 /C, 2N/, 7,2-7,8 /m, 8H/ memorial plaques

Example 11. 1-/bestien-2-yl/-3-/1- /phenylmethyl/-4-piperidinyl/-1-propanone.

1H-NMR (CDCl3): d 1,1-2,0 /m, N/, 2,8-2,95 /m, 2N/, 3,05 /t, 2N/, 3,5 /C, 2N/, 7,2-7,5 /7H/, 7,8-7,9 /m, 2N/, 7,95 /C, 1N/ m D.

Example 12. Benzofuran-2-yl-2-/1-/phenylmethyl/- 4-piperidinyl/vinyl ketone.

To a solution of Diisopropylamine /0.5 ml, 3.6 mmol/ 15 ml dry THF added 2.5 M n-utility /1.3 ml, 3.3 mmol/ at -78oC. After stirring at -78oC for 20 at this temperature for 1.5 h

The mixture is quenched with water and brine and extracted with ethyl acetate. The organic layer is dried and concentrated, obtaining 1,117 g of the product as oil. The oil is dissolved in 15 ml of methylene chloride and treated with methylchloride /of 0.24 ml, 3 mmol/ triethylamine /at 0.42 ml, 3 mmol/ at room temperature.

The mixture is stirred at room temperature overnight, then quenched with water and extracted with methylene chloride. The organic layer is dried and concentrated, obtaining 0,827 g of the crude product, which was purified by chromatography on silica gel, using as additionally separated by chloroform with 5% methanol in chloroform, getting 430 mg of white crystals. So pl. 186-188oC.

1H-NMR (CDCl3): d 1,8-3,0 /m, 7H/, 3.1 to 3.4 /m, 2N/, 4,0 /SHR. with 2N/, 6,9 /s, 0,4 H/, of 6.96 /s, 0,6 H/ 7,1 /d, or 0.6 H/ 7,15 /d, 0,4 H/, 7,2-7,7 /m, 10H/ memorial plaques

Example 13. Benzofuran-2-yl-3-/1-/phenylmethyl/- 4-piperidinyl/propanone.

The solution benzofuran-2-yl 2-/1-/phenylmethyl/-4 - piperidinyl/vinylketones /410 mg/ ethanol /70 ml) and ethyl acetate /40 ml/ treated with platinum oxide /80 mg/ and hydronaut at 3.1 kg/cm2within 1 h

The mixture is filtered through Celiteand the filtrate is concentrated to dryness, obtaining white solid, which is recrystallized ISM, 7H/, 2,4-2,6 /m, 2N/, 2,97 /t, 2N/, 3,3-3,5 /m, 2N/, 4,01 /ABq, 2H/, 7,1-7,7 /m, 10H/ memorial plaques

Example 14. 1-/2-/N-phenylsulfonyl-6-methyl - indolyl/-3-/1-/phenylmethyl/-4-piperidinyl-2-propen-1-ol.

A solution of N-phenylsulfonyl-6-methylindole /1.18 g, 4,34 mmol/ in 30 ml of dry THF cooled to -78oC and treated with 3.5 ml /5.2 mmol/ 1.5 M of sitedisability in cyclohexane at -78oC.

After stirring at -78oC for 1 h, a solution of 3-/1-/phenylmethyl/-4-piperidinyl/-2 - propenal /1.0 g, 4,36 mmol/ 5 ml dry THF added at -78oC and stirred at this temperature for 40 minutes

The mixture is quenched with water and extracted with chloroform. The organic layer is dried and concentrated, obtaining of 2.23 g of orange oil. The oil is purified by chromatography on silica gel, using as additionally separated by 2% methanol in chloroform, and obtain 1.0 g mentioned in the title compound as a yellow oil.

1H-NMR (CDCl3): d 1,4-1,8 /m, 4H/, 1,9-2,1 /m, 3H/, 2,45 /C, 3N/, 2,85-2,95 /m, 2N/, 3,3 /Shir. s, 1H/, 3,5 /C, 2N/, 5,6-5,9 /m, 3H/, 6,55 /C, 1H/, 7,02 /DD, 1H/, 7,2-7,9 /m, N/ memorial plaques

Example 15. N-phenylsulfonyl-6-methyl-indol-2 - yl-2-/1-/phenylmethyl/-4-piperidinyl/vinylmation.

A solution of 1-/2-/N-phenylsulfonyl-6-methyl - indolyl//-3-/1-/phenylmethyl-4-piperidinyl-2-propen-1-ol /1,/P> The mixture is stirred for 4 hours at boiling under reflux, cooled to room temperature and filtered through Celite.

The filtrate is concentrated, receiving a yellow oil which is purified by chromatography on a column of silica gel, using as additionally separated by chloroform with 2.5% methanol in chloroform, getting 740 mg /exit 62%/ mentioned in the title compound as a yellow oil.

1H-NMR (CDCl3): 1,4-1,8 /m, 4H/, 1,9-2,1 /m, 2N/, 2,15-2,3 /m 1H/, 2,5 /3H/, to 2.85-3.0V /m, 2H/, 3,5 /C, 2N/, 6,55 /C of 0.45 H/ 6,55 /C of 0.55 H/ 6,9 /d, of 0.55 H/ 6,98 /d, 0,45 H/ 7,0 /C, 1H/, 7,1 /l, 1H/, 7,25-7,55 /m, 9H/, a 7.9-8.1 README /m, 3H/ memorial plaques

Example 16. 1-/1-phenylsulfonyl-6-methyl-indol - 2-yl/-3-/1-/phenylmethyl/-4-piperidinyl-1-propanone.

A solution of N-phenylsulfonyl-6-methyl-indol-2-yl-2-/1-/phenylmethyl/-4-piperidinyl/vinylketones /360 mg, 7.2 mmol/ in a mixture of THF/ethanol /25 ml/25 ml/ process pjatiokisi platinum /PtO2/ /40 mg/ and hydronaut when b kg/cm2within 75 minutes

The mixture is filtered through celite Celite. The filtrate is concentrated to dryness, obtaining a dark oil, which was purified by chromatography on silica gel using chloroform as additionally separated by and receiving 200 mg specified in the title compound as a yellow oil.

1H-the EP 17. 1-/6-methyl-indol-2-yl/-3-/1- /phenylmethyl/-4-piperidinyl/-1-propanone.

A suspension of N-phenylsulfonyl-6-methyl-indol-2 - yl-2-/1-/phenylmethyl/-4-piperidinyl/ethylketone /150 mg/ 20 ml of methanol is treated with 1.5 ml of 2N sodium hydroxide /NaOH/, heated to boiling under reflux and stirred at this temperature for 70 minutes

The mixture is quenched with water and extracted with chloroform. The organic layer is dried and concentrated, receiving 100 mg specified in the title compound as a brown solid.

1H-NMR (CDCl3): d 1,2-1,8 /m, 7H/, 1,8-2,0 /m, 2N/, 2,42 /C, 3N/, 2,8-3,0 /m, 4H/, 3,5 /C, 2N/, 6,95 /l, 1H/, 7,1 /C, 1H/, 7,2-7,35 /m, 6H/, 7,55 /l, 1H/ memorial plaques

Example 18. 1-/2-benzothiazolyl/-3-/1-/phenylmethyl/-4-piperidinyl/-2-propen-1-ol.

A solution of benzothiazole /0,243 g, 1.8 mmol/ 5 ml dry THF is treated with 1.5 M of sitedisability in cyclohexane /a 1.45 ml/ -78oC and stirred at this temperature for 15 minutes a Solution of 3-/1-/phenylmethyl/-4 - piperidinyl/propenas /452 mg, 1.97 mmol/ in 3 ml of dry THF added at -78oC and stirred at this temperature for 30 minutes

The mixture is quenched with water and extracted with chloroform. The organic layer is dried and concentrated, obtaining a yellow viscous oil is 2N/, 7,2-7,6 /m, 7H/, 7,9 /l, 1H/, 8,0 /l, 1H/ memorial plaques

Example 19. 2-/benzothiazolyl-2-/1- /phenylmethyl/-4-piperidinyl/-vinylmation

A solution of 1-/2-benzothiazolyl/-3-/1-/phenylmethyl/-4-piperidinyl/-2-Proen-1-ol /654 mg, 1.8 mmol/ in 25 ml of methylene chloride is treated MnO2/0,782 g, 9 mmol/ and heated to boiling under reflux. After 3 h the mixture is filtered through Celiteand the filtrate is concentrated and receiving 0,655 mg of a dark oil.

The oil is purified chromatographically on silica gel, using as additionally separated by 2% methanol in chloroform, getting 0,487 g of amber oil which becomes solid when standing in for the night.

1H-NMR (CDCl3): 1,5-1,9 /m, 4H/, 2,0-2,15 /m, 2N/, 2,3-2,5 /m 1H/, 3,5 /C, 2N/, 7,2-7,6 /m, N/, 8,0 /DD, 1H/, 8,2 /DD, 1H/ memorial plaques

Example 20. 1-/benzothiazol-2-yl/-3-/1-/phenylmethyl/-4-piperidinyl/-1-propanone.

A solution of 2-benzothiazolyl-2-/1- /phenylmethyl/-4-piperidinyl/vinylketones /146 mg, 0.4 mmol/ in a mixture of ethyl acetate/ethanol /10 ml/10 ml/ PtO handle2/20 mg/ and hydronaut at 3.5 kg/cm2within 3 hours

The mixture is filtered through Celiteand the filtrate is concentrated to dryness, obtaining 0,154 g of a dark oil. The oil is purified by chromatography on a column of silica gel, using as additionally separated by the /CDCl3/: 1,2-1,4 /m, 3H/, 1,7-1,85 /m, 4H/, 1.85 to 2.1 a /m, 2N/, 2,8-3,0 /m, 2N/, 3,3 /DD, 2H/, 3,5 /C, 2N/, 7,2-7,4 /m, 5H/, 7,45-7,65 /m, 2N/, 7,95 /DD, 1H/, 8,2 /l, 1H/ memorial plaques

Example 21. N-phenylsulfonyl-5-nitroindole

A solution of 5-nitroindole /of 1.62 g, 10 mmol/ in 30 ml of dimethylformamide /DMF/ treated with 60% sodium hydride /of 0.44 g, 11 mmol/ at room temperature. After 3 minutes add benzosulphochloride /up 1.766 g, 10 mmol/.

The mixture is stirred at room temperature overnight and treated with 250 ml of water. The precipitate is filtered, receives a yellow solid, which pumped in vacuum, obtaining 2.7 g/89%/ specified in the connection name.

1H-NMR /CDCl3/: d 6,82 /l, 1H/, 7,45-7,55 /m, 2N/, 7,6 /l, 1H/, 7,72 /l, 1H/, 7,9 /m, 2H/, 8,1 /l, 1H/, 8,2 /DD, 1H/, 8,5 /l, 1H/ memorial plaques

Example 22. N-phenylsulfonyl-5 - nitroindole-2-yl-2/1-/phenylmethyl/-4-piperidinyl/vinylmation.

A solution of N-phenylsulfonyl-5-nitroindole /646 mg, 2.14 mmol/ 10 ml of dry THF is treated with lifedisabilities /1.5 M in cyclohexane /1.7 ml, 2.6 mmol/ at -78oC.

After 1 h, add a solution of 3-/4- /N-femalecelebrities//propenas /490 mg, 2.14 mmol/ 2 ml dry THF at -78oC.

After 40 min reaction at -78oC the mixture was quenched with water and extracted with methylene chloride. Ola, process MnO2/1.86 g, 21,4 mmol/ and heated to boiling under reflux for 4 hours Add an additional 900 mg MnO2and the mixture is heated to boiling under reflux during the night.

The mixture is filtered through Celiteand the filtrate is concentrated, getting a brown oil which is purified by chromatography on a column of silica gel, using as additionally separated by chloroform, getting mentioned in the title compound as a brown oil.

IH-NMR /CDCl3/: 1,45-1,95 /m, 4H/, 1,95-2,1 /m, 2N/, 2,15-2,4 /m 1H/, 2,9-3,05 /m, 2N/, 3,55 /C, 2N/, 6,55 /s, 0.5 H/, 6,62 /s, 0.5 H/, 6,98 /d, 0.5 H/, 7,05 /l, 1H/, 7,1 /C, 1H/, 7,2-7,4 /m, 4H/, 7,5-7,7 /m, 4H/, 8,05-8,15 /m, 2N/, 8,2-8,4 /m, 2N/, 8,5 /l, 1H/ memorial plaques

Example 23. N-phenylsulfonyl-5-nitroindole-2-yl-2-/1-/phenylmethyl/-4-piperidinyl/ ethylketone.

A solution of N-phenylsulfonyl-5 - nitroindole-2-yl-2/1-/phenylmethyl/-4-piperidinyl/vinylmation. /187 mg, 0.35 mmol/ in a mixture of ethyl acetate/ethanol /20 ml/8 ml/ PtO handle2/50 mg/ and hydronaut at 2.8 kg/cm2within 1.5 hours

The mixture is filtered through Celiteand the filtrate is concentrated and getting 177 mg /100%/ brown oil.

1H-NMR /CDCl3/: 1,1-2,0 /m, N/, 2,75-2,9 /m, 2N/, 2,92 /t, 2N/, 3,42 /C, 2N/, 6,68 /l, 1H/, 6,72 /DD, 1H/, 6,8 /1H">

A solution of N-phenylsulfonyl-5 - nitroindole-2-yl-2-/1-phenylmethyl/-4-piperidinyl/ethylketone /160 mg, 0.32 mmol/ in 3 ml of methanol and 2 ml of 2N NaOH are heated at the boil under reflux for 2 h

The mixture is concentrated to dryness, and the residue diluted with brine and extracted with chloroform. The organic layer is dried and concentrated to dryness, obtaining 144 mg of a brown solid, which is purified chromatographically on a column of silica gel, receiving 31 mg specified in the connection name in the form of a brown solid product.

1H-NMR /CDCl3/: 1,1-2,0 /m, N/, 2,8-3,0 /m, 4H/, 3,5 /C, 2N/, 6,76 /DD, 1H/, 6,9 /C, 1H/, of 6.96 /C, 1H/, 7,1-7,3 /m, 6H/ memorial plaques

Example 25. 1-/1-ethyl-2-methyl-1H-benzimidazole/-5-yl/-3-//1-/phenylmethyl/-4-piperidinyl/-2-propen-1-it.

A mixture of 0.1 g /0.5 mm/ 1-ethyl-2 - methylbenzimidazole-5-yl of the ketone and 0.1 g /0.5 mm/ 4-formyl-N-benzylpiperidine in 10 ml of tetrahydrofuran (THF /THF/ cooled to -78oC in nitrogen atmosphere.

To this mixture are added dropwise 0.5 ml /0.5 mm/ 1M solution of lithium bis/(trimethylsilyl)//-amide in THF. The reaction mixture was stirred at -78oC for 1 h, then warmed to room temperature. To the reaction mixture add 10 ml of water and adjusted pH to 2.0 1N hydrochloric acid /Hcl/.

An ethyl acetate extracts at pH 5.0 and 6.5 combine, dried over sodium sulfate /Na2SO4/ and evaporated, receiving 50 mg /26%/ mentioned in the title compound in the form of butter.

Conducting thin-layer chromatography of the product /10: 1 CHCl3:CH3OH/, Rf 0,58.

1H-NMR /CDCl3/: d by 8.22 /C, 1H/, 7,88 /l, 1H/, 7,30 /m, 5H/, 6,90 /m, 3H/, 4,14 /q, 2H/, 3,50 /C, 2N/, 3,05 /m, 2N/, 2,85 /m, 2N/, 2,61 /C, 3N/, 1,4-2,1 /m, 5H/, 1,40 /t, 3H/ memorial plaques

Example 26. 1-/1-ethyl-2-methyl-IH-benzimidazole-5-yl/-3-/1-/phenylmethyl/-4-piperidinyl-1-propanone hydrochloride.

To the solution mentioned in the title compound from example 25 0.14 g /0.36 mm/ in 20 ml of ethanol is added 10 mg PtO2and the mixture hydronaut at 3.5 kg/cm2within 1 h the Reaction mixture was filtered, and the ethanol is evaporated.

The residue is suspended in 50 ml of 1:1 mixture of ethyl acetate, water and the pH adjusted to 8.5 with 1N sodium hydroxide /NaOH/.

An ethyl acetate layer is dried /Na2SO4/ and evaporated, receiving 0.1 g /72%/ free grounds specified in the connection name in the form of butter.

TLC/10:1 CHCl3:CH3OH/, Rf of 0.64

1H-NMR /CDCl3/: d compared to 8.26 /c, 1/, 7,92 /l, 1H/, 7,28 /m, 6H/, 4,18 /q, 2H/, 3,48 /C, 2H/, 3,05 /m, 2H/, 2,85 /m, 2H/, 2,54 /3H/, 1,4-2,0 /m, 9H/, 1 the config in the air. The precipitate was filtered and triturated with hexane, getting 0,105 g mentioned in the title compound as a hygroscopic white solid.

So pl. 165-167oC.

Mass spectrum: 389,2 /p/, 298,0 /R-91/, 172,0 /R-217/, 90,9 /R-298, the main peak/.

Example 27. 1-/2-methyl-6 - benzothiazolyl/-3-/1-/phenylmethyl/-4-piperidinyl-2-propen-1-it.

The mixture 0,191 g /0.001 M/ 2-methyl-6-benzothiazolyl of ketone /received as described S. S. Sawhney, J. Singh and Bansal, J. Ind. Chem. Soc. 12, 561 /1975/ and 0,203 g /0.001 M/ 4-formyl-N-benzylpiperidine in 5 ml of THF cooled to -78oC in nitrogen atmosphere.

To this solution is added dropwise to 0.73 ml /0.001 M/ sitedisability /1.5 M solution in THF/. The reaction mixture was stirred at -78oC for 1 h and then heated to 0oC.

The reaction mixture was quenched with 5 ml of water and extracted with ethyl acetate. The ethyl acetate extracts are dried /Na2SO4/ and evaporated, gaining 0.4 g of a brown resin.

This residue chromatographic on 30 g of silica gel using a 98:2 mixture of CH2CL2:CH3OH as additionally separated by. The appropriate fractions are combined to a receiving 0,122 g /32%/ mentioned in the title compound as amorphous solid. TLC /10:1 CH2Cl2:CH3OH/ 7H/.

Mass spectrum: 376.1600. Calculated for C23H24N2OS: 2,6 M. D.

Example 28. 1-/2-methyl-6 - benzothiazolyl/-3-/1-/phenylmethyl/-4-piperidinyl-/1-propanone hydrochloride.

The solution 0,120 g /0,319 mm/ free grounds specified in the title compound from example 27, dissolved in 50 ml of ethanol. To this solution was added 50 mg PtO2and the mixture hydronaut at 3.5 kg/cm2within 1 h

The reaction mixture is filtered and the ethanol evaporated, getting 0,112 g /100%/ specified in the connection name /free/ base in the form of an amorphous solid.

TLC /10:1 CH2Cl2:CH3OH/, Rf 0,5

IH-NMR /CDCl3/: d 8,45 /C, 1H/, 8,02 /DD, 2H/, 7,25 /m, 5H/, 3,5 /C, 2H/, 3,02 /m, 2H/, 2,85 /m, 2H/, 2,83 /3H/, 1,4-2,0 /m, 9H/.

Mass spectrum: 378 /p/, 287 /p-91/, 172 /p-206/, 91 /p-287, the main peak/.

This residue is dissolved in ethyl acetate, to which is added HCl dissolved in ethyl acetate /EtOAc/. The precipitate is filtered and dried in vacuum to yield 92 mg /70%/ specified in the connection name.

So pl. 110-112oC.

Example 29. N-acetyl-4-aminoacetophenone.

A mixture of 5 g /0,37 M/ 4-aminoacetophenone, and 3.8 ml /0.04 M/ acetic anhydride and 5.5 /0.04 M/ triethylamine dissolved in 50 ml of methylene chloride /CH2Cl

TLC /1:1 CH2Cl3:tO/, Rf 0,61

IH-NMR /CDCl3/: d 8,58 /Shir. s, 1H/, of 7.90 /d, 2H/, of 7.64 /d, 2H/, 2,56 /3H/, 2,19 /3H/.

Example 30. N-benzoyl-4 - aminoacetophenone

A mixture of 5.0 g /0,37 M/ 4-aminoacetophenone, 4,7 ml /0.04 M/ benzoyl chloride and 5.5 ml /0.04 M/ triethylamine dissolved in 50 ml of methylene chloride /CH2Cl2/ and stirred at room temperature for 18 hours

The precipitate is filtered and washed with water. The residue is dissolved in chloroform /CHCl3/ and dried over Na2SO4. Evaporated CHCl3getting to 4.2 g /47%/ N - benzoyl-4-aminoacetophenone.

So pl. 206-208oC.

1H-NMR /CDCl3+ DMSO/: d 9,58 /Shir. s, 1H/, 7,80 /m, 6H/, 7,34 /m, 3H/, 2,44 /3H/.

Example 31. N-acetyl-2-nitro-4-aminoacetophenone

To 10 ml of fuming nitric acid cooled to 0oC add portions of 1.0 g /5.6 mm/ N-acetyl-4 - aminoacetophenone. The temperature of the support below the 5oC to prevent excess nitration of the benzene ring.

The solution is stirred for 15 min at 0oC and then carefully poured into ice. Precipitated yellow solid and collecting filter 1H-NMR /CDCl3/: d 8,9 /l, 1H/, 8,77 /C, 1H/, 8,16 /c, IH/, 2,64 /c, 3H/, 2,34 /c, 3H/.

Example 32. N-benzoyl-3-nitro-4-aminoacetophenone.

To 10 ml of fuming nitric acid cooled to -5oC add portions of 2.5 g /0,01 M/ N-benzoyl-4 - aminoacetophenone. The temperature of the support below the 0oC. the Reaction mixture was stirred for 10 min and the resulting solution was poured into ice.

Get the precipitated yellow solid, which is collected by filtration. The solid is dissolved in CHCl3and chromatographic on silica gel using CHCl3as additionally separated by.

The appropriate fractions are combined and evaporated, obtaining 1.0 g /35%/ mentioned in the title compound as a yellow solid.

1H-NMR /CDCl3/: d 9,12 /l, 1H/, 8,84 /C, 1H/, 8,25 /l, 1H/, of 7.96 /d, 2H/, 7,6 /m, 3H/, 2,66 /3H/.

Example 33. 3-/1-/1-phenylmethyl/-4-piperidinyl/-1-/3-nitro-4-acetamidophenyl/2-propen-1-it.

A solution of 2.6 g /11.7 mm/ N-acetyl-3 - nitro-4-aminoacetophenone in 25 ml of THF is cooled to -60oC in nitrogen atmosphere. To the solution was added to 4.7 ml /11.7 mm/ N-utility /2.5 M in hexane/, keeping the temperature below -60oC.

The reaction mixture is stirred for 15 minutes is Added dropwise restou the mixture is stirred for 1 h and then warmed to room temperature. At room temperature the reaction mixture was quenched with 10 ml of water and extracted with ethyl acetate. An ethyl acetate extracts are combined, dried over /Na2SO4/ and evaporated getting dark oil.

This oil chromatographic on silica gel using 5:1 CHCl3tO as additionally separated by. The appropriate fractions are combined to a receiving 1.2 g /25%/ mentioned in the title compound in the form of oil, which slowly crystallizes.

TLC /10:1 CHCl3:CH3OH/, Rf of 0.45

1H-NMR /CDCl3/: d 8,90 /l, 1H/, 8,76 /C, 1H/, 8,14 /l, 1H/, 8,30 /m, 5H/, 3,53 /C, 2H/, 2,94 /m, 2H/, 2,32 /3H/, 1,5-2,15 /m, 5H/.

Example 34. 3-/1-/-phenylmethyl/-4-piperidinyl/-1-/3-nitro-4-benzoyl-AMINOPHENYL/-2-propen-1-it.

A solution of 0.80 g /2,90 mm/ mentioned in the title compound of example 32 in 30 ml of anhydrous THF is cooled to -70oC in nitrogen atmosphere.

To the solution are added dropwise 1.2 ml /2.9 mm/ N-utility /2.5 M solution in hexane/, getting a dark solution. The solution was stirred at -70oC for 10 minutes

To this mixture is added dropwise a solution of 0.6 g /2.9 mm/ 4-formyl-N-benzylpiperidine in 10 ml of THF. The reaction mixture was allowed to slowly warm to room temperature and stirred for 18 h

The reaction mixture is up.

The remainder chromatographic on silica gel using 1:1 CHCl3tO as additionally separated by. The appropriate fractions are combined to a receiving 0.45 g /34%/ mentioned in the title compound as amorphous solid.

TLC /10:1 CHCl3:CH3OH/, Rf of 0.67

1H-NMR /CDCl3/: d 9,14 /l, 1H/, 8,82 /c, 1H/, by 8.22 /l, 1H/, 7,98 /d, 2H/, 7,55 /m, 3H/, 7,32 /m, 5H/, 7,10 /m 1H/, 6,85 /m 1H/, 3,54 /C, 1H/, 2,95 /m, 2H/, 1,4-2,3 /m, 7H/.

Example 35. 1-/3-amino-4-acetamidophenyl/-3-/1-phenylmethyl/-4-piperidinyl/-1-propanone.

To a Solution of 0.9 g /2.2 mm/ mentioned in the title compound from example 33 in 50 ml of ethanol is added 20 mg PtO2the mixture hydronaut at 3.5 kg/cm2within 1 h the Mixture is filtered and the ethanol evaporated, obtaining 0.9 g /100%/ mentioned in the title compound in the form of butter.

1H-NMR /CDCl3/: d 7,6 /C, 1H/, 7,2-7,5 /m, 7H/, 3,5 /C, 2H/, 2,85 /m, 4H/, 2,21 /3H/, 1,2-2,0 /m, 9H/.

Mass spectrum: to 379.2 /R/, 202,3 /R-176,9/, 172,3 /R-206,9/, 91,0 /-288,3, the main peak/.

Example 36. 1-/2-methyl-1H - benzimidazole-5-yl/-3-/1-/phenylmethyl/-4 - piperidinyl/-1-propanol hydrochloride.

A solution of 0.6 g /1.6mm/ free base mentioned in the title compound of example 35 in 10 ml of acetic acid is heated on the steam bath /80-90oC/ within 1 h of Acetic acid is evaporated, elaut layer of ethyl acetate from the aqueous layer and then the aqueous layer was sequentially adjusted to pH 5.0, 6,0 and 9,0, every time extragere with ethyl acetate.

An ethyl acetate extract with a pH of 9.0 dried over /Na2SO4/ and evaporated, gaining 0.4 g /69%/ free grounds specified in the connection name /free/bottom.

1H-NMR /CDCl3/: d 8,08 /C, 1H/, 7,80 /C, 1H/, 7,47 /m 1H/, 7,25 /m, 6H/, 3,47 /C, 2H/, 2,8-3,0 /m, 4H/, 2,59 /3H/, 1,90 /m, 2H/, 1,64 /m, 4H/, 1,25 /m, 3H/.

TLC /10:1:0.1 to CHCl3:CH3OH:NH4OH/ Rf /base/ 0,50.

Solid amorphous substance was dissolved in ethyl acetate and added a solution of hydrogen chloride in ether /HCl/. The precipitate is filtered and dried, obtaining 0.26 g /62%/ mentioned in the title compound in the form of a solid reddish-brown product.

Mass spectrum: 361,3 /p/, 270,2 /p-to 91.1/, 172,3 /R-189/, 91,1 /0-270,2, the main peak/.

Example 37. 1-/3-Amino-4-benzoylmethyl/-3-//1-phenylmethyl/-4 - piperidinyl-1-propanone.

To a solution of 0.45 g /1.0mm/ connection specified in the title of example 34, 50 ml of ethanol is added 25 mg PtO2and the mixture hydronaut at 3.5 kg/cm2within 1 h

After filtration to remove the catalyst, evaporate the ethanol, getting mentioned in the title compound as amorphous solid.

1H-NMR /CDCl3/: d is in example 38 without further purification.

Example 38. 1-/2-phenyl-1H-benzimidazole-5-yl/-3-//1-phenylmethyl/-4 - piperidinyl-1-propanone hydrochloride.

The connection specified in the title of example 37, dissolved in a 50:50 mixture of ethanol and acetic acid and heated at 75oC for 3 hours, the Reaction mixture was cooled to room temperature and diluted with water.

the pH of the mixture was adjusted to 9.5, and the mixture is extracted with ethyl acetate. An ethyl acetate extracts are dried over /Na2SO4/ and evaporated, getting to 0.19 g /45%/ free grounds specified in the connection name.

TLC /10:1:0.1 to CHCl3:CH3OH:NH4OH/, Rf of 0.40.

1H-NMR /CDCl3/: d 8,14 /d, 2H/, 7,86 /l, 1H/, 7,2-7,6 /m IIH/, to 3.58 /C, 2H/, 2,92 /m, 4H/, 1,2-2,1 /m, 9H/.

The residue is dissolved in ethyl acetate and this solution added dropwise an ethereal solution of HCl. The precipitate is collected by filtration and dried, obtaining specified in the title compound as a tan solid product.

So pl. >300oC.

Mass spectrum: 424,2 /p+1/.

Example 39. 1-/2-methyl-6 - benzothiazolyl/-3-/4-piperidinyl/-1-propanone.

A mixture of 0.90 g /2,38 mm/ 1-/2-methyl-6-benzothiazolyl/-3-/1-/phenylmethyl/-1-propanone /Example 27/ and 0.33 ml /3.1 mm/ 1 claritinclaritin in 10 ml of 1,2-dichloroethane is boiled with Eatery and diluted with 15 ml of water. This mixture is extracted with twice 20 ml of ethyl acetate.

An ethyl acetate extracts are combined, dried over /Na2SO4/ and evaporated, obtaining 1.0 g /100%/ 1-/2-methyl-6-benzothiazolyl/-3-//1-characiformes/-4-piperidinyl/-1-propanone in the form of butter.

TLC /10:1 CH2Cl2:CH3OH/, Rf 0,86.

1H-NMR /CDCl3/: d 8,4 /c, 1H/, 7,9 /m, 2H/, 6,55 /q, 1H/, 2,65-3,2 /m, 4H/, 2,77 /3H/, 1,83 /d, 3H/, 1,4-1,95 /m, 9H/.

13C-NMR /CDCl3, M. D./ 198.1, 171.3, 155.8, 137.4, 135.8, 133.4, 125.9, 122.1, 83.3, 44.2, /2/, 35.7, 35.3, 32.0, 30.4, /2/, 25.4, 20.3.

A methanol solution /5 ml/ 0.9 g /2,28 mm above the oil is refluxed for 1 hour While cooling the formed yellow precipitate. The residue is dissolved in 4 N HCl and the solution extracted with ether.

The HCl solution was adjusted to pH 9 with sodium carbonate /Na2CO3/ and extracted with ethyl acetate. An ethyl acetate extracts are dried over /Na2SO4/ and evaporated, getting 0,250 g /38%/ mentioned in the title compound as an amorphous yellow solid substance.

TLC /10:1 CH2Cl2:CH3OH/, Rf 0,01.

1H-NMR /CDCl3/: d 8,5 /C, 1H/, 7,95 /m, 2H/, 3,2 /m, 2H/, 2,85 /C, 1H/, 2,6 /m, 2H/, 1,1-1,8 /m, 9H/.

13C-NMR /CDCl3, M. D./ 198.1, 156.3, 136.0, /2/, 132.0, 125.9, 122.3, 122.1, 46.4, /2/, 35.8, 35.7, 33.0�drochloride.

A mixture of 250 mg /0.87 mm/ connections specified in the title of example 39, 0,160 mg /0.87 mm/ 2-methyl-4-chloromethylthiazole and 0.36 ml /2,60 mm/ triethylamine is refluxed in 5 ml of methylene chloride for 12 hours

The reaction mixture is cooled to room temperature and diluted with 10 ml of water. The mixture is extracted with ethyl acetate, and an ethyl acetate extracts are combined and dried /Na2SO4/ and evaporated, getting 0.27 g of a yellow resinous product.

This substance chromatographic 10 ml of silica gel using 98:2 CHCl3: CH3OH as additionally separated by. The appropriate fractions are combined and evaporated, receiving 100 mg /29%/ mentioned in the title compound as a yellow amorphous substance.

TLC /10:1 CH2Cl2:CH3OH/, Rf 0.21 in.

1H-NMR /CDCl3/: d 8,50 /c, 1H/, 7,9 /m, 2H/, 6,87 /C, 1H/, 3,62 /C, 2H/, 3,0 /m, 4H/, 2,87 /3H/, 2,69 /3H/, 2,0 /t, 2H,/, 1,7 /m, 4H/, 1,35 /m, 3H/.

Mass spectrum: 399,2 /p/, 287,2 /R-112, main peak/, 223,1 /R-176,1/, 193,1 /R-206,1/, 176,0 /R-223/, 112,0 /R-287/, 71,0 /p-328/.

This substance is dissolved in ethyl acetate and added an ethereal solution of gaseous HCl. The precipitate is filtered and recrystallized from CH2Cl2/ether, receiving 92 mg specified in the connection name.

Solution 1-/1-phenylsulfonyl-5 - amino-indol-2-yl/-3-/N-phenylmaleimide-4-yl/-1-propanone /160 mg, 0.32 mmol/ in 3 ml of methanol and 2 ml of 2N NaOH solution heated to boiling under reflux for 2 h

The mixture is concentrated to dryness, and the residue diluted with brine and extracted with chloroform. The organic layer is dried and concentrated to dryness, obtaining 144 mg of a brown solid product, which is purified by chromatography on a column of silica gel, receiving 31 mg specified in the title compound as a brown solid product.

1H-NMR /CDCl3/: d 1,1-2, 0/m, N/, 2,8-3,0 /m, 4H/, 3,5 /C, 2N/, 6,76 /DD, 1H/, 6,9 /C, 1H/, of 6.96 /C, 1H/, 7,1-7,3 /m, 6H/ memorial plaques

Example 42. 1-/5-N-acetylamino - indol-2-yl/-3-/phenylmethyl/-4-piperidinyl/-1-propanone.

Solution 1-/5-amino-indol-2-yl/-3-/ 1-/phenylmethyl/-4-piperidinyl/-1-propanone /18 mg, 0.05 mmol/ in 0.5 ml of methylene chloride is treated with a solution of triethylamine /6 mg, 0.06 mmol/ in 0.5 ml of methylene chloride and the solution acetylchloride /4,7 mg, 0.06 mmol/ 0.5 ml methylene chloride at room temperature, and the mixture is stirred at room temperature for 4 h

The mixture is quenched with water and extracted with methylene chloride. The organic layer is dried and concentrated, gaining 11 mg of the specified E, 1H/, 9,35 /C, 1H/ memorial plaques

Note:

(a) In the calculation of theoretical activity of medicinal substances from 76,4%

(b) Microcrystalline cellulose (Avicel PH102) is added in accordance with the small change of activity with the objective of maintaining a constant weight of the tablet.

For compounds of example 28 provides data on toxicity. LD1His defined as the oral dose that is lethal for 50% of the test animals within 1 h after administration.

For compounds of example 28 LD1Hequal to 57 mg/kg when tested on mice. Rats LD1Hhigher than the highest dose used in these experiments. For example, the oral LD1HCognex (taken hydrochloride) USFDA known medication for the treatment of Alzheimer's disease, equal to 56 mg/kg for mice and 70 mg/kg for rats.

1. Heteroaromatic General formula

< / BR>
where the ring And benzene;

R1benzyl or alkyldiethanolamine;

R2and R3independently selected from hydrogen, C1- C6-alkyl, phenyl, NO2, NH2or CH3C(O)-NH group and one of R2, R3and a side chain containing a group may be attached both to the benzene ring, and ring;

X is nitrogen or CH;

Y is oxygen, up to 4;

q each independently is 1 or 2;

Z is oxygen, provided that any CHqgroup, where q 1, must be attached to the one and only such other CHqgroup, where q 1;

* indicates the carbon atom to which may be attached a side chain,

or their pharmaceutically acceptable salts.

2. Connection on p. 1 having the formula

< / BR>
where X is CH or N;

Y NH, NCH3, NCH2CH3, S, O, or NSO2C6H5;

R2and R3independently selected from the group consisting of C1WITH4-alkyl, amino and

R1benzyl.

3. Connection on p. 2, in which X is CH or N, Y is NH, N-CH3, sulfur or oxygen, R2and R3independently selected from the group consisting of C1WITH4-alkyl, amino and R1benzyl.

4. Connection on p. 3 in which R2and R3independently selected from the group consisting of C1WITH4-alkyl, amino and

5. Connection on p. 1, selected from the group consisting of 1-(2-methyl-1H-benzimidazole-5-yl)-3-[1-(phenylmethyl) 4-piperidinyl]- 1-propanone hydrochloride, 1-(2-phenyl-1H-benzimidazole-5-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone hydrochloride, 1-(1-ethyl-2-methyl-1H-benzimidazole-5-yl)-3-[1-(phenylmethyl) -4-Piperi, 1-(2-methyl-6-benzothiazolyl)-3-[1-(2-methyl-4-thiazolyl)methyl-4-piperidinyl]-1-propanone, 1-(5-methyl-benzo[b]Tien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone, 1-(6-methyl-benzo[b]Tien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone, 1-(3,5-dimethyl-benzo[b] Tien-2-yl)-3-[1-(phenylmethyl) -4-piperidinyl] -1-propanone, 1-(benzo[b]Tien-2-yl)-3-[1-(phenylmethyl) -4-piperidinyl] -1-propanone, 1-(benzofuran-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone, 1-(1-phenylsulfonyl-6-methyl-indol-2-yl)-3 -[1-(phenylmethyl)-4-piperidinyl]-1-propanone, 1-(6-methyl-indol-2-yl) -3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone, 1-(1-phenylsulfonyl-5-amino-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl] -1-propanone, 1-(5-amino-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl] -1-propanone and 1-(5-acetylamino-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone.

6. The pharmaceutical composition inhibiting the acetylcholinesterase and containing the active ingredient and pharmaceutically acceptable carrier, characterized in that the active ingredient it contains an effective amount of the compounds on p. 1.

 

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< / BR>
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