SU1396964A3 - Method of producing 4-(bicycloheterocyclilemethyl)piperidine or pharmaceutically acceptable salts of addition acids thereof - Google Patents

Abstract

The method of obtaining 4- (bicycloheterocyclylmethyl) piperidines of the general formula 1 ... ITA; AZ and Rq and R, where AJ AJ-AJ AA is a bivalent radical of the formula -CH -CRj-CR, pCH- (a); -independently hydrogen, methyl, hydroxy, methoxy or halo; -N CH-CH CH- (in). (c) (d) or -CH CH-CH N-; (e) -hydrogen, methyl, phenyl, benzyl, unsubstituted or substituted by one or two groups, such as halo, methyl, methoxy; cyclohexyl, benzhydryl, phenethyl, furanylmethyl, (5- -methyl-2-furanyl) methyl, 4-thiazolylmethyl, pyridinylmethyl, 2-thienylmethyl, pyrazine methyl, me-. Tyl-2-yenylmethyl, naphthalenyl-3-dimethylaminocarbonyl-3,3-diphenyl-propyl, hydrogen, isopropl, group -CH g-CH d-CO-CH-B, where R, is hydrogen, or bromine; ethoxycarbonyl, methyl or benzoyl or a group (CH ,,) „, y (CHj), where a is O or 1; B about or 2; oh; S or -phenyl, 4-fluorofensh1, 2-pyrimidinyl, 2-pyridinyl, the radical NS or the radical G hell i SU) with Od; about cm 1 or LJ - (CH) (.-., Where with 1, 2, 3 or four;

Description

. - hydroxyl,

NIL, hydroxyphenyl, methoxyphenyl, dimethoxyphenyl, ethoxycarbonyl, ethoxy, carboxyl, ethenyl, A-fluorophenylcarbo-. NIL, isopropylaminocarbonyl, aminocarboxy, 2-pyridiyl, 2-thienyl, 2- -methyl-4-thiazole1, 2-oxo-3-oxazolidinyl, 2,4-dioxo-3- (1H ) -pyrimidinyl, 2,3-dihydro-2- -oxo-1H-benimide-ZOL-1-IL, 2,3-di-hydro-2-thioxo-1H- -beysimidazol-1- -yl, 2 -pyrimidinyl-aminocarbonyl or benzimidazolyl forT

mules g or h

radical of the general form.

1396964

cyanofermal formula

2,3-dihydro-1,41- (benzimidazoldazol-2-yl; rad

, R.

Ke

R - merk

chlorine; .

Group; radical

ABOUT

CHS

radical of the formula

Ov

shl- "jl1

II o

2,3-dihydro-1,4benzodioxan-2-yl, 1- (benzimidazol-2-yl-methyl) benzimidazol-2-yl; radical of the formula

, R.

Ke

R is mercapto or methylthiogde; RJ is hydrogen or

chlorine; .

Group; radical of the formula

,

J

 n o

- chggde where x o or s, or

A5 5

/ T vn

where AJ is N- or

or L is the radical L. - And- (CH) -,

where RJ., R ,, R — y is hydrogen or methyl

or R and Ry form O or S, a dotted line means no link or a simple link, provided that if the dotted line represents the link Rr and R / are missing; 4-morpholinyl, styryl, bis (4-fluorophenyl) methyl, 1-ethyl-5-oxotetrazol-4-np, 5-methylthiazol-4-yl, 2-oxo-2H-i-benzopyran-3- silt or radical radical

S CHZ

RB-LIJ

{CH2) d

where d 1

II

ABOUT

2, the dotted line indicates the presence or absence of a bond; R% is methyl, hydrogen.

eleven

de

eleven

L. 2 or 4; hydrogen or methyl; hydrogen, methyl, benzyl, 2-sh1ridinylmetip 2-pyridinyl, 5-chloro-2-pyridinyl, 4-nitro-I-oxypyridin-3-yl, pyrazinyl, 3-pyridazinyl, 4 (lH) -oxopyridium - nyl-2-yl, 4-chloro-6-methyl--2-pyrimidinyl or pyrimidinyl radical of the formula

"VS KAM

mg

- water

MOH

genus or chlorine;

hydrogen or amino group;

imidazol-2-yl, nitrophenyl,

3-chloro-5-pyridazinyl; 2-chloro-4-methyl-6-pyrimidinyl, 2-pyrimidinyl or

thiazolyl radical of formula

Where

H

H.4

methyl, phenyl, hydrogen or ethoxycarbonyl; 1-methyl-4-nitro-1H-imida-ZOL-5-IL, 1-methyl-1H-imidazol-5-yl, benzimidazol-2-ilthiazolo (4,5-b) pyridine--2- yl, 1-phthalazinyl, 9H-purin-6-yl, unsubstituted or substituted in position 8 or 9 by methyl or oxygroup of the formula

n

jj radical formir

ly

rVr

where a ch or

Lj is 4-chloro-1-phthalazinyl or L is a radical of the formula

L - C - NH - (CH) m

L,

 2 or 4;

- phenyl or a radical of the formula

. .R.

hydrogen, amino, methylamino, —N — CO — CH;

N

SNS

MAIN

one

This invention relates to the chemistry of heterocyclic compounds, in particular, to a process for the preparation of new 4- - (bicycloheterocyclylmethyl) piperidines of the general formula

or 4-pyridinyl, 2-methoxy-3-gidiridi-nyl, 1-methyl-1H-pyrrol-2-yl, wounded, 2-thienyl, 3-thienyl, 2-tenoyl, thiazolyl, 1-methyl- 1H-indol--2-yl, 4-OXYHINOLIN-2-yl, 2-amino-3-pyrazinyl, 2-thienylcarbonyl, 3-thienylmethyl, 2-oxo-2H-1-benzopyran-3--yl , ethylamine, dimethylamine, ethoxy or radical

R

II /

C-n

R

f7

R r

L

n

methyl, phenyl or 2-furanyl; 2-pyrimidinyl, 2-furanyl acetyl, pyridinyl-3-carboxyloxy istil, 1-methyl ethyl tetrazolyl-2-mercaptoethyl, methylaminoethioxo-methylethyl, 3-naphthalenyl-2-hydroxypropyl or cyclohexyl.

or their pharmaceutically acceptable acid addition salts, about tl and - which is reacted by reacting a compound of the formula

with an aromatic diamine of the formula

one

HN

H2: to - Az

where W is (Sh) 0-C, -C-alkyl or

-SI, -COOH in an inert solvent

RI

LA

whether they are pharmaceutically acceptable acid attachments, where, Aj-Aj A is the divalent radical of the formula Formula -CH CR2-CR3 CH- (a) 5 .and RI is independently hydrogen, methyl, etoxy, hydroxy or halo:

(B)

(with)

(d) or 10

N CH — CH CH — CH CH — CH N — R.

(e)

L L Hydrogen methyl, phenyl; benzo zyl unsubstituted or substituted by one or two i groups such as halo, methyl, methoxy; cyclohexyl; benzhydryl, phenethyl; furanyl-methyl; (5-methyl-2-furanyl) methyl, 4-thiazolylmethyl; pyridinylmethyl; 2-tiiiylmethyl; pi 20 rasinylmethyl; methyl 2-thienylmethyl; naphthalenylmethyl; 3-dimethylaminocarbonyl-3, 3-diphenylpropyl} hydrogen, isopropyl; group 25 —CH2 — R4J where H is hydrogen or bromine; ethoxycarbonyl; methyl or benzoyl; or a group (CH) - (CH) -, where a is O or 1; B O or 2; in ZO O, S or phenyl, 4-fluorophenyl, 2-pyrimidinyl, 2-pyridinyl, radical

 S.

or the radical f || |

L. li J

35

-1 -N

or a group (CH) (-5 where with 1, 2, 3, or 4; hydroxyl, cyanophenyl, oxyphenyl, methoxyphenyl, dimetho-dO syphenyl, ethoxycarbonyl, ethoxygroup, carboxyl group, ethenyl, 4-fluorophenylcarbonyl , isopropylaminocarbonyl, aminocarbonyl, 2-pyri-DZ dinyl, 2-thienyl, 2-methyl-4-thiazolyl, 2-oxo-3-oxazolidinyl, 2,4-dioxo-3 (H) -pyri- midin, 2,3-dihydro-2-oxo--1H-benzimidazol-2-yl, 2,3-JQ-dihydro-2-thioxo-1H benzimidazol-1-yl, 2-pyrimidinylaminocarbonyl, or benzimidazolyl of the formula

-kt

55

or radical of the formula

where RJ., Eg, R-p is hydrogen or methyl or Rg and R, form O or S; a dashed line means no link or simple link, provided that if the dotted line corresponds to a simple link, and R is missing; 4-morpholinyl, styryl, bis (4-fluorophenyl) methyl, 1-ethyl-5-oxotetrazol-4-yl, 5-methyl-thiazol-4-yl, 2-oxo-2H-1-benzopyran-3 -yl or radical of the formula

to.

(

where d is 1 or 2, dashed line

means the presence or absence of a connection; Rg is methyl, hydrogen; radical of the formula

SNS

0.x WY%

2,3-dihydro-1,4-benzodioxan-2-yl, 1- (benzimidazol-2-yl-methyl) benzimidazol-2-yl; radical of the formula:

rVr

N iiRg

where Rg is hydrogen or chlorine;

R jij - hydroxy group, mercapto or methylthio group, a radical of the formula

SNS

.

iT

about

n

 ABOUT

X O or S, or

AJ --N or -CH, L - radical

L —N- (CH,),, 5 N

4.JJ-J

de

P

L

Bs

2 or 4;

hydrogen or methyl; 2o

hydrogen, methyl, benzyl, 2-pyridinylmethyl, 2-pyridyl, 5-chloro-2-pyridinyl, 4-nitro-1-oxypyridin-3-yl, pyrazinyl, 3-pyridazi-25 NIL, 4 ( 1H) -oxopyrimidinyl-2-yl, 4-chloro-6-methyl-2-pyrimidinyl or a pyrimidinyl radical of formula

R r

12

one

N

de N 3

13

hydrogen or chlorine;

hydrogen, or amino, 35

imidazol-2-yl, nitrophenyl,

3-chloro-5-pyridazinyl, 2-chloro-4-methyl-6-pyrimidine,

2-pyrimidinyl or thiazolyl radical of formula

thirty

f

where R. is methyl, phenyl, hydrogen or

ethoxycarbonyl;

1-methyl-4-nitro-1H-imidaz, 1- -methyl-1H-imidazol-5-yl, benzimidazol--2-ylthiazolo (4,5-b) pyridin-2-yl, 1- 50 phthalazinyl, 9H -purin-6-yl, substituted or unsubstituted in the positions 8 or 9 by methyl or hydroxyl; radical of the formula

n in

: N

139696

A6

radical of the formula

Ab

where A is -CH or

L3 is 4-chloro-1-phthalazinyl, or L is a radical of formula O

-c-m- (mn,) where m 2 or 4

L is phenyl or a radical of formula

d where is hydrogen, amino group meX

SNS

thylamino, —N — CO — CH or radical

SzN7-CO

OSSN

or 4-pyridinyl, 2-methoxy-3-pyridinyl, 1-methyl-1H-pyrrol-2-yl, 3-furanyl, 2-thienyl, 3-thienyl, 2-thoyl, thiazolyl, 1-methyl - - H-indol-2-yl, 4-α-hydroxyquinolin-2-yl, 2-amino-3-pyrazinyl, 2-thienylcarbonyl, 3-thienyl methyl ,. 2-oxo- (2H) -1-benzopyran-3-yl, ethylamine, dimethylamine, ethoxy group, or or radical

About R

17

45

and

- C - N de N

Rh

whether l

methyl, phenyl, or 2-furanyl;

2-pyrimidinyl; 2-furanyl-acetyl, pyridinyl-3-carbonyloxyethyl, 1-ethyl-tetrazolyl-2-yercaptoethyl, methylaminothio-oxymethyl, 3-naphthylenyloxy-2-oxypropyl or cyclohexyl, which are potential antagonists of the antagonists of the antagonists who are potential antagonists of the antagonists who are potential antagonists of the antagonists who are potential antagonists of the antagonists who are potential antagonists of the antagonists who are potential antagonists of the antagonists who are potential antagonists of the antagonists who are potential antagonists of the antagonists, serotonin and can be used in medicine, the production of intermediate compounds. Example 1. A mixture of 302 h of ethyl -2 -2 -C1- (phenylmethyl) -4-piperidinylidene acetate hydrochloride and 200 parts of glacial acetic acid is hydrogenated under normal pressure at 24-36 C in the presence of 4 h of platinum oxide. After uptake of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is washed with 1, l-oxy-bis-ethane, j5 is alkalinized with sodium hydroxide, and extracted with 1,1-oxy-bis-ethane. The obtained cjoaaT extract over potassium carbonate and evaporated. The oily residue is distilled in vacuo, as a result of which 205 parts of an impure oily free base are obtained. One part is taken from this oil to prepare a hydrochloride

re. The reaction mixture is evaporated. The resulting residue is stirred at 2400 parts of acetonitrile. The resulting duct is filtered off, washed with 560 parts of acetonitrile and, dried to obtain 200 parts (85.7%) of O-ethyl-1nylmethyl) -4-piperidine ethanimide chloride (3).

In a similar way, 0-methyl-1- (phenylmethyl) -4-pyridine ethanimidate hydrochloride (4) is also obtained.

Example 3. A mixture of 180 parts of chloro-3-nitropyridine, 122.0 parts of 2-tons of phenmethanamine, 191.0 parts of sodium carbonate, 1 part of potassium iodide and 810 hours of K, K-dimethylacetamide is stirred for 1.5 h at 100 ° C. The reaction mixture is drunk in about 4000 hours dy. The entire contents are stirred overnight at room temperature. The precipitate is filtered off and su under vacuum at, the result is 251.5 hours 3-nitro-N- (2

reed It is dissolved in 1, l-oxy-bis-25-nylmethyl) -2-pyridinamine, m.p.

 (five).

- ethane and hydrogen chloride gas are introduced into the solution; semisolid salt precipitates. The solvent is decanted, the resulting residue is again dissolved in a mixture of 6 hours. ethanol; and 4 parts. 1,1-oxy-bis-ethane. The resulting solution was concentrated to 5 hours. 12 parts of 1,1-hydroxy-bis-ethane were added to the residue, after which the solid portion was precipitated. It is filtered and dried. as a result, 0.2 parts of ethyl-1- (phenylmethyl) -4-piperidine acetate hydrochloride are obtained, m.p. 122.5-137 C (intermediate compound 1).

A mixture of ethyl 1- (phenylmethyl) -4-piperidine acetate hydrochloride and 80 parts of dilute hydrochloric acid for 8 hours is stirred and refluxed for 4 hours. After cooling

 (five).

In the same way, using equivalent amounts of the corresponding starting materials, the following is also prepared: 30 N- (2-nitrophenyl) -3-pyridine-methane-1 amine (6);

AND- (4-fluorophenylmethyl) -3-nitro-2-pi-ridinamine, mp 76 ° C (7);

N- (3-nitro-2-pyridinyl) -2-pyridine methaneamine, m.p. 113, (8);

2-nitpo-N- (2-thienyl methyl) benzamine (9);

4-methyl-K- (2-nitrophenyl) b enzolmethanamine, m.p. 65 C (lO) i 40N (A-methylphenyl) methyl-3-nitro-2-pyridinamine, m.p. 80-87, (11

N - (4-fluorophenyl) methyl -2,3-diridinediamine (12);

N - (4-fluorophenyl) methyl -3-nitro35

the reaction mixture is evaporated. The residue dz -4-pyridinamine, so pl. 136, (13);

washed with 2-propanone and the solvent is again evaporated. The solid residue is washed with 2-propanone, filtered and dried to obtain 6 hours. 1- (phenylmethyl) -4-piperidine acetic acid hydrochloride; t square 137-145 ° C (2). Example 2. 2350 parts of hydrogen chloride are passed through 5600 hours of chilled ethanol (ice bath) at 10 ° C. Then, dropwise, in 45 minutes, 1500 parts of 1- (phenylmethyl) -4-piperid 11 acetonitrile is added dropwise. After the addition is complete, everything is stirred for 20 hours at room temperature; W- (+ -Fluorophenyl) methyl-4-nitro-3-pyridine amine-1-oxide (14);

4-fluoro-y- (4-methox-2-nitrophensh1) benzeneethanamine (15);

4-fluoro-I- (5-labels si-2-nitrophenyl) benzenemethanamine (16);

4-fluoro-K- (4-methyl-2-nitrophenyl) benzenemethanamine, so pl. 99.9 ° C (17).

Example 4. To a stirred and cooled mixture 40 parts of K- (4-fluorophenyl) methyl J-4-nitro-3-pyridinamine 1-oxide and 1050 parts of trichloromethane are added dropwise 47 parts of phosphoric chloride at temperature between o and

re. The reaction mixture is evaporated, the resulting residue is stirred at 2400 parts of acetonitrile. The resulting product is filtered, washed with 560 parts of acetonitrile and, dried to obtain 200 parts (85.7%) of O-ethyl-1 (phenylmethyl) -4-piperidine ethanimidate hydrochloride (3).

In a similar way, 0-methyl-1- (phenylmethyl) -4-piperidineethanimidate hydrochloride (4) is also prepared.

Example 3. A mixture of 180 parts of 2-chloro-3-nitropyridine, 122.0 parts of 2-thiophenemethanamine, 191.0 parts of sodium carbonate, 1 part of potassium iodide and 810 parts of K, K-dimethylacetamide is stirred for 1.5 h at 100 ° C. The reaction mixture is drunk in about 4000 parts of water. The entire contents are stirred overnight at room temperature. The precipitate was filtered off and dried in vacuo at, resulting in 251.5 parts of 3-nitro-L- (2-thienylmethyl) -2-pyridinamine, m.p.

 (five).

In the same way, using equivalent amounts of the corresponding starting materials, one also obtains: N- (2-nitrophenyl) -3-pyridine-methane-1 amine (6);

And- (4-fluorophenylmethyl) -3-nitro-2-pyridinamine, m.p. 76 ° C (7);

N- (3-nitro-2-pyridinyl) -2-pyridine-methaneamine, m.p. 113, (8);

2-nitpo-N- (2-thienyl methyl) benzamine (9);

4-methyl-K- (2-nitrophenyl) b-enzolmethanamine, m.p. 65 C (lO) i N (A-methylphenyl) methyl-3-nitro-2-pyridinamine, m.p. 80-87, (11);

N - (4-fluorophenyl) methyl -2,3-diridinediamine (12);

N - (4-fluorophenyl) methyl -3-nitro

-4-pyridinamine, so pl. 136, (13);

h -4-pyridinamine, so pl. 136, (13);

P

W- (+ -Fluorophenyl) methyl -4-nitpo-3-pyridinamine-1-oxide (14);

4-fluoro-y- (4-methox-2-nitrophensh1) benzeneethanamine (15);

4-fluoro-I- (5-labels si-2-nitrophenyl) benzenemethanamine (16);

4-fluoro-K- (4-methyl-2-nitrophenyl) benzenemethanamine, so pl. 99.9 ° C (17).

Example 4. To a stirred and cooled mixture 40 parts of K- (4-fluorophenyl) methyl J-4-nitro-3-pyridinamine 1-oxide and 1050 parts of trichloromethane are added dropwise 47 parts of phosphoric chloride at temperature between o and

-10 ° C. After the addition is complete, everything is stirred and refluxed for 1 hour. With stirring, the reaction mixture is cooled. The precipitate formed is filtered off, stirred in water and alkalified with ammonium hydroxide. The product obtained is extracted with trichloromethane. The extract obtained is dried, filtered, evaporated and evaporated. The residue is stirred in 2,2-oxy-bis-propane. The resulting product is filtered and dried, resulting in a gain

22.2 parts of N- (4-fluorophenyl) methyl-4-nit-15 ro-3-pyridinamine, m.p. 91, {18) s

Example 5. A mixture of 100 h, H-C (4-labels of siphenyl) methyl-3-nitro-2-pyridinamine, 3h thiophene solution

Example 6. A mixture of 9.7 parts of 4-α-fluoro-1 .- (4-fluorophenyl) benzene butanoyl chloride, 4.1 parts of 2,6-dimethylpyridine and 68 parts of tetrahydrofuran is hydrogenated at normal pressure and at room temperature with two parts of 10% palladium on carbon as a catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 8.5 parts of 4-fluoro-ag (4-fluorophenyl:) 1 benzenebutanol (34).

Example 7. To the stirred mixture 26 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5-thione, 13.8 parts of potassium carbonate and 240 parts of 2-propanone. 376 h. 1,2-dibromoethane.

in methanol (4% and 480 parts of methanol, 20 After the addition is complete, the mixture is stirred with ammonia, hydrogenated under normal pressure at 50 ° C with 5 hours. 10% palladium on coal as a catalyst. After absorption, the calculation is continued overnight The precipitate is filtered off and the filtrate is evaporated, resulting in 45 parts of (957) 5- (2-bromoethyl)

continued overnight. The precipitate is filtered off and the filtrate is evaporated, resulting in 45 parts of (957) 5- (2-bromoethyl)

thirty

The amount of hydrogen is 25 tio -1-ethyl-1H-tetrazole as a residue and the resulting filtrate (35) is filtered off.

Example 8. To a stirred and cooled (O — C) mixture of 59 parts of 2-propanamine and 650 parts of dichloromethane, were added dropwise 376 parts of 1,2-dibromoethane. After the addition is complete, stirring is continued overnight. The precipitate formed is filtered off and the filtrate is evaporated, to obtain 45 parts (95%) of 5- (2-bromoethyl) tis -1-ethyl-1H-tetrazole (35).

Example 8a. To the stirred and cooled solution of 59 parts of 2-propanamine in 650 parts of dichloromethane, 94.2 parts of 3-bromopropanoyl chloride are added dropwise. After the addition is complete, stirring is continued for 5 minutes. Then everything is washed with water. The organic layer is separated, dried, filtered and evaporated. The residue is recrystallized from a mixture of 2,2-oxy-bis-propane and hexane. The resulting product is filtered and

35

40

evaporated, resulting in a gain of 88.4 parts of R (methoxyphenyl) methyl -2-3-pyridinamine, so pl. 118.1 ° C (19).

In a similar way receive:

N- (3-pyridinemethyl) -1 2-benzenedi--amine (20);

(4-fluorophenyl) methyl} -2,3-pyridin (21);

N - (2-pyridylmethyl) -2,3-pyridine-amine, m.p. 134, (22);

N - (2-furanylmethyl) -2,3-pyridine-amine (23);

(2-thienylmethyl) -1,2-benzenediamine (24);

N - (2-thienylmethyl) -2,3-pyridinedi-amine, m.p. 92, (25);

 (4-methylphenyl) methyl -1,2-benzenediamine (26);

 C (4-methylphenyl) methyl -2,3-pyridinediamine, m.p. 125.1 С (27);

 (4-fluorophenyl) methyl-3,4-pyridinediamine, m.p. 63.7 ° C (28);

 (4-fluorophenyl) methyl-3,4-pyridinediamine, m.p. 159.6 ° C (29);

jjl (4-fluorophenyl) methyl-4-methoxy--1,2-6 enzenoldiamine (30);

 C (4-fluorophenyl) methyl J-4-methoxy--1,2-6enzenediamine (31);

and - | (4-Fluorophenyl) methylJ-4-methyl- 55 -1,2-6-benzenediamine (32);

N- (5-methyl-2-furanyl) methyl3-1,2-benzene diamine (33).

45

50

dried, resulting in a gain of 70 parts (73%) of 3-bromo-K- (1-methyl-ethyl) propanamide, t, pl. (36).

Example 9. A mixture of 4.76 parts of b-chloro-N-methyl-4,5-pyridinediamine, 26.6 parts of 1,1,1-trichloroethane and 30 parts of acetic anhydride is stirred and refluxed within 3 hours. The reaction mixture is evaporated. The residue is crystallized from a mixture of hexane and methylbenzene.

Example 6. A mixture of 9.7 parts of 4-α-fluoro-1 .- (4-fluorophenyl) benzene butanoyl chloride, 4.1 parts of 2,6-dimethylpyridine and 68 parts of tetrahydrofuran is hydrogenated at normal pressure and at room temperature with two parts of 10% palladium on carbon as a catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 8.5 parts of 4-fluoro-ag (4-fluorophenyl:) 1 benzenebutanol (34).

Example 7. To the stirred mixture 26 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5-thione, 13.8 parts of potassium carbonate and 240 parts of 2-propanone. 376 hours are added dropwise. 1,2-dibromoethane.

After the addition is complete,

After the addition is complete,

continued overnight. The precipitate is filtered off and the filtrate is evaporated, resulting in 45 parts of (957) 5- (2-bromoethyl)

thio -1-ethyl-1H-tetrazole as residue 30

35

40

45

dried, resulting in a gain of 70 parts (73%) of 3-bromo-K- (1-methyl-ethyl) propanamide, t, pl. (36).

Example 9. A mixture of 4.76 parts of b-chloro-N-methyl-4,5-pyridinediamine, 26.6 parts of 1,1,1-trichloroethane and 30 parts of acetic anhydride is stirred and refluxed within 3 hours. The reaction mixture is evaporated. The residue is crystallized from a mixture of hexane and methylbenzene.

The product obtained is filtered off and dried, whereby 5.3 parts (96.3%) of 6-chloro-8,9-dimethyl-9H-purine (37) are obtained.

Example 10. A mixture of 4.76 parts of b-chloro-N -methyl-4,5-pyrimidinediamine and 7.2 hours, the ureas are stirred and natyl -1H-benzimidaeol, t, pl.

124.8 C (3).

In a similar way, receive: 1-phenyl-2- (phenylmethyl) -4-piperidinylJ methyl -1H-benzimidazole,

mp: 141.6 ° C- (4);

(phenylmethyl) -4-piperidinyl

methyl -1- (3-pyridinylmethyl) -1H-benzgreeyut for 1 h at 180: C.

After cooling, the residue is suspended 10 imidazole, m.p. 125, (5). in water. The resulting product is filtered- Example 13. A mixture of 116.5 hours

Happen and dried, with the result that 0-ethyl-1- (phenylmethyl) -4-piperidine obtain 3.3 parts (60%) of 6-chloro-9-methyl-ethanimidate hydrochloride, 61 {5h. N - {14-9H-purin-8-ol (38) .- methylphenyl) methyl -1,2-benzenediamine

Obtaining target compounds. 15 and 400 parts of methanol are stirred and kiPrimer 11. To 73 parts of hot melt under reflux, (-) polyphosphoric acid is added 27 parts of 1-Sphenylmethyl) -4-piperichenia overnight. Another portion of 40 parts of 0-ethyl-1- (phenylmethyl) -4-piperidine-ethanimidate hydrochloride is added and

the temperature is up to 100 ° C. After-20 stirring is continued for the duration of completion of the addition in parts of 4 hours under reflux. The reaction mixture is evaporated. Water was added to the residue. The resulting solution is treated with ammonium hydroxide. 25 The resulting product is extracted with trichloromethane. The resulting extract of succinacetic acid hydrochloride.

14 parts of 1,2-benzenediamine are added and stirring and heating is continued for 50 minutes at 170 ° C. The hot reaction mixture is poured into 300 parts of warm water. Acid solution

alkalinized with a solution of hydroxide ,. Shat, filter and evaporate. Potassium residue. The precipitated free base is crystallized from acetonitrile. The mixture is semi-filtered, washed with water and the filtered product is filtered off and extracted with trichloromethane. The resulting 30 shat is obtained, as a result of which 74.5 hours is obtained, the new extract is dried and evaporated. (63%) 1-4-methylphenyl} methyl -2-l- The solid residue is recrystallized from a mixture of 2-propanone and methanol to give 17 hours. - (Phenylmethyl) -4-piperidinyl methyl J-, -1H- benzimidazole, t. pl. 221.5 - (Phenylmethyl) -4-piperidinyl methyl - - 1P-benzimidazole, so pl. 124, (b).

222 C (compound 1).

In the same way, using equivalent amounts of the corresponding starting materials, 2-1 C1-phenylmethyl-4-piperidine 1 methyl 1- (2-thienylmethyl) -1-benzimidazol, t. Pl. 156, (7);

In the same way, using equivalent amounts of the corresponding starting materials, 2-1 C1-phenylmethyl-4-piperidine 1 methyl 1- (2-thienylmethyl) -1-benzimidazol, t. Pl. 156, (7);

In a similar way, (phenylmethyl) -4-piperidinylmethyl} -1H-imidazo 4,5-c -pyridine, 3-C4-fluorophenylmethyl) -2-1- (phenyl-t. Pl. 172, (2) .methyl) -4-piperidinyl -methyl} -ZH-imide. Example 12. Mixture of 27.3 parts of azolo 4,5-o pyridine, t. pl. 103.2 0-methyl-1- (phenylmethyl) -4-piperidine-105.8 ° C (8);

ethanimidate dihydrochloride, 14 h. N- (2-2-C 1- (phenylmethyl) -4-piperidinyl mefuranylmethyl) -1,2-benzendiate and thyl-3- (2-pyridinomethyl) -ZN-imidazo

250 hours, acetic acid is mixed with 4,5-b pyridine, so pl. 118.5-120.9 С

overnight at room temperature- (9)

tour. The reaction mixture was evaporated, 3- (2-furanylmethyl) (phenylmethyl) was added to the residue. All this is 4-piperidinyl -methyl-ZN-imidazo

alkalinize with sodium carbonate and 50 4, 5-b pyridine, t. pl. 118.5-119.8 ° C

extracted with 4-methyl-2-pentanone. (S); GG with

The extract obtained is dried, filtered-1 -. (4-methoxyphenyl) methyl (fermented and evaporated. The remainder of the crystalline methyl) -4-piperidinide-methyl-J-1H is obtained from 1,1-hydroxy-bis-ethane. By - benzimidazole, t. Pl. 95.2 C (P);

the resulting product is filtered off, 552- - (phenylmethyl) -4-piperidinyl is missed, resulting in a ethyl-3- (2-thienylmethyl) -HH-imidazo

15 5 h. (57%) - (2-furanylmethyl), 5-b pyridine, t. Pl. 115.2 C (12);

-U- (phenylmethyl) -4-shsheridinyl me-1- (phenylmethyl) (phenylmethyl) -4til -1H-benzimidaeol, t, pl.

124.8 C (3).

In a similar way, receive: 1-phenyl-2- (phenylmethyl) -4-piperidinylJ methyl -1H-benzimidazole,

mp: 141.6 ° C- (4);

(phenylmethyl) -4-piperidinyl

methyl -1- (3-pyridinylmethyl) -1H-benzimidazole, m.p. 125, (5). Example 13. A mixture of 116.5 hours

Shat, filter and evaporate. The residue is crystallized from acetonitrile. The resulting product is filtered off and dried, resulting in a gain of 74.5 h, (63%) 1-4-methylphenyl} methyl -2-l-

- (Phenylmethyl) -4-piperidinyl methyl - - 1P-benzimidazole, t. Pl. 124, (b).

Shat, filter and evaporate. The residue is crystallized from acetonitrile. The resulting product is filtered off and dried, resulting in a gain of 74.5 h, (63%) 1-4-methylphenyl} methyl -2-l-

In the same way, using equivalent amounts of the corresponding starting materials, 2-1 C1-phenylmethyl-4-piperidine 1 methyl 1- (2-thienylmethyl) -1-benzimidazol, t. Pl. 156, (7);

3- C4-fluorophenylmethyl) -2-1- (phenylmethyl) -4-piperidinyl-methyl} -NH-imide-piperidish methyl J-1H-benzimide azole, so pl. (13);

3- (4-methoxyphenyl) methylJ-2-CL1- (phenylmethyl) -4-piperidinyl-methyl J-3.H- -imidazo 4,5-b pyridine, t. Pl. 83.4 C (14);

1- (4-fluorophenyl) methyl-5-methoxy-2- - 1- (phenylmethyl) -4-piperidinyl methyl} -1H-benzimidazole, so pl. 112.6 S Yu 160 C (23);

(15);

1- (3-Feranylmethyl) -2- | .1- (phenylmethyl) -4-piperidinyl megyl - W-benzimidazole, t. Pl. 102.0 ° C (16);

1- (4-fluorophenyl) methyl-6-methoxy-2 C1- (phenylmethyl) -4-piperidinyl methyl -1H-benzimidazole, mp,

(17);

5-fluoro-2-C1- (phenylmethyl) -4-piperidimethyl) -4-piperidinyl-methyl-3H-imidazo4.5-c pyridine, m.p. 116.9 С (22).

Example 15. According to the methods of Examples 12-14, 1-benzoyl-4-C (1-methyl-1H-benzimidazol-2-yl) methyl pyridine is also prepared, t, pl.

15

20

25

Nyl Methyl - H-Benzimidazole, m.p. 206, (18);

1 -, (5-methyl-2-furanyl) methyl J-2- 1 - .- (phenylmethyl) -4-piperidinyl methyl - -1H-benzimidazole, t, mp, 96 ° C (19). Example 14, A mixture of 43 parts of 1- - (phenylmethyl) -4-piperidineacetic acid hydrochloride, .31.5 parts of (4- -fluorophenyl) methyl -2,3-pyridinediamine, 850 hours, phosphoryl chloride and 20 hours, H, M-diethylbenzene amine is stirred for 6 hours at reflux temperature. The reaction mixture is evaporated, methylbenzene is added twice to the residue and each time it is evaporated. The ultimate. the residue is poured into ice water and the whole is made alkaline with a dilute sodium hydroxide solution. The resulting product is extracted twice with dichloroethyl-4- (1-methyl-1H-benzimidazol-2- -yl) methyl-β-piperidine carboxylate, m.p., 98 ° C (24);

1- (4-fluorophenyl) methyl -2- 1- (phenylmethyl) -4-piperidinylZ-methyl j 1H-6eH3-imidazole, t, Sh1, (25); (phenylmethyl) -4-piperidinyl me- (4-thiazolylmethyl) -1H-benzimidazole, m.p. 98-G06 C (26); 2- (4-piperidinylmeth1) -1H-benzimidazole, t, mp, 195-196, (27); 1- (phenylmethyl) -2- (4-piperidinylmethyl) -1H-benzimidazole monohydrate, mp; 72.5 ° C (28);

2- (4-piperidinylmethyl) -3- (2-pyridinylmethyl) -3H-imidazo 4,5-b} pyridine- (E) -2-butandioate (2: 3), t, mp, 191-194 ° С (29);

1-phenyl-2- (4-piperidinylmethyl) -1H- -benzimidazole, t, pcs. 142.5 ° C (30); 1. (4-Fluorophenyl) methyl -2- (4-piperidinylmethyl) -1 H-imidazo 4, 5-b pyridine- (E) -2-butanedioate, t, mp, 214.5 C (31);

2g (4-fluorophenyl) methyl -2- (4-piperidinylmethyl) -1H-imidazo 4,5-c pyridine-ethanedioate (2: 3) monohydrate, t, pl. 173 ° C (32); . 1- (4-fluorophenyl) methyl-5-methoxy-2 methane. The combined extracts twice twice (- 4-piperidinylmethyl) -1H-6-benzimidazolides are washed with water, dried, filtered and evaporated. The residue is purified on a chromatographic column with silica gel, using as eluent a mixture of

t, pl.

dihydrochloride monohydrate,

214 ° C (33);

ethyl 4-C1- (2-thienylmethyl) -1H-benz-

imidazol-2-yl methylJ-1-piperidinecarbonyl chloromethane and methanol, saturated with 5 boxylate monohydrochloride, t, pl.

ammonia (95: 5 by volume). Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The resulting product is filtered and dried, resulting in 30 h, (50.2%) of 1- (4-fluorophenyl) methyl-2-tEl- (phenylmethyl) -4-piperidinyl methyl -1H-imidazo 4, 5-py pyridine, m. Pl. 140.7 ° C (20).

In the same way, - (4-fluorophenyl) methyl -2- - (phenylmethyl) -4-piperidinyl-methyl -1H-imidazo 4, 5-c pyridine, t, Sh1 is obtained. 139.1 ° C (21); 3- (4-fluorophenyl) methyl (phenyl 178, 5 ° C (34); ethyl 4-; - (4-thiazolylmethyl) -1 H-b imidazol-2-yl methyl -1-piperidine monohydrochloride bauxylate, mp 197.5-199 ° C (35);

1- (2-furanylmethyl) -2- (4-piperidish methyl) -1K-benzimidazole- (E) -2-bute dioat (2: 3), t, mp, 219.5 C (36); 1- (3-furanylmethyl) -2- (4-piperidine methyl) -1H-benzimidazole, t, pl. 18 (37);

1- (5-methyl-2-furanyl) methyl -2- (4 peridinylmethyl) -1H-benzimidazole, t, mp, 90 ° C (38) .;

 160 C (23);

methyl) -4-piperidinyl-methyl-3H-imidazof4,5-c pyridine, t. pl. 116.9 С (22).

Example 15. According to the methods of Examples 12-14, 1-benzoyl-4-C (1-methyl-1H-benzimidazol-2-yl) methyl pyridine is also prepared, t, pl.

160 C (23);

ethyl 4- (1-methyl-1H-benzimidazol-2- -yl) methyl- - piperidine-carboxylate, t, mp, 98 ° C (24);

1- (4-fluorophenyl) methyl -2- 1- (phenylmethyl) -4-piperidinylZ-methyl j 1H-6eH3-imidazole, t, Sh1, (25); (phenylmethyl) -4-piperidinyl me- (4-thiazolylmethyl) -1H-benzimidazole, m.p. 98-G06 C (26); 2- (4-piperidinylmeth1) -1H-benzimidazole, t, mp, 195-196, (27); 1- (phenylmethyl) -2- (4-piperidinylmethyl) -1H-benzimidazole monohydrate, mp; 72.5 ° C (28);

2- (4-piperidinylmethyl) -3- (2-pyridinylmethyl) -3H-imidazo 4,5-b} pyridine- (E) -2-butandioate (2: 3), t, mp, 191-194 ° С (29);

1-phenyl-2- (4-piperidinylmethyl) -1H- -benzimidazole, t, pcs. 142.5 ° C (30); 1. (4-Fluorophenyl) methyl -2- (4-piperidinylmethyl) -1 H-imidazo 4, 5-b pyridine- (E) -2-butanedioate, t, mp, 214.5 C (31);

(4-fluorophenyl) methyl -2- (4-piperidinylmethyl) -1H-imidazo 4,5-c pyridine-ethanedioate (2: 3) monohydrate, t, pl. 173 ° C (32); . 1- (4-fluorophenyl) methyl-5-methoxy-2t, pl.

dihydrochloride monohydrate,

214 ° C (33);

ethyl 4-C1- (2-thienylmethyl) -1H-benz-

imidazol-2-yl methylJ-1-piperidinecarboxylate monohydrochloride, t, pl.

178.5 ° C (34); ethyl 4-; - (4-thiazolylmethyl) -1H-benzimidazol-2-yl methyl -1-piperidinecar — monohydrochloride boxylate, mp 237.5-199 ° C (35);

1- (2-furanylmethyl) -2- (4-piperidish-methyl) -1K-benzimidazole- (E) -2-butenoate (2: 3), t, mp, 219.5 C (36); 1- (3-furanylmethyl) -2- (4-piperidinylmethyl) -1H-benzimidazole, t, pl. 180 C (37);

1- (5-methyl-2-furanyl) methyl -2- (4-piperidinylmethyl) -1H-benzimidazole, t, mp, 90 ° C (38) .;

- (4-fluorophenl) methyl -2- (4-piperidinylmethyl) -1Y-benzimidazol-5-ol, so pl. (39);

3- (4-fluorophenyl) methyl J-2-C 1-G2- (2- pyridinyl) ethyl-4-piperidinyl methyl-3H-imidazo 4,5-b pyridine ethanoate (1: 3), t pl. (40);

  l - (4-fluorophenyl) methyl -1H-benz imidazol-2-yl methyl -1-piperidinyl - -2-butane ethanedioate (2: 5), so pl. (41);

1- (4-fluorophenyl) methyl 2- (2- -pyridi NIL) ethyl-4-piperidinyl 1-methyl-3-benzimidazoleethanoate (1: 3), monohydrate, m.p. (42); 1-phenyl-1H-benzimidazol-2-yl) methyl -1-piperidine ethanol, m.p. 113.5 ° C (43);

(4-fluorophenyl) methyl -1H-benzimidazol-2-yl methyl -1-piperidinato-anol, m.p. (44); (4-Fluorophenyl) methyl -2H-imide-30 4,5-b pyridin-2-yl-methyl J-o / - (1-naphthalyloxy) methyl -1-piperidine ethanol- (E) -2-butandioate. (2: 3), mp: 143.5 ° C (45);

 (4-fluorophenyl) methyl -1H-benzimidazol-2-yl-methyl - (2-naphthalenyl oxy) methyl -1-piperidine ethanol ethanedioate (1: 2) so pl. 152 s (46);

3- (4-fluorophenyl) methyl -2- 1- 2- (2- -thienyl) ethyl-4-piperidinyl} methyl - ZN-imidazo 4,5-b pyridine dihydrochlo-RID, monohydrate, m.p. 210, (47); I- (4-fluorophenyl) methyl -2- 1- 2- (2- -thienyl) 3 thyl-4-piperidine 1 methyl -1 -1H-benzimidazoleethanoate (1: 2) hemihydrate, t. Rai. 142.0 C (48); tl-C (4-fluorophenyl) methyl-Sh- -benzimidazol-2-yl -oxy -1-piperidi, 4- (1H, 3N) quinazolinedione, m.p. (49);

3- (4-fluorophenyl) methyl -2- | 1- (2-propenyl) -4-piperidinylZ-methyl 3-ZN-imidazo- (4,5-b pyridine dihydrochloride, monohydrate, so pl. ( (50); 4.3- (4-fluorophenyl) methyl-3H-imidase L4,5-b pyridin-2-yl 1-methyl -Y- (1-methylkethyl) -1-piperidinepropanamide, mp 134 ° C ( 51);

1- C 4-fluorophenyl) methyl -2- 1- (2-propyl) -4-piperidinyl} -methyl -1H-back imidazoleethioate (1: 2), t. Pl. (52);

(4-fluorophenyl) metsh1 -1H-benzimidaz ol-2-yl-me (1-methylethyl -1-piperidinepropanamide- (E) -2-butandioate (2: 3), mp. 138 s3 (53);

3- (4-fluorophenyl) methylJ-2-CC 1 G2- (phenylsulfonyl) ethyl-4-piperidinyl} methyl-ZN-imidazo {4,5-b pyridine ethanoate (2: 3), t. square 159 ° C (54); 3- (4-fluorophenyl) methyl -2-tC1- 2- (phenyl thio) ethyl-4-piperidinyl methyl-3H-α-imidazo 4,5-b-pyridine ethanethioate (1: 2), mp. (55); (4-fluorophenyl) methyl j-3H-imidazo 4, 5-b pyridin-2-yl-methyl-1-pyperidine acetamide, t. Pl. 153.4 ° C (56); .1 (4-fluorophenyl) methyl-H-benzimidazol-2-yl methyl -1-piperidineacetamide, m.p. 187.5 ° C (57); 4-C L1- (4-fluorophenyl) methyl J-1H-benz-imidazol-2-yl methyl-M, M-dime, -diphenyl-1-piperidinbutanamide, mp

 l51.4 C (58);

1 - (4-fluorophenyl) methyl -2- 1 - 2- (4- -methoxyphenyl) ethyl-4-piperidinyl - -methyl -1H-imidazo 4,5-c pyridine-ethanedioate (1: 2), mp. . 193 ° C (59); 1- (4-fluorophenyl) methyl -2- l- 2- (4- -methoxyphenyl) methyl} -4-piperidinyl methyl -1 H-ykidazo 4,5-b pyridines tandioate (1: 1), m.p. 176.7 ° C (60); 3- (4-fluorophenyl) methyl -2-l-l2- (4- -methoxyphenyl) ethyl-4-piperidinyl methyl -ZN-imidase o 4,5-s W ridine tandioate (1: 2), t. square 191, (61); 1- (4-fluorophenyl) methyl-J- - 1H-ben zimidaz ol-2-yl methyl -1-peridinyl ethyl thiazolo 5,4-b} pyridine-2-aminetanedioate, (1: 3), t. square 148 ° C (62);

1 .h

2- - (4-fluorophenyl) methyl-1H-benzimidazol-2-yl methyl-J1-piperidinyl ethyl amino} -4 (1H) -pyrimidinone, m.p. (63);

(4-fluorophenyl) methyl} -1H-benzimidazol-2-yl methyl -1-piperidnnyl ethyl thiazolo 4,5-c IShridine-2-amine-ethanethioate (1: 3), m.p. 188 C (64); (4-Fluorophenyl) methyl -1H-benzimidazol-2-yl methyl -1-piperidinyl methyltilT 2-pyrindinamine, m.p.

(65); ;

i

(1-Phenyl-1H-benzimidazol-2-yl) methyl 3-1-piperidinyl-ethyl -2-pyrimidinamine- (E) -2-butandioate (1: 1), tons. 211 ° C (66); , 4- Cl- (4-fluorophenyl) methyl Sh-benz-imidazol-2-ylZ methyl-11- (1-methyl-4-nitro-1H-imidazol-5-yl) -1-piperidine-ethanamine, t pl. 131 ° C (67); b-chloro-N- 2- 4- CD (4-fluorophenyl) methyl - 1 Ib-benzimidaz ol-2-yl methyl} -117

piperidinyl etsh1 J-3-pyridazinamine, so pl. 175, (68); 1- (4-fluorofene) methyl -1H-- -benzimidazol-2-yl methyl -1-piperidinyl ethyl-4-nitro-3-pyridinnamine, 1-oxide, t. Pl. (69); 4-chlorop-N-C2- 4- 1- (4-fluorophenyl) methyl - 1H-b-benzimide with ol-2-yl methyl J-1 -PIP-peridinyl-Jethyl J-1-phthalazinamine, so pl. 169, (70); 4-chloro-I-2-G4-1-C (4-fluorophenyl) mr-3-sh-benzimidazol-2-yl methyl -1- -piperidinyl ethyl-6-methyl-2-pyridine-aminethanedioate (1: 2 ) t. pl. 166 ° C (71);

2-chloro-Y-2-L4- 1- (4-fluorophenyl) methyl -1H-benzimidazol-2-yl3-methyl2-1-piperidinyl ethyl 3-6-methyl-4-pyridine-amine, m.p. (72); b-Chloro-N-C2-4-tCl-1 (4-fluorophenyl) methyl J-1 Nbbenzimidaz OL-2-IL} methyl J-1-piperidinyl eth J-4-pyridinamine-ethanedioate (2 : 5), so pl. 174.4 C (73)

139696418

(2-Thienylmethyl) -1H-benzimidazol-2-cl} methylJ-1-piperidinipethyl J-1H-imidazo 4,5-c} pyridine-2-amins - (E) -2-butandioate (1: 3), - monohydrate, so pl. 197, (82);

N-2-4-GGZ- (2-furanylmethyl) -ZN-imidazo C4,5-b} pyridin-2-yl7-methyl -1-pyrididinyl} ethylZ-1H-imidazo (4,5-cJnK10 Ridin-2-amine- (E) -2-butandioate (1: 3) monohydrate, mp (83); N-f2-4-3- (2-pyridinylmethyl) -ZH- -imidazo 4,5- B is pyridin-2-yl-J methyl-1-piperidinyl) ethyl; -1H-imidazo

15 4,5-c pyridine-2-aminethanedioate (1: 4), t. Pl. 191 C (84);

N- (4-metshlfesh l) methyl J-lH-benzimidazol-2-yl J-methyl J-1-piperidinyl ethyl -1H-imidazo 4,5-c pyridine 20-aminoethanethioate (1: 3), t pl.

. (85);

NC tt 1 (phenylmethyl) -1H-benzimidazol-2-ylJmethyl3-l-piperidinylZethyl-1 H-imidazole (4,5-c pyridine-2-aminethane 3-t2-t4- - (4-fluorophenyl) methylJ- 1H-25 dioat (1: 4), V. Pl. (86);

-benzimidazol-2-yl methyl -1-piperidi-nsh1Dethyl -2-oxazolidinoneethioate (2: 5), t. Sh1. 147, (74);

thirty

2- 2- 4- 1 -1 (4-fluorophenyl) methyl - -1H-benzim1azd-2-yl} -methyl -1-pyrididinyl ethyl thio-thiazolo 5,4-b3 pyridine ethanedioate (1: 2), t. square (75);

(4-fluorophenyl) methyl -1H-benzimidazol-2-yl j-methylJ-1-piperidinyl ethyl thio-thiazolo 5,4-c} pyridine t. Pl. (76);

4-. 3- (4-fluorophenyl) methyl} -ZH-imide-, 5-b pyridin-2-yl-methyl-N- (2- pyrimidine O 1 piperidine acetamide - (E) -2-butenioate (1: 2), mp 159 ° C (77);

1- (4-fluorophenyl) me (2-pyrimidinyloxy) ethyl 3-4-piperidinylJ

(4-methylphenyl) methyl} -ZH-imidazo 4,5-b} pyridin-2-nl1methylJ-1-piperidinyl ethyl -1H-indazo

4,5-c pyridine-2-aminethanedioate (1: 5)

m.p. 161 C (87J;

and 2-4-3-1 (4-fluorophene l) methyl-3H

-and # 1 azo f 4,5-b} pyridin-2-yl methyl 2-1 -., - piperidinyl} ethyl} -2-pyridine methanamine - - (E) -2-butandioate (J: 2i, t. pl. (88);

N-1.2- 4- 1 - (4-fluorophenyl) methyl J-H- -benzimidazol-2-yl methyl} -1-piperi: - dinyl Zethyl 3-K-methylthiourea ethane-dioate (1: 2), mp: . 167, (89); 40 K-ethyl-and -E; 2- 4- |; 3- (fluorophenyl) methyl-3H-imidazo4, 5-b pyridin-2-yl J methyl J-1-piperidinyl ethyl urea, t. Pl. (90);

... / 1lG H-etsh1-N-2-G4-GG1-G (4-fluorophenyl)

methyl 1-1H-benzimidazoleethioate, dsiuyu ip

 . .- 45 methylJ-1H-benzimidazole-2-sh1 methyl -1-piperidinylylethyl jourea, m.p. (91);

(4-fluorophenyl) methyl 1 H- -benzimidazol-2-ylJmethylJl-piperidi-} -Zthiofencarboxamideethanedioate (1: 2), so pl. 177 C (92); (4-fluorophenyl) methyl-imidazo 4,5-b pyridin-2-sh1 ZmethylJ-1-piperidinyl ethyl-3-furancarbox-55 amide, t. Pl. 138, (93);

N-2- 4- 1- (4-fluorophenyl) methyl} - lH-benzimidazol-2-yl methyl J-1-piperidinyl ethide -1-methyl-1H-pyrrole-2-carb. square 161.4 ° C (78); 1- (2-furanylmethyl) -2- (2-pyridyloxy) ethyl J-4-piperidinylJ-methyl 3-1H-benzimidazoleethanoate (1: 2), monohydrate, m.p. 179, (79); 3- (4-fluorophenyl) methyl J-2-C 1 - 2- (2-pyridine methoxy) ethyl-4-piperidinyl methyl-3H-imidazo 4,5-b pyridine trihydrochloride, t, pl. 129, (80); N-C2H CC1 - C (-fluorofenyl) methyl} -1H-. -Benzimidazol-2-yl methyl -1-piperidinyl ethyl -1 H-imidazo 4,5-vZpyridin-. -2-amine- (E) -2-butandioate (1: 3), so pl. 183.5 ° C (81);

9696418

(2-Thienylmethyl) -1H-benzimidazol-2-cl} methylJ-1-piperidinipethyl J-1H-imidazo 4,5-c} pyridine-2-amins - (E) -2-butandioate (1: 3), - monohydrate, so pl. 197, (82);

N-2-4-GGZ- (2-furanylmethyl) -ZN-imidazo C4,5-b} pyridin-2-yl7-methyl -1-pyrididinyl} ethylZ-1H-imidazo (4,5-cJnK10 Ridin-2-amine- (E) -2-butandioate (1: 3) monohydrate, mp (83); N-f2-4-3- (2-pyridinylmethyl) -ZH- -imidazo 4,5- B is pyridin-2-yl-J methyl-1-piperidinyl) ethyl; -1H-imidazo

15 4,5-c pyridine-2-aminethanedioate (1: 4), t. Pl. 191 C (84);

N- (4-metshlfesh l) methyl J-lH-benzimidazol-2-yl J-methyl J-1-piperidinyl ethyl -1H-imidazo 4,5-c pyridine 20-aminoethanethioate (1: 3), t pl.

. (85);

NC tt 1 (phenylmethyl) -1H-benzimidazol-2-ylJmethylZ-l-piperidinylZethyl-1 H-imidazole (4,5-c pyridine-2-aminethane 25 dioat (1: 4), V. pl (86 );

5 dioat (1: 4), V. pl. (86);

0

(4-methylphenyl) methyl} -ZH-imidazo 4,5-b} pyridin-2-nl1methylJ-1-piperidinyl ethyl -1H-indazo

4,5-c pyridine-2-aminethanedioate (1: 5)

m.p. 161 C (87J;

and 2-4-3-1 (4-fluorophene l) methyl-3H

-and # 1 azo f 4,5-b} pyridin-2-yl methyl 2-1 -., - piperidinyl} ethyl} -2-pyridine methanamine - - (E) -2-butandioate (J: 2i, t. pl. (88);

N-1.2- 4- 1 - (4-fluorophenyl) methyl J-H- -benzimidazol-2-yl methyl} -1-piperi: - dinyl Zethyl 3-K-methylthiourea ethane-dioate (1: 2), mp: . 167, (89); 0 K-ethyl-and -E; 2- 4- |; 3- (fluorophenyl) methyl-3H-imidazo4, 5-b pyridin-2-yl J methyl J-1-piperidinyl ethyl urea, t. Pl. (90);

H-etsh1-N-2-G4-GG1-G (4-fluorophenyl)

oxamidet1gdioate (2: 5), m.p., 165.5 ° C (94);

 L-C (4-fluorophenyl) methyl J-IH-benzimidazol-2-yl} methyl J-1-piperidine-dinyl ethyl-3-furancarboxamide ethanedioate (2: 5), hemihydrate, etc. (95);

2- 4- 3- (4-fluorophenyl) mktil J-3H- -imidazo 4,5-b pyridin-2-yl} methyl -1 10 -piperidinyl} ethyl 1-3-pyridinecarboxylate latantandioate (1: 3), t , pl. 149 s (96); H-amino-N- {2- 4- - (4-fluorophenyl) methyl -1H-benzimidazol-2-yl methyl -1 -1-piperidinyl1-ethyl -2-pyrazinecarbox-5 amide ethanedioate (1: 2), so pl. 167.5 C (97);

(Fluorophenyl) methyl-1H-benzimidazol-2-yl methyl | -1-piperidinyl ethyl-4-thiazole carboxamide ethane-20 oat (1: 2), t. Pl. 169 s (98); (4-fluorophenyl) methyl -1 H- -benzimidazol-2-yl methyl J-1-piperidi- | -2-methoxy-3-piperidinecarb-oxamide ethanethioate (2: 5), mp 25

181.5 С (99);

  C D - C (4-fluorophenyl) methyl -1H-6enzimidazol-2-yl 1-methyl-D-1-piperidi- -o-oxo-2-thiophenecetamide-ethan-diato-CH1: 2, t. Pl. 181 ° C (100);

N-2- 4- (4-fluorophenyl) methyl -1H-benzimidazol-2-yl-methyl-1-piperidinyl ethyl-3-thiophenecetamideethanethiothene (2: 5), so pl. 184.5 ° C (101); 1- (4-Fluorophenyl) methyl -1H-benzimidazol-2-ylZmethyl-1-piperidinyl ethyl -2-methoxy-5- (1-oxobutyl) benzamidethanethioate (1: 2), so pl. (102);

N- | 2-C4- 1- (4-fluorophenyl) methyl -1H- to -benzimidazol-2-yl methyld-1-piperidinyl ethyl} -1-methyl-1H-indole-2-carbooxamide, mp . 136.5 C (103); (4-fluorophenyl) methyl} -H- -benzimidazol-2-ylJmethyl 3 1-piperid-5-dynyl J etyl-2-thiophencarb aq Samid e tangoate (1: 2), so pl. (104); N-2-C4- 1- (4-fluorophenyl) methylJ-lH-benzimidazol-2-yl methyl -1-piperidinyl ethyl} -4-hydroxy-2-quinolinecarbox-amide, so pl. 263.5 ° C (105); t 1- t (4-fluorophenyl) methyl -1H-benzimidazol-2-yl} methyL J-1-piperidinyl ethyl J-2-OKCO-2H-1-benzopyran-3-carboxamide. m.p. 135 C (106); C 2-14- 1- (+ -fluorofensh1) methyl -1H- -benzimidazol-2-yl-methyl} -1-piperidinyl ethyl -2-thiazolecarboxamide-etavdioate (1: 2), t. ta. 177 ° C (107);

y-2- 4- 1- (4-fluorophenyl) methyl} -111-benzimidazol-2-nl -methyl J-1-pylIepidinyl-ethyl J-4-II and hydrophenylcarboxylicidethane diorate (, 1: 3), monohydrate, so pl. 163 ° C (108);

N (4-fluorophenyl) methyl-β-3H-imidazo 4, 5-b, pyridin-2-ylJmethyl-1-piperidinyl2 e, H-dimethylmochevinaethanedioate (2: 5), so pl. 96 ° C (109);

4-C D (4-fluorophenyl) methyl-lH-benz-imidazol-2-yl phenyl} -N- (1-methyl-1H- -imidase OL-2-IL) -1-piperidine tanamine- (E) -2-butandioate (1: 2), monohydrate, so pl. 1 18, (110); i Lt 1 {(4-fluorophenyl) methyl j-1H-benzimidazol-2-sh1} metnl 3-M- (1H-i2chidazol--2-yl) -1-piperidinatanaminethanedioate (1: 2), monohydrate, t pl. 126,

(111);

i t 1 (fluorophenyl) methyl J-1H-benz-imidazol-2-yl methyl -H- (4-phenyl-2-thiazolyl) -1-piperidineethanamine, t, pl. (112);

ethyl-2- | 1-4-ctl (4-fluorophenyl) methyl-lH-benzimidazol-2-yl methyl-l-piperidinyl ethyl ethyl amino-4-thiazocarboxylate latethanedioate (1: 2), t. pl. 178 C (113);

(4-fluorophenyl) methyl-1H-benzimidazol-2-yl methyl-K- (4-methyl-2- -thiazolyl) - 1-piperidinatanaminethanethioate (2: 7), so pl. 148 seconds (114); four- - . (Fluorophenyl) methyl -1H-benzimidazol-2-yl methyl} -1-piperidiuyuacetic acid dihydrochloride, monohydrate, t. Pl. 208, (115); - {(4-fluorophenyl) methyl -2-CG1-12- (2- -methyl-4-thiazolyl) ethyl-4-piperidinyl methyl methyl-lH-benzimydazole-ethylate (2: 5), so pl. (116); (4-fluorophenyl) methyl -1H-benzimidazol-2-yl methyl -1-piperidinyl, 3-DIHYDRO: -2-TIOOKSO-4

(1H) -quinazolinone, m. Pl. 219 ° C (117) 3-C2-4-C1- (2-furanylmethyl) -1H- -benzimidazol-2-yl methyl J-1 piperidinyl ethyl -2,3-dihydro -2-thiooxoc-4 ( 1H) -quinazolinone, m. Pl. 215.5 C (118);

(4-fluorophenyl) methyl -1H-benzimidazol-2-yljmethylJ-1-piperidi, 3-dihydro-6-methyl-2-thioxothieno (2,3-d) pyrimidine-4 (1H) oni-hydrochloride monohydrate, m.p. (119);

 (2-furanylmethyl) -1I-benz imidazol-2-ylZmethyl1-1-piperidinyl 1

, 3, -dihydro-6-methyl-2-thioxothieno 2, 3-d nMpHMHflHH-4 (1H) -oH, t. Pl. 192 ° C (120) j

(2-furanylmethyl) -ZH-imidazo 4,5-b} pyridin-2-ylJmethyl-1-pyrididinyl ethyl 1-2.3 dihydro-6-methyl--2-thiooxy hyeno 2,3- (1 pyrimidine-4 (W) - - -one, mp 196 ° C (121) ;.

2-amino - K-C2-4-E tl- (2-furanylmethyl) -10 -1 H-benzimidazol-2-yl methyl -1-piperidinyl ethyl benzyl, t. Pl. 126, (122);

N-2-11 (4-fluorophenyl) methyl} -1H- -benzimidazol-2-yl methylJ-1-piperidi-15 nyl ethyl 5-2-methylamino benzamide, so pl. (123);

2-aMMHO-N- 2-G4- 1- (4-fluorophenyl) methyl J-1 H-benzimidazol-2-yl | methyl} - 1- -piperidinyl ethyl benzamide, mp 2027 ° C (124) ;

 (4-fluorophenyl) methyl J-3H- -imidazoC4, 5-bzpyridin-2-yl methyl 3 -1 -1-piperidinylJ ethyl J-2- (methylamino) benzamidethanethioate (2: 5), m.p.

173 C (125);

2,3-dihydro-2,2-dimethyl-3- 2-4-CVD- - (2-pyridinylmethyl) -ZN-imidazo 4,5-Ъ-pyridin-2-yl methyl7-1-pi-pyridine ethyl-4- CIH) -quinazolinone ethodioat zo (1: 1), t. Pl. 2U ° C (126); 3-C2-G4-CC1- (4-fluorophenyl) methylJ-1H-benzimidazol-2-yl-methyl-1-piperidinyl j ethyl} -2-methyl-4 (3N) quinazolinone- (E) -2-butenioate ( 1: 1), so pl. 209.5 ° C (127);

(2-furanylmethyl) -1H-b enz-imidazes OL-2-IL} methyl J-1-piperidinyl J ethylZ-2-methyl-4 (3N) -quinazolinone trihydrochloride, dihydrate, m.p. , ./ (128);

 L3- (2-furanyl methyl) -ZN-im-, 5-b pyridin-2-ylCmethyl -1-pyridine-epyl -2-methyl-4 (3N) -quinazolinone- (E) -2- butendioate (1: 3), t. pl. ds (129);

3- 2- |; 4-L1- (4-fluorophenyl) methyl J-1H-b e: nzimidaz ol-2-yl methyl) -1 -pipedidridyl} eth13-2,3-dihydro-l -methyl-2- -tiooxco-4 (1H) -quinazolinone, t, pl. : 148.5 ° C (130); °

  C 4-fluorophenyl) methyl -1H- - -benz imidazol-2-yl J-methyl-1-1-pipyrididyl-butyl 3-2,4 (1H, 3N) -quinazolin-dione, so pl. 188 ° C (131); (4-fluorophenyl) methyl -1H-benzimidazol-2-yl-methyl-1-piperidinyl, 3-dihydro-2H-benzimide-ZOL-2-TION, so pl. (132);

6-chloro-9- 2- 4- 1- (4-fluorofsnln) methyl -1H-benzimidazol-2-yl jmethItp3-l- -piperidins ztilj-9H-purin-8-ol, t. 2440s ( 133)}

(; (4-fluorophenyl) methyl 7-1H-benimidazol-2-yl methyl -1-piperidinyl ethyl 911-purine-8-thiol, mp 164.5 ° C (134);

(2-furanylmethyl) -ZH-im-, 5-b pyridin-2-yl methyl} -1-piperidinyl ethyl-6-methylthieno 2 j 3-b J pyrimidine-2,4- (1H, 3N) -gion, monohydrate, so pl. 135 ° C (135); 3-C2- 4- 1-G (4-fluorophenyl) methyl -1H-benzimidazol-2-ylZmethyl | -1-piperidinyl ethyl-6-methylt, yeno 2,3-d pyrindine-2,4- (1H, 3N) -dione dihydrochloride dihydrate, so pl. 233.5 ° С () Зб); (4-fluorophenyl) methyl -H- -benzimidazol-2-yl-methyl-1-piperidinyl ethyl-6, 7,8,9-tetrahydro-2-mb-methyl-4H-pyrido 1,2-aj pyrimidine-4- on-ethanedioate (1: 2), so pl. 92 ° C (137); (4-Fluorophenyl) methyl -1Hi-b en-imidaz ol-2-yl methyl J-1-piperidinyl ethyl j-2-pyridine aminoethanedioate, t. Pl. 157 С (138);

 (4-fluorophenyl) methyl -1H- -benzimidazol-2-Krt J methyl 1 -1-piperidinyl ethyl-3-pyridazinamine 1-hydrochloride, monohydrate, m.p. 1-99, (139);

 4-0C (4-fluorophenyl) methyl -1 H- -benzimide 3ol-2-yl} methyl -1-piperidylnyl-ethyl 2-4-pyrimidinamine, mp, 61.5.H (140); .

 - (4-fluorophenyl) methyl-1H-benzimidazol-2-yl} methyl -1-piperidinyl ethyl-9H-purin-8-ol, so pl. 125 "C (141);

 1- (4-fluorophenip) methyl -H- -benzimidazol-2-yl methylJ-1-piperi-

.dinyl ethyl phenol, t. pl. 132 ° C (142) - (4-fluorophenyl) methyl 4-α-oxyphenyl ethyl | -4-piperidinyl methyl -1H-benzimidazol-6-ol, monohydrate, m.p. 167.5 ° C (143); 9- 2- 4- - (4-fluorophenyl) methyl -1H-b, benzimidazol-2-yl} methyl -1-piperidinyl} (methylthio) -9H-purine, so pl. 134, (144); (4-f torphenyl) methyl J-1H-benzimidazol-2-yl methyl -1-piperidinyl ethyl -N- (2-pyrimidinyl) benzamide, so pl. 109.5 C (145); N-C2-4-CC 1- (2-furanylmethyl) -N-benzimidazol-2-yl methyl -1-piperidinyl J ethyl -I- (2-pyrimpdinyl) -2-furancarbg;

oxamide ethanedioate (l: 2) m. pl.

(146);

(4-fluorophenyl) methyl -1H-benzimidazol-2-yl methyl -1-piperidinyl} ethyl-H- (2-piperidinyl) acetamide-ethanedioate (1: 2), t. Pl. (147); 2- (acetylmethylamino) -K-C2-4- 1- (2- -furanylmethyl) -1H-benzimidazol-2-yl} methyl} -1-piperidinyl | ethyl benzamide-ethanedioate (2: 5), so pl. (148); 4- 1- (4-Fluorophenyl) methyl J-1H-6 Enz-imidazol-2 yl methyl-H-methyl-N- (phenylmethyl) -1-piperidine ethanamine ethanidoate (1: 2), t. Pl. (149);

4-11-C (4-fluorophenyl) methyl J-1H-benz-imidazol-2-yl Zmethyl j-N-mvtil-1-piperidine ethane-aminethanedioate (1: 2), m.p. 205 ° C (with decomposition) (150); (4-fluorophenyl) methyl-1H- -benzimidazol-2-yl} -methyl -1-piperidinyl ethyl-N-methyl-2-pyridinamine, m.p. 136.5 ° C (151); 1- (2-Fluorophenyl) methyl -2- (4-methoxyphenyl) ethyl J-4-piperidinyl methylZ-.SH-benzimidazole, m.p. (152);

2- (4-methoxyphenyl) ethyl-4-piperidinyl methyl -1- (2-phenylethyl) -1H-benzimidazole dihydrochloride, monohydrate, tons. 175 ° C (153): 1 -1 diphenylmethyl) -2 -1 -2- (4-methoxy-phenyl) ethyl-4-piperidinyl methyl 3-1H-benzimidazole ethanoate (2: 5), mp. 175, (154);

1-f (2,5-dimethylphenyl) methyl} -2- (4-methoxyphenyl) ethyl-4-piperidinyl 3 methyl 1-1H-benzimidazole, so pl. 117 C (155);

1- (2,6-dichlorophenyl) methyl -2- - (4-methoxyphenyl) ethyl J-4-piperidinyl methyl} -1H-benzimidazole, so pl. (156);

1- (3-chlorophenyl) methyl 1-2-D l2- (4-methoxyphenyl) ethyl-4-piperidinyl methyl -1H-benzimidazole dihydrochloride, m.p. 172, (157); (4-methoxyphenyl) ethyl-4-piperidinyl metsh1 J-l- (l-naphthalenylmethyl) K-benzimidazole ethanoate (2: 5), so pl. 186 ° C (

1-cyclohexyl-2- 1- 2- (4-methoxyphenyl) ethyl-4-piperidinyl-methyl - H- -benzimidazole dihydrochloride, monohydrate, so pl. (159); 2- (4-methoxyphenium, p) ethyl-4-piperidinyl methyl -1- (3-thienylmethyl) -1 -1H-benzimidazoleethanoate (1: 2), so pl. 186.5 ° C (160);

2-l-t2- (4-methoxyphenyl) ethyl-4-pyrididinyl methyl} -1- (2-pyrazinylmethyl) -1H-benzimidaz ol- (E) -2-butandioate (1: 1), t pl. 180 C (161);

(4-methoxyphenyl) ethylZ-4-piperidinyl methyl} -l-f (5-methyl-2-tie-NILE) methylJ-1H-benzimidazoleethanedioate (1: 2), so pl. 195, (162); G2 (4-methoxyphenyl) ethyl-4-piperidinyl methyl | -1-G 3-methyl-2-thienyl) methyl 1-1 H-benzimidaz olethanedioate (1: 2), monohydrate, m.p. (163); 6-chloro-5-methoxy-2- 1-phenylmethyl) -4-pi-peridinyl methyl -1H-b-enimimidazol. T. Pl. 190.0 ° C (164);

- (4-fluorophenyl) methyl} -5,6-dimethoxy--2-tCl- Sphenylmethyl) -4-piperidinyl methyl-Sh-benzimidazole ethanedioate (1: 2), t.p. 169, (165); 5-chloro-1- (4-fluorophenyl) methylJ-6-methoxy si-2-C 1- (phenylmethyl) -4-piperidinylSmethyl -1H-benzimidazole, t pl. 131.9 C (166);

1- (4-fluorophenyl) methyl-5,6-dimethoxy-2- (4-piperidinylmethyl) -1H-benzimide-azoleethanoate (1: 2), so pl. 161.1 ° C (167);

1- (4-ft6rphenyl) methyl} -2-CC1-C2- (2- -thienyl) ethyl} -4-piperidinyl} methyl31H- -benzimidazol-6-ol, so pl. 212.1 C (168);

1- (4-fluorophenyl) methyl -2- (phenylthio) ethyl-4-piperidine-methyl -1H-benzimidazol-5-yl hemihydrate, so pl. 193, (169);

5-chloro-1- (4-fluorophenyl) methyl-6-methoxy-2- (4-methoxyphenyl) ethyl-4-4-piperidinyl methyl j-1H-benzimidazole- (E) -2-butandioate (1 : 2), so pl. 210, (170);

1 (4-fluorophenyl) methyl -2- tl- 2- (2- -methoxyphenyl) ethyl} -4-piperidinyl} methyl -1H-b benzimidaz ol-5-yl- (E) -2-bundioate (2: 1), t. Pl. 214, (171); 1- 1 (4-fluorophenyl) methyl 3-5,6-dimethoxy-2-tl-t2 (4-methoxyphenyl) -piperidinyl methyl-1H-benzimidazol-ethanedioate (1: 2), so pl. 177.6 ° C (.172) 2- (3,4-dimethoxyphenyl) ethyl - -4-piperidinyl methylZ-1-t (4-fluorophenyl) methyl-6-methoxy-1 H-b benzimide azole ethanoate (1: 2 ) t. pl. 171, (.173); 1- | (4-fluorophenyl) methyl 3-6-methoxy-2- (3-methoxyphenyl) ethyl 5 4-pyrididinyl} methyl -1H-benzimidazole-ethoxylate (1: 2), t. Sh1. 194.2 ° C (174); 1 (4-fluorophenyl) methyl-6-methoxy-2-tt.l-C2- (2-methoxyphenyl) -ethyl-4-potel test of the protective effect of the drug.

The EDSd values of the compounds of formula (l) are given in the first column of the table. tab. 1-4. The indicated ED values are in mg / kg

deaths from the invoked 48/80 compound.

Compounds of formula (I) and their headlamps25139696426

peridinyl metsh1 -1H-benzimidazol- (E) - not more than 2.8%. Therefore survival

-2-butendioate (2: 3), so pl. 190.5 with 4 hours is considered as Udas (175);

1- (4-fluorophenyl) methyl -2- Cl-C2- (4-

-oxiphenyl) ethyl 3-4-piperidinyl methyl} -1H-benzimidazol-5, 6-dioldihydrobro1N, so pl. 231, (176);

6-chloro-1- (4-fluorophenyl) methyl -2-0-.

(4-hydroxy-1) ethyl-4-piperidine {| 10 live weight at which the test

methyl -1H-benzimidazol-5-ol, m. pl. compounds protect 50% of test housings 241.7 ° C (177);

5-chloro-1- (4-fluorophenyl) methyl} -2- (4-hydroxyphenyl) ethyl J-4-piperidinyl J Methyl -1 H-benzimidazole-6-ol dihydrobro 5 automatic acceptable salts of promicide, t.p. 255.5 C (178); the single acids are also strong 1 -C4-fluorophenyl) methyl -2-CC1-12- (4-antagonists of serotonin, Poten-oxyphenyl) ethyl-4-piperidinyl methyl 11 -1H-benzimidazol-6-ol, t. Pl. As sero250, 8 C (179) antagonists; 20 nina are clearly visible from the results,

1-С (4-fluorophenyl) methyl -2-CD- 2- (2-obtained in follow-up tests, where

-oxiphenyl) ethyl-4-piperidinyl methyl} -1H-benzimidazol-5-one, so pl. 157.4 ° С

(180).

In a similar way, the compounds obtained in Table 25 are obtained. 1-11.

The beneficial antihistamine properties of the compounds of formula (l) are demonstrated in the following test procedures.

thirty

Protection of rats against mortality caused by the connection 48/80.

Compound 48/80, a mixture of oligomers obtained by condensation of 4-methoxy-K-methyl benzene ethanamine and formaldehyde, has been described as a potential histamine releasing agent. Protection against the lethal collapse of blood circulation caused by 48/80 is an easy way to quantify the antihistamine activity of test compounds. In this experiment, male rats of an inbred Wistar strain weighing 240-260 g are used. After the rats are not allowed to eat overnight, they are transferred to laboratory conditions (temperature, relative humidity 65 + 5%).

Rats are given orally or subcutaneously injected test compound or vehicle (NaCl solution, 0.9%). After 1 hour after administration of the compound, they administered the 48/80 subcutaneous compound (freshly dissolved in water at a dose of 0.5 mg / kg / 0.2 MP / 100 g of live weight). In control experiments in which 250 animals were injected with a solvent, and then the standard dose of compound 48/80, after 4 hours survived

The antagonistic activity of the target compounds with respect to serotonin is tested.

Antagonistic activity against serotonin in the test with lesions of the stomach.

Lesions due to 48/80.

Compound 48/80 (a mixture of oligomers obtained by condensation of 4-methoxy-N-methylbenzeneethanamine and formaldehyde) is a potential agent that releases vasoactive amines from endogenous sources such as histamine and serotonin. Y: a rat with which the 48/80 compound is administered, subsequent changes in the blood flow are observed in various vessels; the cyanosis of the ears and extremities becomes noticeable 5 minutes after the injection of the compound; rats die from cheek after 30min. Shock followed by death can

45 Avoid if rats pre-enter the classic HI antagonist.

35

50

55

However, the stimulating effects on gastric secretion are not inhibited, so that in rats that have been given compound 48/80 and protected from the cheek with histamine H 1 antagonist, all the symptoms of intensive activity of the gastric gland can appear: an autopsy demonstrates dilated stomachs with abnormal contents and irregular, bright red spots all over the mucous membrane, a salt-protective criterion for the protective effect of the drug administration.

The EDSd values of the compounds of formula (l) are given in the first column of the table. tab. 1-4. The indicated ED values are in mg / kg

.

 live weight at which the test

deaths from the invoked 48/80 compound.

The compounds of the formula (l) and their caps are acceptable acceptable salt salts.

The antagonistic activity of the target compounds with respect to serotonin is tested.

Antagonistic activity against serotonin in the test with lesions of the stomach.

Lesions due to 48/80.

Compound 48/80 (a mixture of oligomers obtained by condensation of 4-methoxy-N-methylbenzeneethanamine and formaldehyde) is a potential agent that releases vasoactive amines from endogenous sources such as histamine and serotonin. Y: a rat, to which compound 48/80 is administered, subsequent changes in blood flow in various vascular systems are observed: the blueness of the ears and extremities become noticeable 5 minutes after the injection of the compound; rats die from cheek after 30min. . Shock followed by death can

avoid if rats pre-enter the classic HI antagonist.

However, the stimulating effects on gastric secretion are not inhibited, so that in rats that have been given compound 48/80 and protected from the cheek with histamine H 1 antagonist, all the symptoms of intensive activity of the gastric gland can appear: an autopsy demonstrates dilated stomachs with abnormal contents and irregular bright red spots across the mucous membrane, with

corresponding areas of the destroyed glands. A number of serotonin antagonists, such as, for example, methysergide, ziproheptadine, cyanserin, mianserin, gspamperone, spiperone, pizothiphene and methergoline, completely prevent the blueness of the ears and extremities, as well as lesions of the gland zone of the stomach and expansion of the stomach.

Method.

The male strain of the Vibor strain inbreed, weighing 220-250 g, is not given food overnight, water is given without restriction.

SRI. Test compounds are administered orally not given to limit the invention, but only as an example of the useful pharmacological activity of all compounds in the volume of the form. (P) (I))

Considering antihistamine and serotonoin-antagonistic properties, the compounds of formula (l) and their acid addition salts are very effective in treating allergic diseases, such as allergic rhinitis, allergic conjunctivitis, chronic Witicaria, allergic asthma, and the like.

but in the form of a solution or in the form of a suspension in an aqueous medium. Rats in control or blank experiments introduced a test compound. After 1 hr, all rats were injected subcutaneously (diphenyl 20 methyl) -1-piperazinyl-methyl -1-methyl--1H-benzimidazol-2-methanol at a dose of 2.5 mg / kg. Two hours after the test compound was orally or subcutaneously injected, compound 48/80, freshly dissolved in water at a concentration of 0.25 mg / mp, was administered intravenously at a dose of 1 mg / kg with the exception of blank rats. After 4 hours

Suitable doses of daily intake after intravenous administration of the compound of the patient range from 0.1 to 48/80 rats, remove the heads and 80 mg of the patient, and more preferably 1 - involve the stomachs. Then the stomachs are examined for expansion and maintenance (blood, liquid, spitz) and washed thoroughly. Macroscopic lesions are graded O

50 mg.

Thus, the proposed method produces compounds of general formula I, which possess valuable pharmacological properties.

7

- 39696428

to +++, moreover, O corresponds to the absence of visible lesions, and +++ corresponds to bright red uneven nths covering more than half of the gland section.

In the second column of the table. 12 presents a series of compounds of formula (l) in doses (mg per kg of live weight), in 10 of which the expansion of the stomach as well as the lesion of the stomach glands is completely absent in 50% of the tested rats (ED- value).

The compounds listed in Table. 12,

Suitable doses for daily patient intake vary from 0.1 mg to 100 mg and, more preferably, 1 -

50 mg.

Thus, the proposed method produces compounds of general formula I, which possess valuable pharmacological properties.

Table 1

29

I

CH,

4-F-C H CH,

(4-F-C H4) H CH (CH2) s

1 1/2 (E) -2-bundioate; ethanedioate (1: 2), monohydrate; ethanedioate (1: 2)

Lr (CH,) s-lOcH2.

eleven

YG-KS Nb

4t-morpholinyl

1 -K11 o

NN-C2H5

CjHjO: i99 4-F-C H C (0) 1396964

thirty

Continuation of table 1

N CH CH CH-i

157 212.5

Table

2 4-F-CgH4CH2 N 2 (COOH) 2 205 2 4-F-C H CH-i. 2 (COOH), 2 182

2 4-F-C H4CH2 N 2HC1

H-jO

180

3 N 2HC1 167

Continuation of table 2

213

four

SNS

214

215

L-n.

&

216

N o

but

217

0.0

218

..

Ujc

219

.

SNS

H

U

4Av.if, 0

221

H

,about

about

H

v «0

irV

Continued table.

2 4-F C H -CH 195

2 4-F-C6H4-CH 174.7

2 4-F-C H -CH 187

2 4-F-C H4-CH Basis 168

2 2-Furanyl CH 2HC1 240

2 2-Furanylsi ZNS1 197

2 2-FuranilN ZNS1 250

3 2-Furanil N Foundation 198

2 2-Furanil N 2HC1 227.5

2 2-Furanil N Foundation 199

3 4-F-C H - N Base 183.5

35

224

Ifs

about

2 2-furanil

225

2 2-furanil

226

227

228

229

230

H f.

fr

Ni O

.. h

O. “1 NZS-K. (

ABOUT

 il

about

SNS

R

P

ABOUT

2 2-Furanyl CH Basis 175

2 2-Furanyl N 2HC1 HjO 182

2 4-F-CjH4- N ЗНС1 - 229.7

2 2-Furanil N 183.5

2 2-F-C H - N 2HCl.Hj0241

231

N

SNS

2 2-furanil

N II

About SNG-SNZ

nrV- n-if

2 4-F-CjH4233 ff IT 233 -JLQjj

2 4-F-C H4-CH Basis 101

1396964

36 Continuation of table 3

N 3HCl-2HjO 186.8

(different)

N 2HC1 204

(rael.)

N 2 1/2 163 (COOH) NgO

CH 2 1/2 161 (COOH)

L-lCH s-O

Table3

CH2

fA

39

252fJ Y V 2

CHS-L.j Jk

J-с „О

A-F-C H CH, -CH 2 (COOH) 2

139696Д

40

Continuation of table.5

140

four,

 : (E) -2-butenioate (2: 3): (E) -2-butenioate (1: 2)

1396964

42 Continuation of table 5

Ry

L, - (CH,)

K (E) -2-Butandioate (2: 3) XX (E) -2-Butandioate (1: 2) XXX (E) -2 Butandioate (1: 1-)

L Y (CH 2) 5 - 0272

rrv h. and

.l v-СНз

2 2-Pyridinsh1metil N Basis151,6

Ry

Table 6

Table 7

CH-R

1-0.

-G

t-r (si, - n, n,

V- /

277

4-СНзО-С Н г Т

 ABOUT

4-CH O-CjH r J N N

281Г I U

four..

G

282 4-CHjO-CjH Table 8

sn,

sn,

/

Yyt

L v -xAi

2 (COOH} 4

155.7

 1 / 2H20171,8

2 (COOH) l / 2-H, 0 169.6

2 (COOH) 2

s

MAIN

163.9

2 (COOH) 4 H O178.3

Hio

/

OH

""

215.5

but

283 4-SNEO-S (

HE

 : (E) -2-butenioate (2: 3): (E) -2-butandioate (1: 1)

RI

sn,

N

A-F-CjH-CH-i

c, n,

2-Pyridinylmethyl

C-CN-CH3-SNG-G) -Connection

2-11iridinyl2-furanyl

2-Tiaz olil2-Four anil

2-11irimidine12-thienyl

2-11 irimidinyl4-CH (E) -2-butandioate (1: 3) (E) -2-butandioate (2: 3)

Continuation of table.8

Base

210.7

RI

IS

Table 9

base)

1A6

141.4

138

Table 10

eng-to-sn.lu

Foundation 4 (

2 1/2 (COOH) i

103

159.6

184.6-188.6

160.5

L-HH-CH

2-rarNj CHjJjy k

sTable 11

s51139696D

Continued table. 12

52 Continued table. 12

551396964

Continued table. 12

56 Continued table. 12

Claims (1)

The method of obtaining 4- (bicycloheterocyclylmethyl) piperidines of the general form where A ₍ = A ₂ ~ A ₃ = A ₊ is a bivalent radical of the formula -CH = -CK _g CHu = CH- (a); and K2 and Kz are independently hydrogen, methyl, hydroxy, methoxy, or halo; -No = CH-CH = CH- (v) / _CH = D-CH = CH- (s) -CH = CH-H = CH- (a) or -CH = CH-CH = I-; (e) - hydrogen, methyl, phenyl, benzyl, unsubstituted or substituted by one or two groups, such as halogen, methyl, methoxy; cyclohexyl, benzhydryl, phenethyl, furan anylmethyl, (5-methyl-2-furanyl) methyl, 4-thiazolylmethyl, pyridinylmethyl, 2-thienylmethyl, pyrazinite, me. thyl-2-t'ienylmethyl] naphthynylmethyl; L - 3-dimethylaminocarbonyl-3,3-diphenylpropyl, hydrogen, isopropyl, the group -CH ₂ -CH _and -CO-CH ₄ -k ₄ , where B * is hydrogen, or bromine; ethoxycarbonyl, methyl or benzoyl or the group 1 ^ - (CH,) (CH _g ) _h -, where a = 0 or 1; B = 0 or 2; y = 0; 8 or 80 ₂ ; E ₁ - phenyl, 4-fluorophenyl, 2-pyrimidinyl, 2 pyridinyl, radical 8TS 1396964 AZ or [radical 1 or group - (CH ₂ ) _with -., ¹ where c = 1, 2, 3 or 4; ь „1396964 hydroxyl, cyanophenyl, oxiphenyl, methoxyphenyl, dimethoxyphenyl, ethoxycarbonyl, ethoxy, carboxyl, ethenyl, 4-fluorophenylcarbo-. Nile, isopropylaminocarbonyl, aminocarbonyl, 2-pyridinyl, 2-thienyl, 2-methyl-4-thiazolyl, 2-oxo-3-oxazolidinyl, 2,4-dioxo — 3— (1H) -pyrimidinyl, 2,3-dihydro- 2-oxo-1H-benimidazol-1-yl, 2,3-dihydro-2-thioxo-1H-bazimidazol-1-yl, 2-pyrimidinylaminocarbonyl or benzimidazolyl forradical of formula CH ₃ -B ' II about 2,3-dihydro-1,4-benzodioxan-2-yl, 1- (benzimidazol-2-ylmethyl) benzimidazol-2-yl; radical of the formula / L-’" Νγ ¹ —ΝΚθ where K is hydrogen or chlorine; K - mercapto or methylthio; radical of the formula OU ” ^{1 X} II about SP mules sn _; or II about where H _£ , K ₄ , TO. radical of the general formula & 5 WITH II 0 Where Where or X = 0 or 8, or a ₅ b - Ν- or -CH =; - the radical L ₃ - hydrogen or methyl or p? £ and K ₇ Where η = 2 or 4; are 0 or 2, point - hydrogen or TO, 15 I 2 / η tare line means no link or simple link, provided that if the dotted line represents a link, Ku and ^ are absent; 4-morpholinyl, styryl, bis (4-fluorophenyl) methyl, 1-ethyl-5-oxotetrazol-4-yl, 5-methyltaazol-4-yl, 2-oxo-2H--benzopyran-3-yl or forhydrogen radical , methyl, benzyl, 2-pyridinylmethyl 2-pyridinyl, 5-chloro-2-pyridinyl, 4-nitro-1-oxypyridin-3-yl, pyrazinyl, 3-pyridazinyl, 4 (1H) -oxopyrimidinyl-2-yl, 4 -chloro-6-methyl-2-pyrimidinyl or pyrimidinyl radical of the formula where Κ _ί2 - vodomuly SNS where a = 1 or (CH ₂ ) Y * n '13 2, the dotted line indicates the presence or absence of communication; K _% - methyl, hydrogen, genus or chlorine; hydrogen or amino group; imidazol-2-yl, nitrophenyl, 3-chloro-5-pyridazinyl; 2-chloro-4-methyl-6-pyrmidinyl, 2-pyrimidinyl or thiazolyl radical form1396964 mules Where ΚιΛΓ methyl, phenyl, hydrogen or ethoxycarbonyl; 1-methyl-4-nitro-1H-imidazol-5-yl, 1-methyl-1H-imidazol — 5-yl, benzimidazol-2-ylthiazolo (4,5-b) pyridin-2-yl, 1-phthalazinyl, 9H-purin-6-yl, unsubstituted or substituted in position 8 or 9 by methyl or oxy group, a radical of the formula n CH = or -Ν =; - 4-chloro-1-phthalazinyl or b is a radical of the formula B ₄ - C - ΝΗ - (CH _? ) _T or 4-pyridinyl, 2-methoxy-3-pyridinyl, 1-methyl-1H-pyrrol-2-yl, 3- ^ furanyl, 2-thienyl, 3- thienyl, 2-thenoyl, thiazolyl, 1-methyl-1H-indole ~ 2 -2, 4-hydroxyquinolin-2-yl, 2-amino-3-pyrazinyl, 2-thienylcarbonyl, 3-thienylmethyl, 2-oxo- 2H-1-benzopyran-3-yl, ethylamine, dimethylamine, ethoxy or radical P to _<7 II Ζ K ^ -C-Ν, where V. is methyl, phenyl or 2-furanyl; In _p - 2-pyrimidinyl, or b is 2-furanyl-acetyl, pyridinyl-3-carbonyloxyethyl, 1-ethyltetrazolyl-2-mercaptoethyl, methylaminothio-oxymethylethyl, 3-naphthalenyloxy-2-hydroxypropyl or cyclohexyl, or their pharmaceutically acceptable acid addition salts, which are reacted by reacting a compound of the formula where w = 2 or 4; 1 * 4 - phenyl or a radical of the formula ' ^K 15 where Κ _ί5 is hydrogen, amino, methylamino, -Ν-CO-CH; x ^{1 * 3 * n} HE, radical С ₃ Н ₇ ~ СО Es ₃ where VI is CH ^ -0 (= ΝΗ) = 0-0, -0,} is alkyl or -sy 4-soon in an inert solvent „ Κι one