前苏联专利SU1676451A3 Method for preparation of benzimidazol derivatives in the form of mixture or individual isomers in t

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专利摘要:
New pharmacologically active benzimidazoline-2-oxo-1-carboxylic acid derivatives which are 5-HT receptor antagonists useful as antiemetic agents and as gastric prokinetic agents of the following formula: <CHEM> wherein R represents a hydrogen atom, C1-6 alkyl, C1-6 alkenyl or C1-6 alkynil; R1 and R2 may be at the same time or not a hydrogen atom, halogen, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 acyl, carboxyl, C1-6 alkoxycarbonyl, hydroxy, nitro, amino optionally C1-4 alkyl N-mono or di-substituted, C1-6 acylamino, C1-6 alkoxycarbonylamino, carbamoyl optionally C1-4 alkyl N-mono or di-substituted, cyano, C1-6alkylsulphinyl, C1-6 alkylsulphonyl, amino sulphonyl optionally C1-4 alkyl N-mono or di-substituted, C1-4 alkyl N-mono or di-substituted aminosulphonylamino, aminosulphonylamino; Y is oxygen or is N - R3 in which R3 is a hydrogen, a C1-6 alkyl or optionally substituted by one or more C1-6 alkoxy benzyl; A is a group selected from: <CHEM> wherein p is 0, 1; r is 0, 1, 2, 3; R4 is hydrogen atom or a C1-4 alkyl; R5 is a hydrogen atom, C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl C1-4 alkyl,substituted phenyl C1-4 alkyl or R5 is a group of formula <CHEM> wherein R6 is hydrogen atom, C1-4 alkyl or an amino group and R7 is hydrogen atom or C1-6 alkyl, tautomers thereof and acid addition salts of the aforesaid compounds. The processes for the preparation of the compounds of formula (I) as well as pharmaceutical compositions containing them are also described.
公开号:SU1676451A3
申请号:SU884356601
申请日:1988-09-22
公开日:1991-09-07
发明作者:Туркони Марко；Донетти Артуро；Микелетти Розамария；Уберти Аннамария；Никола Массимо；Жакетти Антонио；Монтанья Эрнесто
申请人:Иституто Де Анджели С.П.А. (Фирма)；
IPC主号:

专利说明:

2 U15 g of 2, 3-Digdro-2-oxo-1H-benzimidachol-1-carbonyl chloride and) are extensively mixed with 1.55 g of endo-8-methyl-8-azabicyclo and 2, Loktan-Z-ol , and the resulting melted and left standing for 10 minutes at the melt temperature. Then absorbed in acidic water and washed with ethyl acetate. The aqueous veil is strongly alkalized and the sheaf is extracted. The extracts are dried, the solvent is evaporated and the target product is crystallized from acetonitrile Obtain 0.4 g of the specified target product with Tduu 190-192 Cc
Calculated,%: C 63, //; H 6.36; N 13.95s
C, 6Ht, K, () 3
Found,%: C 63.45; H 6.41; N 13.81.
The following compounds are prepared analogously:
1-Azabicyclo 2 2 c2 oct-4-yl ester 2, 3-digpdro-2-oKco-1H-benzimidazole-1-carboxylic acid (compound 2). T, pg 254-256 ° C (hydrochloride) s
Calculated,%: C 55.64; H 5.60; N 12.98.
C, 5K17N -HC1
Found, / ,; C, 54.96; H 5, L; N 12, / 5.
Exo-2-methyl-2-azabicyclo 202o 2J-oct-5-yl esters 2, 3-dihydro-2-oxo--1H-benzimidazole-1-carboxylic acid (compound 3) s, 208-211 ° С (hydrochloride ) with
Calculated,%: from 56.89; H 5.9 /; N 12.43,
C (6H1c, N UyHCl
Found,%: C 56.88; H 6.12; N 12,250
Endo-2-methyl 2-azabicyclo2 0 20 2J-oct-5-ylove 1 2,3-dihydro-2-oxo--1H-benzimndazole-1-carboxylic acid ester (compound 4) t T, pl0 / 3- / 5 ° C (citrate) with
Calculated,%: C 53.55; H 5.52; N 8.52,
С16Н „ЛеОуСьН807
Found,%: C 52.96; H 5.64; N 8.39 „
Endo-9-methyl-9-aeabnciklo 30301 - non-3-ilyl ether 2, 3-dihydro-2-oxo--1H-benzimidac- (1 -carboxylic acid (compound S. T, pl 96-100 ev (citrate).
MS: 316 m / o II
Calculated,%: C 52.0 /; H 5, / 6; N 8.28
с, 7нг, к, о, .свкво7
Found,%: C 51.36; H 5.91; N /./4.
Exo-9-methyl-9-azabicyclo 3 "3o1J-non-3-yl ester 2, 3-dihydro-2- -oxo-1H-benzimidaeol-1-carboxylic acid (compound 6) T m„ II- 80 ° C (citrate) o MS: 316 m / e Ql + H.
Calculated,%: C 52V0 /; H 5, / 6; N 8,280
C, 7H7, NjO CeHgO
Found,%: C 51.09; H 5.86; N /, 9 / „
Example 2 “Endo-8-methyl-8-azabicyclo 302.L oct-3-yl ester H-methyl-2, H-dihydro-2-oKco-1H-benimidazole-1-carboxylic acid (compound /) o
A suspension of 1.5 g of Z-methyl-2,3-di-hydro-1H-benzimidazol-2-one and 2.43 ml of trichloromethyl chloroformate in 150 ml of dry o-dichlorobenzene is stirred at 80 ° C overnight, After cooling to 10 The reaction mixture is filtered and the filtrate is stirred in and added to a solution of 1.41 g of endo-8-methyl-8-azabicyclo 2 O IJoK-tan-3-ol in 20 ml of pyridine at room temperature. After the addition is complete, the reaction mixture is stirred at 80 C for 2 hours. After evaporation of the solvent and conventional workup, 0, / g of the pure indicated compound is obtained in the form of hydrochloride "TL" 250 ° C "MS: 352 m / e M +
Calculated,%: C 58.04; H 6.30; N 11.94 „
c (7H2 (N3 ° yHcl
Found,%: C 5 /, 85; H 6.36; N 11.83.
Example 30 K-Endo-8-methyl-8-azabicycloGz „201J oct-3-yl-2,3-di hydro-2-oxo-1H-benzimidazole-1-carboxyamide (compound 8)„
1.5 g of 2,3-dihydro-2-oxo-1H-benimimazole-1-carbonyl chloride is dissolved in 40 ml of tetrahydrofuran, and a solution of endo-8-methyl-8-azabicyclo-X20 L is added to the resulting solution. octane-3-amine in 5 ml of tetrahydrofuran at room temperature. After the addition is complete, the solid is separated and the reaction mixture is stirred for 30 minutes, evaporated to dryness and taken up in dilute hydrochloric acid. The aqueous phase is washed with ethyl acetate, basified with saturated sodium carbonate and extracted again. The organic layers are evaporated to dryness. 0.7 g of crude product is obtained, which, after crystallization from acetonitrile, gives 0.1 / g of pure product. T „pl„ 205-207 ° С „MS: 301 m / e m + H
IR spectrum (cm -1): 1/30, 1690,
Calculated,%: C, 63.98; H 6.71; N 18.65.
CteHMN404
Found,%: C 62.83; H 6, / 5; N 18.01.
Similarly, the following compounds are prepared.
M- | endO-9-methyl-9-azabicyclo-Ј3.3 „ljHOH-3-yl - 2,3-dihydro-2-oxo--1H-benzimidazole-1-carboxamide (compound 9) o Topl„ 269- 2/0 ° C (hydrochloride). MS: 315 + H
Calculated,%: C 58.19; H 6.61; N 15.9 / „
C17 HCl
Found C, 58.40; H 6.62; N 15.91.
N-1 -Azabicyclo 2.2.2 | oct-3-yl--2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxamide (compound 10). T „pl0 196-198 ° С„ KS: 28 / +
Calculated,%: C, 62.92; H 6.34; N 19.5 / s
, gN4Oe
Found,%: C 62.34; H 6.32; N 19.34.
B} - {Endo-1-azabicyclo Z.Z.1J non-4-yl 1-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide (compound 11) 0 So pl. 245-248 ° С „MS: 301 m / e m + ..
Calculated,%: C, 63.98; H 6.71; N 18.65.
Ci6HZoNa ° Z
Found,%: C 64.18; H 6.80; N 18,56
M- {Endo-9-methyl-9-azabicyclo Soz.ljHOH-3-yl | -3-methyl2,3-dihydro-2-OXO-1H-benzimidazole-1-carboxamide (compound 12) „T, pl„ G / 5-176 ° C, MS: 329 m / e (1 + H
Calculated,%: C, 65.83; H / 36; N G /, 06.
S / l Ng, N Og
Found,%: C 65.39; H 7.32; N 16.92.
Y-Endo-8-methyl-8-azabicyclo 3.2.1 Doct-3-yl | -3-methyl-2,3-dihydro-2-oxo-1H-benzimizazol-1-carboxamide
about u0
.

(Compound P) T.lgl ,, 269-2 / OrtC (hydrochloride), MS: 315 m / e) IIJ Calculated,%: C 58.19; I 6.6 G; N 15.9 /,
from 7th December
HCl
Found,%: C 58.14; H 6.49; N 16.01.
N-Methyl-K- | endo 9-methyl-9-acaGsh- Yu cyclo Z.Z. ij non-3-yl) G-2, 3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide (compound 14), T., pl „198-200 ° C“ MS 329 m / e And + ,,
Calculated,%: C, 65.83; H /, 3 /; 15 N 1 / y060
g1v "k4 ° g
Found,%: C 65, / 2; H /, 53;
N 16.85.
M-Epdo-9-methyl-9-aabicyclo2® h.3.1 | non-3-yl-Y-G (2,4-dimethoxy-phenyl) methyl + J-2,3-dihydro-2-oxo-1M-benzimidazole -1-carboxamide (compound 15) „T„ pl, 100-104 ° Co MS: 465 m / e m +.
25 Calculated,%: C 6 /, 20; H 6.95; N 12.0 / o
sgbnzgn4o4
Found,%; C 66.31; H 6.89; N 12.31. 30K-Endo-9-methyl-9-azabitsnklo ZoZ .. non-3-yl | -2, Z-dihydro-2-oxo--1H-benzimidazole-1-carbox No. 1d (compound 16). T pl 180-182 ° C
Calculated,%: C 64.95; H /, 05; 35 N 1 / .82.
s17kp og
Found,%: C 64.83; N /, 02; N G /, / 5o
K- {Endo-8-aeabicyclo Zs 20 Poct-3-40-yl} -2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide (compound 17), ToPLO 250 C (hydrochloride).
Calculated,%: C 55.81 ,; H 5.93; N 17.36. 45 Cl6-H, eN402-HCl
Found,%: C 55.64; H 5.96; N 1 / .21.
1 p and me 4 4 "Endo-8-azabicycloSZo2 complex; Poct-3-yl ester 50; 2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxylic acid (compound 18),
A suspension of 1.3 g of 2, 3-dihydro-2-oxo-1H-benzimidazole-1-carbonyl chloride and 1.0 g of endo-8-aza-55 hydrochloride bicyclo 3.2; 1 octan-3-ol in 5 ml o-dichlorobenzene is heated at 180 ° C for one hour with stirring. The reaction mixture is then allowed to cool and the solvent is removed.
by filtration, the resulting crude product is washed with ethanol and crystallized from ethanol. Obtain 1.1 g of the specified target product with ToPL. 260 С MS: 288 m / e m +
Calculated,%: C 55.64; H 5.60; N 12.98,
C, H, 7MgOONS1
Found,%: C 55.15; H 5.61;
N 12, / 0.
Analogously to Examples 1-4, the following compounds are obtained:
Endo-8-methyl-8-azabicyclo J3 „2. 1j - oct-3-yl ester of 5-methoxy-2,3-dihydro-2-oKco-lH-benzimidazol-1-carboxylic acid (compound 19) , ToPL. 1 / 7-178 ° С „MS: 332 m / e M + N.
Calculated,%: C, 61.62; H 6.39; N 12.68.
C47H21N, H
i Found,%: C 61.45; H 6.35; N 12.72.
Endo-8-methyl-8-azabicyclo 3,2 „ij is 5-methyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid oct-3-yl ester (compound 20 ) „T„ pl. 187-189 ° Се МС: 316 м / е | + N.
Calculated,%: C 64, M; H 6.71; N 13.33,
С17Нг3Кэ (b
Found,%: C 64.23; H 6.73; N 13.39.
2,3-dihydro-2-oxo -1H-benzimidazole-1-carboxylic acid hydrochloride-1-az abicyclo 2 2 2 02J-oct-3-yl ester 2,3-dihydro-2-oxo -1H-benzimidazole-1-carboxylic acid (Compound 21) m / e M + IR Spectrum (): 1760, 1720 (wide) with
Calculated,%: C 55.04; H 5.60; N 12.98,
C, 5-H (7N3Oy HCl.
Found,%: C 55.1 /; H 5.62; N 12.75.
Exo-8-methyl-8-azabicyclo 3, 2, oct-3-yl 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid ester (compound 22). T „pl0 255-256 ° C (hydrochloride) o
Calculated,%: C, 56.83; H 5.97; N 12.44 „
C16HV) N50, - HCl
Found,%: C 56.53; H 6.01; N 12.21,
E and to-8-ethyl-8-az abicyclo-3,201J-oct-3-yl ester of 2,3-dihydro-2-oxo -1H-benzimidazole-1-carboxylic acid (compound 23). Tspl0 268-270 ° С (hydrochloride) „
76451

ten

20
25
- ,, -.
8 C 58.03; H 6.30;
Calculated, N 11,94 „
CoH2 N-i ° i Hcl
Found,%: C 57.65; H 6.37;
N 11, / 2 „
Endo-8-methyl-8-azabicyclo p.2. H-oct-3-yl ester of 5-chloro-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid (compound 24) „T0pl 236– 238 ° С (hydrochloride) o
Calculated,%: C, 51.62; H 5.14; N 11.29
Found,%: C 50.93; H 5.21; N 11.03. Endo-8-methyl-8-azabiglclo (3 „2, 1J-oct-3-yl ester 6-fluoro-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid (compound 25) T , pl0 261- 263 ° С (hydrochloride) o
Calculated,%: C 54.00; H 5.38; N 11.81o
C, 6H, 8FN303-HC1
Found,%: C 53.65; H 5.45; N 11.69.
Endo-8-methyl-8-azabicyclo 3 2 f-oct-3-yl ester 5,6-dimethyl-2,3-di-hydro-2-6 x-1-benzoimidazole-1-carboxylic acid (compound 26) „ToplO 260 ° С (hydrochloride).
Calculated,%: C 59.09; H 6.61; N 11.49.
cl8H23N3 ° yHcl
Found,%: C 58.51; H 6.65;
N 11,27 about
Endo-8-methyl-8-azabicyclo r.2 „1J-oct-3-yl ester 5-fluoro-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid (compound 27)„ T „pl ,, 257-258 ° С (hydrochloride) o
Calculated,%: C 54, H 5.38; N 11,810
C16H, gFN303- HCl
Found,%: C 53.89; H 5.41; N 11.71.
Endo-8-methyl-8-azabicyclo Zo2O1} - 6-acetyl-2.3-dihydro-Q -2-oxo-1H-benzimidazole-1-carboxylic acid oct-3-yl ester (compound 28); mp. 260 C (hydrochloride).
Calculated,%: C 56.91; H 5.84; N 11.06 s
Hcl
Found,%: C 56.69; H 5.85;
N11.03.
Endo-8-methyl-8-azabicyclo j31 2.1J-oct-3-yl ester 6-acetylamino-2,340
-dihydro-2-oxo-1H-benchimidazole-1-carboxylic acid (compound 29) ",
Calculated,%: C 54, / 5; H 5.62; N 14.19.
C18H22N404.HCl
Found,%: C 54.02; H 5.88;
N13.51.
Endo-8-methyl-8-azabicyclo 3,2 "1J-oct-3-yl ester / -methyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid (compound 30 ). T0pl0 250-251 ° C (hydrochloride) o
Calculated,%: C 58.03; H 6.30; N 11.94 ,,
С17Н71МЪ ° Э НС1
Found,%: C 5 /, 58; H 6.36;
N 11, / 3.
Endo-8-methyl-8-azabicyclo 3 “2,1j-oct-3-yl ester of 5-trifluoromethyl-2,3-dihydro-2-oxo-1H-benzimide-1-carboxylic acid (compound 31)" T „ pl, 222-224 ° C (hydrochloride).
Calculated,%: C 50.31; H 4, / 2; N 10.36o
Ci7Hf8F, N3OyHCl
Found,%: C 49.8 /; H 4.75; N 10.23
Endo-8-methyl-azabicyclo 3 „2, ij - oct-3-yl ester of 6-methoxy-2,3-di-hydro-2-oxo-1H-benzimidazole-1-carboxy acid (compound 32) 0 T w 260 ° C (hydrochloride).
Calculated,%: C 55.51; H 6.03; N 11.42 „
C17HZ1NW Hcl
Found,%: C 54.9 /; H 6.09;
N 11,210
Endo-8-methyl-8-azabicyclo 3. oct-3-yl ester of 6-nitro-2-oxo-1H-benzimidazole-1-carboxylic acid (compound 33) with T “plo 260 ° C (hydrochloride) o
%: C 50.20; H 5.00;
Calculated
N 14.64,
Cf6H | eN405 Found,%
N 14.46.
HC1 C 49V10; H 4.98;
ten
/ 6451I)
Zndo-8-amidi o-8-azlbncicchs 1 2 tj-oct-3-sew ether 2, 3-dihydro. -oxo-1H-benznmides1zap-1-carboxylic acid (compound 35) "M.p., 0/ ° S (5Calculated,%: C 52.53; H 5.51;
N 19.14.
С к Н «NSOv HC1
Found,%: C 51, / 3; H 5.45; N 19.1 / o
Biological testing. Reflex Bezolda-Yarish anesthetized rats o
Rats weighing 250-2 / 5 g are anesthetized, with urethane (1.25 g, intraperitoneally). 0 Blood pressure is measured on the left femoral artery. Heart rate is measured with a cardiotachometer. The Bezold-Yarish effect is caused by intravenous injection of 5-HT. (20 µg / kg) For 5 minutes before the injection of 5-HT, increasing doses of antagonists were injected in order to determine their effect on the vagus-induced reflex stimulation of the initial sudden deceleration of the heart rate and a drop in blood pressure.
In another experiment, with the use of platinum electrodes at 10 for 2 ms, the right vagus nerve is stimulated in order to induce bradycardia.
In both experiments, the dose is determined by the use of the following compounds, which provides 50% inhibition of undesirable effects (ED 50) „
The results of the experiments are given in table about
20
25
thirty
Endo-8-iminomethyl-8-azabicyclo-Io2. IJoKT-3-yl 2,3-dihydro -2-OXO-1H-benzimidazole-1-carboxylic acid ester (compound 34). M.p. 210- 212 С (hydrochloride) „
Calculated,%: C 54, / 8; H 5.46; N 15.9 /.
C "H, 8N4 (y HCl
Found,%: C 53.96; H 5.51; N 15.620
Granisetron-K-Gende-9-methyl-9-aza-bicycloses „3. G-non-3-yl | -1-methyl-indazole-3-carboxamide) Comparison of the data in the table indicates a higher biological activity of the new compounds compared to the known, New compounds are classified as non-toxic.

权利要求:
Claims (1)
[1]
Invention Formula
Puzzy & n5 Benzimidazole Derivative Formulas Method
O-GTU-A
- R |
Y A
hydrogen, C-Cg-alkyl; oxygen or NH group; radical of general formula
((CH2) „N-R2
V
or
where R, C, b, -alkyl or group
LR3
Where
five
five
VCHDOR 41 or amino group; p 2 or 3, in the form of a mixture of isomers or individual isomers in free form or in the form of their physiologically acceptable salts, characterized in that the compound of the general formula
R1
N
g °
NT I
where RJ has the indicated value;
X is a removable group, reacted with a compound of the general formula
WELL AND
where Y and A have the indicated meanings, followed by isolation of the desired product in free form, as a mixture of isomers or as isomers, or as their physiologically acceptable salts

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引用文献:

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

IT8721997A|IT1231413B|1987-09-23|1987-09-23|BENZIMIDAZOLIN-2-BONE-1-CARBOXYLIC ACID DERIVATIVES USEFUL AS 5-HT RECEPTOR ANTAGONISTS|

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