CS229095B1 - Esters of 2-hydroxyalkylbenzimidazoles - Google Patents

Abstract

The invention relates to esters of 2-hydroxyalkylbenzimidazoles of the general formula I (CH2,nOCOR (I) in which n denotes 1 or 2 and the group RCO- is the residue of 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetic acid, 4-chlorophenylacetic acid, 4-methoxyphenylacetic acid, 4-fluorophenylacetic acid, 4-nitrophenylacetic acid, 3,4-dimethoxyphenylacetic acid, phenoxyacetic acid, 2-chlorophenoxyacetic acid, 4-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid, phenoxyisobutyric acid, 4-chlorophenoxyisobutyric acid, 4-chlorobenzoic acid, nicotinic acid and isonicotinic acid. The substances of the general formula I, which are new, were tested for analgesic activity in comparative tests with aminophenazone (1-phenyl-2,3-dimethyl-4-dimethylamino-5-pyrazolone). An interesting Analgesic activity in these tests was demonstrated in particular by substances 24 and 28 (Table 2), as can be seen from Table 1.

Description

The invention relates to esters of 2-hydroxyalkylbenzimidazoles of the general formula I (CH ₂ , _n OCOR (I) in which n denotes 1 or 2 and the group RCO- is the residue of 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetic acid, 4-chlorophenylacetic acid, 4-methoxyphenylacetic acid, 4-fluorophenylacetic acid, 4-nitrophenylacetic acid, 3,4-dimethoxyphenylacetic acid, phenoxyacetic acid, 2-ochlorophenoxyacetic acid, 4-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid, phenoxyisobutyric acid, 4-chlorophenoxyisobutyric acid, 4-chlorobenzoic acid, nicotinic acid and isonicotinic acid.

The compounds of general formula I, which are new, were tested for analgesic activity in comparative tests with aminophenazone (1-phenyl-2,3-dimethyl-4-dimethylamino-5-pyrazolone). In these tests, especially compounds 24 and 28 (Table 2) demonstrated interesting analgesic activity, as can be seen from Table 1.

229095 2

Table 1

Substance LD ₅₀ g/kg Analgesic efficacy ED ₅₀ mg/kg 24 <1 160 28 <1 150 aminophenazone 0.8 104

The invention also relates to a process for the production of compounds of general formula I. According to the invention, compounds of general formula I are prepared, for example, by first reacting an acid of general formula II

RCOOH (IX) in which the RCO- group has the same meaning as in formula I, is converted by reaction with 1,1-carbonyldiimidazole to the corresponding imidazolide, which reacts in situ with a benzimidazole derivative of general formula III.

H (III) <ch ₂ )„oh in which n means the same as in formula I.

The reaction is preferably carried out in a dichloromethane environment at room temperature, and is complete within 24 h.

All intermediates used are known and can be prepared by known procedures.

Details of the method of carrying out the invention are given in the following examples.

Example 1

To a solution of 0.02 mol of 1,1'-carbonyldiimidazole in 50 ml of dichloromethane is added at room temperature 0.02 mol of 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetic acid, the mixture is stirred for 5 minutes, and to the imidazolide thus prepared is added 0.02 mol of 2-hydroxymethylbenzimidazole. Stirring is continued at room temperature for 6 h, the mixture is left undisturbed until the next day, diluted with dichloromethane, the solution is washed with water and the solvent is distilled off under reduced pressure to dryness. The residue gives, after crystallization from 2-propanol, 7.58 g of the desired ester, m.p. 197-198 °C (substance 1).

Example 2

In the same manner as described in Example 1, 5 g of an analogous derivative (substance 2) was prepared from the same batch of the same acid and 2-(2-hydroxyethyl)benzimidazole, m.p. 131-132°C (benzene).

Example 3 * In the same manner as described in Example 1, esters 3 to 30 are prepared.

The isolation method for esters 17, 25 and 30 differs from that described in that the product crystallizes % from the reaction mixture before or during washing with water. After filtering off the crystals, it is possible to obtain a further portion of the reaction product from the mother liquors treated in the described manner.

Table 2 (Substances 3 to 30)

Substance R n Temperature °C Solvent 3 4-ClC ₆ H,CH ₂ 1 161 to 162 benzene 4 2 115 to 116 benzene 5 4-CH,OC,H.CH, 1 118 to 119 2-propanol 6 J O 4 <£ 2 89 to 90 benzene : cyclohexane 7 4-FCrH.CH, 1 92 to 93 benzene P, 2 120 to 121 benzene 9 4-NO,C _fi H, CH,, 1 142 to 143 2-propanol 1 0 2 o 4 ά 2 125 to 126 2-propanol 1 1 3,4-(CH-O) _? CcH-CHj, 1 160 to 161 2-propanol 12 2 94 to 95 benzene : hexane ’ .3 C.H-0CH, 1 1 62 to !63 nitromethane f 4 at 3 o'clock 2 127 to 128 nitromethane 15 2-C1C.H.OCH, 4 100 to 101 benzene 16 2 114 to 115 2-propanol 17 4-ClC,H.OCH~ 1 162 to 163 2-propanol 18 2 102 to 103 benzene : cyclohexane 19 2,4-Cl,C,H,OCH„ 1 140 to 141 benzene 20 2 133 to 134 2-propanol 21 C _fi H-OC(CH,) ₉ 1 97 to 98 cyclohexane 22 2 101 to 102 nitromethane 23 4-C1C/-H.OC (CH,), 1 76 to 78 benzene : cyclohexane 24 D 4 J í 2 112 to 1.3 benzene 25 4-C1C.H, 1 214 to 215 2-propanol 26 at 4 2 .33 to 134 nitromethane 27 1 135 to 136 benzene 28 2 136 to .37 nitromethane 29 1 187 to .88 benzene : ethyl alcohol 30 \ ₌ J About 126 to 127 nitromethane

Claims (2)

SUBJECT OF THE INVENTION 1. Esters of 2-hydroxyalkylbenzimidazoles of the general formula I (CH2 INOCOR in which n represents 1 or 2 and the RCO group- the residue of 1- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indolylacetic, 4-chlorophenylacetic, 4- methoxyphenylacetic, 4-flourphenylacetic, 4-nitrophenylacetic, 3,4-dimethoxyphenylacetic, phenoxyacetic, 2-chlorophenoxyacetic, 4-chlorophenoxyacetic, 2,4-dichlorophenoxyacetic, phenpxyisobutyric, 4-chlorophenoxyisobutyric, 4-chlorophenoxyisobutyric, 4-chlorophenoxyisobutyl, 4-chlorophenoxyisobutyl, 4-chlorophenoxyisobutyl, 4-chlorophenoxyisobutyl, 2. A process for the preparation of esters of 2-hydroxyalkylbenzimidazoles of formula (1) according to claim 1, characterized in that the acid of formula (11) is: RCOOH (IX) in which the group RCO- denotes the same as in formula I, by reaction with 1,1'-carbonyldiimidazole, converts to the corresponding imidazolide which reacts longer in situ with the benzimidazole derivative of the general formula III (III) h (ch ₂ ) in which n denotes the same as in formula I.