CS229095B1 - 2-hydroxyalkylbenzimidazol esters - Google Patents

Abstract

The invention relates to esters of 2-hydroxyalkylbenzimidazoles of the general formula I (CH2, nOCOR (AND) wherein n is 1 or 2 and the RCO group is 1- (p-chlorobenzoyl) -5-methoxy-2- -methyl-3-indolylacetic, 4-chlorophenylacetic, 4-methoxyphenylacetic, 4-fluorophenylacetic, 4-nitrophenylacetic, 3,4-dimethoxyphenylacetic, phenoxyacetic, 2-chlorophenoxyacetic, 4-chlorophenoxyacetic, 2,4-dichlorophenoxyacetic, phenoxyisobutyric, 4-chlorophenoxyisobutyric, 4-chlorobenzoic, nicotinic and isonicotinic. The new compounds of formula I were tested for analgesic activity in aminophenazone (1-phenyl-2,3-dimethyl-4-dimethylamino-5-pyrazolone) comparative tests. In particular, compounds 24 and 28 (Table 2) showed interesting analgesic activity in these tests as shown in Table 1.

Description

The invention relates to esters of 2-hydroxyalkylbenzimidazolů formula I (CH ₂ OCOR _n (I) wherein n is 1 or 2 and the group RCO radical of 1- (p-chlorobenzoyl) -5-methoxy-2-methyl-3- indolylacetic, 4-chlorophenylacetic, 4-methoxyphenylacetic, 4-fluorophenylacetic, 4-nitrophenylacetic, 3,4-dimethoxyphenylacetic, phenoxyacetic, 2-chlorophenoxyacetic, 4-chlorophenoxyacetic, 2,4-dichlorophenoxychlorobutyl, 4-chlorophenoxyacetate, phenoxyisobenzoate nicotinic and isonicotinic.

Compounds of formula I that are novel have been tested for analgesic activity in comparative tests with aminophenazone (1-phenyl-2,3-dimethyl-4-dimethylamino-5-pyrazolone). In particular, compounds 24 and 28 (Table 2), as shown in Table 1, showed an interesting analgesic activity in these tests.

229095 2

Table 1

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

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

RCOOH (IX), in which the group RCO- denotes the same as in formula I, is converted by reaction with 1,1-carbonyldiimidazole into the corresponding imidazole, which reacts in situ with a benzimidazole derivative of the general formula III

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

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

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

Details of the embodiment of 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 hours. minutes, and to the thus prepared imidazolide is added 0.02 mol of 2-hydroxymethylbenzimidazole. Stirring at room temperature was continued for 6 h, the mixture was allowed to stand until the next day, diluted with dichloromethane, washed with water, and the solvent was distilled off to dryness under reduced pressure. The residue was crystallized from 2-propanol to give 7.58 g of the desired ester, m.p. 197-198 ° C (Compound 1).

Example 2

In the same manner as described in Example 1, S g of an analogous derivative (Compound 2), mp 131-132 ° C (benzene), was prepared from the same batch of the same acid and 2- (2-hydroxyethylbenzimidazole).

Example 3 * In the same manner as described in Example 1, esters 3 to 30 were 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 the water wash. After filtering off the crystals, a further proportion of the reaction product can be obtained from the mother liquors treated as described above.

Table 2 (Substances 3 to 30)

Substance R n M.p. 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, a C 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) 2 _? CcH-CH3, 1 160 to 161 2-Propanol 12 2 94 to 95 benzene: hexane .3 C.H-OCH, 1 1 62 to 63 nitromethane f 4 o 3 é 2 127 to 128 nitromethane 15 Dec 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 Dec 2,4-Cl, C, H, OCH 3 1 140 to 141 benzene 20 May 2 133 to 134 2-Propanol 21 _Cf H-OC (CH3) ₉ 1 97 to 98 cyclohexane 22nd 2 101 to 102 nitromethane 23 4-ClC / -H.OC (CH3), 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 o 4 2 , 33-134 nitromethane 27 Mar: 1 135 to 136 benzene 28 2 136 to 37 nitromethane 29 1 187 to 88 benzene: ethyl alcohol 30 \ ₌ J O 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.