1-(2'-Aroyl eth-1'yl) 2-(4"-acetamido piperazine-1"yl methyl) benzimidazoles and their therapeutical applications

Abstract

Compounds of the formula ##STR1## where Ar is phenyl, substituted phenyl, .alpha.-furyl or .alpha.-thienyl, andR is NH.sub.2, NHR.sup.1 wherein R.sup.1 is alkyl or cycloalkyl, or NR.sub.1 R.sub.2 whereinR.sub.1 and R.sub.2 are alkyl or --N.sub.1 R.sub.1 R.sub.2 is piperidino, pyrrolidino, morpholino or hexamethyleneimino. The compounds are prepared by reacting the corresponding Ar-substituted chloromethylated benzimadazole with the corresponding R-substituted piperazine. The compounds possess gastric antisecretory, anti-ulcerous, spasmolytic, anti-cholinergic, anti-bronchoconstrictive, analgesic, anti-inflammatory, anti-hypertensive and diuretic properties.

Description

The present invention concerns 1-(2'-aroyl eth-1' yl) 2-(4"-acetamido piperazine-1" yl methyl) benzimidazoles, their method of preparation and their application in therapeutics.

The compounds of the invention correspond to the following general formula (I): ##STR2## in which: Ar designates:

A phenyl nucleus which may be substituted by methoxy alkyl having 1 to 4 carbon atoms, nitro, or halogen, or .alpha.-furyl or .alpha.-thienyl, and R designates: --NH.sub.2, Nhr' where R' is alkyl having from 1 to 4 carbon atoms, or cycloalkyl having at least 6 carbon atoms, or Nr.sub.1 r.sub.2 where R.sub.1 and R.sub.2 designate an alkyl group having 1 to 4 carbon atoms or form together with the nitrogen atom to which they are linked, a heterocyclic radical chosen from piperidino, pyrrolidino, morpholino and hexamethyleneimino.

The method of the invention consists of condensing a compound of formula (II): ##STR3## where Ar has the same significance as in formula (I), with a piperazine of formula (III): ##STR4## in which R has the same significance as in formula (I).

This condensation is effected in an ethyl acetate medium and in the presence of sodium carbonate.

The compounds of formula (II) are obtained by reacting an alcohol of formula (IV): ##STR5## where Ar has the same significance as in formula (I), with thionyl chloride of formula (V):

so cl.sub.2 (V) the preparation of the derivatives of formula (IV) being described in French application No. 72.19540 published under the No. 2 186 251.

The following preparations are given as examples to illustrate the invention.

EXAMPLE 1

1-(2'-benzoyl eth-1' yl) 2-(4"-N-isopropylacetamido piperazine-1" yl) benzimidazole dimaleate -- Code number: 73 0442

First step: 1-(2'-benzoyl eth-1' yl) 2-(chloromethyl) benzimidazole -- code number: 72 370

To a suspension of 0.62 mole of 1-(2'-benzoyl ethyl) 2-methanol benzimidazole in 480 ml of chloroform was added, at 15.degree. C and within 1 hour, a solution of 0.95 mole of thionyl chloride in 270 ml of chloroform. After contacting for 2 hours at room temperature, the excess thionyl chloride was evaporated and the methanol solution of the chlorhydrate was neutralized with sodium bicarbonate. After filtration and evaporation, the crude base was recrystallized in ethyl acetate.

Melting point : 109.degree. C

Yield: 67 %

Empirical formula: C.sub.17 H.sub.15 Cl N.sub.2 O

Elementary analysis:

______________________________________ C H N______________________________________Calculated (%) 68.34 5.06 9.38Obtained (%) 68.14 5.18 9.24______________________________________

Second step: 1-(2'-benzoyl eth-1' yl) 2-(4"-N-isopropyl-acetamido piperazine-1" yl) benzimidazole dimaleate Code number: 73 0442

To a suspension of 0.1 mole of 1-(2' benzoyl-eth-1' yl) 2-(chloromethyl) benzimidazole obtained in the previous step, in 250 ml of ethyl acetate, was added 0.15 mole of sodium carbonate then 0.12 mole of 1-(N-isopropylacetamido) piperazine. After a reflux of 6 hours, the reaction medium was taken up with 600 ml of water. The organic phase was decanted, then dried. After evaporation of the ethyl acetate, the crude mass was salified in 200 ml of acetone by means of maleic acid.

Melting point: 151.degree. C

Yield: 82 %

Empirical formula: C.sub.34 H.sub.41 N.sub.5 O.sub.10

Elementary analysis:

______________________________________ C H N______________________________________Calculated (%) 60.08 6.08 10.30Obtained (%) 59.90 6.08 10.45______________________________________

EXAMPLE 2

1-(2'-benzoyl eth-1' yl) 2-(4"-pyrrolidinocarbonylmethyl piperazine-1" yl methyl) benzimidazole Code number : 73 0458

To a suspension of 0.1 mole of 1-(2'-benzoyl eth-4' yl) 2-(chloromethyl) benzimidazole obtained in the first step of example 1, in 250 ml of ethyl acetate was added 0.15 mole of sodium carbonate, then 0.12 mole of 1-pyrrolidinocarbonylmethyl piperazine. After a reflux of 1 hour, the sodium carbonate was separated by filtration and the ethyl acetate phase was concentrated.

The crude base obtained was purified by recrystallization in ethanol.

Melting point: 196.degree. C

Yield: 80 %

Empirical formula: C.sub.27 H.sub.33 N.sub.5 O.sub.2

Elementary analysis:

______________________________________ C H N______________________________________Calculated (%) 70.56 7.24 15.24Obtained (%) 70.58 7.38 15.40______________________________________

The compounds shown in table I following were prepared according to the operating mode of the second step of example 1.

TABLE I__________________________________________________________________________ ##STR6## Melt-Code Mole- ingnum- Empirical cular point Yield Elementary analysisber Ar R formula weight (.degree. C) (%) C H N__________________________________________________________________________74 0145 ##STR7## NH CH.sub.3 C.sub.32 H.sub.37 N.sub.5 O.sub.10 651.66 152 69 Calculated (%) Obtained 58.98 58.68 5.72 5.85 10.75 10.5974 0144 ##STR8## NH C.sub.2 H.sub.5 C.sub.33 H.sub.39 N.sub.5 O.sub.10 665.69 142 90 Calculated (%) Obtained 59.54 59.50 5.91 5.92 10.52 10.6574 0159 ##STR9## NH C.sub.3 H.sub.7 (n) C.sub.34 H.sub.41 N.sub.5 O.sub.10 679.71 128 50 Calculated (%) Obtained 60.08 60.07 6.08 6.24 10.30 10.1074 0186 ##STR10## NH C.sub.4 H.sub.9 (n) C.sub.35 H.sub.43 N.sub.5 O.sub.10 693.73 132 67 Calculated (%) Obtained 60.59 60.63 6.25 6.41 10.10 10.0474 0187 ##STR11## NH C.sub.4 H.sub.9 (i) C.sub.35 H.sub.43 N.sub.5 O.sub.10 693.73 137 71 Calculated (%) Obtained 60.59 60.79 6.25 6.24 10.10 10.0574 0180 ##STR12## N (CH.sub.3).sub.2 C.sub.33 H.sub.39 N.sub.5 O.sub.10 665.69 170 86 Calculated (%) Obtained 59.54 59.36 5.91 5.78 10.52 10.3074 0453 ##STR13## N (C.sub.3 H.sub.7(i)).sub.2 C.sub.37 H.sub.47 N.sub.5 O.sub.10 721.78 110 40 Calculated (%) Obtained 61.57 61.80 6.56 9.70 9.7474 0184 ##STR14## N (C.sub.2 H.sub.5).sub.2 C.sub.35 H.sub.43 N.sub.5 O.sub.10 693.75 154 78 Calculated (%) Obtained 60.59 60.50 6.25 6.37 10.10 9.9274 0196 ##STR15## N (C.sub.3 H.sub.7(n)).sub.2 C.sub.37 H.sub.47 N.sub.5 O.sub.10 721.79 143 78 Calculated (%) Obtained 61.57 61.63 6.56 6.80 9.70 9.6574 0160 ##STR16## ##STR17## C.sub.35 H.sub.41 N.sub.5 O.sub.11 707.72 187 88 Calculated (%) Obtained 59.40 59.70 5.84 5.64 9.90 9.7074 0195 ##STR18## ##STR19## C.sub.37 H.sub.45 N.sub.5 O.sub.10 719.77 149 77 Calculated (%) Obtained 61.74 61.61 6.30 6.56 9.73 9.9174 0655 ##STR20## NH C.sub.4 H.sub.9 (t) C.sub.35 H.sub. 43 N.sub.5 O.sub.10 693.73 166 50 Calculated (%) Obtained 60.59 60.57 6.25 6.47 10.10 10.0474 0656 ##STR21## ##STR22## C.sub.37 H.sub.45 N.sub.5 O.sub.10 719.770 150 55 Calculated (%) Obtained 61.74 61.47 6.30 6.57 9.73 9.6074 0698 ##STR23## NH C.sub.3 H.sub.7 (i) C.sub.32 H.sub.39 N.sub.5 O.sub.11 669.672 161 50 Calculated (%) Obtained 57.39 57.24 5.87 5.73 10.46 10.2674 0699 ##STR24## NH C.sub.3 H.sub.7 (i) C.sub.32 H.sub.39 N.sub.5 O.sub.10 S 685.738 170 62 Calculated (%) Obtained 56.04 55.89 5.73 5.43 10.21 10.2274 0700 ##STR25## NH C.sub.3 H.sub.7 (i) C.sub.35 H.sub.43 N.sub.5 O.sub.11 709.734 150 62 Calculated (%) Obtained 59.23 59.31 6.11 6.07 9.87 9.7975 0009 ##STR26## NH C.sub.3 H.sub.7 (i) C.sub.35 H.sub.43 N.sub.5 O.sub.10 693.734 146 61 Calculated (%) Obtained 60.59 60.44 6.25 6.24 10.10 10.1175 0012 ##STR27## NH C.sub.3 H.sub.7 (i) C.sub.34 H.sub.40 ClN.sub.5 O.sub.10, H.sub.2 732.157 151 45 Calculated (%) Obtained 55.77 55.66 5.78 5.74 9.57 9.5775 0010 ##STR28## NH C.sub.3 H.sub.7 (i) C.sub.35 H.sub.43 N.sub.5 O.sub.11 709.734 122 60 Calculated (%) Obtained 59.23 58.93 6.11 6.31 9.87 9.7875 0011 ##STR29## NH C.sub.3 H.sub.7 (i) C.sub.35 H.sub.43 N.sub.5 O.sub.11 709.734 154 60 Calculated (%) Obtained 59.23 59.00 6.11 6.14 9.87 9.8775 0102 ##STR30## NH.sub.2 C.sub.31 H.sub.35 N.sub.5 O.sub.10 , 1,75 H.sub.2 O 669.158 140 50 Calculated (%) Obtained 55.64 55.48 5.80 5.56 10.47 10.3774 0751 ##STR31## ##STR32## C.sub.36 H.sub.43 N.sub.5 O.sub.10 705.744 150 85 Calculated (%) Obtained 61.26 61.01 6.14 6.10 9.92 9.7074 0747 ##STR33## NH C.sub.3 H.sub.7 (i) C.sub.34 H.sub.40 N.sub.6 O.sub.12 724.708 134 59 Calculated (%) Obtained 56.34 56.18 5.56 5.64 11.60 11.43__________________________________________________________________________

The compounds of formula (I) were tested on laboratory animals and showed gastric antisecretory, anti-ulcerous, spasmolytic in vivo, anti-cholinergic and antibronchoconstrictive, analgesic, anti-inflammatory, anti-hypertensive and diuretic properties.

(1) Gastric antisecretory properties

Administered intraduodenally to a rat, the compounds of formula (I) are capable of reducing gastric secretion measured after Shay ligature.

As examples, table II following gives the results obtained.

Table II______________________________________ Reduction of volumeCode No of Dose administered of gastric secretiontested compound (mg/kg/i.d.) (%)______________________________________75,009 10 6273 0458 2 1975 0010 25 8273 0442 2.1 6875 001- 25 7574 0145 1.6 8875 0012 10 6374 0144 1.6 8575 0102 10 9174 0159 1.5 7774 0186 1.5 6774 0187 1.5 7874 0180 1.5 8674 0184 1.5 7774 0196 1.5 7474 0160 1.5 4574 0751 4.5 69______________________________________

(2) Anti-ulcerous properties

Compounds of formula (I), administered orally, reduce the area of ulcerations caused in a rat under stress for 7 hours.

Thus, table III gives the results obtained by administration of the different compounds of formula (I).

TABLE III______________________________________ Percentage reductionCode No of Dose administered of stress ulcerstested compound (mg/kg/p.o.) (%)______________________________________73 0458 5 7773 0442 5.2 9974 0145 7.7 10074 0144 7.7 9974 0159 7.5 10074 0186 7.4 9874 0187 7.4 10074 0180 7.7 10074 0184 7.4 10074 0196 7.3 8874 0160 6 7674 0195 7.1 5975 0009 20 9075 0010 20 7775 0011 20 5175 0012 20 6475 0102 10 100______________________________________

Furthermore, the compounds of formula (I) administered intraduodenally reduce the ulceration area caused by ligature of the pylorus of a rat (Shay's ulcers).

The results obtained are shown in table IV.

TABLE IV______________________________________ Percentage reductionCode No of Dose administered of Shay's ulcertested compound (mg/kg/i.d.) (%)______________________________________73 0458 10 9075 0009 20 5673 0442 7.6 8875 0010 40 8674 0145 15.5 10075 0011 40 7874 0144 15.5 9875 0012 10 7374 0159 15.1 10075 0102 10 7474 0186 14.8 7574 0187 14.8 9474 0180 7.7 9474 0453 7.3 8274 0184 7.4 10074 0196 7.3 9074 0160 15 9974 0195 14.2 8674 0751 10 89______________________________________

(3) Spasmolytic in vivo properties

The compounds of formula (I), administered intraduodenally are capable of reducing the contractions of the jejunal ansa of a rabbit, caused by electric stimulation.

The results obtained are shown in table V following:

TABLE V______________________________________ Diminution of contractionsCode No of Dose administered of the jejunum for moretested compound (mg/kg/i.d.) than an hour - (%)______________________________________75 0102 25 8073 0442 26.5 6774 0144 15.5 4374 0180 15.4 5074 0184 14.9 39______________________________________

The same test was studied with the uterine horn of a female rabbit.

For example, compound No 73.0442, administered at a dose of 53 mg/kg/i.d. reduces by 85 % for more than an hour, the contractions of the uterine horn of a female rabbit caused by electric stimulation.

(4) Anticholinergic and antibronchoconstrictive properties

Injected intravenously or intraduodenally, the compounds of formula (I) are capable of opposing bronchoconstriction caused in a guinea-pig by intravenous injection of acetylcholine and evaluated by Konzett's method. Table VI following shows the results obtained.

TABLE VI______________________________________Code No of Mode of Dose Percentage inhibition ofcompound adminis- administered the bronchoconstrictiontested tration (mg/kg) (%)______________________________________73 0458 i.d. 100 6773 0442 i.d. 25 10074 0145 i.v. 0.5 7574 0144 i.v. 4 10074 0159 i.v. 5 10074 0186 i.v. 2 10074 0187 i.v. 5 10074 0180 i.v. 5 10074 0453 i.v. 2.5 10074 0184 i.v. 4 10074 0195 i.d. 25 60______________________________________

(5) Analgesic properties

The compounds of formula (I), administered orally to a mouse, are capable of reducing the number of painful stretchings following intraperitioneal injection of acetic acid.

The result obtained are shown in table VII.

TABLE VII______________________________________ Percentage diminutionCode No of Dose administered painful stretchingscompound tested (mg/kg/p.o.) (%)______________________________________73 0442 100 8074 0145 10 7074 0144 40 9274 0159 50 4074 0186 40 7774 0187 50 4274 0180 50 5374 0184 50 6374 0195 50 53______________________________________

(6) Anti-inflammatory properties

These properties are revealed, by a diminution following oral administration of the compounds of formule (I), of the local oedema caused in a rat by sub-plantar injection of a phlogogenic agent, such as carragenine.

Table VIII gives as examples the results obtained with different compounds of formula (I).

TABLE VIII______________________________________ Percentage reduction of sub-plantarCode No of Dose administered oedemacompound tested (mg/kg/p.o.) (%)______________________________________74 0145 10 4074 0144 30 3574 1059 50 5774 0186 40 4874 0187 50 4774 0180 50 4774 0184 50 6574 0160 50 50______________________________________

(7) Anti-hypertensives properties

The compounds of formula (I) are capable, 4 hours after their oral injection, of bringing the arterial pressure down to normal in genetically hyperstressed vigil rats (S.H.R.).

Thus, administration of compounds No 750 011 and 740 747 respectively at doses of 10 mg/kg/p.o. and 150 mg/kg/p.o. are capable of bringing the arterial pressure down to normal in 4 animals out of 7.

(8) Diuretic properties

The compounds of formula (I), administered orally to a rat, increase the volume of urine emitted, relative to controls, the volume being measured for the 6 hours following administration.

For example, compound 750 011 has a DE 50 equal to 1 mg/kg/p.o.

In addition, since the compounds of formula (I) are not very toxic, as can be seen from table IX following, the difference between pharmacologically active doses and lethal doses is sufficient, for these compounds, to permit their use in therapeutics.

TABLE IX______________________________________Code No of Lethal dose 50 (mouse)compound tested (mg/kg/p.o.)______________________________________73 0458 >2 00075 0009 1 80073 0442 79875 0010 1 20074 0145 18075 0011 12074 0144 31075 0012 1 30074 0159 1 25075 0102 1 30074 0186 36074 0187 1 60074 0180 71674 0453 1 00074 0184 1 30074 0196 2 10074 0160 1 70074 0195 >2 00074 0751 1 10074 0747 2 200______________________________________

The compounds of formula (I) are principally indicated on the treatment of gastroduodenal ulcers, hyperchlorhydrias, visceral spasms, asthma, hypertension oedemas, pains of different, particularly inflammatory, origin.

They will be administered orally in the form of tablets, pills or gelules containing 25 to 200 mg of active ingredient (1 to 5 per day), in the form of drops containing 0.25 to 5 % of active ingredient (10 to 40 drops -- 1 to 3 times per day), parenterally in the form of injectable ampoules containing 5 to 150 mg of active ingredient (1 to 3 per day) and rectally in the form of suppositories containing 10 to 100 mg of active ingredient (1 to 3 per day).

The gastric antisecretory, anti-ulcerous and spasmolytic properties of different compounds according to the invention were compared with a reference compound will-known in its use in gastroenterology, diphemanil (methylsulfate).

__________________________________________________________________________1.degree.) Comparison of gastric antisecretory properties Dose Reduction of volumeCompound tested DL 50 (mouse) (mg/kg/p.o.) administered (mg/kg/i.d.) of gastric secretion - (%) ##STR34##__________________________________________________________________________73 0442 798 2.1 68 2.675 0009 1800 10 62 5.574 0180 716 1.5 86 2.173 0458 >200 2 19 <174 0145 180 1.6 88 975 0010 1200 25 82 2174 0144 310 1.6 85 5.275 0012 1300 10 63 874 0159 1250 1.5 77 1.275 0102 1300 10 91 874 0186 360 1.5 67 4.274 0751 1100 4.5 69 474 0187 1600 1.5 78 0.974 0184 1300 1.5 77 1.274 0196 2100 1.5 74 0.774 0160 1700 1.5 45 0.9Diphemanil 317 50 52 160__________________________________________________________________________

This table shows that the compounds of the invention present gastric antisecretory properties generally superior to diphemanil (methylsulfate) at substantially lower doses.

__________________________________________________________________________2.degree.) Comparison of anti-ulcerous properties Dose Percentage ReductionCompound tested DL 50 (mouse) (mg/kg/p.o.) administered (mg/kg/p.o.) of stress ulcers - (%) ##STR35##__________________________________________________________________________73 0442 798 5.2 99 6.575 0009 1800 20 90 1174 0180 716 7.7 100 1175 0010 1200 20 77 1773 0458 >2000 5 77 >2.574 0145 180 7.7 100 4375 0011 120 20 51 17074 0144 310 7.7 99 2575 0012 1300 20 64 1574 0159 1250 7.6 100 675 0102 1300 10 100 874 0186 360 7.4 98 2174 0751 1100 11 (DE 50) -- --74 0187 1600 7.4 100 4.674 0184 1300 7.4 100 5.774 0196 2100 7.3 88 3.574 0160 1700 6 76 3.574 0195 2000 7.1 59 >3.5Diphemanil 317 100 91 315__________________________________________________________________________

This table shows that the compounds of formula (I) present anti-ulcerous properties very much superior the diphemanil since, administered at a dose such that the ratio ##EQU1## is at least equal to 170, they bring about a percentage reduction of stress ulcers between 51 and 100 %, whereas diphemanil administered at a dose such that the ratio ##EQU2## is equal to 315 brings about a percentage reduction of 91 %.

__________________________________________________________________________3.degree.) Comparison of spasmolytic in vivo properties Diminution of Dose contractions ofCompound tested DL 50 (mouse) (mg/kg/p.o.) administered (mg/kg/i.d.) the jejunum of a rabbit - (%) ##STR36##__________________________________________________________________________73 0442 798 26.5 67 3374 0180 716 15.4 50 2174 0144 310 15.5 43 5074 0184 1300 14.9 39 1174 0195 >2000 14.2 30 > 7Diphemanil 317 20 70 63__________________________________________________________________________

This comparison shows that the compounds according to the invention enable a spasmolytic effect in vivo to be obtained, at least equal to that resulting from the administration of diphemanil by administration of a dose representing a smaller fraction of the lethal dose.

This study then shows that the compounds of formula (I) provide an important technical progress as regards the prior art.

Claims

1. A compound having the formula ##STR37## wherein Ar is .alpha.-furyl, .alpha.-thienyl, phenyl or phenyl substituted by one substituent selected from the group consisting of methoxy, alkyl having one to 4 carbon atoms, nitro and chloro, and the pharmacologically acceptable acid addition salts thereof.

2. A compound as claimed in claim 1 in which Ar is phenyl.

3. A pharmaceutical composition for use in the treatment of gastroduodenal ulcers, hypochlorohydrias, visceral spasms, asthma, hypertension, oedemas, and pains, comprising an effective amount of a compound as claimed in claim 1, in combination with a pharmaceutically acceptable carrier.

4. A pharmaceutical composition according to claim 3 in the form of a tablet, pill or gelule containing 25 to 200 mg of said compound.

5. A pharmaceutical composition as claimed in claim 3 in the form of an injectable composition in an ampoule wherein said ampoule contains 5 to 150 mg of said compound.