100451

4,851,424

1

l-PHENYL-LOWER ALKYL-IMIDAZOLE 4- OR 5-C ARBOXAMIDE COMPOUNDS WHICH ARE USEFUL IN THE TREATMENT OF EPILEPSY

The invention relates to novel aralkylimidazole de-rivatives, especially 1-phenyl-lower alkylimidazoie-4-and/or -5-carboxamides of thc formula

Rj    0)

Ph—ilk—N    N

Ri    Rj

in which Ph represents phenyl substituted by lower alkyl and/or by halogen, alk represents lower alkyli-dene, one of the radicals Ri and Rj is carbamoyl option-ally substituted by lower alkyl or by lower alkanoyl and the other is hydrogen, lower alkyl, or carbamoyl op-tionally substituted by lower alkyl or by lower alkanoyl, and R3 represents hydrogen or lower alkyl, for use in a method for the therapeutic treatment of the human or animal body, to pharmaccutical preparations containing them and to their use as the active ingredients of medi-caments and to the compounds themselves, with the proviso that, in compounds of the formula I in which Ri and R2 arc the same and each represents carbamoyl or N-methylcarbamoyl, if R3 represents hydrogen at least one substituent of Ph is bonded in thc o-position, and to processes for their man ufać turę.

Tlte phenyl radical Ph contains, for examplc, up to and including 3, especially 1 or 2, of the mentioned substituents, preferably one lower alkyl or halogen substituent or one or two halogen substituents, or one lower alkyl and one halogen substituent, preferably at least one of the mentioned substituents being bonded in an o-position. As examples there may be mentioned: o-halophenyl, 2,6- and also 2,5-, 2,3- and 2,4-dihalophe-nyl, and also c-lower alkylphenyl, especially 2,6-difluorophenyl.

Optionally lower alkyl- or lower alkanoyl-substituted carbarnoyl Ri and, where appropriate, Ri is, for exam-ple, carbamoyl or N-lower alkyl-, N.N-di-lower alkyl* or, secondly, N-lower alkanoyl-carbamoyl.

Hereinbefore and hereinafter there are to be under-stood by “lower” organie groups and compounds preferably those groups and compounds that contain up to and including 7, especially up to and including 4, carbon atoms (C atoins).

Lower alkyl is, for exarapłe, Ci-Ca-alkyl, such as methyl, ethyl, propyl, isopropyl. butyl, and also second-ary butyl, isobutyl or tertiary butyl, but may also be a Cs-Cj-alkyl group, such as a pentyl, hexyl oc heptyl group.

Halogen is, for exampic, halogen having an atomie dTimber of up to and including 35, such as fluorinc, chlorine or, secondly, bromine.

Lower alkylidenc is, for examplc, Ci-C4-alkylidene. especially l,l-Ci-C*-alkylidene, such as methylcnc, and also ethylidene, 1,1-propylidene or 1,1-butylidene, but may also bc 2,2-C3-C4-alkylidene, such as 2,2-propyli-dene (isopropylidene) or 2,2-butyiidcne.

N-lowcr alkylcarbamoyi is, for esample, N-C1-C7-alkyIcarb3moyl, especially N-Ci-C*-alkytcarbamoyl. such as methyl- or ethylcarbamoyl.

2

N,N-di-lower alkylcarbamoyi is, for example, N,N-di-Ci-Ca-alkylcarbamoyl, such as dimethylcarbamoyl, and also diethyl- or di-n-propyl-carbamoyl.

N-lower alkanoylcarbamoyl is, for example, N-C2-C7-alkanoylcarbamoyl, especially N-C2-C4-alkanoyicarbamoyl, such as acetyl-, propionyl- or buty-ryl-carbamoyl, but may also tormylcarbamoyl or Ń-C5-C7-alkanoylcarbamoyl, such as pivaloylcarbamoyl.

The compounds of the formula I have valuable phar-macological properties, especially a pronounced anti-convulsive activity which can be demonstrated, for esample, in mice on the basis of a distinct metrazolc antagonism in a dosage rangę of approximately 10 mg/kg and above p.o. and in mice and rats on the basis of a marked protective action against convul$ions trig-gered by electric shock in a dosage rangę of approxi-rnately 3.5 mg/kg and above p.o.. The compounds of the formula I are accordingly excellencly suitablc for the treatment of convulsions of various origins, for example for thc treatment of epilepsy. Ttacy can accordingly be used as anticonvulsive, for cxample antiepilep-tic, active ingredients in medicaments.

The invention relates especially to compounds of the formula I in which Ph represents phenyl that is mono-, di- or tri-substituted by lower alkyl and/or by halogen, alk represents lower alkylidcne, one of the radicals Ri and R2 is carbamoyl, N-lower alkylcarbamoyi, N,N-di-lower alkylcarbamoyi or N-lowcr alkanoylcarbamoyl and the other is hydrogen, lower alkyl, carbamoyl, N-lower alkylcarbamoyi, N,N-di-lower alkylcarbamoyi or N-lower alkanoylcarbamoyl. and Rj represents hydrogen or lower alkyl, for use in a method for the therapeutic treatment of thc human or animal body, and also to thc above-deftned compounds themseWes, with thc proviso that, in compounds of the formula I in which R\ and Ri arc thc same and each represents carbamoyl or N-methylcarbamoyl, if Rj represents hydrogen at least one substituent of Ph is bonded in thc o-position. and preferably to those in which at least one of the mentioned substituents of Ph is bonded in the o-position and/or alk represents oiethylene, R| represents hydrogen or carbamoyl and R2 represents carbamoyl.

The invention relates morę especially to compounds of thc formula I in which Ph represents phenyl that is monosubstituted by Cj-Ca-alkyl or disubstituted by halogen or by halogen and Ci-Ca-alkyl, wherein Ci-Ca-alkyl is, for exarople, methyl and halogen has an atomie number of up to and including 35 and is, for cxample, fluorinc or, secondly, chlorine, alk represents 1,1- or 2,2-Ct-C4-alkylidene, such as methylcnc or ethylidene, one of the radicals Ri and R2 is carbamoyl, N-Ci-Ct-alkyl- or N,N-di-Ci-C*-alkyl-carbamoyl, such as methyl- or dimethylcarbamoyl, or N-C2-C7-alkanoylcarbamoyl, such as acetyl- or pivaloyl-carbam-oyl, and the other is hydrogen. carbamoyl, N-C1-C4-alkyl- or N.N.-di-Cj-Cł-aikyl-carbamoyl, such as methyl- or dimethylcarbamoyl, or N-C2-C7-alkanoylcar-baraoyl, such as acetyl- or pivaloyl-carbamoyl, and Rj represents hydrogen or, secondly, Ci-Gi-alkyl, such as methyl. for use in a method for the therapeutic treatment of the human or animal body. and also to thc above-defined compounds theraseWes, with the proviso that, in compounds of the formula I in which Ri and Ri are thc same and each represents carbamoyl or N-inethylcarbamoyl, if Rj represents hydrogen at least one substituent of Ph is bonded in the o-position. and prefer-ably to those in which at least one of the mentioned substituents of Ph is bonded in the o-position and/or alk