Claims
- 1. 2-{[1-{1-[(4-Fluorophenyl)methyl]-1H-benzimidazol-2-yl}-4-piperidyl]methylamino}-4-pyrimidinol.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 85 13453 |
Sep 1985 |
FRX |
|
Parent Case Info
This is a continuation of application Ser. No. 906,279 filed Sept. 10, 1986, now U.S. Pat. No. 4,820,710.
The present invention relates to benzimidazole derivatives, the preparation thereof and their application in therapy.
The present invention provides compounds of formula (I) ##STR2## in which X is CH or N; R.sub.1 is hydrogen; unsubstituted benzyl; benzyl substituted by up to 3 substituents chosen from halogen, trifluoromethyl, (C.sub.1-4) alkyl, (C.sub.1-4) alkoxy, cyano, methylthio, methylsulphinyl and methylsulphonyl radicals; or heterocyclylmethyl in which the heterocyclic moiety is pyridyl, thienyl or furyl and is unsubstituted or substituted by one or more substituents;
Substituents on the heterocyclic moiety when R.sub.1 is heterocyclylmethyl are suitably selected from halogen, trifluoromethyl, (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, cyano, methylthio, methylsulphinyl and methylsulphonyl radicals.
Suitable acid addition salts include those of pharmaceutically acceptable organic acids or inorganic acids.
The preferred compounds of the invention are those in which X is CH or N, R.sub.1 is a 4-fluorobenzyl radical and R.sub.2, R.sub.3 and R.sub.4 have the meanings given in claim 1.
Among the compounds of the invention in which X is CH, the compounds of choice are those in which R.sub.1 is a benzyl radical bearing one or two substituents, and more especially those which bear at the 4-position a single substituent which is a fluorine or chlorine atom or a methyl, methoxy, methylthio, trifluoromethyl, cyano or methylsulphinyl radical.
When R.sub.3 is hydroxy and R.sub.4 is hydrogen the compounds may exist in several tautomeric forms such as ##STR3## All tautomeric forms of the compounds are part of the invention.
According to the invention, the compounds (I) can be produced by various methods as shown in Schemes I and II: ##STR4##
The Methods A, B, C and D are illustrated below by means of examples.
The most general method, method C, is applied to all the compounds, whereas method D is only applicable to the compounds in which R.sub.2 is other than hydrogen. Methods A and B are only applicable when R.sub.1 is other than hydrogen.
The process of the invention consists in reacting a compound of formula (II) with a 4-[(R.sub.2)(R) amino]piperidine of formula ##STR5## in which R.sub.2 is hydrogen or (C.sub.1-4)alkyl and R denotes either a hydrogen atom,
According to method A, a compound (II) is condensed with a [(R.sub.2)(alkoxycarbonyl)amino]piperidine (III) by heating to approximately 150.degree. C., and the compound (IV) obtained is then hydrolysed using hydrobromic acid in acetic acid medium to compound (V) which is reacted with a pyrimidine (VI) in which Y is a leaving group such as methylthio or halogeno especially chloro, bromo or iodo, in the presence or absence of a solvent, at a temperature of 50.degree. to 200.degree. C.
According to method B, a compound (II) is reacted with a [(R.sub.2)amino]piperidine in the presence of potassium carbonate in an alcoholic solvent, and the compound (V) is condensed with a pyrimidine (VI), in the presence or absence of a solvent, at a temperature of 50.degree. to 200.degree. C.
According to method C, a compound (II) is reacted with a compound (VIII) [obtained by alkylation of a 1-benzyl- or 1-ethoxycarbonyl-4-aminopiperidine with a 2-halo- or 2-alkylthiopyrimidine (VI), followed by catalytic debenzylation or hydrolysis to remove the protective group in the 1-position], in an alcoholic solvent at the reflux temperature.
According to method D, the starting material is a compound (II) in which R.sub.1 is hydrogen, and this is condensed with a (R.sub.2)(alkoxycarbonyl)amino piperidine (III) by heating to 150.degree. C., the compound obtained (X) is alkylated by the action of an alkyl halide to obtain the compound (IV) which is hydrolysed, and the compound (V) is then condensed with a pyrimidine (VI) as in method A.
The compounds of formulae (II, in which X is CH), (VI) and (VII) are described in the literature; the compounds of formulae (II, in which X is N), (III), (IV), (V) and (VIII, in which R.sub.3 is hydroxy) are new.
The compounds of the invention have histamine antagonist activity and can be used for the treatment of allergies such as respiratory allergies, skin allergies and eye allergies, and various allergic manifestations.
Some of the compounds of the invention are very selective for histamine (H.sub.1) receptors and are devoid of anticholinergic and antiserotoninergic activity at the therapeutic doses. They possess long-lasting action and their availability when taken orally is very high.
The invention comprises, in consequence, all pharmaceutical compositions containing the compounds and/or their salts as active principles, in combination with all excipients suitable for administering them, especially orally or parenterally.
The administration routes can be the oral and parenteral routes.
The daily dosage can range from 1 to 100 mg.
The examples which follow illustrate the invention. The analyses and the IR and NMR spectra confirm the structure of the compounds.
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
| 4281005 |
Baldwin et al. |
Jul 1981 |
|
Non-Patent Literature Citations (1)
| Entry |
| Chemical Abstracts, vol. 107, No. 1, Abstract No. 7211f, p.7212, Jul. 6, 1987. |
Continuations (1)
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Number |
Date |
Country |
| Parent |
906279 |
Sep 1986 |
|
Patent Grant
4912219
