IE41846B1 - Imidazodiazepine derivatives - Google Patents

Description

This invention .relates to imidazodiazepines which are pharmacologically active, and to pharmaceutical compositions containing them.

According to the present invention there is provided 5 a series of compounds of the general formula wherein R1 is hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, substituted phenyl, pyridyl or aralkyl; Rj is hydrogen or lower alkyl; R^ is hydrogen or lower alkyl; Rg is phenyl, monosubstituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl but is not nitro substituted; R? is hydroxy, acyl or an aromatic or aliphatic sulfonyl group; and^Jjjis selected from the group consisting of (a) wherein R^ is hydrogen, halogen, cyano, trifluoromethyl, lower alkyl, hydroxy lower alkyl or lower alkanoyl; X is hydrogen, chlorine, bromine or iodine; and T is hydrogen or lower - 2 41846 ιυ alkyl; and the pharmaceutically acceptable salts thereof.

As used herein, the term lower alkyl comprehends bot^i straight and branched chain· (C^-Cy) carbon-hydrogen radicals, preferably C^-C^ carbon-hydrogen radicals such as methyl, ethyl, propyl, isopropyl and butyl.

By the term lower alkanoyl as used herein, an acyl moiety of a C^-Cy, preferably a C^-C^, alkanoic acid is intended, e.g. acetyl, propionyl and butyrvl i.e. moieties of the formula 20 . 20 R -C— wherein R is O.-C^ aliphatic Hydrocarbyl or hydrogen. Also as used herein» 1 ° the term lower alkanoyl comprehends a protected aLdehyde or ketone such as an acetal or ketal having 2 to 7 carbon atoms, e.g. a group of the formula wherein R is Cj-Cg α1ιΡ1ΐ3ί::,·ε uydrocarbyl or hydrogun. Thu ketal or acetal utilized to prevent conversion of the contained ketone 20 or aldehyde (R -C-) in oxidation, reduction and condensation reacts. 5 The term halogen is used to include all four forms 2u thereof, i.e. chlorine, bromine, fluorine and iodine.

The terms aromatic and aliphatic sulfonyl group comprehends compounds of the formula SC^X' wherein X· is a branched or straight chain C^-Cy, preferably C^C^, aliphatic hydrocarbyl group e.g., methyl or a substituted or unsubstituted - 3 41846 aromatic group such as a phfenyl or substituted phenyl group e.g., tolyl.

The phenyl moiety Rg may be mono- or di-substituted provided that such di-substitution occurs in the 2,3; 2,5; or, most preferably, in the 2,6 position of the phenyl moiety.

When the phenyl ring is mono-substituted the substituent is preferably halogen or nitro and preferably it is substituted in the 2-position of the phenyl moiety. When the phenyl ring is di-substituted the preferred substituents are 2,6 or 2,5 dihalogen or 2,6 or 2,5 halogen-nitro. In the case of monosubstituted pyridyl, the preferred substituents are halogen and nitro.

When Rj is lower alkyl, optical isomerism will occur and such optical antipodes and racemates are within the ambit of this invention.

By the term aryl is meant a substituted or unsubstituted monocyclic aromatic moiety such as phenyl, chlorophenyl or tolyl.

By the term alkoxy is meant a straight or branched chain saturated hydrocarbyloxy group containing from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms, such as methoxy, ethoxy and propoxy.

By the term aralkyl is meant a hydrocarbon group having both aromatic and aliphatic structures, that is, a hydrocarbon group in which a lower alkyl H atom is substituted by a monocylic aryl group, e.g. phenyl or tolyl.

Preferred compounds are those wherein R^ is hydrogen or lower alkyl, preferably methyl Rj is hydrogen; (20; wherein R^ is located preferably in the 8-position of the imidazobenzodiazepine molecule and is hydrogen or halogen, preferably chlorine; and wherein Rg is phenyl or halo-, nitro-, - 4 418 4 6 or lower alkyl-substituted phenyl, preferably halo- e.g. fluoro-, substituted phenyl with the fluoro substituted in the 2-position of the phenyl moiety. s The compoundj^of general formula IA herein may be prepared from compounds of the general formula 1U IS (in which (t!L· RpRg.Rj and Rg are as above) which fonnula IA* compounds, and their production are described ln patent;Specification No.

. These compounds IA' may be converted to IA compounds having an ft^-radical other than hydroxy by reaction with an alkyl or aryl sulfonyl halide, e.g. tosyl chloride or mesyl chloride, or • a lower alkanoyl group providing agent, e.g.acetyl chloride.

This process is conveniently effected in the presence of an inert organic solvent such as an alkanol, e.g. ethanol or methanol, an ether such as diethyl ether or tetrahydrofuran, or dimethylformamide. Suitably, an acid acceptor is provided to the reaction zone to accept the hydrogen halide formed when utilizing a halide, e.g. an aryl sulfonyl (e.g. tosyl) halide or an alkyl sulfonyl (e.g. mesyl) halide, with a compound of the formula IA' above. Suitable acid acceptors are tertiary amines, e.g. triethylamine and pyridine.

Compounds of formula IA wherein R^ is hydroxy may be prepared by reducing, with hydrogen in the presence of a platinum catalyst and acetic acid, a compound of the general formula - 5 41846 · wherein <3C , K.j <Ε3 aad Rg are as Compounds of formula IA, and their production, Patent Specification No. above. are described in Compounds of the formula IA and their pharmaceutically acceptable acid addition salts are useful as muscle relaxants, sedatives and anticonvulsants and many are particularly useful when utilized in intravenous and intramuscular preparations because of the acid addition salts' solubility in aqueous solution. As contemplated by this invention, the novel compounds of the formula IA and their acid addition salts can be embodied, in pharmaceutical dosage formulations containing from about 0.1 to about 40 mgs. most preferably 1-40 mg with dosage adjusted to species and individual requirements. The novel compounds and their pharmaceutically acceptable salts can be administered internally, for' example parenterally or enterally, in conventional pharmaceutical dosage forms. For example, they can be incorporated in conventional liquid or solid vehicles such as water, gelatin, starch, magnesium stearate, talc and vegetable oils to provide tablets, elixirs, capsules, solutions and emulsions according to acceptable pharmaceutical practices.

Examples involving the preparation of compounds of general formula IA are given in our patent Specification No. to which attention is directed.

Claims (8)

1. A compound of the general formula IA F ιυ wherein R^ is hydrogen, lower alkyl, phenyl, alkoxy lower alky}, substituted phenyl, pyridyl or aralkyl; Rg is hydrogen or lower alkyl; R^ is hydrogen or lower alkyl; Rg is phenyl, mono-substituted phenyl, di-substituted phenvl, pyridyl or mono-substituted pyridyl, but is not nitro sutstituted R^ is hydroxy, acyl or an aromatic or aliphatic sulfonyl group; and (gjj^is selected from the group consisting of (¾) (c)

2. wherein R^ is'hydrogen, halogen, cyano, trifluoromethyl, lower alkyl, hydroxy lower alkyl or lower alkanoyl; Σ is hydrogen, chlorine, bromine or iodine; and T is hydrogen or lower alkyl; and the pharmaceutically acceptable salts thereof. A compound according to claim 1 wherein R^ is hydrogen or lower alkyl.

3. · A compound according to claim 1 or 2 wherein Rj is hydrogen. - 7 41846

4. wherein A compound according to any of claims 1 to 3

5. A compound according to claim 4 wherein R^ is hydrogen or halogen.

6. A compound according to any of claims 1 to 5 wherein Rg is phenyl or halo-, or lower alkyl-substituted phenyl.

7. A compound according to Claim 6 wherein Rg is 2fluoro-phenyl.

8. A pharmaceutical composition comprising, as active ingredient, a compound as claimed in any of claims i to 7 together with a solid or liquid carrier and/or an excipient.