IE43766B1 - Intermediates for the preparation of diazepine derivatives - Google Patents

Description

The present invention relates to intermediates for the preparation of diazepine derivatives.

In Patent Specification No. 43762 there are . described and claimed pharmacologically active imidazo/~1,55 -s7/”1»4,7 diazepine compounds. These compounds are of the ·' general formula wherein A represents -C(Rg)=N-; R^ represents hydrogen, lower alkyl, hydroxy lower alkyl, acyloxy lower alkyl, phenyl, alkoxy lower alkyl, halo lower alkyl, amino lower alkyl, substituted amino lower alkyl, substituted phenyl, pyridyl, aralkyl or the group -COR1Q (wherein RjQ represents hydrogen or lower alkyl) or -COOR (wherein R represents lower alkyl); Rg represents bhloro, bromo, iodo, hydroxy lower alkyl, acyloxy lower alkyl, alkoxy lower alkyl, halo lower alkyl, amino lower alkyl, cyano, cyano lower alkyl, acylamino, lower alkoxycarbonylamino , aralkyloxycarbonylamino, !0 substituted amino lower alkyl, the group - 2 -43766 -COOR,θ(wherein R^q represents hydrogen or lower alkyl), the group -COR^Q (wherein R^Q represents hydrogen or lower alkyl) or a derivative thereof, i.e. a) the group -C(R1Q) ssN-R^ , wherein R^ represents hydrogen, lower alkyl, hydroxy, alkoxy, amino, mono or dialkylamino or arylamino and R^q represents hydrogen or lower alkyl; h) the group -CONR^gRjj» wherein R and R,, represent individually 12 hydrogen, lower alkyl, hydroxy lower alkyl, lower .alkenyl, aryl or the group -(CHg)^^14^15 (wherein R^ and R^ represent individually hydrogen, lower alkyl, hydroxy lower alkyl or lower alkenyl, or R^ and R^ together form a part of a heterocyclic ring, and n is 1 to 4), or and R^ together form a part of a heterocyclic ring; or c) the group -CGN(R^g)N(R^R^8), wherein one of R^g, Rj? and R.|g represents, hydrogen or lower alkyl or the group -(CHg^NtR^R^) (wherein n is 1 to 4 and R^ and R^ represent individually hydrogen, lower alkyl, hydroxy lower alkyl or lower alkenyl or R^z_ and R^ together form a part of a heterocyclic ring) and the remaining R^g,R^ and R^Q represent hydrogen or lower alkyl; and R2 represents additionally hydrogen or lower alkyl in the case where R^ represents hydroxy lower alkyl, acyloxy lower alkyl, halo lower alkyl, amino '43766 lower alkyl,' substituted amino lower alkyl, the group -COR^q (wherein R^q represents hydrogen or lower alkyl) or -COOR (wherein R represents lower alkyl); R^ represents hydrogen or lower alkyl; Rg represents phenyl, mono-substituted phenyl; di-substituted phenyl, pyridyl or monosubstituted pyridyl; and (fjTrepresents the group 'γχ ,/y c) d) wherein X is hydrogen, chlorine, bromine or iodine,.T is hydrogen or lower alkyl, R^ I represents hydrogen, halogen, nitro, cyano, trifluoromethyl,·lower alkyl, substituted amino, amino, hydroxy lower alkyl or lower ·* .alkanoyl and R^ represents hydrogen and additionally alkanoyloxy or hydroxy in the casewhere ^represents the group a), b) or o) above, analogs thereof corresponding to formula I but, wherein A represents the group 9) 437GC Misrepresents the group a), b) or c) above, Rcj is hydrogen, R^, Rg, Rj and Rg are as in formula I above, and V represents hydrogen or lower alkyl, and pharmaceutically acceptable acid addition salts of these compounds which in the case of compounds of formula I wherein is R^-phenyl, A' is C(Rg)=li- and R5 is hydrogen, have a structure in which the diazepine ring is opened by cleavage of the C/N-double bond in the 5>6-position.

The compounds of the invention can be used to prepare compounds of formula I.

According to the invention there is provided a compound of the formula .

XXXVIII I wherein A is the group -C(Rg)=H- or -C(Rg)=H(->0)-; Rg is phenyl or mono- or di-substituted phenyl; R- is hydrogen or lower alkyl; is the group ,<χ 'τχ ’-σ a) b) c) -5· -S'? 6* wherein X is hydrogen, chlorine, bromine or iodine and is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, amino or substituted amino other than tertiary amino, hydroxy lower alkyl or lower alkanoyl, R^ is hydrogen, lower alkyl, hydroxy lower alkyl, acyloxy lower alkyl, phenyl, alkoxy lower alkyl, halo lower alkyl, amino lower alkyl, substituted amino lower alkyl, substituted phenyl, pyridyl,' aralkyl or the group -COR^Q (wherein Rlo represents hydrogen or lower alkyl) or -COOR (wherein R represents lower alkyl); and R22 is hydrogen, lower alkyl, lower alkoxy alkyl or acyloxy lower alkyl.

As used in this disclosure, the term lower alkyl comprehends both straight and branched chain (C^-C^) hydrocarbon radicals, preferably C^-C^carbon-hydrogen radicals such as methyl, ethyl, propyl, isopropyl, butyl and the like. The term lower alkyl comprehends also oyolio hydrocarbon radicals, such as cyclopropyl.

By the term lower alkanoyl as utilized herein, an acyl moiety of a Cj-C? preferably a Cj-C4 alkanoic acid is intended, e.g., acetyl, propionyl, butyryl and the like, i.e. moieties of the formula -COR2Q, wherein R2Q is C-^-Cg or hydrogen. - 6 4 3 766 . AIbo as utilized herein, the term lower alkanoyl comprehends a protected ketone such as an acetal or ketal having 2 to 7 carbon atoms, e.g. an ethylenedioxy group. The ketal or ’ aldehyde protecting group is utilized to prevent conversion . of the contained ketone or aldehyde in oxidation, reduction and condensation reactions.

The term halogen is used to include all four forms thereof, i.e. chlorine, bromine, fluorine and iodine.

I The Eg phenyl moiety 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. Suitable mono-substituents include halogen and nitro and preferably are substituted in the 2-position of the phenyl moiety. Suitable di-substituents are 2,6 or 2,5 di-halogen and 2,6 or 2,5 halogen-nitro. In the case of mono-substituted pyridyl, suitable substituents include halogen and nitro.

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

By the term alkoxy is meant straight or branched chain saturated hydrocarhonoxy group containing from 1 to 7 carbon atoms, preferably from 1 to 4 carbons atoms, such as methoxy, ethoxy, propoxy and the like. 437 G 6 By the term substituted emino herein is meant an -HHg group which may be mono or disubstituted by lower alkyl, e.g. bethylamino or dimethylamirio groups, and an acyl amino group e.g., acetamino which may then be substituted on the nitrogen atom by a lower alkyl e.g., methyl,group.

By the term aralkyl is meant a hydrocarbon group having both aromatic and aliphatic structures, that is, a » hyarocarbon group in which a lower alkyl H atom is substituted by a monocyclic aryl group, e.g.,. phenyl, tolyl and the likeThe compounds in. the general reaction NO. 43762 as follows: are prepared and used as shown scheme E of Patent Specification XLI XLII - 8 - _ 437G6 • ste'p XXXVH-> XXXVIII-XXLI Formula XXXVIII compounds are obtained by reacting corresponding formula XXXVII compounds with a peracid such as meta chloro perbenzoic acid or peracetic acid. In the instances where ie lower alkyl and R2 ie hydrogen, a compound of the formula XLI ia formed by subsequent reaction with an acid anhydride. The reaction step XXXVII-^ XXXVIII ia conveniently effected in an inert eol'ent. Suitable solvents are hydrocarbons, e.g. hexane, toluene; chlorinated hydrocarbons, e.g. methylene chloride, organic aciis, e.g. acetic acid. Preferably the reaction ia conducted at a temperature between about 0°C and 50°C.

It ie evident that any acyl group and preferably also any hydroxyalkyl group present should be protected during thia reaction step. An acyloxy alkyl group present may be transformed into a hydroxyalkyl, a haloalkyl, an aminoalkyl, a substituted aminoalkyl or a cyanoalkyl group subsequent to the formation of the compound of formula XXXVIII.

The treatment with an acid anhydride, e.g. acetic acid anhydride for the conversion XXXVIII—> XLI is conveniently effected in an inert solvent. Suitable solvents are hydrocarbons, e.g. hexane, toluene; chlorinated hydrocarbons, e.g. methylene chloride; ethers, e.g. tetrahydrofuran; dimethyl25 formamide; dimethylsulfoxide. Acid anhydrides taking part in the reaction can also be used as solvents. This reaction step is advantageously effected at a temperature between room temperature and about 150°C, preferably between about 80 C and 100°C. • - 9 '43706 it is evident that any amino group present will be acylated and any hydroxyalkyl group present with be esterified during this reaction step.

Step XLI—> XLII Formula XLII compounds wherein A is as in formula XXXVIII are obtained by reacting corresponding formula XLI compounds with an alkali metal alkoxide or hydroxide. This reaction step is conveniently effected in an inert solvent. Suitable solvents * * are hydrocarbons, e.g. hexane, toluene; chlorinated hydrocarbons, e.g. methylene chloride; ethers, e.g. tetrahydrofuran; alcohols, e.g. methanol, ethanol; dimethylformamide; dimethylsulfoxide; hexamethyl phosphoric triamide; pyridine, amines, e.g. triethylamine. This reaction is preferably conducted at a « temperature between about 0°C and the boiling point of the reaction mixture depending on the reagent used.

Step XLIX—> XXXIX Formula ΧΧΧΪΧ compounds wherein A is as in formula XXXVIII are formed by oxidation .oF formula XIV compounds by known oxidants such as chromium trioxide and manganese dioxide. This oxidation is conveniently conducted in an inert solvent.

Suitable solvents are hydrocarbons, e.g. hexane, toluene; chlorinated hydrocarbons, e.g. methylene chloride; ketones, e.g. acetone; organic acids, e.g. acetic acid;, pyridine, 437C6 i i dimethylformamide, dimethylsulfoxide. The oxidation ie preferably performed at a temperature between about -50°C and the boiling point of the reaction mixture, most preferably at about 0°C and room temperature.

It is evident that any substituent present as R^ and/or R^ in the meaning of hydroxyalkyl must be protected in the usual manner during this reaction step.

For specific examples.of the preparation and use of the compounds of the invention reference should be made to Patent Specification No. 43762 .

Claims (2)

1. WHAT .WE CLAIM IS: wherein A is the group -C(Rg)=H- or -C(Rg)=N (-^0)-; Rg is phenyl or mono-'or di-substituted phenyl; S.^ is hydrogen or lower alkyl; (z( is the group wherein X is hydrogen, chlorine, bromine or iodine and R4 is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, amino or substituted amino other than tertiary amino, hydroxy lower alkyl or lower alkanoyl, R 1 is hydrogen, lower alkyl, hydroxy lower alkyl, acyloxy lower alkyl, phenyl, alkoxy lower alkyl, halo lower alkyl, amino lower alkyl, substituted amino lower alkyl, substituted phenyl, pyridyl, aralkyl or the group -CORjQ (wherein R^ o represents hydrogen or lower alkyl) or -COOR (wherein R represents lower alkyl), and Rgg is hydrogen, lower alkyl, lower alkoxy alkyl or acyloxy lower alkyl. -12 ί 3 7 6 6

2. - A compound as claimed in Claim 1, vzherein R 22 is hydrogen.