IE43763B1 - 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. 43763 there are described and claimed pharmacologically active imidazo[ 1,5-a] [1,4] 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 -COR^ (wherein R^q represents hydrogen or lower alkyl) or -COOR (wherein R represents lower alkyl); R2 represents chloro, 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, substituted amino lower alkyl, the group -COOR^Q (wherein R^Q represents hydrogen or lower alkyl), the group -COR^Q (wherein Rlo represents hydrogen or lower alkyl) or a derivative thereof, i.e. a) the group -C(R^Q)=N-R^^, wherein R^^ represents hydrogen, lower alkyl, hydroxy, alkoxy, amino, mono or dialkylamino or arylamino and R represents hydrogen or lower alkyl; b) the group -CONR^R^, wherein R^2 and R, _ represent individually hySrogen, lower alkyl, hydroxy lower alkyl, lower alkenyl, aryl or the group - (CH2) ^NR^R^g (wherein R^ and R^. represent individually hydrogen, lower alkyl, hydroxy lower alkyl or lower alkenyl, or R,. and R._ it> together form a part of a heterocyclic ring, and n is 1 to 4), or R12 and R^ together form a part of a heterocyclic ring; or c) the group -C0H(R,,)N(R R,.), wherein one of R , R._ lo 1 / lo lo 17 and R,_ represents hydrogen or lower alkyl or the group lo - (CH ) N(R R ) (wherein n is 1 to 4 and R,. and R,_ repre2 n 14 15 14 15 sent individually hydrogen, lower alkyl, hydroxy lower alkyl or lower alkenyl or R and R^g together form a part of a heterocyclic ring) and the remaining R , R and R._ lo 17 18 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 lower alkyl, substituted amino lower alkyl, the group -COR1O (wherein R represents hydrogen or lower alkyl) or -COOR (wherein R represents lower alkyl); R^ represents hydrogen or lower alkyl; R represents phenyl, mono-substituted phenyl, di-substitute^ phenyl, pyridyl or monosubstituted pyridyl; and (z|l represents the group 3/63 wherein X is hydrogen, chlorine, bromine or iodine, T is hydrogen or lower alkyl, 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 case where ( Zί represents the group a), b) or c) or above, analogs wherein A represents thereof corresponding to formula 1 but the group represents the group a), b) or hydrogen, R^, R^, R3 and Rg are as in V represents hydrogen or lower alkyl. c) above, R_ is 5 formula I above, and and pharmaceutically acceptable acid addition salts of these compounds which in the case of compounds of formula I wherein Qzjj^ is R^-phenyl, A is C(R^)=N- and R^ 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 437G3 wherein Q is OH or Br, R is hydrogen or lower alkyl; R is J o phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl; is the group wherein X is hydrogen, chlorine, bromine or iodine, T is hydrogen or lower alkyl, R^ is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, 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^O (wherein R^q represents hydrogen or lower alkyl) or -COOR (wherein R represents lower alkyl), and Rj is chloro, bromo, iodo, hydroxy lower alkyl, acyloxy lower alkyl, alkoxy lower alkyl, halo lower alkyl, amino lower alkyl, cyano, cyano lower alkyl, acylamino, lower alkoxy15 43703 carbonylamino, araIkyloxycarbonylamino, substituted amino lower alkyl, the group -COOR^Q (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(R10^=N_R1^' wherein R^ represents hydrogen, lower alkyl, hydroxy, alkoxy, amino, mono or dialkylamino or arylamino and R^q represents hydrogen or lower alkyl; b) the group -CONR R , wherein R and R represent X^ X«3 individually hydrogen, lower alkyl, hydroxy lower alkyl, lower alkenyl, aryl or the group ” (wherein and R^5 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 R^^ and Rj3 together form a part of a heterocyclic ring; or c) the group -C0N(R1c)N(R. Rn ), wherein one of R , R Xb X / Xo lb 17 and R represents hydrogen or lower alkyl or the group lo ~(CH„) N(R .R, ) (wherein n is 1 to 4 and R, „ and R n 14 15 14 15 represent individually hydrogen, lower alkyl, hydroxy lower alkyl or lower alkenyl or R,. and. R._ together form 14 lb a partcf a heterocyclic ring) and the remaining R._, R. _ lb 17 and R.„ represent hydrogen or lower alkyl; and R_ represents lo 2 additionally hydrogen or lower alkyl in the case where R^ represents hydroxy lower alkyl, acyloxy lower alkyl, halo lower alkyl, amino lower alkyl, substituted amino lower alkyl, the group -C0R1Q (wherein R^Q represents hydrogen or lower alkyl) or -COOR (wherein R represents lower alkyl).

As used in this disclosure, the term lower alkyl comprehends both straight and branched chain (C^-C?) hydrocarbon radicals, preferably carbon-hydrogen radicals such as methyl, ethyl, propyl, isopropyl, butyl and the like. The term lower alkyl comprehends also cyclic hydrocarbon radicals, such as cyclopropyl. 437C3 By the term lower alkanoyl as utilized herein, an acyl moiety of a c^-C? preferably a C^-C^ alkanoic acid is intended, e.g., acetyl, propionyl, butyryl and the like, i.e. moieties of the formula -COR__, wherein R._ is C -C. or hydrogen. Also as 20 20 1 b utilized herein, fhe 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.

The Rg 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 monosubstituents include halogen and nitro and preferably are substituted in the 2-position of the phenyl moiety. Suitable disubstituents are 2,6 or 2,5-di-halogen and 2,6 or 2,5 halogennitro. 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, and the like. When various moieties are set herein to form a part of a heterocyclic ring, it is intended that the moieties, together with the nitrogen atom to which they are attached form, preferably, a 5 or 6 membered ring which contains at the most one additional hetero atom, preferably nitrogen or oxygen as the hetero atom. Thus, by the heterocyclic ring, there is intended such moieties as morpholino, piperazino, piperidino and pyrroiidino.

By the term alkoxy” is meant straight or branched chain saturated hydrocarbonoxy group containing from 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy and the like. - 8 By the term substituted amino herein is meant an -NH^ group which may be mono or disubstituted by lower alkyl, e.g. methylamino or dimethylamino 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 hydrocarbon group in which a lower alkyl H atom is substituted by a monocyclic aryl group, e.g. -, phenyl, tolyl and the like.

The compounds of the invention may have one of the following formulae: 437 ΰ 3 wherein ^J3|j < Rjy R2' R3 an<^ Rg are as ^ejE^ne<^ above.

The compounds of the invention may be used to prepare compounds of formula I wherein A is Thus, a compound of formula ID may be reacted with phosphorus tribromide to form a compound of formula ID”’which can then be reacted with ethanolamine or a 1- or 2-alkyl substituted ethanolamine to give a compound of formula I wherein A is as above.

The reaction of the compound of formula ID with phosphorus tribromide is effected preferably in an inert organic solvent such as dichloromethane at about room temperature although such temperature is not critical.

The reaction of the compound of formula ID’ with ethanolamine or 1-alkyl or 2-alkyl substituted ethanolamine is effected in situ, i.e., with a suitable inert solvent such as dichloromethane, at a temperature range of -10°C to reflux, with about room temperature preferred.

A compound of formula ID can be prepared by reaction of a corresponding closed ring compound with sodium nitrite in the presence of a compatible solvent such as water or dilute mineral acid. The temperature of the reaction may be -10°C to room temperature.

Claims (4)

1. CLAIMS: .1» A compound of the formula: wherein Q is OH or Br, R is hydrogen or lower alkyl: R is J 6 phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl wherein X is hydrogen, chlorine, bromine or iodine, T is hydrogen or lower alkyl, R^ is hydrogen, halogen, nitro, cyano, trifluoro10 methyl, lower alkyl, 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 R^ Q represents hydrogen or 5 lower alkyl) or -COOR (wherein R represents lower alkyl) and R^ is chloro, bromo, iodo, hydroxy, lower alkyl, acyloxy lower alkyl, alkoxy lower alkyl, halo lower alkyl, amino lower alkyl, cyano, cyano lower alkyl, acylamino, lower alkoxycarbonylamino. 437G3 aralkyloxycarbonylamino, substituted amino lower alkyl, the group -COOR 1q (wherein R represents hydrogen or lower alkyl), the group -C0 R l0 (wherein R represents hydrogen or lower alkyl) or a derivative thereof, i.e., a) the group -C (R 1q ) *»N-R , wherein R represents hydrogen, lower alkyl, hydroxy, alkoxy, amino, mono or di-alkylamino or arylamino and R represents hydrogen or lower alkyl; b) the group -CONR R , wherein R and R represent individually it* X«5 X2 lj hydrogen, lower alkyl, hydroxy lower alkyl, lower alkenyl, aryl or the group -(CH ) NR R (wherein R and R represent 2 XI X4 X5 X4 Xd 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 R^ 2 and R·^ together form a part of a heterocyclic ring; or c) the group -CON(R )N(R R ), wherein one of R , R._ and R. lb 17 18 16 17 18 represents hydrogen or lower alkyl or the group -(CH„) N(R..R,_) (wherein n is 1 to 4 and R^ and R^ represent individually hydrogen, lower alkyl, hydroxy lower alkyl or lower alkenyl or R and R^g together form a part of a heterocyclic ring) and the remaining R.,, R. _ and R 1r) represent hydrogen or lower alkyl; and R 2 represents additionally hydrogen or lower alkyl in the case where R^ represents hydroxy lower alkyl, acyloxy lower alkyl, halo lower alkyl, amino lower alkyl, substituted amino lower alkyl, the group -COR^ Q (wherein represents hydrogen or lower alkyl) or -COOR (wherein R represents lower alkyl).
2. 2. A compound of the formula 43703
3. 3. A compound of the formula
4. 4. A compound as claimed in any one of the preceding is the group claims, wherein (Zfl claims. . A compound as claimed in any one cf the preceding wherein R^ is hydrogen.