IE43764B1 - 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 imidazo2~1,55 -a7/~1,47 diazepine compounds. These compounds are of the general formula \ wherein A represents -0(Κθ)=Ν-; E^ 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^q (wherein represents hydrogen or lower alkyl) or -COOR (wherein R represents lower alkyl); Rg 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, aralkyloxvcarbonylamino, substituted amino lower alkyl, the group -'2 43764 -COOR^θ (wherein R^ θ represents hydrogen or ·. lower alkyl), the group -COR^q (wherein R^ represents hydrogen or lower alkyl) or a derivative thereof, i.e. a) the group -O(R^q) =N~R.|p wherein R^ represents hydrogen, lower alkyl, hydroxy, alkoxy, amino, mono or dialkylamino or arylamino and R^ represents hydrogen or lower alkyl; h) the group -COHR^R^, wherein R and R._ represent individually 12 hydrogen, lower alkyl» hydroxy lower alkyl, lower alkenyl, aryl or the group (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 R^2 and R^ together form a part of a heterocyclic ring; or c) the group · -CORiR^jNiR^R^g), wherein one of R^g, R^y • and Ε^θ represents hydrogen or lower alkyl or 20 the group -(CH2)nN(R1^R1 g) (wherein n is 1 to and R^ and R^ represent individually hydrogen, 'lower alkyl, hydroxy lower alkyl or lower alkenyl or R^ and together form a part of a heterocyclic ring) and the remaining R^g,R^ and R^g 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 - 5 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 (^([represents the group a) ~b) wherein X is hydrogen, chlorine, bromine or iodine, T is hydrogen or lower alkyl, R^ < 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 (^represents the group a)’, b) or c) above, analogs thereof corresponding to formula I but, wherein A represents the group ¢) X «5 «« f) represents the group a), h) or c) above, Rj is hydrogen, R^, R2, R^ 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)=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 wherein R is lower alkyl; A is -C(Rg)=N~; R^ is hydrogen or lower alkyl; Rg i3 phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl; is the group - 5 43764 T a) b) · c) ' d) wherein X is hydrogen, chlorine, bromine or iodine, T is hydrogen or lower alkyl,is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, hydroxy lower alkyl or lower alkanoyl ,and Q is the group -COOR, -HH2 or 1-iHCOR^ , wherein I R is as defined above and R^ is hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, substituted - phenyl, pyridyl or aralkyl.

As used in this disclosure, the term lower alkyl comprehends both straight and branched chain (C^-Ογ) hydrocarbon radicals, preferably -0^ 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.

By the term lower alkanoyl as utilized herein, an acyl moiety of a C^-C? preferably a alkanoic acid is intended, e.g,, acetyl, propionyl, butyryl and the like,.i.e. moieties of the formula -C0R2Q, wherein R2Q is C^-Cg or hydrogen - 6 Also 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.

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 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 hydrocarbonoxy group containing from 1 to 7 carbon atoms, preferably from 1 to 4 carbons atoms, such as methoxy, ethoxy, propoxy and the like. - 7 43764 By the term substituted amino herein is meant an -NHg group which may he mono or disubstituted by lower alkyl, e.g. methylamino or dimethylamino groups, and an acyl amino group e.g., acetamino which may then he 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 E atom is substituted by a monocyclic aryl group, e.g., phenyl, tolyl and the like.

She compounds of the invention may have one of the following formulae:- IV VII - 8 or 437C4 RjOC x'N\yz'COOR defined above.

The compounds are prepared and used as shown in the general reaction scheme A of Patent Specification No. 43762 as follows: - 9 4376/3 A Thus, a compound of the invention of formula VII can be used to prepare a compound of the formula I, wherein Rg is -COOR i.e. a compound of formula XII, directly by reaction with an alkanoic acid ortho ester of the formula R^C(OR)^, wherein u R is lower alkyl and R^ is hydrogen, lower alkyl, alkoxy lower alkyl or halo lower alkyl, or with a technical equivalent of the ortho ester, any amino or alkylamino group being present in a protected form during the-reaction.

The reaction VII—>XII is optionally in the presence of an acid catalyst, e.g,, an organic or inorganic acid, e.g. ρ-toluene sulfonic acid, phosphoric acid, etc., and afc room temperature or above, i.e., 25°C to 150°C, in which instance the cyclization to compound XII occurs spontaneously. Technical equivalents of the above ortho ester include ortho amides, e.g. the dimethyl acetal of N,N-dimethyl formamide; Ν,Ν,Ν',N',N,N-hexamethylmethanetriamine; nitriles, e.g., acetonitrile; ester imidates, e.g.

Also, as shown in general reaction scheme A compounds of formula VII may be converted to compounds of formula XII via compounds of formula XIII.

Compounds of the formula XIII are thus formed by the reaction of formula VII compounds with an aldehyde of the formula R^CHO, wherein R^ is as in formula I, but any amino or substituted amino group and preferably any RCO-group should be present in protected form. The protecting moiety can be removed after- 11 wards, e.g. subsequent to the formation cfthe compouidof formula XII. Solvents suitable for this reaction step are hydrocarbons such as benzene, alcohols, ethers, chlorinated hydrocarbons, DMF, DMSO, etc., with or without the presence of water-binding agents, eg.malecuLar sieves at above or below room temperature, preferably from room temperature to reflux temperature of the solvent.

Compounds of the formula XIII may be converted to formula XII compounds by oxidation in situ by oxidising agents such as manganese dioxide, air, oxygen, etc.

A compound of the invention of formula XI may be used to prepare a compound of formula I, wherein R^ is as defined » above for Rj snd Rg is -COOR, directly by dehydration with concurrent cyclization.by heating. This reaction step may be carried out with or without solvent, e.g., DMF, ethylene.glycol, hexamethyl phosphoric triamide, at a temperature range of 100°C to 300°C, preferably at 150°C to 25O°C, e.g., 200°C, with or without the presence of catalysts arid water binding agents.

Compounds of formula XI may be formed by the acylation of formula VII compounds with a compound of the formula R^COX or (R^C0)20 I wherein X is halo and Rj is hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, substituted phenyl, pyi’idyl or aralkyl.

Solvents for the above process step include methylene chlorine, ethers, chlorinated Hydrocarbons, etc., preferably in oombina- 12 4 3 764 tion with an acid, acceptor such as an organic or inorganic base such as triethylamine, pyridine or an alkali metal carbonate. The reaction may be effected at above or below room temperature but preferably is carried out at room temperature. Compounds of the formula XI are isomeric in nature, that is, may exhibit either of the following stereochemical structures Either isomer may be used as described above and both are within the scope of the invention.

A compound of the invention of formula IV may be ) o converted via compounds of formulae V and VI to a compound c£ formula VII and thence directly or via a compound of formula XI or XUIto a compound of formula XII.

The steps are as follows :Step IV—>V -)5 Compounds of the formula V are produced by the decarboxylation of compounds of the formula IV by reacting the formula IV compound with an alkali metal hydroxide such as NaOH or KOH in a suitable solvent such as alcohols, ethers or - 13 4 3 7 6 4 DMSO at a temperature range of room temperature to reflux temperature, preferably 60°C to 100°C.

Step V-v> VI Compounds of formula VI are produced by the nitrosation of compounds of formula V by reacting same with nitrous acid generated from, for example, an alkali metal nimrite, alkyl nitrite or nitrosyl chloride, by reaction with organic or inorganic acid. Suitable solvents for the nitrosation reaction include ethers, alcohols, water, acids, e.g., acetic acid, DMF, DMSO and chlorinated hydrocarbons. The reaction may he carried out at about room temperature although such temperature is not critical.

Step VI—> VII Compounds of the formula VII are produced by the 15 reduction of compounds of formula VI e.g. with Raney nickel and hydrogen or with zinc and acetic acid. This reduction results in the predominant production jf compounds of formula VII with concurrent side production of small amounts of several possible isomers, i.e., compounds of the formulae - 14 <3764 It should be noted that the above reductive step would reduce vulnerable groups, if present, as E^, such as a 7-position NCg or a 7-position CH. These groups may be replaced by methods known in the art and set forth in Patent Specification No. 43762.

A compound of formula Γ7 may be prepared from II via III or Till via IX by the following sequencessStep II -> III Compounds of formula III are produced by the nitrosation of compounds of formula II. Such a. nitrosation may he effected by in situo formed nitrous acid. Reagents which may be employed include (1) alkali metal nitrites, i.e. sodium nitrites, in the presence of organic or inorganic acids, i.e., glacial acetic acid, and aqueous or non-aqueous solver.ts; (2) alkyl nitrites, i.e., methyl nitrites, in the presence of an inert solvent such as an alcohol, chlorinated hydrocarbon or, for example, dimethylformamide,· and (3) a nitrosyl chloride gaseous solution in an inert solvent and in the presence of an acid acceptor such as pyridine. Such a nitrosation reaction should be effected at around or below room temperature, i.e., lu the range of -20°C to 25°C. An amino group of an alkylamino group present in the molecule may be protected during the nitrosation reaction, e.g. by means of acylation. Such protecting group car. be removed at a convenient later stage of the reaction sequence. - 15 4 3 7 6 4 Step VIII—>IX Compounds of formula IX may be produced by the reaction of the compounds of formula VIII with dimorpholinophosphinic chloride. The reaction of formula VIII compounds with the phosphorylating agent to yield compounds of formula IX is accomplished by treatment of formula VIII compounds with a strong base sufficient to ionize the formula VIII compound to form the corresponding anion. Suitable bases include alkali metal alkoxides, such as pocassium tert.-butoxide or sodium methoxide, and alkali metal hydrides, such as sodium hydride, and alkyl lithium compounds, such as n-butyl lithium. The reaction temperature ranges from ..0°C to 100°0 and the.reaction Is carried out preferably in an aprotic polar inert solvent, i.e., one that would solubilize the ambient salts of the formula VIII compounds totally or at- least partially. Preferred solvents are ethers, e.g., tetrahydrofuran or dioxane or 1 tertiary amides, e.g., dimethylformamide.

It is evident that any amino or substituted amino group should be present in protected form in this reaction step and the protective moiety can be removed, afterwards at any convenient stage, e.g. subsequent to the formation of compound of formula XII.

Step I,J or IX—>IV Compounds of formula III or formula IX may be condensed with the anion generated from malonic ester of the formula - 16 4S7G4 COOR CH \ COOR wherein R is lower alkyl, to produce compounds of formula IV. The anion is generated by deprotonating malonic ester with a suitabJ s strong base such as alkali metal or alkaline earth metal alkoxides, hydrides or amides. The reaction of the formula III or IX compounds with the malonic ester anion is preferably effected in a solvat such as hydrocarbons, e.g., benzene, toluene, hexane, ethers e.g., dioxane, THE1, diethyl ether, DMF, DMSO etc. at a temperature range of below room temperature to 150°C, preferably 0°C to 100°C, most preferably room temperature.

Also, a compound of formula XI may be prepared from IX via X as follows :Step IX-T>X Compounds of the formula X may be formed by the condensa tion reaction of a compound of the formula IX with the anion generated from acyl amino malonic ester of the formula COOR Θ / C -NHCOR, \ 1 COOR - 17 S7G4 wherein R is lower alkyl and R^ is hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, substituted phenyl, pyridyl or aralkyl, to produce a compound of formula X._ The anion is generated 5 by deprotonating acylamino malonic ester with a suitable strong base such as alkali metal or alkaline earth metal alkoxides, hydrides or amides. The reaction of the formula IX compounds with the acyl amino malonic ester anion is preferably effected in a solvent such as hydrocirbons e.g., benzene, toluene, hexane, ethers e.g., dioxane, THF, diethyl ether, DMF, DMSO etc., at a temperature range of below room temperature to 150°G. preferably 0°C to 100°C, most preferably room temperature. ✓ g-bep X—j»xi Compounds of formula XI and isomers thereof are formed by the decarboxylation of formula X compounds with an alkali metal alkoxide in a solvent such as ethers, alcohols, DMSO, DMF, etc., at above or below room temperature, preferably at room temperature. Compounds if formula X and XI need not be. isolated but can be converted in situ into compounds of formula XIIAnother method for the preparation of compounds of formula XII wherein R^ is nitro or cyano consists in preparing a corresponding compound of formula VII. The latter compound can be prepared by reacting a corresponding compound of formula IX with a protected amino malonic ester of the formula 42764 COOR Θ / C -NHZ \ COOR wherein R is lower alkyl and Z is benzyloxycarbonyl, converting the compound of formula X, wherein R^ is henzyloxy and R^ is nitro or cyano, thus obtained to a corresponding compound of formula XI as described above for step X—£>XI and subjecting the compound thus obtained to a treatment with hydrogen bromide in glacial acetic acid yielding a compound of formula VII wherein R^ is nitro or cyano. The intermediates of formula X and XI need not he isolated. The compound of formula VII thus obtained is further converted to the final compound of formula XII via reacting steps VII-—->XIII and XIIIXII described above.

Compounds of formulae VI and X are the subject of Patent Specification No.' 43764.

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

Claims (3)

1. VfHAT WE CLAIM iS:1. A. compound of the formula wherein R is lower alkyl; A is -C(Rg)=N-; R^ is hydrogen or lower alkyl; Rg is phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mon-substituted pyridyl; (zj£ is the group a) b) 'η Λ c) d) wherein X is hydrogen, chlorine, bromine or iodine, T is hydrogen or lower alkyl, R^ is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, hydroxy lower alkyl or lower alkanoyl, and Q 1 is the group -COOR, -NHg or -UHCOR^, wherein I R is as defined above and R^ is hydrogen, lower alkyl, phenyl, alkoxy lower alkvl, - 20 4 S 7 0 1 substituted phenyl, pyridyl or aralkyl.

2. A compound of the formula IV md gfe

3. wherein R, A, R^ and are as defined in claim 1 A compound of the formula VII wherein R, A, R^ andare as defined in claim 1 A compound of the formula claim