IE43765B1 - Intermediates for the preparation of diazepine derivatives - Google Patents

Description

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

In Patent Specification No, 43762 there are described and claimed pharmacologically active imidazo/-!,5 -a72”l,4,7 diazepine compounds. These compounds are of the general formula wherein A represents -C(Rg)=H-; Rj 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 R^ 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, aralkylcxycarbonylamino, substituted amino lower alkyl, the group - 2 437GS -COOR^θ (wherein represents hydrogen or lower alkyl), the group -COR1O (wherein Η^θ represents hydrogen or lower alkyl) or a derivative thereof, i.e. a) the group -C(Rj0) =R-R^, wherein R^ represents hydrogen, lower alkyl, hydroxy, alkoxy, amino, mono or dialky lamino or arylamino and represents hydrogen or lower alkyl; b) the group -COKR^R^, wherein R and R,, represent individually 12 i··5 hydrogen, lower alkyl, hydroxy lower alkyl, lower alkenyl, aryl or the group -(CELjJ^NR^R^ (whereiri R^ and R^ represent individually hydrogen, lower alkyl, hydroxy lower allyl or lower alkenyl, or R^ and R^ together fora a part of a heterocyclic ring, and n is 1 to 4), or R^ and Rjj together form a part of a heterocyclic ring; or c) the group .· -CON/R^g)N(R^R1g), wherein one of R^g. R^y and R^g represents hydrogen or lower alkyl or 20 the group -(CHg^R/R^R^) (wherein n is 1 to and R^ and R^ represent individually hydrogen, lower alkyl, hydroxy lower alkyl or lower alkenyl or R.J4 and R^ together form a part of a heterocyclic ring) and the remaining Κ^,Ρ^γ and R^g represent hydrogen or lower alkyl; and R^ represents additionally hydrogen or lower alkyl in the case where ^represents hydroxy lower alkyl, acyloxy lower alkyl, halo lower alkyl, amino - 3 A the group -COR^θ'(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 ^jTrepreeents the group T a) b) c) d) 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 2nd represents hydrogen and additionally alkanoyloxy or hydroxy in the case where (^represents the group 2), b) or c) above, analogs thereof corresponding to formula I but, wherein A represents the group ¢) ii . s) - 4 0 437G5 represents the group a), b) or e) above, R^ io hydrogen, , Rg ^5 and 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)=R- and R^ is hydrogen, have a structure in which the diazepine ring is opened by cleavage of the C/K-double bond in the 5)6-position.

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

According to the compound of the formula invention there is provided a wherein R is lower alkyl; A is -C(Rg)=ff-; R^ is hydrogen or lower alkyl; Rg is phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl; is'the group - 5 Λ <* a G 5 'τ a) b) c) d) wherein X is hydrogen, chlorine, bromine or iodine, T is hydrogen or lower alkyl, R^ is hydrogen, halogen, nitro,cyano, tri-_ fluoromethyl, lower alkyl, substituted amino, amino, hydroxy lower alkyl or lower alkanoyl, and Q.| is -COOR, wherein R is as defined above I I and Q2 is -MH-C0R1, wherein R^ is hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, • substituted phenyl, pyridyl or aralkyl, or Q1 aud Q2 together are =ΪΓ-ΟΗ in which case R^ is not amino or alkylamino.

As used in this disclosure, the term lower alkyl comprehends both straight and branched chain (C^-Ογ) hydrocarbon radicals, preferably C^-C^ 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^-Ογ preferably a C^-C^ alkanoic acid is intended, e.g., acetyl, propionyl, butyryl and the like, i.e. moieties of alkyl the formula -CORgO, wherein is C^-Cg/or hydrogen. Also as - 6 437GB 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 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 ]q 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 carbon atoms, such as methoxy, ethoxy, propoxy and the like. · By the term substituted am-i.no1’ herein is meant an -NHg group which may be mono or disubstituted by'lower alkyl, e.g.. methylamino or dimethylamino groups, and an acyl amino - 7437G3 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 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 formulaeί- or defined above. - 8 43765 The compounds are prepared and used as shown in the general reaction scheme A of Patent Specification No. 43762 as follows: - 9 437G5 VIII NHCH, C«3 IV * - 10 43705 Thus, a compound, of the invention of formula VI can he used to prepare a compound of formula I, wherein Rg is -COOR, i.e. a compound of formula XII, via a compound of formula VII, compounds of formulae VII and XI or compounds of formula VII and XIII. Also, a compound of formula VI can be prepared via compounds of formulae II, III, IV and V or VIII, IX, IV and V. Compounds of formula IV, VII and XI are the subject of our co-pending Application No. 43764.

Similarly, a compound of the invention of formula X can be used to prepare a compound of formula XII via a compound of formula XI by the alternative routes X —> XI XII; Χ-» XI—?-VII—> XII; and X -r>XI-t> VII-> XI3 XII.

Again preparation can be from a compound of formula VIII via a compound of formula IX.

More specifically the following sequences may be used: i : t I ! I fi 3,7 C 5 ' Step II—> III • - Compounds of formula III are produced by the nitrosation of compounds of formula II. Such a nitrosation may be 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 ncid, and .aqueous or non-aqueous solvents; (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., in the range of >-20°C to 25°C. An amino group or an alkylamino group present in the molecule may be protected during the nitrosation reaction, e.g. by means of acylation.'Such protecting group can be removed at a convenient later stage of the reaction sequence.

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 potassium text,-butoxide or sodium - 12 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°C 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 tertiary amides, e.g., dimethylformamide.

It is evident that any amino or substituted amino group 10 should be present in protected form in this reaction step the protective moiety can be removed afterwards at any convenient stage, e.g. subsequent to the formation of compound of formula XII.

Step III or IX—> IV Compounds of formula III or formula IX may be condensed with the anion generated from malonic ester of the formula /° © / 00R CH :00R wherein R is lower alkyl, to produce compounds of formula IV. The anion is generated by 20 deprotonating malonic ester with a suitable 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 solvent - 13 437G5 such as hydrocarbons, e.g., benzene, toluene, hexane, ethers .e.g., dioxane, THF, diethyl ether, DMF, DMSO etc. at a tempera ture range of below room temperature to 150°C, preferably 0°C to 100°C, most preferably room temperature.

Step IV—» V 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 DMSO at a temperature range of room temperature to reflux temperature, preferably 60°C to 100°C.

Step 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 nitrite, 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 be .carried out at about room temperature altough such temperature is not critical.

Step VI-» VII Compounds of the formula VII are produced by €he. reduction of compounds of formula VI e.g. with Raney nickel and - 14 4 3 7 G 5 .hydrogen or with zinc and acetic acid. This reduction results in the predominant production of compounds of formula VII with concurrent side production of small amounts of several possible isomers, i.e., compounds of the formulae VIIΔ VIIΘ . VIIC VII D It should be noted that the above reductive step would reduce vulnerable groups, If present, as R^, such as a 7-position NO^ or a 7~position CH. These groups may be replaced by methods known in the art and set forth in Patent Specification No. 43762 .

Step’ VII-> XII Compounds of the formula XII are then formed by tjie « reaction of formula VII compounds with an an alkanoic acid .ortho ester of the formula R^C(OR)3 wherein R is lower alkyl and R^ is hydrogen, lower' alkyl, alkoxy lower alkyl or halo lower alkyl, optionally in the presence of an acid catalyst, e.g., an organic or inorganic acid, e.g., p-toluene sulfonic acid, phosphoric 2o acid, etc., and at room temperature or above, i.a., 25°C to 150°C, in which instance the cyclization to compound-XII occurs spontaneously. Technical equivalents of the above ortho ester - 15 43765 include ortho amides, e.g. the dimethyl acetal of N,Ndimethyl formamide; Ν,Ν,Ν',Ν',N,N-hexamethylmethanetriamine; nitriles, e.g. acetonitrile; ester imidates, e.g. ch3-c(=nh)-oc2h5.

It is evident that any amino or alkylamino group present has to be protected during this reaction.

Step VII—» XI Compounds of formula XI may be formed by the acylation of formula VII compounds with a compound of the formula R^COX or (r'jCO^O wherein X is halo and R^ is hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, substituted phenyl, pyridyl or aralkyl.

Solvents for the above process step include methylene chloride, ethers, chlorinated hydrocarbons, etc., preferably in combination 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 NHCOR, COOR COOR XI A ' - 16 XI B 4S7G5 Step XI XII Compounds of the formula XII may also he formed bydehydration of formula XI compounds or isomers thereof with concurrent cyclization by heating. This reaction step may be carried out with or without solvent, e.g., BMP, ethylene glycol, hexamethyl phosphoric triamide, at a temperature range of 100°C to JOO°C, preferably at 150°C to 250°C, e.g. 200°C, with or without the presence of catalysts and water binding agents.

Step IX-» X Compounds of the formula X may be formed by the condensation reaction of a compound of the formula IX with the anion generated from acyl amino malonic ester of the formula Θ/ COOR C — IIHCOR.

COOR 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 by deprotonating acylamino malonic ester with a suitable strong base such as alkali metal or alkaline earth metal alkoxides, - 17 437 6 5 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 hydrocarbons 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°C, preferably 0°0 to 100°C, most preferably room temperature.

Step X-»XI Compounds of formula XI and isomers thereof are formed by the decarboxylation of formula X compounds with an alkali metal alkoxides in a solvent such as ethers, alcohols, DMSO, DMF, etc., at above or below room temperature, preferably at room temperature. Compounds of formula X and XI need not be isolated but can be con-'-erted in situ into compounds of formula XII.

Step VII -> XIII Compounds of the formula XIII are 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 2o amino or substituted amino group and preferably any RCO-group should be present in protected form. The protecting moiety can be removed afterwards, e.g. subsequent to the formation of compound of 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, e.g. molecular -184 3 7 G 5 sieves at above or below room temperature, preferably from room temperature to reflux temperature of the solvent.

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

Another 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 , /COOR i Θ / ! c-NHZ ; \ i 'COOR ί wherein R is lower alkyl and Z is benzyloxycarbonyl , converting the compound of formula X, wherein R^j is benzyloxy 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 - 19 4S7GS be isolated. The compound of formula VII thus obtained, is further converted to the final compound of formula XII via reacting step's VII—=> XIII and XIII—> XII described above.

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

Claims (2)

1. A compound of the formula wherein R is lower alkyl; A is -C(Rg)=N-: Rj is hydrogen or lower alkyl; Rg is phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl; (z|| is the group Χ γχ ‘γχ A. a) bj cJ d) wherein X is hydrogen, chlorine, bromine or iodine, T is hydrogen or lower alkyl, R^ is hydrogen, halogen, nitro, cyano, trifluoro10 methyl, lower alkyl, substituted amino, amino, hydroxy lower alkyl or lower alkanoyl, and is -COOS, wherein R is as defined above and I t Q 2 is -NH-COR^, wherein is hydrogen, lower 4376S alkyl, phenyl, alkoxy lower alkyl, substituted phenyl, pyridyl or aralkyl, or and Q 2 together are =N-OH in which case R.^ is not amino or alkylamino. 5

2. A compound of the formula in claim 1. •3· A compound of the formula defined OH VI - 22 4 3 7 G S