HU181885B - Process for producing benzo-, thieno- and pyrazolo-imidazo-diazepine derivatives - Google Patents

Abstract

A process for the preparation of imidazo [1,5-2] [1,4] diacepinic compounds of the general formula ** (Formula) ** wherein A represents C (R6) = N-; R1 represents hydrogen, lower alkyl, phenyl, lower alkoxy alkyl, substituted phenyl, pyridyl or aralkyl, R2 represents the group COOR10 (wherein R10 represents lower alkyl), R3 represents hydrogen or lower alkyl; R6 represents phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl.

Description

The present invention relates to novel imidazo [1,5-a] - [1,4] diazepine compounds of the formula: wherein:

A is -C _(R6) = N-group of the formula ₅ in which

R ₆ fenij group, a mono- or dihalo-phenyl or pyridyl groups,

R represents a hydrogen atom, a "lower alkyl group, a-hydroxy (lower) - _J0 alkyl, a- (lower) -alkanoyloxy (lower) alkyl, phenyl, a- halo (lower) alkyl, a-amino (lower) alkyl, lower alkyl substituted with 15 alpha or 5-amino (lower) alkyl, pyridyl a phenyl, lower alkyl or a -CHO group,

R ₂ is chloro, bromo, iodo, α-hydroxy (lower) alkyl, α-lower alkanoyloxy (lower) alkyl, α (lower) alkoxy (small) lower alkyl, a-halo-lower alkyl, a-amino-lower alkyl, cyano, a-cyano-lower alkyl, lower alkanoylamino, lower alkoxycarbonylamino, phenyl (lower) alkoxycarbonylamino, lower alkyl substituted amino (lower) alkyl, -COORjo (wherein Rj ₀ hydrogen or lower alkyl), -COR ₁₀ (wherein R _{10 is} hydrogen or lower alkyl), -CH = N-R 11 (wherein R 1 is hydroxy, lower alkoxy); -csopo R 1 or di- (lower) alkylamino), -CONR ₁₂ R 3 (wherein R _{12 is} hydrogen, lower alkyl, phenyl or - (CH 2) ₁₁ NR ₁₄ R _{). 5} represents a group of formula, in which R 4 represents wherein: R _{1 S-lower} alkyl radical and n is an integer from 1 to 4; R ₁₃ is hydrogen, a lower alkyl group or a phenyl group, or R _J2 R _J3 form together with the nitrogen atom pyrrolidino group), or -CONH-NR] ₇ R ₈ group (wherein R ₁₇ and R ₁₈ hydrogen or lower alkyl) or, when R1 is formyl or hydroxymethyl, R2 may also be hydrogen,

R ₃ is hydrogen or lower alkyl, and (N 1) is (a), (b) or (d) wherein λ is chlorine, bromine or iodine,

-1181885

T and Υ are lower alkyl, and

R _{4 is} hydrogen, halogen, nitro, cyano, trifluoromethyl or lower alkyl - and N-oxides of formula (I ') and (I'') of compounds of formula (I') 5,6-dihydro derivatives of the general formula (II) - wherein in the latter formulas (gX (a) or (b), wherein R ₄ and X are as defined above,

R ₂ has the same meaning as R ₂ above, except hydrogen

R 1, R ₃ and R ₆ are as defined above and for the preparation of pharmaceutically acceptable salts of the compounds of formula (I), (”") and R "other than hydrogen.

These compounds are novel and have valuable therapeutic effects.

The closest structural analogues of the new compounds of the present invention are disclosed in German Patent Publication Nos. 1 695 211, 2 237 592 and 2 221 558.

As used herein, the term "lower alkyl" is straight or branched

C 1-4 hydrocarbon groups (e.g., methyl, ethyl, propyl, isopropyl, butyl and the like).

The term "lower alkanoyl" refers to acyl groups (e.g., acetyl, propionyl, butyryl and the like) of C 1-5 alkanecarboxylic acids, i.e., -COR ₂₀ (wherein R ₂₀ is 1-4). C 1 -C 4 alkyl or hydrogen).

The term "halogen" embraces all four halogens, i.e., chlorine, bromine, fluorine and iodine.

The term "lower alkoxy" refers to straight or branched (1-4C) groups (e.g., methoxy, ethoxy, propoxy, etc.).

The term "lower alkyl substituted amino" refers to one or two lower alkyl substituted amino groups (e.g., methylamino or dimethylamino).

A preferred group of compounds of the present invention are compounds of formula (IB):

R 1 is hydrogen or lower alkyl, preferably methyl;

R ₄ is a nitro group or a halogen atom, preferably a chlorine atom, and this substituent is preferably attached to the 8-position of the fused benzene ring of the imidazobenzodiazepine molecule;

R 1 is phenyl optionally substituted with one or two halogen atoms, wherein the halogen atom, preferably the fluorine atom, is preferably attached to the 2-position of the phenyl ring;

R ₂ is hydroxy (lower) alkyl (e.g. hydroxymethyl group.) Carboxylic group (-CONHNH ₂₎ or carboxyl-benzyloxycarboxamido group (i.e., -CONH ₂₎ -.

Another preferred group of compounds of formula (I ') are compounds of formula (IC) wherein R 1, R ₂ , R ₁ and R ₃ are as defined above and R ₃ is methyl.

Also preferred are compounds of formula 0 ') wherein they are 8-chlorobenzo or

8-chloro-thieno [3,2-f] alkyl; R 1 is hydrogen or methyl; R 'is acetyl, carboxamido or dimethylcarboxamido; R ₆ is 2'-fluoro or 2'-chlorophenyl and R ₃ is hydrogen. *

The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable inorganic or organic acids (e.g. hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, methanesulfonic acid, methanesulfonic acid). means. The salt formation may be carried out by methods known to those skilled in the art.

The novel diazepine derivatives, i.e., the compounds of formulas 0 ', (I ") and 0"') and their pharmaceutically acceptable salts, as defined above, are prepared according to the present invention by the following process variants:

A) for the preparation of compounds of formula 0 'wherein R 1 is hydrogen or lower alkyl, R _{2 is} -COOR 10 wherein R _{10 is} lower alkyl, while (Z 1, A and R ₃ are) are as hereinbefore defined, a ₃₅ (VII) - wherein R is a lower alkyl group and (ZjQ A and R ₃ are as defined above -, or an N-oxide, optionally an acid catalyst at room temperature at or above its ₄₀ ) with an alkanoic acid orthoester of formula RjC (OR) ₃ , wherein R is as defined above, and Rj is hydrogen or lower alkyl, or _45B ) for the preparation of compounds of formula 0 'wherein R' - COOR10 represents a lower alkyl group, while Rio represents a lower alkyl group; , R, and _R3 are as hereinbefore defined, (XIII), a compound of ₅₀ formula - wherein the above, R is as defined in process a) @ 5, R, and R ₃ is - with a suitable oxidizing agent, preferably manganese dioxide, air or oxygen ; obsession

C) reacting a (T ⁵⁾ compounds of formula I wherein R, is hydrogen, a lower alkyl group or a phenyl group, R2 -COORio group and this is Ri 0-lower alkyl groups of the formula, 60 ^m Ig and R3 denotes in the introduction a compound of formula XI wherein R 'is hydrogen, lower alkyl or phenyl, and A and R ₃ are as defined above, and R is as defined in Process A, or N-. oxide, if appropriate

-2181885 in the presence of a solvent, a catalyst and / or a water scavenger, heated to 100-300 ° C and subjected to dehydration and ring closure; obsession

D) (for preparing Γ) compounds of formula, wherein R ₅ is phenyl or pyridyl radical, (ZjC (a) represents a group of formula R ₂ COOR a, or -CONR i R _{i 2} represents a group of formula ₁₃ (wherein represented by R _b R _{i 2} and R _J3 lower alkyl group) and a and R ₃ to 'are as defined in the introduction, (IX') a compound of formula - wherein R _3, R ₄ and R ₆ are as defined in the introduction - a With a nitrone of formula (XLVI) j wherein R _{2 is a} phenyl or pyridyl group and R ₂₄ is a lower alkoxy or di- (lower) alkylamino group;

Following procedure A), B), C) or D)

(a) for the preparation of compounds of formula (I ') wherein R j is as defined in the introduction, but from α-(lower) -alkanoyloxy-(lower) -alkyl and α-halo-(lower) -alkyl other than hydrogen, R ", COOR o a group of formula and, R is _J0 are hydrogen and A and R ₃ are as initially ²⁵ hereinbefore defined formula (XII) with a compound of formula - wherein R '" is hydrogen, lower alkyl groups, and -hydroxy (lower) -alkyl, phenyl, a-halo-lower-alkyl, a-amino (lower) -alkyl, with lower alkyl substituted a- or 0-amino (lower) alkyl, pyridyl, phenyl (lower) alkyl, or -CHO, and R ₃ , A and (Z 6 are as defined above); And R 35 is as defined for process A) k is preferably carried out in the presence of alkali metal hydroxides; optionally followed by aa) a front (Γ) of compounds of formula ^40; 's-'sá.ra wherein R ^11, R Y as defined below either of the substituents is R _"2 -CONRj Ri3 group of the formula (wherein R _{J 2} and 77 ₃ are defined in the introduction), and A, R ₃ and (ZY_ are as defined in the introduction, a ⁴⁵ (XVIIF) compound of formula - wherein R Y ⁿ _ is hydrogen, a lower alkyl group, a phenyl group, a- amino (lower) alkyl group, a substituted lower alkyl group, a- or 0-amino (lower) alkyl * ⁵⁰ moiety, pyridyl, phenyl (lower) alkyl radical or -CHO represents a group and a, R 3 and (zT is as defined above - the acid chloride of a HNR12Ri3 amine compound - wherein R12 and R13 have the above ^five specified - is reacted, if desired, the compounds of formula (I ') shortage for the preparation of compounds of formula (XXVIII) bb, wherein R ('is as defined above for RY ¹¹ and A, R3 and as defined above for ⁶⁾ , the corresponding carbamoyl compound is subjected to dehydration; or b) for the preparation of (I ') are compounds of formula wherein R meghatáro65 method, aa) in -RVII substituents is R "CONH-, -NR ₁₇ R _j8 is a group of formula (in which R ₇ and R ₈ are as initially ) and A, R ₃ and (E ₁ C) are acid chloride of a compound of formula (XVIII ') where RY ^{11 is} A, R ₃ and as defined above is represented by H ₂ N-NR ₁₇ R _8. with hydrazine - where R ₁₇ and R ₁₈ are as defined above - or ac) for the preparation of compounds of formula I 'wherein R ^{1 is a} substituent R * ¹ as defined below, R 2 is chlorine, bromine or iodine and A, R 3 and (Z} T is a decarboxylate of the introductory compound of formula XVIII 'wherein RY ⁿ is R * ¹ as defined below and A, R3 and are as defined above. nk and then the compound of formula XXX where R ^{1 is} lower alkyl, phenyl, lower alkyl substituted with a or 0-amino-lower alkyl, pyridyl; a phenyl, lower alkyl or -CHO; and A, R ₃ and the above are reacted with a chlorinating agent, a brominating agent or an iodinating agent, preferably N-chlorosuccinimide, bromine or N-bromosuccinimide. ; or id) for the preparation of compounds of formula I 'wherein R 1 is a substituent RY ¹¹¹ as defined below, R' is a lower alkoxycarbonylamino group or a phenyl (lower) alkoxycarbonylamino group, and A, R 3 and (ZK) are as defined in the introduction of a (S ⁵⁾ is a carboxylic acid of formula azidját, i.e., (XXIV), a compound of formula - wherein RY ¹¹¹ is hydrogen, a lower alkyl group, a phenyl group, a pyridyl group, a phenyl (lower) alkyl or -CHO, and is heated with A, R3 and (ZJY as defined above) with a lower alkanol or a phenyl (lower) alkanol, and optionally to produce compounds of formula (I) wherein R R Y ¹¹¹ represents a substituent as defined above, gives the process a), R ₂ represents a lower alkanoylamino group are idle, and the symbol R ₃ is intended to mean the radicals defined above and in the introduction, provided that R _{4 in} the group (a) can only be a substituent other than nitro and cyano, in the general formula (XXV) obtained in the above manner the compound of formula - wherein R means 9 benzyl radical, R Y ^H is as defined above, a and R ₃ are as defined above, and (Zl £ is as defined above - is hydrogenated, and the resulting free amine is reacted with a lower alkanecarboxylic acid or halide ; obsession

b) for the preparation of compounds of general formula (XIV) which are a narrower group of compounds of formula I ', wherein A and R ₃ are as defined in the introduction, R''is as defined in process a) except for the formyl group;

-3181885, with the proviso that R _{4 in} the group represented by formula (a) may only be a substituent other than nitro and cyano, a compound of formula (XII) wherein A and R ₃ is as defined above, R '' is as defined above

a), (Zj is as defined above and R is

Reduction according to process A), preferably using lithium aluminum hydride as the reducing agent; and if desired, ba) 'preparation of compounds of the formula) from the group of compounds of formula (XIX) - R' (I ^v is hydrogen, lower alkyl group, a phenyl group, the-halo (lower) alkyl A, or O- [di- (lower) alkylamino] - (lower) alkyl, pyridyl, or phenyl (lower) alkyl, A and R3 is as defined in the introduction, R is as defined in Method A) ²⁰ and is listed in the introduction, with the proviso that R4 in the formula (a) can only be a substituent other than nitro and cyano - (XIV) starting compound of formula ²⁵ a- general - where a and R ₃ are as defined above, R "'is R) ^V is of the same and is as defined above - optionally in the presence of an acid acceptor abbr acylating with an alkane carboxylic acid anhydride or chloride; 30 or bb) the preparation of compounds of the formula: Among the compounds of formula (I '), (XX) - wherein R y is hydrogen, lower carbon atom number ³⁵ alkyl group, a phenyl group, the hydroxy (lower) alkyl a, lower alkyl substituted with α or (3-amino (lower) alkyl, pyridyl, or phenyl (lower) alkyl, ⁴⁰ X 'halogen) and R ₃ is as defined in the introduction, and (Ζ1Γ the groups in the introduction, with the proviso that (a) the group of formula R ₄ of the indicated groups stands for an nitro- and cyano-group substituent - (XIV) a compound of formula wherein A and R ₃ are as defined above, R '' has the same meaning as RY and is ^{as defined above} , a halogenating agent, preferably a phosphorus halide; or and thionyl chloride, if desired, to form a compound of formula (I ') wherein R 1 is R 1, R' is lower alkoxymethyl, aminomethyl, cyanomethyl or aminomethyl substituted with lower alkyl, A and R ₃ are as defined above and are introductory, provided that R _{4 of} the formula (a) is only nitro, and may represent a different substituent cyano group - one (XX) is a compound of formula - wherein R y, X ', A- and R ₃ are as defined in the present method, and (ZJL is as defined above - with ammonia, a lower alkyl group substituted by a primary or reacting with a secondary amine, a lower alkoxide, or a cyanide; or be) for the preparation of compounds of formula (Γ) wherein R 1 is hydrogen, lower alkyl, phenyl, α-halo-lower alkyl, α-amino-lower alkyl; a lower alkyl group, a-or O-amino-lower alkyl, pyridyl or phenyl-lower alkyl, R _{2 is} formyl, A and R _{3 has the} meaning given in the introduction and (ZJC means the groups enumerated in the introduction, with the proviso that R _{4 in} the formula (a) may only be a substituent other than nitro and cyano, in the general formula (XIV) compound - wherein a, R _3, R 'represents and b) given in the process - preferably oxidized with chromium trioxide or manganese dioxide, dioxide, and then reacting the compound (XV) - wherein R, R ₃ , A and above mean -

The aldehyde group at the 3-position is optionally reacted with a lower alkyl Grignard or lithium reagent; and, if desired, preparing compounds of formula (I ') wherein R 1 is hydrogen, lower alkyl, phenyl, a-halo-lower alkyl, a-amino (lower) -alkyl, lower-alkyl substituted a- or O-amino-lower alkyl, pyridyl or phenyl-lower alkyl, R ₂ -COR ₁₀ is a group (wherein Rio is a lower alkyl group), and R ₃ and A are as defined in the introduction, and (ZjJ ^ Substitution of these in the introduction, with the proviso that (a) the group of the formula the meaning of R ₄ is therein only a substituent other than nitro and cyano may be substituted with an alcohol of formula XXII obtained above - wherein Rf ¹ is as defined above for R ¹ , and A and R ₃ are as defined above. only mean the same as defined above, _0-lower alkyl group, and is as defined above - with an oxidizing agent, preferably chromium trioxide or manganese dioxide in the presence, if desired, for the preparation of (I ') are compounds of formula I wherein R! hydrogen, lower alkyl, phenyl, α-amino (lower) alkyl, lower alkyl substituted α- or γ-amino (lower) alkyl, pyridyl or phenyl (lower) alkyl, R ' ₂ ' is -CH = N-R 1 (wherein R 1 is as defined above) and R ₃ , A and (Z 1) are as defined above , a compound from the group of the compounds of formula (XV), (XXXIV) - wherein A, R ₃ and (ZK is a hydrogen atom as defined above, R ₀ represents and Ry ¹ represents the last time, the meaning of R for reporting! - hydroxylamine, a lower alkoxy 4181885

with an amine or a hydrazine of the formula H ₂ NR ₂₀ - wherein R _{20 is} a lower (lower) alkylamino group and optionally to produce a compound of the formula (I ') wherein R 1 is as defined for R * below R 'represents an aminomethyl group, and A, R ₃ and represents a compound of formula XXXV above wherein R ^{x is} hydrogen, lower alkyl, phenyl, a-amino- lower alkyl substituted with lower alkyl or lower alkyl, pyridyl or lower alkyl, R 10 is hydrogen, R _{2 is} hydroxy or lower alkoxy, A and R ₃ are as defined in the introduction and are listed in the introduction, with the proviso that the group of formula (a) R ₄ can only be a substituent other than nitro and cyano, hydrogen in the presence of a reducing agent, preferably Raney nickel; obsession

c) for the preparation of compounds of formula (I *) wherein R1 is hydrogen, lower alkyl, phenyl, a-amino-lower alkyl, a- or O-amino substituted with lower alkyl. is (lower) alkyl, pyridyl, or phenyl (lower) alkyl, R ₂ is -CONR ₁₂ R ₁₃ (wherein R _{3 is} hydrogen and R ₍₂ in introduction)). and R ₃ , A and are as defined above, a compound of formula (ΧΠ) - wherein R ₃ , A and R are as defined above, R is as defined in Process A, and R 'is a ) except for the α-halo and α-hydroxy (lower) alkyl group and the -CHO group are ammonolized with an amino compound of the general formula H ₂ NR ₁₂ where R ₂ is as defined above. ; obsession

d) for the preparation of compounds of formula (I *) wherein R ₁ represents the substituents listed in process (c), R ₂ -CONHNR ₁₇ R ₁₈ (wherein R ₁₇ and R ₁₈ are as defined in the introduction), and A, R ₃ and are as defined in the introduction, one (ΧΠ) a compound of formula - same, wherein R _3, a and Lock-in above, R is as defined under process a), and R "'is R, above, respectively - a H ₂ N-NR ₁₇ R _With a compound of Formula ₁₈ wherein R, ₇ and R 15 are as defined above for direct hydrazinolysis; obsession

e) for the preparation of compounds of formula I 'wherein R 1 is a substituent R [ ^x ] as defined below, R _{2 is} -COOR _1; Denotes a group of the general formula ₀ wherein R ₁₀ is a lower alkyl group, R _{3 is} a lower alkyl group and A and a compound of the general formula XII 'as given in the introduction where R is as defined in process A) , A and (Z ^ are as defined in the introduction, and R \ ^x is hydrogen, a lower alkyl group, a phenyl group, a lower alkyl group substituted by the 0-amino (lower) alkyl group, pyridyl alkyl, phenyl, lower alkyl, or -CHO, at the 4-position is alkylated with a lower alkyl halide; obsession

E) for preparing compounds of the group of the compounds of formula (I '), (XLII) - wherein _R10 is H, A, and R ₃ are as defined at the outset - formula (XLI) wherein the compound of formula

- where Ac represents a lower alkanoyl group, Rio A, R ₃ and represents an alkali metal alkoxide or hydroxide as defined above and, if desired, to form a more limited group of compounds of formula I '- wherein R ₁₀ is hydrogen, A, R ₃ and is a compound of formula (XLII) as defined above wherein R _{10 is} A, R ₃ and is as defined above treated with an oxidizing agent, preferably chromium trioxide or manganese dioxide; and thereafter of the general formula (I ')

For the preparation of 5,6-dihydro compounds - wherein R 1, R ₂ ,. R ₃ , R ₆ and are as defined in the introduction, a compound of formula (I) prepared by any of the above A, B, C or D processes wherein R _1} R ₂ , R ₃ , A and in the introduction, the groups (I ') and (I'') in the introduction, except for the groups which may be reduced under the conditions used, are treated with hydrogen or zinc in the presence of a platinum oxide catalyst or in the presence of acetic acid; or N-oxides of formula (I)

- where R 1, R ₂ , R ₃ , R ₆ and as defined in the introduction - a compound of formula (I) prepared by any of the above A, B, C or D - wherein R _x , R ₂ , R ₃ , A and A are as defined in the introduction to Formulas (I ") and (I") - an organic persa, preferably peracetic acid, perpropionic acid or m-chloroperbenzoic acid; and / or, if desired, converting a compound of formula (I ') (I') or (I '') represented by any one of the above processes wherein R 'is other than hydrogen into a pharmaceutically acceptable salt.

General procedures for the preparation of compounds of formula (I *) are illustrated in Schemes A to E. Wherein R is a lower alkyl group and A, R _ls R _3, R ₄ and R ₆ are defined as provided in Formula (Γ) that "otherwise stated. The reactions shown in Scheme A may also be carried out with the corresponding N-oxides, [A = -C (R ₆ ) = N-] or the corresponding N-oxide group, but the N-oxide group in the compounds of formula VI it is cleaved at the transition (VI) -> (VII).

-511 ξ (II) -> (III)

Compounds of formula (III) are prepared by nitrosation of compounds of formula (II). ⁵ The nitrosation is carried out "in situ" formed nitric acid. The following reactants may be used; 1. alkali metal nitrides, e.g. sodium nitrite in the presence of an inorganic or organic acid (e.g. glacial acetic acid) in an aqueous or non-aqueous solvent. 2. alkilnitritek (eg. Methyl nitrite) in the presence of an inert solvent (eg. Alcohols, chlorinated hydrocarbons or ¹⁰ eg. Dimethylformamide). 3. Solvents of nitrosyl chloride gas in an in solution solution in the presence of an acid scavenger (e.g. pyridine). The nitrosation is at about or below room temperature i.e. - ¹⁵ may be carried out at a temperature between 25 ° C and 20 ° C.

e (VIII) + (IX)

Compounds of formula (IX) may be prepared by reaction of compounds of formula (VIII) with dimorpholinophosphine / acid. The reaction of the compounds of formula VIII and the phosphorylating agent to the compounds of formula IX may be accomplished by first treating the compound of formula VIII with a base of sufficient strength to ionize to the appropriate anion. For this purpose, e.g. alkali metal alcoholates (eg potassium tertiary butylate or sodium methylate), alkali metal hydrides (eg sodium hydride) or alkyl lithium compounds (eg n-butyl lithium) may be used. The reaction is preferably carried out at 0-100 ° C and in an aprotic polar inert solvent in which the salts of the compounds of formula VIII are completely or at least partially soluble. The reaction media are preferably ethers (e.g. tetrahydrofuran or dioxane) or tertiary derivatives (e.g. dimethylformamide).

Steps (III) or (IX) to (IV) ⁴ θ

The compounds of formula (III) or (IX) are converted to the compound of formula (IV) by reaction with an anion of a malonic acid ester of the formula ROOC-CH-COOR (wherein R is a lower alkyl group). The anion may be formed by deprotonating the malonic ester with a suitable strong base (e.g., an alkali metal or alkaline earth metal hydroxide, anhydride, or an amide). The reaction of the compound of formula (III) or (IX) with the malonic acid ester anion 50 is preferably carried out in a solvent (e.g., a hydrocarbon such as benzene, toluene, hexane, an ether such as dioxane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, etc.). can do 55. The reaction may be carried out at a temperature below room temperature to 150 ° C, preferably at 0-100 ° C, most preferably at room temperature.

compound is reacted with an alkali metal hydroxide (e.g., sodium or potassium hydroxide) in a suitable solvent (e.g., alcohol, ether or dimethylsulfoxide). The reaction may be carried out at a temperature between room temperature and the reflux temperature of the reaction mixture, preferably 60-100 ° C.

£ (V) -> (VI)

Compounds of formula (VI) may be prepared by nitrosation of compounds of formula (V). The nitrosation can be carried out, for example, from nitric acid with an organic or inorganic acid, for example from alkali metal nitrite, alkyl nitrite or nitrosyl chloride. As the reaction medium, e.g. ethers, alcohols, water, acids (e.g. acetic acid), dimethylformamide, dimethylsulfoxide or chlorinated hydrocarbons. The reaction may be carried out at about room temperature, although the reaction temperature is not critical.

<(VI) * (VII)

Compounds of formula (VII) may be prepared from compounds of formula (VI), e.g. It can be prepared by reduction with Raney nickel and hydrogen or by zinc acetic acid system. During the reduction, the compounds of formula (VII) are obtained as the main product, while a small amount of the isomeric compounds are formed as a by-product. Note that the reduction step attacks groups sensitive to the reduction (e.g., a 7-nitro or cyano group at the R ₄ position). Therefore, such groups should be formed by methods known per se and described herein.

(VII) -> (XII "). [Procedure A]

Compounds of formula (ΧΠ) are compounds of formula VII and alkanecarboxylic acid esters of formula RiC (OR) ₃ (wherein R is lower alkyl and R 1 is hydrogen or lower alkyl) optionally an acid. in the presence of a catalyst (e.g., organic or inorganic acids such as p-toluenesulfonic acid, phosphoric acid, etc.) at room temperature or at a higher temperature (e.g., 25-150 ° C). spontaneous cyclization occurs. Compounds equivalent to the above orthoesters may also be used in the reaction, e.g. orthoamides such as Ν, Ν-Dimethylformamide dimethylacetal: nitriles, e.g. acetonitrile; ester imidates, e.g. CH ₃ -C (= NH) -OC ₂ H ₅ or, when R _{3 is} methyl, N, N, N ', J' N 'N' -hexamethyl methanetriamine may also be used.

Steps (IV) to (V)

Compounds of formula (V) may be prepared by reacting a compound of formula (IV) 55 (VII) (XI).

Compounds of formula XI are compounds of formula VII which are R '/ COX

Is prepared by acylation with a compound of the general formula -613 or (R "CO) 10 (where X is halogen and R" is hydrogen, lower alkyl or phenyl). The acylation is preferably carried out in a solvent (e.g., methylene chloride, ethers, chlorinated hydrocarbon) in the presence of an acid scavenger (e.g., organic or inorganic bases such as triethylamine, pyridine or alkali metal carbonate). The reaction may be carried out at a temperature above or below room temperature, but preferably at room temperature. Compounds of formula (XI) have an isomeric structure and may exist as stereoisomers of the general formula (XIA) or (XIB).

<?; Steps (XI) through * (XII ") [Procedure C]

Compounds of formula (XII) may be prepared by dehydration and cyclization of compounds of formula (XI) or isomers thereof upon heating. The reaction may be carried out in the presence or absence of a solvent. As a solvent, e.g. dimethylformamide, ethylene glycol, hexamethylphosphoric triamide. The reaction may be carried out at 100-300 ° C, preferably at 150-250 ° C (e.g. 200 ° C), optionally in the presence of a catalyst and a water scavenger.

Steps (IX) - * (X)

Compounds of formula (X) may be prepared by reacting a compound of formula (Dg) with an acylaminomalonic acid ester of formula (ROOC) ₂ -C-NHCORV (wherein R is lower alkyl and R '' is hydrogen, lower). The anion is formed by deprotonating the acylaminomalonic acid ester with a sufficiently strong base (e.g., an alkali metal or alkaline earth metal alcoholate, anhydride, or an amide) The compound of formula (IX) and the acylaminomalonic acid moiety reaction of the anion in a solvent medium (e.g., a hydrocarbon such as benzene, toluene, hexane; an ether such as dioxane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethylsulfoxide, etc.) at or below room temperature (0-150 ° C) preferably at 0-100 ° C, m.p. particularly preferably at room temperature).

(X) -7 (XI)

Compounds of formula (XI) and their isomers may be prepared from compounds of formula (X) by decarboxylation with alkali metal alcoholate in a solvent medium (e.g., ethers, alcohols, dimethylsulfoxide, dimethylformamide, etc.). The reaction may be carried out at a temperature above or below room temperature, but preferably at room temperature. Compounds of formula (X) and (XI) can be converted, without isolation, to compounds of formula (XII) after in situ formation.

Steps (VII) to (XIII)

Compounds of formula (XIII) is prepared by ¹⁰ reacting a compound (VII) is reacted with an aldehyde of formula RjCHO (R is as defined in formula (Γ) wherein). Groups preferably are in protected form, ^HCO-15 present during the reaction. The protecting group may be removed after the reaction, i.e. the formation of the compounds of formula (XIII). The reaction solvents are hydrocarbons (eg. Benzene), alcohols, ethers, chlorinated hydrocarbons, amide ²⁰ dimethylformamide, dimethyl sulfoxide, etc. It can be used. The reaction may optionally be carried out in a dehydrating agent (eg. Molecular sieves) at a room temperatures lower or higher temperature (preferably at room temperature and the reaction temperature increases ^{to 25} to the boiling point).

(XIII) -> (XII ') step [Method B)] ³⁰ (XII "compounds of formula) can be prepared from compounds of formula (XIII) with an oxidizing agent (e.g. manganese dioxide, air, oxygen, etc.) performed in situ by oxidation...

The resulting compounds of formula ³⁵ (XII "), wherein R ₄ is amino, as mentioned above, can be converted to the corresponding compounds of R _4, which are nitro or cyano by the Sandmeyer reaction.

The compounds of formula (XH ') containing ⁴⁰ cyano or nitro groups wherein R ₄ is cyano may also be prepared via the corresponding compounds of formula VII. The latter compounds can be prepared by reacting the corresponding compound of formula IX with an anion of a protected aminomalonic acid ester (ROOC) 2 ° C-NH 2 of ⁴⁵ N (where R is lower alkyl and Z is benzylcyclcarbonyl). group), and the resulting R] 'is benzyloxy and R4 (X) CN or a compound of formula nitro containing ⁵⁰ (X) and - * (XI) in the conversion of methods into the corresponding (XI) with a compound of formula and the resulting product is treated with hydrogen bromide in glacial acetic acid. The product obtained is a compound of formula (VII) wherein R ₄ is nitro _or cyano. The intermediates of formulas X and XI do not need to be isolated. The obtained (VII) is a compound of formula (VII) - "is converted into the desired pathway ⁶⁰ (+ XII (XII)," a compound of formula) -> (XIII) and (XIII).

Steps XII - + XVIII [Procedure a]

Compounds of formula (XVIII) can be prepared from compounds of formula (XII) 65 by hydrolysis7

-7181885 they're coming out. The hydrolysis is preferably carried out with alkali metal hydroxides (e.g., sodium or potassium hydroxide). The hydrolysis is preferably carried out in an inert solvent. The reaction media may be alcohols (e.g. methanol, ethanol), ethers (e.g. dioxane, tetrahydrofuran) dimethylformamide or mixtures thereof with water. The reaction is preferably carried out at room temperature to the reflux temperature of the reaction mixture.

In this reaction step, the haloalkyl group present can be converted to the corresponding hydroxyalkyl group which can be converted to the haloalkyl group in the usual manner at later stages of the process.

(XII) - * (XIV), Procedure (b)]

The compounds of formula (XIV) may be prepared from the compounds of formula (XII) by reduction, preferably with lithium aluminum hydride or other equivalent reducing agent. The reduction is preferably carried out in an inert solvent. Suitable solvents are hydrocarbons (e.g. hexane, toluene) ethers (e.g. diethyl ether, tetrahydrofuran, 2-dimethoxyethane) or mixtures thereof. The reduction is carried at a temperature between -50 ^o C and the reflux temperature, preferably - be carried out at 20 ° C and 0 ° C.

The nitro and cyano groups present may be transformed in the present reduction step and therefore need to be formed at later stages of the synthesis.

<ξ- (XIV) - * (XIX) [Procedure ba]

Compounds of formula (XIV) wherein R '' is an amino (lower) alkyl monosubstituted with a-hydroxy (lower) alkyl, a-amino (lower) alkyl or lower alkyl; acylation with acid anhydrides or acid chlorides other than formyl and formyl, optionally in the presence of an acid acceptor, to form compounds of formula XIX wherein R1 is hydrogen, lower alkyl, phenyl, a-halo-lower alkyl, di- (lower) alkylamino (lower) alkyl, pyridyl or phenyl (lower) alkyl. The acylation is preferably carried out in an inert solvent (e.g. a hydrocarbon such as hexane, toluene; a chlorinated hydrocarbon such as methylene chloride; an ether such as tetrahydrofuran; or dimethylformamide). The acylation is preferably carried out at about -50 ° C to 150 ° C. The reaction may be carried out in the presence of an acid scavenger (e.g., pyridine, triethylamine, potassium carbonate).

<· Steps (XIV) to * (XV) [process]

Compounds of formula XV are compounds of formula XIV wherein R '' is hydrogen, lower alkyl, a-halo-lower alkyl, a-amino-lower alkyl, such as lower alkyl substituted amino, lower alkyl, pyridyl or phenyl lower alkyl, may be prepared with known oxidizing agents such as chromium trioxide or manganese dioxide. The oxidation is preferably carried out in an inert solvent. Suitable solvents include hydrocarbons (e.g. hexane, toluene), chlorinated hydrocarbons (e.g. methylene chloride), ketones (e.g. acetone), organic acids (e.g. acetic acid), pyridine, dimethylformamide, dimethylsulfoxide and the like. It can be used. Preferably, the oxidation is effected for approx. The reaction may be carried out at a temperature of from -50 ° C to the reflux temperature of the reaction mixture, particularly from 0 ° C to room temperature.

Steps XIV to * XX (Procedure bb)

(XX) compounds of formula I are prepared by reacting the formula (XIV), a compound of formula - hydroxy at the 3-position substituent of ²⁵ - where R '' a-hydroxy (lower) alkyl and other than formyl group group is replaced with halogen. The reaction is preferably carried out with a phosphorus halide (e.g., phosphorus trichloride, phosphorus tribromide) or thionyl chloride. The reaction can ³⁰ Juk preferably performed in an inert solvent, but can also be carried out without solvent.

Suitable solvents are hydrocarbons (e.g. hexane, toluene), chlorinated hydrocarbons (e.g. methylene chloride), ethers (e.g. tetrahydrofuran). The reaction is generally carried out at a temperature between -50 ° C and 100 ° C, preferably about ³⁵ ° C. It can be carried out at a temperature between 0 ° C and room temperature.

⁴⁰ 43 (XX) ->(XVI); (XXI), (XVII) [Step bb)

Compounds of formula (XX) wherein R 1 is hydrogen, lower alkyl, phenyl, ⁴⁵ alpha-amino (lower) alkyl, lower alkyl substituted with a- or β-amino (lower) ) alkyl, pyridyl or phenylll- (lower) alkyl represents a group - halogen substituent in the 3-position by nucleophilic reaction, ⁵⁰ may replace other nucleophilic groups. Nucleophilic agents include amines ((XVI), R 'and R' are hydrogen or lower alkyl); alcoholates [(XXI)] or cyanides [(XVII)] may be used.

⁵⁵ (XX) - * (XVI) is the conversion of (XX) the compound of formula is treated with ammonia or mono- or dialkilaminokkal. The reaction may be carried out in the presence or absence of an inert solvent. Hydrocarbons (e. Hexane, toluene), ethers employed as a solvent ⁶⁰ (eg. Diethyl ether, tetrahydrofuran), dimethylformamide, dimethyl sulfoxide, etc.). The reaction is preferably carried out for about 1 hour. The reaction may be carried out at a temperature of from about 0 ° C to the reflux temperature of the reaction mixture at a pressure of ₆₅ or more.

-8181885

The conversion (XX) * (XXI) can be carried out by reacting a compound of formula (XX) with an alkali metal alcoholate, preferably in an inert solvent. Suitable solvents are hydrocarbons (e.g. hexane, toluene), ethers (e.g. tetrahydrofuran), dimethylformamide, dimethylsulfoxide, or alcohols corresponding to the alcoholates used. Alternatively, the compound of Formula XX may be treated with alkanol in the presence of an organic base such as pyridine or triethylamine. The reaction is usually carried out for about 10 minutes. At a temperature between -50 ° C and the reflux temperature of the reaction mixture, preferably at room temperature to about 50 ° C. At a temperature of 100 ° C, it can be carried out at atmospheric pressure or higher. 15

Conversion (XX) to (XVII) may be carried out by reaction of a compound of formula (XX) with an alkali metal cyanide, preferably in an inert solvent, such as hydrocarbons (e.g. hexane, toluene), ethers (e.g. tetrahydrofuran), dimethylformamide or dimethylsulfoxide. The reaction is preferably carried out at a temperature between room temperature and the reflux temperature of the reaction mixture, particularly preferably at a temperature in the range of about 10 ° C to about 50 ° C. 20-160 ° C.

Steps (XV) -> (XXII *) [After Step Procedure]

Compounds of formula (XXII ') are an aldehyde of formula (XV) wherein R _{4 is} hydrogen or halogen, lower alkyl or nitro, and an organic metal reagent (e.g., Grignard compound or alkyl lithium). compound). The reaction is preferably carried out in an inert solvent. Solvents include hydrocarbons (e.g., hexane, toluene); chlorinated hydrocarbons (e.g. methylene chloride), ethers (e.g. diethyl ether, tetrahydrofuran, dimethoxyethane) may be used. The reaction is preferably carried out for about 1 hour. -100 ° C to 50 ° C, especially approx. It can be carried out at temperatures between -20 ° C and room temperature.

* Steps (XII) or (XVIII) - + (XXVII) [Methods (c) and (aa)]

Compounds of formula (XXVII) are compounds of formula (XII) wherein R 1 'is other than α-halo or α-hydroxy (lower) alkyl and -CHO with a compound of formula H ₂ NR ₁₂ direct ammonolysis or a compound of formula (XVIII) with - where R '' is as defined above, but a formyl group may be - a acyl chloride (for example by means of phosphorus pentachloride.), and then the acid chloride or a HNRi ₂ R _I3 amino compound obtained reaction. In the formulas, R ₁₂ and R ₃ are as defined for formula (Γ).

Steps (XII) to (XXVII) may be carried out with or without an inert solvent. Solvents include hydrocarbons (e.g. hexane, toluene), ethers (e.g. tetrahydrofuran), alcohols (e.g. methanol, ethanol), dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide and the like. It can be used. The reaction was allowed to proceed for approx. 50-200 ° C, preferably ca. It can be carried out at 100-150 ° C at atmospheric pressure or at a higher pressure.

The conversion of (XVIII) to * (XXVII) is preferably carried out in an inert solvent. Suitable solvents are hydrocarbons (e.g. hexane, toluene), ethers (e.g. tetrahydrofuran), chlorinated hydrocarbons (e.g. methylene chloride, chlorobenzene). The reaction is preferably carried out at a temperature of from -20 ° C to the reflux temperature of the reaction mixture, more preferably from ca. It can be carried out at 0-50 ° C.

· Steps * - (XXVII) - * (XXVIII) [Step aa after Procedure]

The compounds of formula (XXVIII) may be prepared by dehydrating a compound of ₁₃ is hydrogen (XXVII), R ₁₂ and R of formula. The reaction may be carried out with suitable dehydrating agents (e.g., phosphorus pentoxide, phosphorus oxychloride) in an inert solvent. Solvents include pyridine, hydrocarbons (e.g. hexane, toluene), chlorinated hydrocarbons (e.g. methylene chloride). The reaction is preferably carried out at room temperature to the reflux temperature of the reaction mixture, particularly preferably at a temperature in the range of ca. It can be carried out at 50-120 ° C.

> Steps (XII) or (XVIII) - * (XXIX) [Methods (d) and (b)]

Compounds of formula (XXIX) may be prepared by direct Hdrazinolysis of compounds of formula (XII) wherein RJ 'is other than o-halo or a-hydroxy (lower) alkyl and formyl, or a compound of formula (XVIII). The compounds may be prepared first by conversion to the acid chloride (e.g., phosphorus pentachloride) followed by hydrazine treatment. In the compounds of formula (XXIX), R 17 and R ₁₈ are as defined for formula (I '). The reaction conditions described for the conversion of (XVIII) to * (XXVII) may also be used in steps (XVIII) to (XXIX).

Steps (XII) - * (ΧΧΊΧ) are preferably carried out with or without an inert solvent. Suitable solvents are hydrocarbons (e.g. hexane, toluene), ethers (e.g. tetrahydrofuran), alcohols (e.g. methanol, ethanol). The reaction is preferably carried out for about 1 hour. It can be carried out at 50-150 ° C, particularly preferably at 80-100 ° C.

<Steps 5- (XVIII) -> (XXX) [First Step of Procedure (c)]

Compounds of formula (XXX) are prepared by decarboxylation of compounds of formula (XVIII), optionally in the presence of a catalyst and optionally in a solvent. The reaction is usually carried out under heating, e.g. At a temperature of 100 ° C to 350 ° C, it is particularly preferred to have a temperature of about 100 ° C to about 350 ° C. 150-230 ° C 9181885

can be done. Suitable solvents are hydrocarbons (e.g. mineral oil), halogenated hydrocarbons, ethers, alcohols (e.g. ethylene glycol), dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide. As a catalyst, e.g. 5 metals such as. copper powder or metal salts (e.g. Cu ⁺ or Ag ⁺ salts) may be used.

(XVIII) - * (XXV) [Procedure d]

Compounds of formula (XXV) are prepared by a modified Curtius reaction by reacting a compound of formula (XVIII) wherein R 'is hydrogen, lower alkyl, phenyl, pyridyl, phenyl (lower) alkyl or 15 CHO groups with a phosphorylase azide [e.g. By reaction with N ₃ PO (OC ₆ H ₅ ) ₂ ] to give the azide (XXIV) which is then heated with the alcohol involved in the reaction. Generation of the azide can generally be carried out in an inert solvent. As reaction medium, e.g. hydrocarbons (e.g. hexane, toluene), ethers (e.g. tetrahydrofuran) may be used. The reaction is preferably carried out for about 1 hour. It can be carried out at 0-100 ° C, preferably at room temperature, if desired under a pressure higher than atmospheric. 25

The azides of formula (XXIV) are preferably converted by reaction with the appropriate alcohol to the carbamic acid esters of formula (XXV) (wherein R ₉ is lower alkyl or phenylalkyl). The alcohol used as the reactant preferably also acts as the reaction medium. However, the reaction may also be carried out in the presence of other inert solvents (e.g. hydrocarbons such as hexane, toluene; chlorinated hydrocarbons such as methylene chloride; ethers such as tetrahydrofuran, pyridine, triethylamine). The reaction is preferably carried out for about 1 hour. At a temperature of 50-200 ° C, it is particularly preferred to have a temperature of about 50 ° C. 80-160 ° C.

Steps (XXV) - * (XXVI) [Procedure d] ₄₀

Compounds of formula (XXVI) may be prepared by hydrogenating a compound of formula (XXV) wherein R ₍ 9 is benzyl) and R ₄ is, for example, halogen in the presence of palladium, and the resulting free amine is acylated with an acid halide or anhydride. The free amine is preferably prepared in an inert solvent such as hydrocarbons (e.g. hexane, toluene), ethers (e.g. ₅₀ tetrahydrofuran), alcohols (e.g. methanol, ethanol), organic acids (e.g. acetic acid), acid anhydrides (e.g. . acetic anhydride) can be used, in which case, the acylation in situ proceeds temperatures the reaction is preferably from room temperature to about 100 ° C for ₅₅ thereto, if desired, can be carried out under superatmospheric pressure acylation of (XIV) -...> (xix) reaction conditions described herein.

* Steps (XII) through * (XXXIII) [Procedure e]

Compounds of formula (ΧΧΧΙΠ) may be prepared from alkylation of compounds of formula (XII) wherein R 'is other than α-halo, α-hydroxy, α-alkanoyloxy (lower) alkyl in the presence of a strong base (e.g. with methyl iodide in the presence of potassium tert-butylate). The reaction is preferably carried out in an inert solvent such as a hydrocarbon such as hexane, toluene, an ether such as tetrahydrofuran, dimethylformamide or dimethylsulfoxide. The reaction was allowed to proceed for approx. At temperatures between -50 ° C and room temperature, particularly preferably at about 50 ° C to about 50 ° C. It can be carried out at temperatures between -30 ° C and -10 ° C.

Substituents containing the active hydrogen must obviously be formed after the above alkylation in order to avoid unwanted alkylation.

Steps (XXII) to * (XXXIV) [post process step]

Compounds of formula (XXXIV) are prepared by oxidation of compounds of formula (XXII) wherein R ₁₀ is lower alkyl. The reaction is carried out as described for the conversion (XIV) to * (XV).

<(XXXIV) - * (XXXI) [following procedure]

Compounds of formula XXXI, wherein R 10 is hydrogen, compounds of formula XXXIV (i.e., a portion of compounds of formula XV), wherein R ^{1 is} α-halo, α-hydroxy, α-alkanoyloxy, other than a lower alkyl or formyl group and a reaction of a hydrazine of the formula NH ₂ R ₂₀ wherein R ₂₀ is a dialkylamino group. The reaction is preferably carried out 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), organic acids (e.g. acetic acid) or pyridine. The reaction is preferably carried out at room temperature to the reflux temperature of the reaction mixture.

Steps 4- (XXXIV) - * (XXXV) [post-procedure step)

Compounds of formula XXXV wherein R ₂ ] is hydroxy or lower alkoxy and R ₁₀ is hydrogen are compounds of formula XXXIV (i.e., a portion of compounds of formula XV) wherein R ¹ is prepared by the reaction of the above with hydroxylamine or lower alkoxyamine. The reaction is preferably carried out 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), organic acids (e.g. acetic acid) or pyridine. Preferably, the reaction is carried out at room temperature and for about 1 hour. It can be carried out at a temperature of 150 ° C at atmospheric pressure or higher than 65.

-10181885 € (XXXV) - * (XXXVI) [post process step)

Compounds of formula XXXVI, wherein R 10 is hydrogen, are prepared by reduction of compounds of formula XXXV. The reduction is e.g. This may be accomplished by hydrogenation in the presence of Raney nickel. The reduction is preferably carried out in an inert solvent. Reaction media include hydrocarbons (e.g. hexane, toluene), ethers (e.g. tetrahydrofuran), alcohols (e.g. methanol, ethanol), dimethylformamide. The reaction is preferably carried out for about 1 hour. The reaction may be carried out at 0-100 ° C, preferably at room temperature, at atmospheric pressure or at a higher pressure.

<(XXXVII) -> (XL) [step two of process (c))

Compounds of formula (XL) wherein X is chlorine, bromine or iodine are compounds of formula (XXXVII) wherein R * ¹ is amino-lower substituted by lower alkyl, phenyl, lower alkyl. C 1-6 alkyl, pyridyl, phenyl (lower) alkyl or CHO, and a suitable halogenating agent (e.g., bromine, N-bromosuccinimide, N-chlorosuccinimide, etc.). The reaction is preferably carried out in an inert solvent. Suitable solvents are hydrocarbons (e.g. hexane, toluene), chlorinated hydrocarbons (e.g. methylene chloride), organic acids (e.g. acetic acid), inorganic acids (e.g. sulfuric acid). The reaction was allowed to proceed for approx. It can be carried out at a temperature between 0 ° C and the boiling point of the reaction mixture, depending on the reactants.

Steps (XXXVII) - (XXXVIII) (XLI)

Compounds of formula XXXVIII

- where Rf ^{11 is} lower alkyl, R 1 is phenyl, mono- or dihydro-phenyl and (z 1 - (a) or (b) - the corresponding compounds of formula (XXXVII) and peracids, e.g. Metaldorperbenzoic acid or peracetic acid) The compound of formula (XLI) is prepared by post-treatment with anhydride A is -C (R e) = N- or -C (R e) = N + O.

The conversion (XXXVII) to (XXXVIII) is preferably carried out in an inert solvent. Suitable reaction media are hydrocarbons (e.g. hexane), chlorinated hydrocarbons (e.g. methylene chloride), organic acids (e.g. acetic acid). The reaction is preferably carried out for about 1 hour. It can be carried out at 0-50 ° C.

The reaction of the compound of formula (XXXVIII) with an acid anhydride (e.g., acetic anhydride) for the compound of formula (XLI) is preferably carried out in an inert solvent. Reaction media include hydrocarbons (e.g. hexane, toluene), chlorinated hydrocarbons (e.g. methylene chloride), ethers (e.g. tetrahydrofuran), dimethylformamide, dimethylsulfoxide and the like. They can be used. The acid anhydride used as a reactant can also act as a solvent. Preferably, the reaction is carried out at room temperature and for about 1 hour. At a temperature of about 150 ° C, preferably about 150 ° C. It can be carried out at 80-100 ° C.

<(XLI) + (XLII) [Procedure E]

Compounds of formula (XLII), wherein A is as defined in the introduction to formula (I '), may be prepared by reaction of the corresponding compound of formula (XLI) with an alkali metal alcoholate or hydroxide. The reaction is preferably carried out in an inert solvent. Suitable reaction media are hydrocarbons (e.g. hexane, toluene), chlorinated hydrocarbons (e.g. methylene chloride), ethers (e.g. tetrahydrofuran), alcohols (e.g. methanol, ethanol), dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, pyridine, amines. The reaction is preferably carried out for about 1 hour. The reaction may be carried out at a temperature of from about 0 ° C to the reflux temperature of the reaction mixture, depending on the reactant used.

Steps (XLII) -> (XXXIX) [Follow Step E]

Compounds of formula XXXIX

- where A is represented by the oxidation methods described in steps (XIV) to (XV) in the introduction to formula (I ').

(Step IX V (XLV) [Procedure D)]

Compounds of formula (XLV) are prepared by reacting a compound of formula (IX ') with a compound of formula (XLVI)

- where R ₂ 3 is phenyl or pyridyl and R ₂₄ is lower alkoxy or di- (lower) alkylamino - and a strong base (e.g. butyllithium, potassium tert-butylate, etc.) reaction with a nitrone anion formed. The conversion (IX ') (XLV) can be carried out in situ without isolation of the resulting intermediates of formula (XLIII) and (XLIV). Inert solvents, e.g. hydrocarbons (e.g. hexane, toluene, etc.), ethers (e.g. tetrahydrofuran), dimethylformamide or dimethylsulfoxide. The reaction was allowed to proceed for approx. The reaction may be carried out at a temperature of from -100 ° C to room temperature, preferably from -80 ° C to 25 ° C. Advantageously, it is possible to first proceed with an approx. After working at -70 ° C, the reaction mixture was warmed to room temperature to induce cyclization in situ.

Compounds of formula (I) may be prepared by converting the corresponding compounds of formula (I ') into N-oxides. The reaction may be carried out by oxidation of the compound of formula (Γ) with inorganic peracid. As inorganic peracids, e.g. peracetic acid, perpropionic acid, m-chloroperbenzoic acid, etc. It can be used. Oxy11

-11181885 may be performed at room temperature or higher or lower.

The compounds of formula (Γ ") is prepared such that (I ') a compound of formula as defined in the introduction is reduced to ⁵ - wherein R _1; R ₂ , R ₃ , R ₆ and are as defined above.

The reduction of compounds of formula (Γ) to the corresponding compounds of formula (Γ) can be carried out with any suitable reducing agent. The reduction is preferably carried out by hydrogenation in the presence of platinum oxide catalyst or by a zinc acetic acid system. If Jrr represents a nitro group, reduction is preferably carried out with an alkali metal borohydride (e.g. sodium borohydride). ¹⁵

Temperature and pressure are not critical to the conversion of the compounds of formula (I ') to the corresponding compounds of formula (I' '). The reaction is preferably carried out at room temperature and atmospheric pressure.

The compounds of formula (I), (I ') and (I' ') and their pharmaceutically acceptable acid addition salts have a muscle relaxant, sedative and' anticonvulsant activity and are particularly preferred in the form of intravenous or intramuscular formulations, the solubility of the acid addition salts in aqueous solutions. through.

The pharmacological activity of some representatives of the compounds of formula (Γ) is determined by standard methods. The following test compounds are used:

8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide (Compound A);

8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid 2,2-dimethylhydrazide (Compound B) ;

8-Chloro-N, N-diethyl-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide (Compound C) ;

8-chloro-3-hydroxymethyl-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine (Compound D);

8-chloro-6- (2-fluorophenyl) -3-hydroxymethyl-

-1-methyl-4H-imidazo [1,5-a] - [1,4] benzodiazepine (Compound E).

The results of the inclined surface test, the foot shock test and the non-anesthetized cat test are summarized in the following table:

Test compound Slope Test pd ₅₀ Foot shock test 100% blocking effect Non-Anesthetized Cat Test MED THE 3 mg / kg p.o. 0.5 mg / kg p.o. B 5 mg / kg p.o. 0.5 mg / kg p.o. 0.5 mg / kg p.o. C 24.5 mg / kg p.o- 1 mg / kg p.o- 2.5 mg / kg p.o. D 20 mg / kg p.o. 5 mg / kg p.o. E 150 mg / kg p.o. 1 mg / kg p.o. 0.25 mg / kg p.o.

The novel compounds of the present invention and their acid addition salts may preferably be formulated in pharmaceutical compositions containing from about 0.1 mg to about 40 mg, most preferably from about 1 mg to about 40 mg, of the active ingredient, depending on the particular ingredient and the _4J requirements. The novel compounds of the formulas (I), (I ') and (Γ) and their pharmaceutically acceptable salts can be used, e.g. form containing administered internally (such as parenterally or enterally), ingredients conventional carriers, known per se in the therapeutic agent ₅₀ formulation lázhatjuk manufacture. The compositions may contain solid or liquid carriers (eg. Water, gelatin, starch, magnesium stearate, talc, vegetable oils, etc.) And coated tablets, elixirs, capsules, ₅₅ solutions, emulsions and the like. can be formulated.

Reference is made herein to several publications and U.S. Patents. These references are cited to complete the description.

Further details of the process are set forth in the Examples, without limiting the invention to the Examples. ₆₅

Example 1

A solution of 200 g (0.695 mol) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one in 2 liters of tetrahydrofuran and 250 ml of benzene was cooled in an ice bath. saturated with methylamine. A solution of 190 g (1 mol) of titanium tetrachloride and 250 ml of benzene is then added via a dropping funnel over 15 minutes, and the reaction mixture is refluxed for 3 hours with stirring. The cooled reaction mixture was slowly poured into 600 mL of water. The inorganic material was filtered off and washed thoroughly with tetrahydrofuran. The aqueous layer was separated and the organic layer was dried over sodium sulfate and evaporated. Crystalline 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine, m.p. 204-206 ° C. Yield: 205 g (98%). After recrystallization from methylene chloride-ethanol, an analytical sample of the product melts at 204-206 ° C.

A) To a solution of 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine (30.15 g, 0.1 mol) in glacial acetic acid (150 mL) in 3 portions 8.63 g (0.125 mole) of sodium nitrite was added. The reaction mixture was stirred at room temperature for 1 hour and then diluted with water

-12181885 and extracted with methylene chloride. The extracts were washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated, and then azeotroped with toluene. 29 g crude

7-Chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H- ⁵ -1,4-benzodiazepine was obtained as a yellow oil.

B) 27.6 g (0.4 mol) of sodium nitrite over 30 minutes in 90.45 g (0.3 mol) of 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4 of benzodiazepine and 400 ml of glacial acetic acid. After completion of the addition, the mixture was stirred at room temperature for 1 hour, then diluted with 1 liter of water and extracted with methylene chloride. The extracts were washed twice with water and then with 10% aqueous sodium carbonate. The solution was dried and evaporated. ¹³ Crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1,4-benzodiazepine is obtained as a yellow oil. Yield: 96 g

The product obtained is dissolved in 300 ml of dimethylformamide and added to a mixture of 150 ml of dimethyl malonate, 40.4 g of potassium tertiary butylate and 500 ml of dimethylformamide at room temperature under stirring for 10 minutes. The reaction mixture was stirred at room temperature under nitrogen overnight, then acidified with 50 ml of glacial acetic acid, diluted with water and saturated aqueous sodium carbonate, dried over sodium sulfate and evaporated. The residue was crystallized from ethanol. In the form of colorless crystals

7-Chloro-1,3-dihydro-2- (bis-carbethoxymethylidene) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine is obtained. Mp 170-172 ° C. Yield: 53.5 g. An analytical purity sample of the product melted at the same temperature after recrystallization from methylene chloride-ethanol.

20 g (0.05 mol) of 7-chloro-1,3-dihydro-2- (bis-cabetbetoxymethylidene) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine, 400 ml methanol and 3.3 g (0.0509 mol) of potassium hydroxide are heated at reflux for 5 hours under nitrogen. Most of the solvent was distilled off, the residue was diluted with water in portions, and the precipitated crystals were collected, washed with water and dried. The resulting 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (methoxycarbonylmethylene) -2H-1,4-benzodiazepine, m.p. 158-160 ° C. An analytical sample of the product, m.p. 161-162 ° C after recrystallization from methylene chloride-hexane, is obtained.

to a mixture of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (methoxycarbonylmethylene) -2H-1,4-benzodiazepine (0.08 mol) in glacial acetic acid (250 ml) 8.8 g (0.125 mole) of sodium nitrite was added. The reaction mixture is stirred at room temperature for 10 minutes and then diluted with 250 ml of water. The crystalline product is filtered off, washed with water, methanol and ether and dried. 7-Chloro-5- (2-fluorophenyl) -hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester is obtained as yellow crystals. 238-241 ° C (dec.).

Methyl 7-chloro-5- (2-fluorophenyl) -α-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid (11.25 g, 0.03 mol) in tetrahydrofuran (750 mL) and methanol (500 mL) hydrogenation in the presence of nickel at atmospheric pressure. The nickel was filtered off and the filtrate was evaporated. The residue was dissolved in methanol (100 ml) and then triethyl ester of orthoacetic acid (11 ml) and 5% hydrochloric acid in ethanol (5 ml) were added. The reaction mixture is heated at reflux for 10 minutes, concentrated and the residue is partitioned between methylene chloride and aqueous sodium bicarbonate solution. The methylene chloride solution was dried and evaporated. The residue was chromatographed on 300 g of silica gel eluting with methylene chloride / ethyl acetate (1: 3). The pure fractions were combined and evaporated and the residue was crystallized from ether. The resulting 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester melted at 162-164 ° C. . An analytical sample of the product is obtained after recrystallization from ethyl acetate-hexane. Yield: 4.5 g (39%).

Example 2

11.25 g (0.03 mol) of methyl 7-chloro-5- (2-fluorophenyl) -α-hydroimino-3H-1,4-benzodiazepine-2-acetic acid in 750 ml of tetrahydrofuran and 500 ml of methanol are heated. while dissolving. The mixture was hydrogenated in the presence of 20 g of Raney nickel at atmospheric pressure for 4 hours. The catalyst is filtered off and the filtrate is evaporated to an azeotropic toluene. The residue was dissolved in methanol (100 ml), then triethyl ortho-formic acid (10 ml) and 5% hydrochloric acid in ethanol (5 ml) were added and refluxed for 10 minutes. The reaction mixture was evaporated and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The methylene chloride layer was separated, dried and evaporated, and the residue was crystallized from ether. The resulting 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5] [1,4] benzodiazepine-3-carboxylic acid methyl ester is crystallized from methylene chloride-ether-hexane. Mp 179-181 ° C. Yield: 4.6 g (41%).

Example 3

8.0 g (0.02 mol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid ethyl ester A mixture of potassium hydroxide (2.24 g, 0.04 mol), methanol (200 ml) and water (6 ml) was heated at reflux for 3.5 hours. A portion of the solvent was distilled off, the residue acidified with glacial acetic acid and diluted with water while hot. After cooling to ice water, the excellent precipitate is filtered off. Analytical purity of the resulting 8-k] h-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methylene chloride methanol ethyl acetate after recrystallization from a mixture, m.p. 271-274 ° C (dec.). Yield: 6.5 g (88%).

Example 4

1.85 g (5 mmol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and 25 ml of 2 The propanol slurry was heated on a steam bath and treated with 2.2 ml of 5N potassium hydroxide solution. After complete dissolution, the potassium salt is crystallized by cooling with ice-water, the crystals are filtered off, washed with 2-propanol and ether and dried in a gentle vacuum (90v). 8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid potassium salt hydrate is obtained in the form of colorless crystals. Mp 245-255 ° C. Yield: 1.5 g.

-13181885

Example 5> 48 g (0.004 mol) of methyl 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] · [1,4] benzodiazepine-3-carboxylic acid, 0.5 A mixture of potassium hydroxide (g, 0.009 mol), methanol (50 ml) and water (2 ml) was heated at reflux for 3 hours under nitrogen. A portion of the methanol was distilled off and the residue was acidified with glacial acetic acid and the still hot solution was diluted with water. The precipitated crystals are filtered off. The mixture was cooled with ice water, the precipitated crystals were filtered off and dried in vacuo. The resulting 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid m.p. 245-247 ° C (dec). Yield: 1.2 g (84%).

Example 6

7.7 g (0.02 mol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid m.p. of ethyl acetate and 100 ml of tetrahydrofuran was added dropwise at 0-5 ° C to a suspension of 2 g (0.05 mol) of lithium aluminum hydride in 100 ml of ether. After the addition was complete, the mixture was stirred for 15 minutes without cooling and then hydrolysed by addition of 15 ml of water. The inorganic material was filtered off and washed with methylene chloride. The filtrate was dried and evaporated. The residue was crystallized from methylene chloride-ether-hexane. An analytical purity sample of the resulting 8-chloro-6- (2-fluorophenyl) -3-hydroxymethyl-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine was recrystallized from ethyl acetate-methanol. m.p. 233-235 ° C. Yield: 6.8 g (95%).

Example 7 8-Chloro-6- (2-fluorophenyl) -3-hydroxymethyl-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, 200ml methylene chloride and 20g activated manganese dioxide the mixture was stirred at room temperature for 1 hour. The manganese dioxide was filtered off and washed thoroughly with methylene chloride. The filtrate was distilled off and the residue was crystallized from methylene chloride-ether-hexane. The resulting 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine was recrystallized from a mixture of methylene chloride-ethyl acetate-hexane. ° C. Yield: 2.5 g (62%).

Example 8

0.71 g (2 mmol) of 8-chloro-6- (2-fluorophenyl) -3-hydroxymethyl-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine and 20 ml of pyridine of the reaction solution was mixed with 2 ml of acetic anhydride. After allowing the reaction mixture to stand at room temperature overnight, the solvent was distilled off in vacuo and the residue was partitioned between methylene chloride and sodium bicarbonate solution. The organic phase is dried and evaporated. The residue does not crystallize. The non-crystallizing residue was chromatographed on 30 g of silica gel and eluted with 1: 3 methylene chloride / ethyl acetate. The homogeneous fractions were combined and evaporated. The obtained 0.5 g of 3-acetoxymethyl-8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine is not crystallized and is characterized spectroscopically. .

NMR (CDCl ₃ ): 2.08 (s, 3H, -COCH ₃ ); 2.58 (s, 3H, --CH ₃ ); 4.0 and 5.3 (AB system, J = 13Hz, _C4 -H); 4.96 and 5.26 (AB system, J = 13Hz, -CH3-O) ppm.

MS: m / e 397 (M &lt; ⁺ &gt;).

Example 9 Potassium tert-butylate (0.232 mol) was added to a mixture of dimethylformamide (300 ml) and dimethyl malonate (50 ml, 0.44 mol). The mixture was stirred under nitrogen for 10 minutes then 66 g (0.209 mol)

A solution of 7-chloro-2- (N-nitrosomethylamino) -5-phenyl-3H-1,4-benzodiazepine-4-oxide and 100 ml of dimethylformamide was added over 10 minutes. The reaction mixture was slowly heated on a steam bath and heated at 65 ° C for 10 minutes.

After cooling to room temperature, glacial acetic acid (40 mL) and water (1 L) were added over 30 minutes with occasional scraping. The precipitated crystals are collected, washed with water and dissolved in methylene chloride. The solution was dried over sodium sulfate and concentrated in vacuo. The product was crystallized by adding hexane. The received

7-Chloro-1,3-dihydro-2- (bis-carbomethoxymethylidene) -5-phenyl-2H-1,4-benzodiazepine-4-oxide m.p. 188-190 ° C. Yield: 66.4 g (81%). After recrystallization from methylene chloride-hexane, an analytical sample of the product melts at 194-195 ° C.

A) 40.8 g (0.1 mol) of 7-chloro-1,3-dihydro-2- (bis

(Carbomethoxymethylidene) -5-phenyl-2H-1,4-benzodiazepine-4-oxide, 250 ml of methanol, 250 ml of tetrahydrofuran and 1 teaspoon of Raney nickel are hydrogenated at atmospheric pressure for 5 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from a mixture of methylene chloride and 2-propanol. The resulting 7-1H-1,3-dihydro-2- (bis-carbomethoxymethylidene) -5-phenyl-2H-1,4-benzodiazepine forms colorless crystals, m.p. 160-163 ° C. An analytical sample of the product, m.p. 165-166 ° C after recrystallization from 2-propanol. In some cases, the product is obtained in the form of a second crystalline modification melting at 138-140 ° C.

B) To a solution of 4-g (0.01 mol) of 7-chloro-1,3-dihydro-2- (bis-carbomethoxymethylidene) -5-phenyl-2H-1,4-benzodiazepine-4-oxide and 10 ml methylene chloride in 4 ml of phosphorus trichloride We are added. The reaction mixture was allowed to stand at room temperature overnight and the solution was washed with 10% aqueous sodium carbonate. The methylene chloride layer was dried and evaporated. The residue was crystallized from 2-propanol and recrystallized from a mixture of methylene chloride and 2-propanol. 7-Chloro-1,3-dihydro-2- (bis-carbomethoxymethylidene) -5-phenyl-2H-1,4-benzodiazepine is obtained. M.p. 163-166 ° C.

115 g (0.3 mol) of 7-chloro-1,3-dihydro-2- (bis-carbomethoxymethylidene) -5-phenyl-2H-1,4-benzodiazepine, 1.5 L of methanol and A mixture of 4 g (0.36 mol) of sodium hydroxide was heated at reflux under nitrogen for 5 hours. The cooled reaction mixture was diluted with 2.5 L of water while cooling with ice. The precipitated crystals are filtered off, washed with water and dried in vacuo at 60 ° C. 7-Chloro-1,3-dihydro-2- (methoxycarbonylmethylene) -5-phenyl-2H-1,4-benzodiazepine, m.p. 167-170 ° C, as an off-white product. The product of analytical purity melted at 171-173 ° C after recrystallization from ether.

2.8 g (0.04 mol) of sodium nitrite 8 g (0.025 mol) 5

A solution of 7-chloro-1,3-dihydro-2- (methoxycarbonylmethylene) -5-phenyl-2H-1,4-benzodiazepine and 100 ml of glacial acetic acid was added. The reaction mixture was stirred under nitrogen for 10 minutes. The product begins to crystallize in a few minutes. The reaction mixture was diluted with water (100 mL), the precipitated product was filtered off, washed with water and recrystallized from tetrahydrofuran-methanol. Methyl 7-chloro-α-hydroxyimino-5-phenyl-3H-1,4-benzodiazepine-2-acetic acid as yellow crystals, m.p. 235-237 ° C (dec). 15

3.6 g (0.01 mol) of 7-chloro-α-hydroxyimino-5-phenyl-3H-1,4-benzodiazepine-2-acetic acid methyl ester are dissolved in 200 ml of tetrahydrofuran and 100 ml of methanol under heating. A teaspoon of 20 Raney nickel was added to the mixture and hydrogenated at atmospheric pressure until the uptake of hydrogen slows down (70 minutes). The catalyst is strained and the filtrate is distilled off - azeotroped with toluene at the end. The residue was dissolved in methanol (20 mL). Then 3 ml of orthoacetic triethyl ester (25 ml) and 0.3 ml of 5% hydrochloric acid in ethanol are added and the mixture is refluxed for 5 minutes. The mixture was evaporated and the residue partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic layer 30 was separated, dried and evaporated. The residue was crystallized from ether. The received

Recrystallization of 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester from methylene chloride-ether-hexane 254-35-256 ° They are C's. Yield: 2 g (54%).

Example 10

Methyl 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, 7.3 g (0.02 mol), 2.24 g ( Potassium hydroxide (0.04 mol) in methanol (200 ml) and water (6 ml) was heated at reflux for 4 hours. A portion of the methanol was distilled under vacuum under vacuum and the residue acidified with glacial acetic acid and the product precipitated by the addition of water. The precipitated crystals are collected, washed with water and dried. Off-white 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid 50 is obtained. Yield: 6.1 g (87%). An analytical sample of the product, m.p. 270-273 ° C (dec.) After recrystallization from ethyl acetate.

Example 11

A solution of 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester (0.73 g, 2 mmol) in tetrahydrofuran (50 mL) was treated with Add a solution of 60 g of lithium aluminum hydride (7.5 mmol) in tetrahydrofuran (20 ml) cooled to -10 ° C. After the addition was complete, the mixture was stirred for 30 minutes without cooling and then hydrolysed by the addition of 2 ml of water. The inorganic material was filtered off and the filtrate was dried and evaporated. Crystallization of the remaining methylene chloride from ether-hexane gave 8-chloro-3-hydroxymethyl-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine as colorless crystals. Mp 252-255 ° C. Yield: 0.5 g (74%).

Example 12

A suspension of 1.5 g of 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] - [1.4] benzodiazepine-3-carboxylic acid and 10 ml of mineral oil is heated to 230 ° C for 5 minutes. FEI. The reaction mixture was partitioned between 1N hydrochloric acid and ether. The aqueous phase was made basic with ammonia and extracted with methylene chloride. The extracts were dried and evaporated. The residue was chromatographed on silica gel (60 g) and eluted with ethyl acetate-methylene chloride (25% v / v methylene chloride). The less polar 8-chloro-6- (2-fluorophenyl) -6H-imidazo [1,5-a] [1,4] benzodiazepine is crystallized from ethyl acetate. Colorless crystals melting point 195-196 ° C. Yield: 350 mg (26.5%).

The more polar component is crystallized from ether. The resulting 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] - [1.4] benzodiazepine, m.p. 150-151 ° C. Yield: 0.8 g (61%).

Example 13 A mixture of 8-chloro-3-hydroxymethyl-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, 300 ml of methylene chloride and 15 g of activated manganese dioxide at room temperature for 1 hour. agitated. The manganese dioxide was born and washed with methylene chloride. The filtrate was evaporated and the residue was crystallized from methylene chloride-ether-hexane. The resulting 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxaldehyde m.p. 218-220 ° C. Yield: 2g (67%).

Example 14

0.74 g (2 mmol) of methyl 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 30 ml of methanolic ammonia in a closed apparatus at 120 ° C. The solvent was distilled off and the residue was recrystallized from methylene chloride / ethanol. 8-Chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide is obtained in the form of colorless crystals.

Mp: 335-340 ° C. Yield: 0.4 g (57%).

Example 15

A solution of 0.74 g of methyl 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 20 ml of ethanol containing 25% methylamine was closed. heat at 120 ° C for 18 hours. The solvent was distilled off and the residue was crystallized from methylene chloride-ethanol eff. The resulting 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3- (N-methyl) carboxamide was obtained at 260-263 ° C.

-15181885 wild (analytical purity of product obtained by recrystallization from tetrahydrofuran-ethanol). Yield: 0.6 g (81%).

Example 16

1.83 g (5 mmol) of methyl 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, 50 ml of methylene chloride and 10 ml of glacial acetic acid 10g of zinc powder are added to the solution. After stirring for 2 hours at room temperature, the inorganic material was strained and the filtrate washed with dilute aqueous ammonia. The methylene chloride solution was dried and evaporated. The residue was crystallized from methylene chloride-ethyl acetate-15-ether. 8-Chloro-5,6-dihydro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester is obtained in the form of colorless crystals. Yield: 1.6 g (87%). Analytical purity of product after recrystallization from ethyl acetate / methylene chloride / methanol = 234-236 ° C.

Example 17 25

7.7 g of methyl 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, 100 ml of isobutanol and The mixture is refluxed for 1 hour. After evaporation of the reaction mixture, the crude product is chromatographed on 250 g of silica gel and eluted with 5% ethanol in methylene chloride-ethanol. The pure fractions were combined and evaporated. The residue was crystallized from methylene chloride ether ether. 8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid hydrazide is obtained in the form of colorless crystals. M.p. 235-237 ° C. Yield: 4.6 g (60%).

Example 18

7.4 g of methyl 8-chloro-5,6-dihydro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, 20 ml a mixture of hydrazine and 200 ml of isobutanol is refluxed for 3 hours. The reaction mixture was concentrated in vacuo and the residue crystallized from ethanol / ether. The resulting 8-chloro-5,6-dihydro-1-methyl-6-phenyl-4H-imidazo- 50 [1,5-a] [1,4] benzodiazepine-3-carboxylic acid hydrazide was obtained.

225-230 ^u C are. Yield: 6.1 g (82%). An analytical sample of the product is mixed with ethyl acetate-methanol! m.p. 228-230 ° C after recrystallization;

Example 19

0.73 g (2 mmol) of methyl 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and 20 ml of anhydrous dimethylformamide the mixture was cooled to -30 ° C with stirring under a nitrogen atmosphere. Potassium tertiary butylate (0.25 g, 2.2 mmol) was then added and stirred for 5 min.

Methyl iodide (0.3 g, 2.1 mmol) was added. The reaction mixture was allowed to warm to room temperature over 1 hour and then partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The methylene chloride phase was washed with water, dried and evaporated. The residue was crystallized from ether. The resulting 8-chloro-1,4-dimethyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester is melted at 217-221 ° C. Yield: 0.5 g (66%). An analytical sample of the product, after recrystallization from ethyl acetate-hexane, melts at 220-222 ° C.

Example 20

0.74 g (2 mmol) of methyl 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and 20 ml of dimethylformamide -30 To the cooled solution was added 0.25 g (2.2 mmol) of potassium tert-butylate. The reaction mixture was treated with methyl iodide (0.32 g, 2.26 mmol) over 5 minutes under nitrogen and allowed to warm to room temperature over 30 minutes. The reaction mixture was partitioned between aqueous sodium bicarbonate solution and methylene chloride, dried and evaporated. The residue was crystallized from ether. The resulting 8-chloro-6- (2-fluorophenyl) -4-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester (0.45 g, m.p. After recrystallization from 59% ethyl acetate / hexane, m.p. 190-191 ° C.

Example 21

3.4 g (0.01 mol) of 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxaldehyde

Partially dissolved in 200 ml of ethanol with heating. Hydroxylamine hydrochloride (1.05 g, 0.015 mol) and triethylamine (4 ml) were added and heated on a steam bath until complete dissolution. The solvent was partially distilled off and the product crystallized by dilution with water. The crystals were collected, washed with ethanol and food, and dried. 8-Chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxaldoxime melted at 280-282 ° C (dec.). Yield: 3.1 g (87%). An analytical sample of the product is obtained after recrystallization from ethanol-tetrahydrofuran.

Example 22

2.1 g of 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxaldoxime are dissolved in 100 ml of ethanol and 100 ml of tetrahydrofuran under heating. The solution was hydrogenated at atmospheric pressure in the presence of Raney nickel (1 teaspoon) for 3 hours. The catalyst was strained and the filtrate was evaporated. The residue was crystallized from a mixture of 2-propanol and ether. An analytical purity sample of 3-aminomethyl-8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine (1.38 g, 68%) was obtained. m.p. 217-219 ° C after recrystallization from ethanol-ether.

-16181885

Example 23

A solution of 1.7 g (0.05 mol) of 8-chloro-3-hydroxymethyl-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine and 5 ml of thionyl chloride was stirred at room temperature for 30 minutes. . 8-Chloro-3-chloromethyl-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine hydrochloride was crystallized by addition of ethyl acetate and ether. The crystals were filtered and partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic phase is dried and evaporated. The residue was crystallized from methylene chloride-ether. The resulting 1.4 g of 8-chloro-3-chloromethyl-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine in 50 ml of methanol containing 0.5 g of sodium methylate was obtained over 10 minutes. The methanol is distilled off and the residue is partitioned between methylene chloride and sodium bicarbonate solution. The organic phase is dried and evaporated. The crude product is chromatographed on 30 g of silica gel, eluting with a 1: 3 mixture of methylene chloride and ethyl acetate. 8-Chloro-3-methoxymethyl-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine is obtained in the form of colorless crystals, m.p. 163-165 ° C (from ethyl acetate-hexane). . Yield: 0.9 g (51%).

Example 24 Triethylamine and 0.5 g of methoxyamine hydrochloride in 0.67 g (0.002 mol) of 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3 Add a warm solution of carboxaldehyde and 40 mL of ethanol. The reaction mixture was allowed to stand for 30 minutes. The solvent is partially distilled off and the product is crystallized by dilution with water. The crystals were collected and dried. The product obtained is 8-chloro-3- (N-methoxyiminomethyl) -1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine. Yield: 0.7 g (96%). The product of analytical purity melted at 193-195 ° C after recrystallization from ether.

Example 25 Pyrrolidine from 1.85 g of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and 1.25 g phosphorus pentachloride was added to a solution of acid chloride in 25 ml of methylene chloride. 100 ml of 10% aqueous sodium carbonate solution are then added and the biphasic system is stirred at room temperature for 1 hour. The organic layer was separated, dried and evaporated. The residue was crystallized from a mixture of 2-propanol and ether. The resulting 1- [8-chloro-6- (2-fluoro-phenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepin-3-ylcarbonyl] -pyrrolidine was ethyl acetate-hexane. recrystallized from the mixture, m.p. 220-221 ° C. Yield:

1.6 g (76%).

Example 26 ml 2,2-Dimethylhydrazine 1.85 g of 8-chloro-6- (2-fluorophenyl) -1-methyl4H-imidazo [1,5-a] [1,4] benzodiazepine-3 carboxylic acid and 1.25 g of phosphorus pentachloride are added to a solution of acid chloride in 250 ml of methylene chloride. Then 100 ml of 10% aqueous sodium carbonate solution was added and the reaction mixture was stirred at room temperature for 30 minutes. The organic phase is separated, dried and separated. The residue was crystallized from ether / ethanol. 8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid (2,2-dimethyl) hydrazide is obtained in the form of a colorless substance. . Yield:

1.3 g (63%). An analytical sample of the product was prepared by chromatography on 30x silica gel, eluting with 10% ethanol in ethanol-methylene chloride and crystallizing from methylene chloride-ethyl acetate-hexane. M.p. 238-240 ° C.

Example 27

1.85 g (5 mmol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid,

A mixture of diphenylphosphoric acid azide (1.5 g), dimethylformamide (30 ml) and triethylamine (2 ml) was stirred at room temperature for 15 minutes, then methanol (6 ml) was added and the reaction mixture was refluxed for 30 minutes. The solvent was evaporated in vacuo to form an xylene azeotrope. The residue was crystallized from ethyl acetate. The resulting 8-chloro-6- (2-fluorophenyl) -3- (methoxycarbonylamino) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, methylene chloride-methanol- m.p. 270-275 ° C after recrystallization from ethyl acetate. Yield: 1.3 g (25%). An analytical sample of the product, after recrystallization from tetrahydrofuran-ethanol, m.p. 272-275 ° C (dec).

Example 28

8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid (1.5 g, 5 mmol), 1.5 g diphenylphosphoric acid azide A mixture of 10 ml of dimethylformamide, 25 ml of toluene and 2 ml of triethylamine was stirred at room temperature for 10 minutes. Benzyl alcohol (10 mL) was added and the mixture was refluxed for 30 minutes. The solvents were evaporated in vacuo and the residue crystallized from ether. The resulting 3- (benzyloxycarbonylamino) -8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, 250-253 ° C. Yield: 1.4 g (60%), m.p. 253-255 ° C after recrystallization from methylene chloride / methanol / ethyl acetate.

Example 29 (Example illustrating an out-of-scope procedure)

Sodium nitrite (1.8 g, 2.5 mmol) was added in portions over 5 minutes to 3.7 g (10 mmol) of 8-chloro-1-methyl-6-phenyl-5,6-dihydro-4H-imidazo [1,5-a] [ 1,4] benzodiazepine-3-carboxylic acid hydrazide and 35 ml glacial acetic acid

-17181885. After stirring for 30 minutes at room temperature, the azide is precipitated by addition of ice water. The solid is filtered off, dissolved in methylene chloride, washed with sodium bicarbonate solution and ice water, dried and evaporated. 5 The residue was dissolved in 100 ml of dimethylformamide and 25 ml of methanol and boiled for 20 minutes under reflux (temperature approx. 103 ^U C). The solvents were evaporated in vacuo and the residue was crystallized from methanol-ethyl acetate. 8-Chloro-3-methoxycarbonylamino-1-methyl-5-nitroso-6-phenyl-5,6-dihydro-4H-imidazo [1,5-a] [1,4] benzodiazepine is obtained in the form of colorless crystals. 255-258 ° C (dec.). Yield: 2.9 g (70%).

An analytical sample of the product melted at the same temperature after recrystallization from tetrahydrofuran-ethanol.

Example 30 (Out-of-scope procedure 2 (illustrative example)

2.06 g (5 mmol) of 8-chloro-3-methoxycarbonylamino-1-methyl-5-nitroso-6-phenyl-5,6-dihydro-4H-imidazo [1,5-a] [1,4] benzodiazepine 200 ml of tetrahydrofuran houra _2; Dissolve in 100 mL of methanol with heating. Then, 2 teaspoons of Raney nickel are added and the mixture is hydrogenated at atmospheric pressure for 1 hour. The catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from methanol to _3, colorless crystals of 8-chloro-5,6-dihydro-3 · methoxycarbonylamino-1-methyl-6-phenyl-4H-imidazo [l, 5-a] [l, 4] benzodiazepine is obtained. 280-290 ° C (dec.). Yield: 1.2 g (63%). The product of analytical purity is swallowed after recrystallization from ethyl acetate / methanol 3.

Example 31 To a solution of 1-acetoxymethyl-8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine (g) in methanol (20 ml) was added 0.3 g of sodium methylate. After allowing the reaction mixture to stand at room temperature for 10 minutes, the precipitated crystals were collected, washed with aqueous methanol, 4 methanol and ether. Colorless 8-chloro-6- (2-fluorophenyl) -1-hydroxymethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine (0.8 g, 89% yield) was of analytical purity. After recrystallization from methylene chloride-ethanol, its sample melts at 258-260 ° C. 5

Example 32

A mixture of 0.2 g of 8-chloro-6- (2-fluorophenyl) -1-hydroxymethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, 20 ml of methylene chloride and 1 g of activated manganese dioxide at room temperature 2 stir for 1 hour. The manganese dioxide is strained, strained on celite and the filtrate evaporated. The residue was crystallized from a mixture of methylene chloride ethyl acetate and hexane. 8-Chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] - [1,4] benzodiazepine-1-carboxaldehyde is obtained as colorless crystals. Mp 182-183 ° C. Yield: 90 mg (45%).

Example 33

13.7 g (0.077 mol) of N-bromosuccinimide in 10 g (0.030 mol) of 8-chloro- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, 450 ml of chloroform and 30 ml of glacial acetic acid are added with stirring. The reaction mixture was refluxed with stirring for 1.5 hours and then cooled. The mixture was washed with saturated sodium bicarbonate solution, the chloroform layer was dried and evaporated. The oily residue is chromatographed on 150 g of Woelm's neutral alumina. The impurities are first removed with methylene chloride and the product is eluted with ethyl acetate. The fractions containing the desired product were collected and evaporated. The residue was crystallized from ether to give 3-bromo-8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine 201-205 ° C. are good. Yield: 4.5 g (36.2%). An analytical sample of the product, after crystallization from ether-hexane, melts at 203-205 ° C.

Example 34

Phosphorus pentachloride (1.25 g, 0.006 mol) was 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] (1.85 g, 0.005 mol). of benzodiazepine-3-carboxylic acid and 250 ml of methylene chloride. After stirring in an ice bath for 30 minutes, diethylamine (15 mL) was added followed by 10% aqueous sodium carbonate (100 mL). The two-phase system was stirred at room temperature for 30 minutes, the organic layer was separated, dried over sodium sulfate and evaporated. Crystallization of the residue from methylene chloride in ether gave 8-chloro-N, N-diethyl-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4]. benzodiazepine-3-carboxamide m.p. 182-188 ° C. Yield: 1.6 g (75%). An analytical sample of the product melted at 183-185 ° C after recrystallization from diethyl acetate-hexane.

Example 35 2-Dimethylaminoethylamine (1.85 g, 5 mmol)

Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and 1.25 g of phosphorus pentachloride are added to a solution of 250 ml of methylene chloride. 100 ml of 10% aqueous sodium carbonate solution are then added and the mixture is stirred for 30 minutes at room temperature. The methylene chloride layer was separated, dried and evaporated. The residue was crystallized from a mixture of 2-propanol and ether. The resulting 8-chloro-N- (2-dimethylaminoethyl) -6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3 -carboxamide, m.p. 209-211 ° C. Yield: 1 g (45%). An analytical sample of the product, m.p. 210-213 ° C, is recrystallized from ethyl acetate-hexane.

EXAMPLE 36 8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-18181885 in 25% ammonia 25%

Add 3-carboxylic acid and 1.25 g of phosphorus pentachloride to a solution of acid chloride in 250 ml of methylene chloride. The reaction mixture was stirred for 10 minutes, then 50 ml of 10% aqueous sodium carbonate solution was added and stirred for 1 hour at room temperature. The methylene chloride layer was separated, dried and evaporated. The residue was dissolved in a mixture of methylene chloride and ethanol. The solution was filtered through a pad of silica gel and the filtrate was evaporated. The residue was crystallized from ethanol. 8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] - [1,4] benzodiazepine-3-carboxamide is obtained in the form of colorless crystals. Yield: 0.7 g (38%). An analytical sample of the product, m.p. 300-305 ° C after recrystallization from ethanol-tetrahydrofuran.

EXAMPLE 37 8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-dimethylamine (1.85 g, 0.005 mol) carboxylic acid and 1.25 g (0.006 mol) of phosphorus pentachloride in a solution of acid chloride in 250 ml of methylene chloride. The reaction mixture was stirred at room temperature for 1 hour, then washed with 10% aqueous sodium carbonate solution, dried and evaporated. The residue was purified by chromatography on silica gel (40 g) eluting with 5% (v / v) ethanol in methylene chloride / ethanol. The combined pure fractions were evaporated. After crystallization of the residue from ether-hexane, 8-chloro-6- (2-fluorophenyl) -1, N, N-trimethyl-4H-imidazo [1,5] as colorless crystals melting at 177-179 ° C. -a] [1,4] benzodiazepine-3-carboxamide is obtained. Yield: 1.1 g (55%). A lower melting point (158-160 ° C) modification of the product was also observed.

Example 38 A solution of 7-cyano-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepin-2-one (150 ml) in 150 ml of anhydrous tetrahydrofuran under argon

2.4 g (0.0537 mol) were treated with 54% sodium hydride and the reaction mixture was heated to reflux for 1 hour with stirring and reflux. To the mixture cooled to 0 ° C was added 13.7 g (0.0537 mol) of phosphorus oxymorpholide chloride. After 18 hours, the reaction mixture was filtered, concentrated to a small volume and ether was added. The precipitate was collected and recrystallized from dichloromethane / ether. 7-Cyano-5- (2-fluorophenyl) -2- [bis (morpholino) phosphinyloxy] -3H-1,4-benzodiazepine is obtained in the form of white bars. M.p. 194-197 ° C. Yield: 11 g (62%).

Example 39

1.6 g (0.036 mol) of 54% sodium hydride in 100 ml of Ν, Ν-dimethylformamide under a nitrogen atmosphere and

8.3 g (0.038 mol) of acetamidodimethyl malonate were added with stirring. After 30 minutes, 10 g (0.02 mol)

7-Cyano-5- (2-fluorophenyl) -2- [bis (morpholino) phosphinyloxy) -3H-1,4-benzodiazepine was added and after 64 hours the reaction mixture was poured into ice water containing 4 ml of acetic acid. The mixture was filtered and the solid was dissolved in dichloromethane (100 mL), washed with water (50 mL), dried over anhydrous sodium sulfate and concentrated to a small volume. The solution was chromatographed on a Florisil column, eluted with 2 L of dichloromethane and the eluate discarded. It is then eluted with 1 liter of dichloromethane-ether mixture and then with 1 liter of ether. The product obtained by evaporation of the ether fractions was recrystallized twice from dichloromethane / ether. Acetylamino- [7-cyano-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-2-yl] -malonic acid diethyl ester is obtained in the form of white prisms, m.p. 138-140 ° C. Yield: 1.5 g (16%).

The column was then eluted with 1.5 L of 10: 1 ethyl acetate-methanol. The eluate was evaporated and the residue was crystallized from ether. After recrystallization from a mixture of dichloromethane and ether, almost white prisms, m.p. 272-274 ° C, 8-cyano-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [ 1,4-Benzodiazepine-3-carboxylic acid ethyl ester is obtained. Yield: 0.3 g (3.8%).

^ 0th example

Ethyl 8-cyano-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid (0.5 g, 0.00129 mol) A solution of ethanol (100 ml) and water (10 ml) was treated with potassium hydroxide (0.14 g, 0.0026 mol). The reaction mixture was refluxed for 30 minutes and water (10 mL) was added. The reaction mixture was acidified with acetic acid, filtered and extracted with dichloromethane (20 mL), separated, dried and evaporated. The filtrate yielded about 0.2 g of hydrolyzed product and obtained the extract as much. The material was added to 3 ml of anhydrous hexamethylphosphoric triamide and heated at 200-205 ° C under argon for 30 minutes. The reaction mixture was cooled and 50 ml of ice water and 1 ml of ammonium hydroxide solution were added. The solution was filtered and the filtrates were extracted with dichloromethane (250 mL) and evaporated to dryness. Water was added to the residue, the solution was filtered, and the combined filtrates were dissolved in dichloromethane and developed on two silica gel plates with 15% methanol in ethyl acetate / methanol. The desired product is recovered from the silica gel (Rp = 0.4-0.5), mixed with methanol, filtered and crystallized from isopropanol / ether. 8-Cyano-5- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine is obtained in the form of almost white prisms melting at 198-203 ° C. Yield: 5 mg (1%).

Example 41

3.75 g (0.01 mol) of methyl 7-chloro-5- (2-fluorophenyl) -α-hydroxyimino-3α-1,4-benzodiazepine-2-acetic acid, 300 ml of tetrahydrofuran and of methanol was hydrogenated at atmospheric pressure for 1.5 hours in the presence of a teaspoon of Raney nickel. The catalyst was filtered off, filtered through celite and the filtrate evaporated in vacuo to a toluene azeotrope

-19181885. The residue was dissolved in pyridine (20 ml) and treated with benzoyl chloride (4 ml). The reaction mixture was allowed to stand for 15 minutes and then partitioned between methylene chloride and 1N sodium hydroxide solution. The organic phase is dried and evaporated to an azeotropic toluene. The residue was crystallized from ether. The resulting 2- [α- (benzoylamino) methoxycarbonylmethylene] -7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine 210-213 ° C. are. Yield: 2.3 g (50%). An analytical sample of the product, after recrystallization from ethyl acetate-hexane, melts at 217-219 ° C after softening at 150-160 ° C.

1.15 g (2.5 mmol) of 2- [α- (benzoylamino) methoxycarbonylmethylene] -7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1, A solution of 4-benzodiazepine and 10 ml of hexamethylphosphoric triamide was heated at reflux for 10 minutes. The dark reaction mixture was partitioned between water and ether-methylene chloride. The organic layer was washed with water, dried and evaporated. The residue was dissolved in methylene chloride and filtered through activated alumina in ethyl acetate. The filtrate was evaporated, chromatographed on silica gel (20 g) and eluted with methylene chloride / ethyl acetate (10% v / v). The combined pure fractions were crystallized from ether-hexane. The resulting 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester was obtained at 208-209 ° C. melted. Yield: 55 mg (4.9%).

Example 42

To a solution of 2.66 g of methyl 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 50 ml of methanol while refluxing, a solution of 755 mg (11.5 mmol) of potassium hydroxide in 10 ml of water was added and the reaction mixture was refluxed for 2.5 hours. The solvent was evaporated in vacuo, the residue was dissolved in 50 ml of hot acetic acid and the solution was diluted with 100 ml of cold water. The product was collected, washed with water and air dried. 8-Chloro-6- (2-fluorophenyl) -1-phenyl-4E-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid is obtained in the form of an off-white solid. Yield: 2.5 g (100%). An analytical sample of the product, m.p. 267-269 ° C after recrystallization from benzene.

Example 43

1.5 g (3.48 mmol) of 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and vigorously stir at 190 ° C for half an hour. The dark slurry was suspended in hexane and extracted twice with 1N hydrochloric acid. The acidic aqueous layer was washed once with hexane and neutralized with 5% aqueous sodium carbonate. The excellent product is filtered off and air dried. The filtrate was evaporated to give an additional amount of 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine as an off-white solid, total yield: 1, 02 g (75%). An analytical sample of the product, after chromatography on silica gel and elution with ethyl acetate, melts at 241-243 ° C.

Example 44

1.0 g (2.31 mmol) of 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [2,4] benzodiazepine-1-carboxylic acid and 5 Thionyl chloride solution was refluxed for half an hour and carefully added dropwise to 70 ml cold 40% aqueous dimethylamine. The brown solid (1.01 g, 95%) was collected, washed with water and chromatographed on silica gel. The eluent was ethyl acetate. N, N-Dimethyl-8-chloro-6- (2-fluorophenyl) -1-phenyl-1,4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide is obtained in the form of a brown foam. . Yield: 500 mg. An analytical sample of the product was obtained by recrystallization three times from acetone-water. Mp 221-223 ° C.

Example 45

8-Chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [2,4] benzodiazepine-3-carboxylic acid (1.0 g, 2.31 mmol) and 5 Thionyl chloride solution was refluxed for half an hour and then carefully added dropwise to 70 ml of cold ammonium hydroxide solution. The pink precipitate was collected, washed with water, air dried and chromatographed on silica gel, eluting with ethyl acetate. 8-Chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide is obtained in the form of a brown foam. Yield: 480 mg. After treatment with acetone, the product is obtained in the form of a white powder with an analytical purity of melting point 260-262 ° C.

Example 46

5.3 g (0.01 mol) of 7-chloro-5- (2-fluorophenyl) -2- [bis (morpholino) phosphinyloxy] -3H-1,4-benzodiazepine in ml diethyl malonate, 20 ml of dimethylformamide and To a mixture of potassium tertiary butylate (2.2 g, 0.02 mol) was added with stirring at room temperature under nitrogen atmosphere for 5 minutes. The reaction mixture was heated on a steam bath with stirring for 15 minutes. After adding 1.5 ml glacial acetic acid, the product was crystallized by adding water in portions. The precipitated solid is filtered off, washed with water and dried in vacuo. There was thus obtained 7-chloro-5- (2-chlorophenyl) -2- (bis-carbomethoxymethylidene) -1,3-dihydro-2H- (3.8 g, 90%).

An analytical sample of 1,4-benzodiazepine, m.p. 205-207 ° C, is recrystallized from ethyl acetate.

12.6 g (0.03 mol) of 7-chloro-5- (2-chlorophenyl) -2-bis-carbomethoxymethylidene) -1,3-dihydro-2H-1,4-benzodiazepine, 300 ml ethanol and A mixture of potassium hydroxide (2.1 g, 0.0375 mol) was heated at reflux under nitrogen for 4.5 hours. Methanol (200 mL) was distilled off and the residue was diluted with water. The precipitated crystals are collected, washed with water and dried. The resulting 7-chloro-5- (2-chlorophenyl) -2,3-dihydro-2 - [(methoxycarbonyl) methylene] -lH-l, 4-benzodiazepin ^u 154-158 C. DEG. Yield:

-20181885

8.8 g (81%). An analytical sample of the product, m.p. 158-159 ° C after recrystallization from methylene chloride / methanol.

2.2 g (0.031 mol) of sodium nitrite in portions under stirring over 5 minutes 7.2 g (0.02 mol)

A solution of 7-chloro-5- (2-chloro-phenyl) -2,3-dihydro-2 - [(methoxycarbonyl) methylene] -1H-1,4-benzodiazepine and 75 ml of glacial acetic acid was added. The reaction mixture is stirred for an additional 15 minutes, diluted with 100 ml of water, the precipitated crystals are filtered off, washed with water, methanol and ether. The crude 7-chloro-5- (2-chlorophenyl) -α-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester (7.8 g, 100%) in tetrahydrofuran-methanol was obtained. after recrystallization from the mixture, it forms light yellow crystals melting at 223-225 ° C (dec.).

3.9 g (0.01 mol) of 7-chloro-5- (2-chlorophenyl) -α-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester. A solution of tetrahydrofuran (100 mL) and methanol (50 mL) was hydrogenated under 2 teaspoons of Raney nickel at atmospheric pressure for 1.5 h. The catalyst is filtered off and the filtrate is evaporated to an azeotropic end with toluene. The residue was dissolved in 20 ml of ethanol. 3 ml of orthoacetic acid triethyl ester and 0.2 ml of 10% ethanol hydrochloric acid are added and the mixture is refluxed for 15 minutes and then evaporated to dryness. The residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated. The residue was crystallized from methylene chloride-ether. The resulting 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester melted at 225-227 ° C. . Yield: 2 g (50%). After recrystallization from a mixture of 2-propanol and ethyl acetate, the product of analytical purity melts at 228-230 ° C.

Example 47

1.2 g (3 mmol) of 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester and 10 of tetrahydrofuran (10 mL) was added to a suspension of lithium aluminum hydride (0.4 g, 10 mmol) in ether (30 mL) cooled to 10 ° C. After the addition was complete, the reaction mixture was stirred for 10 minutes and then hydrolysed with 2 ml of water. The inorganic material was filtered off and the filtrate was evaporated. The residue was crystallized from methylene chloride-ether. The resulting 8-chloro-6- (2-chlorophenyl) -3-hydroxymethyl-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, m.p. 215-217 ° C. Yield: 0.9 g (80%). An analytical sample of the product, after recrystallization from a mixture of tetrahydrofuran-hexane, melts at 217-218 ° C.

Example 48

7.8 g (0.02 mol) of methyl 7-chloro-5- (2-chlorophenyl) -α-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid in 200 ml of tetrahydrofuran and 100 ml of ethanol are heated. while we dissolve. The solution is hydrogenated in the presence of 2 teaspoons of Raney nickel at atmospheric pressure for 2 hours. The catalyst was filtered off with celite and the filtrate was concentrated in vacuo. The residue was crystallized from ethanol. 2- [α-amino-α-methoxycarbonylmethylene] -7-chloro-5- (2-chloro-phenyl) -1,3-dihydro-2H- m.p. 115-117 ° C as orange crystals. 1,4-Benzodiazepine is obtained. Yield: 4.8 g. After recrystallization from ether-hexane, the solvated product melts at 145-150 ° C (dec).

0.25 ml of acetaldehyde in 0.5 g of 2- [α-amino-α-methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-tH-1,4-benzodiazepine and 25 ml of methylene chloride solution. Type 5A molecular sieve is then added, the mixture is stirred for 15 minutes at room temperature, then 1 g of activated manganese dioxide is added and stirring is continued for 30 minutes. The solid was filtered off with celite and the filtrate was evaporated. After crystallization of the residue from ethyl acetate-hexane, 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4-m.p. ] benzociazepine-3-carboxylic acid methyl ester is obtained. Yield: 335 mg (63%).

Example 49 21 g (0.096 mol) of diethyl acetamido malonate (21 g, 0.096 mol) were added in portions to a suspension of g (0.09 mol) of a 54% sodium hydride dispersion in mineral oil and 315 ml of dimethylformamide under stirring under argon. The reaction mixture was stirred for 30 minutes at room temperature and then in one portion

7-Chloro-5- (2-chlorophenyl) -2- [bis (morpholino) phosphinyloxy] -3H-1,4-benzodiazepine (31.4 g, 0.06 mol) was added. After stirring for a further 7 hours at room temperature, the dark mixture was poured into glacial acetic acid with stirring and diluted with water (about 2 liters). The excellent cream colored solid is filtered off, washed with water and air-dried on a filter. The resulting dried acetylamino [7-chloro-5- (2-chlorophenyl) -3H-1,4-benzodiazepin-2-yl] -malonic acid diethyl ester was heated in a little 2-propanol on a steam bath until completely dissolved. After cooling to room temperature, 1 g of an off-white solid (14.6 g, 48.5%) was recrystallized from 8x ethanol. The resulting off-white micro needles had a melting point of 153-155 ° C. Yield: 0.6 g

Sodium ethylate solution was prepared by dissolving 0.8 g (0.04 mole g) of sodium in 50 ml of anhydrous ethanol and protecting with a drying tube. 10.1 g (0.02 mol) of acetylamino- [7-chloro-5- (2-chlorophenyl) -3H-1,4-benzodiazepin-3-yl] malonic acid diethyl ester are added in one portion. and the reaction mixture is stirred at room temperature for 5 hours under a dry atmosphere. The resulting mixture was acidified with acetic acid and concentrated in vacuo. The residue was partitioned between dilute ammonium hydroxide and methylene chloride. The layers were separated, the organic phase was dried over sodium sulfate and evaporated in vacuo. The tan amorphous solid was dissolved in 75 mL of anhydrous ether and added to a warm solution of 4 g of maleic acid in 200 mL of ether. Decant the solution from the brown, gummy, small material on a steam bath for approx. The reaction mixture was concentrated to 100 ml, cooled to room temperature and ca. Crystallize for 30 minutes with occasional scraping. After the crystallization is complete, the orange crystals

-21181885

and washed with ether and air-dried on the filter. The resulting compound (4.4 g, 40%) was 2- [α- (acetylamino) -a-ethoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2 4-benzodiazepine maleate small sample was ethyl acetate (5 mL / g) recrystallization gives yellow microneedles, _s m.p .: 139-142 ° C (dec).

3.2 g (0.0073 mol) of 2- [α- (acetylamino) -a-ethoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H- A solution of 1,4-benzodiazepine and 15 ml of hexamethylphosphoric triamide was heated under nitrogen at 200-210 ° C for 10 minutes. The reaction mixture is cooled to room temperature, the solution is poured into ice water and diluted with water until crystallization is complete. The tan solid was filtered off, washed with water and air dried on the filter. The material was dissolved in ethyl acetate 15 (2 mL / g) with stirring and crystallization started immediately. The tan solid was filtered, washed with ethyl acetate / petroleum ether (1: 1) and air dried. The resulting product (1.7 g; $ 56) was obtained from 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] _-2 [1,4] benzodiazepine-3; The ethyl ester of carboxylic acid is recrystallized from methylene chloride-ethyl acetate. The almost white needle crystals melt at 214-215 ° C.

Example 50

4.1 g (0.01 mol) of ethyl 3-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and 100 ml A solution of methanol in water (3 mL) was stirred with potassium hydroxide (0.2 g, 0.02 mol) under nitrogen at reflux for 4.5 hours and the methanol was evaporated in vacuo. The residue was dissolved in cold water and acidified with acetic acid. The _{3J off} -white solid was air-dried on the filter overnight. The resulting product (3.7 g, 96%) was treated with 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid. After recrystallization from 1: 1 methylene chloride / ethanol, white plates melting at 265-267 ° C are obtained.

Example 51

1.2 g (0.0031 mol) of ethyl 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and 25 To a suspension of 1 ml of methylene chloride was added phosphorus pentachloride (0.7 g, 0.004 mol) in portions while cooling in an ice bath. The reaction mixture was protected with a drying tube and stirred cold for an additional 30 minutes while most of the solid was dissolved. The reaction mixture was further stirred with cooling, and ammonia gas was introduced for 5 minutes and stirred cold for an additional 30 minutes. The reaction mixture was concentrated in vacuo, the light colored solid was stirred with dilute aqueous ammonia and filtered through a coarse sintered glass filter. The product was washed with water and air dried on the filter. The resultant (Ig; 83%) sample of 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide was 2: 1. After recrystallization from methylene chloride-ethanol mixture, m.p. 318-320 ° C (dec.).

Example 52

3.7 g (0.01 mol) of 8-chloro-6- (2-chlorophenyl) -3-hydroxymethyl-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine with stirring Add 20 ml of thionyl chloride. The reaction mixture is stirred for 30 minutes and the hydrochloride of the product is crystallized by addition of 30 ml of ethyl acetate and 100 ml of ether. The crystals were collected, washed with ether and partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The methylene chloride layer was dried, evaporated and the residue crystallized from ether. The resulting 8-chloro-3-chloromethyl-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine forms colorless crystals which do not melt when heated slowly, however, they rapidly melt at 200-210 ° C. Yield: 3.1 g (79%). An analytical sample of the product is obtained after recrystallization from ethyl acetate-hexane.

Example 53 8-Chloro-3-chloromethyl-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, 10 ml dimethylamine and 10 ml tetrahydrofuran The mixture was heated in a sealed tube at 100 ° C for 2 hours. The solvents were evaporated and the residue was partitioned between methylene chloride and 10% aqueous sodium carbonate. The organic phase is dried and evaporated. The residue was crystallized from ether. The resulting 8-chloro-6- (2-chlorophenyl) -3-dimethylaminomethyl-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, m.p. 136-138 ° C. Yield: 1.4 g (68%).

The product obtained is dissolved in 10 ml of methanol and treated with two equivalents of ethanolic hydrochloric acid. After dilution with ether, 1.3 g of crystalline 8-chloro-6- (2-chlorophenyl) -3-dimethylaminomethyl-1-methyl-4H-imidazo [1,5-a] {1,4] benzodiazepine dihydrochloride are obtained as colorless crystals. ethanolate, m.p. 275-277 ° C after recrystallization from ethanol-ether.

Example 54 8-Chloro-3-chloromethyl-6- (2-chloro-phenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, 250 mg of potassium cyanide and 20 ml of dimethylformamide the mixture was heated on a steam bath for 3 hours with stirring. The reaction mixture was diluted with water and extracted with methylene chloride. The extracts were washed with water, dried and evaporated. The residue was chromatographed on silica gel (30 g) eluting with methylene chloride / ethyl acetate (1: 2). Crystallization from the pure fractions gives 8-chloro-6- (2-chlorophenyl) -3-cyanomethyl-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, m.p. 212-214. ° C. Yield: 0.25 g (25%). An analytical sample of the product, after recrystallization from ethyl acetate-hexane, mp 215-217 ° C.

Example 55

To a solution of 29.9 g (0.1 mol) of 1,3-dihydro-5- (2-fluorophenyl) -7-nitro-2H-1,4-benzodiazepin-2-one in 500 ml of anhydrous tetrahydrofuran under argon portions of sodium hydride dis-22181885 (54%) were added in portions and stirred for an additional hour. Then 38 g (0.15 mol) of dimorpholinophosphine chloride were added to the dark solution in one portion and stirred for an additional 8 hours under argon. The resulting dark mixture was filtered with filter aid and the filtrate was concentrated in vacuo at 50 ° C. The dark gum-like residue (76 g) was stirred at room temperature with ethyl acetate (75 ml) and the paste crystallized. After cooling in an ice bath for 30 minutes, the mixture is filtered, the light tan solid is washed with 3 x 35 mL of 2: 1 ether-ethyl acetate, then washed with ether and then air-dried. Nearly pure 5- (2-fluorophenyl) -2- [bis (morpholino) phosphinyloxy] -7-nitro-3H-1,4-benzodiazepine is obtained. Yield: 17 g (33%). Recrystallization from 15x ethyl acetate yields almost white needles, m.p. 169-172 ° C.

A suspension of 0.85 g (0.018 mol) of a 54% sodium hydride dispersion in mineral oil and 55 ml of anhydrous dimethylformamide was treated with 3.5 g (0.016 mol) of diethylacetamido malonate in portions under argon. The mixture is stirred for 30 minutes and then 5.2 g (0.01 mol) of 5- (2-fluorophenyl) -2- [bis (morpholino) phosphinyloxy] -7-nitro-3H-1,4 benzodiazepine was added in one portion and stirred for a further 7 hours under argon. The dark reaction mixture was poured into a mixture of ice and acetic acid with stirring, diluted with water, washed with water and dried on air through a filter. Yield: 4.3 g. The residue was purified by TLC (ethyl acetate) to give three yellow spots, Rf = 0.8, 0.5 and 0.25. After chromatography on silica gel eluting with ethyl acetate, 0.3 g of a pale yellow solid (R _F = 0.25) is 6- (2-fluorophenyl) -1-methyl-8-nitro-4H-imidazo [1 5 -a] [1,4] Benzodiazepine-3-carboxylic acid ethyl ester is obtained. The product was dissolved in hot ethyl acetate (5 mL / g) and cooled in an ice bath. After recrystallization, 0.15 g of yellow prisms melt at 231-233 ° C. 40

Example 56 A solution of 7-bromo-1,3-dihydro-5- (2 g, 63.2 g, 0.2 mol) in 45% sodium hydride dispersion in mineral oil (45 g) was added in one portion with stirring. pyridyl) -2H-1,4-benzodiazepin-2-one and 1 liter of tetrahydrofuran under argon. The reaction mixture was refluxed for 1 hour, the solution cooled to room temperature, and 76.2 g (0.3 mol) of dimorpholinophosphinic acid chloride were added in portions. The reaction mixture was stirred at room temperature for 5 hours. The dark mixture was filtered through celite, the filtrate was concentrated in vacuo and the dark residue was boiled with 55 ether. In the form of tan crystals

7-Bromo-2- [bis (morpholino) phosphinyloxy] -5- (2-pyridyl) -3H-1,4-benzodiazepine is obtained. Yield: 49.5 g (46%). A sample of the product was dissolved in 2 ml of methylene chloride, filtered, diluted with 10 ml of ethyl acetate and cooled in an ice bath. The resulting tan flakes had a melting point of 180-182 ° C (dec).

To a suspension of 10 g (0.2 mol) of 50% sodium hydride in 50% mineral oil in 500 ml of anhydrous dimethylformamide was added ¢ 5. The mixture was stirred at room temperature for 1 hour under argon and heated on a steam bath for 20 minutes. 53.4 g (0.1 mol) of 7-bromo-2- [bis (morpholmo) -phosphinyloxy] -5- (2-pyridyl) -3H-1,4-benzodiazepine are added and the reaction mixture is stirred for 1 hour at room temperature, then heat again on a steam bath for 2 hours. The cooled solution was partitioned between water and methylene chloride / ether. The organic layer was separated, washed with water, dried and evaporated. The residue was crystallized from ethyl acetate / ether during seeding. 8-bromo-m-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3 in the form of off-white crystals, mp 240-243 ° C. ethyl carboxylic acid is obtained. Yield: 6g (14%). The inoculum crystals were prepared by chromatography of the product on silica gel (30x) with ethyl acetate / methanol (5% v / v methanol). An analytical sample of the product, m.p. 243-244 DEG C. after recrystallization from ethyl acetate.

Example 57

Ethyl ester of 8-bromo-1-methyl-6- (2-pyricyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid (2.15 g, 5 mmol) in methanol (50 mL) A mixture of 0.84 g (15 mmol) of potassium hydroxide and 2.5 ml of water was heated at reflux for 5 hours. Most of the methanol is distilled off and the residue is partitioned between water and ether. The aqueous phase was acidified with acetic acid and extracted with methylene chloride. The extracts were dried and evaporated. The residue was crystallized from methylene chloride-ethyl acetate. 8-Bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid is obtained in the form of colorless crystals. Yield: 1.7 g (86%). An analytical sample of the product, after recrystallization from methanol, melts at 245-250 ° C (dec.) After pre-shrinkage.

Example 53

A solution of 1.3 g of 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 20 ml of ethylene glycol was refluxed for 1 hour. while boiling. The reaction mixture was partitioned between water and methylene chloride-toluene. The organic layer was washed with saturated sodium carbonate solution, dried and evaporated. The residue was ether

It is crystallized from a mixture of 2-propanol. 8-Bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine is obtained in the form of tan crystals. Yield: 0.4 g (35%). An analytical sample of the product, after recrystallization from ethyl acetate-hexane, mp 189-190 ° C.

Example 59

A slurry of 7.8 g (0.174 mol) of a 54% solution of sodium hydride in mineral oil in 480 ml of dimethylformamide was stirred in portions of 39 g (0.18 mol) of diethylacetamido malonate. After the reaction was complete (about 30 min), 48 g (0.096 mol)

-23181885

7-Chloro-5- (2-fluorophenyl) -2- [bis (morpholino) phosphinyloxy] -3H-1,4-benzodiazepine was added in one portion and the reaction mixture was stirred at room temperature under argot for a further 5 hours. The dark colored mixture was poured into a mixture of ice and glacial acetic acid, the precipitated tan solid was filtered, washed with water and partially air dried on the filter. The wet solid was dissolved in methylene chloride, the aqueous layer was separated, dried over sodium sulfate and filtered. ^After evaporation, the remaining tan foam was dissolved in isopropanol (4 mL / g) with stirring and allowed to stand at room temperature with occasional scraping. To an off-white crystal was added an equal volume of light petroleum (b.p. 30-60 ° C) and After standing for one minute, it was born, washed with petroleum ether and air-dried on the filter to give the acetylamino- [ 7-Chloro-5- (2-fluorophenyl) -3-yl-1,4-benzodiazepin-2-yl N-malonic acid diethyl ester melts at 150-180 ° C. Exten- pro- duction ^{of 20:} 27.9 g (60%). The product sample was recrystallized from ethanol (10 mg / g) to melt at 185-195 ° C (after softening).

Sodium ethylate solution (0.2 g, 0.01 g atom) in 25 ml of anhydrous ethanol was treated with 2.4 g (0.005 mol) of acetylamino- [7-chloro-5- (2-fluorophenyl) -3H-1, It is mixed with 4-benzodiazepin-2-yl] -malonic acid diethyl ester, protected with a drying tube and stirred for 5 hours at room temperature. The precipitated yellow solid was filtered, washed successively with ethanol and ether and air dried. The solid was partitioned between water and methylene chloride, acidified with acetic acid and extracted again with methylene chloride. The methylene chloride extract was washed with dilute ammonium hydroxide, dried over sodium sulfate and concentrated in vacuo. A tan foam is obtained. A solution of 1 g (0.0024 mol) of base and 25 ml of ether was mixed with a solution of 0.56 g (0.0048 mol) of maleic acid and 25 ml of ether and allowed to stand at room temperature. After standing for a few minutes, scratching produces orange crystals, which are filtered, washed with ether and air-dried. The resulting 2- [? - (acetylamino) -? - ethoxycarbonylmethylene] -7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepine maleate was ca. . 150 ° C. Yield: 0.9 g (71%). The product was recrystallized from ethyl acetate (30 mL) after evaporation to half volume and inoculation. 0.7 g of orange crystals melted at 149-151 ° C.

6.3 g (0.015 mol) of crude 2- [α- (acetylamino) -o-ethoxycarbonylmethylene] -7-chloro-1,3-dihydro-5- (2-fluoro-50-phenyl) -2H -1,4-Benzodiazepine (prepared by ammonium alkalization of the maleate, methylene chloride extraction and evaporation in vacuo) is dissolved in 35 ml of hexamethylphosphoric acid amide and heated at 200-210 ° C for 5 minutes with stirring. The dark solution 55 was cooled and poured into ice water. The precipitated solid is filtered off and partially air dried on the filter. The wet solid was dissolved in methylene chloride, dried over sodium sulfate, evaporated and concentrated in vacuo. In the form of a tan foam 60, 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid ethyl ester is obtained. Yield: 5.7 g (96%). Recrystallize 1 g of the above foam material from 5 ml of ethyl acetate and 5 ml of petroleum ether (b.p. 30-60 ° C). The product (m.p. 176-179 ° C, 0.6 g) is obtained in the form of slightly tan prisms, which slowly solidifies and melts again at 195-198 ° C.

Example 60 Diethyl acetamidomalonate (g, 0.2 mol) was added to a suspension of sodium hydride (50% mineral oil dispersion) (10 g, 0.2 mol) in anhydrous dimethylformamide (500 ml). The mixture was heated at 50 ° C for 30 minutes under argon. 53 g (0.1 mol) of 5- (2-chlorophenyl) -2- [bis (morpholino) phosphinyloxy] -7-nitro-3H-1,4-benzodiazepine are then added and the reaction mixture is heated on a steam bath for 1 hour. heat and cool. The brown mixture was partitioned between water and methylene chloride / ether. The organic layer was washed with water, dried and evaporated. The residue was chromatographed on 1 kg of silica gel and eluted with ethyl acetate. The transparent fractions were combined and evaporated. The residue was crystallized from methylene chloride-ether. 6- (2-Chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid as pale yellow crystals melting at 233-234 ° C ethyl ester is obtained. Yield: 9.5 g (22%). An analytical sample of the product, after recrystallization from ethyl acetate, melted at 234-235 ° C.

Example 61

Ethyl 6- (2-chlorophenyl) -1-methyl-8-nitro-4-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid (4.25 g, 0.01 mol), 10mL methanol, potassium hydroxide (1.12 g, 0.02 mol) and water (4 ml) was heated under reflux for 3 hours under nitrogen. Most of the methanol was distilled off and the residue was partitioned between water and ether. The aqueous phase was washed with ether, acidified with acetic acid and extracted with methylene chloride. The extracts were dried and evaporated. Crystallization of the residue from methylene chloride-ethyl acetate gave 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid 272 M.p. 274 ° C (dec.). Yield: 3 g (75%).

Example 62

A mixture of 1.5 g of 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and 10 ml of ethylene glycol was added for 1 hour. reflux. The reaction mixture was partitioned between methylene chloride / toluene and saturated aqueous sodium bicarbonate. The organic layer was washed with water, dried and evaporated. The residue was dissolved in 10 ml of 2-propanol and 0.6 g of maleic acid was added. The salt was precipitated from the warm solution with ether, filtered, washed with 2 propanol and ether. 6- (2-Chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate is obtained in the form of tan crystals. Yield: 1 g (56%). An analytical sample of the product, after recrystallization from 2-propanol, m.p. 150-152 ° C. The salt liberated after crystallization from ethyl acetate-hexane melts at 170-173 ° C.

-2 449

Example 63

6g (0.125 mol) of a 50% dispersion of sodium hydride in mineral oil 28.1 g (0.1 mol) of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one and 300 of anhydrous tetrahydrofuran. After stirring for 1 hour at room temperature, 30.2 g (0.12 mol) of dimorpholinophosphinic acid are added and the mixture is stirred for an additional 4 hours. The product was crystallized by addition of water and ether. The precipitate which is precipitated is collected and dissolved in methylene chloride. The solution was dried and evaporated. The residue was crystallized from ethyl acetate. The resulting crude 7-nitro-2- [bis (morpholino) phosphinyloxy] -5-phenyl-3H-1,4-benzodiazepine, m.p. 208-209 ° C. Yield: 20 g (42.5%).

A portion of the above product was treated with 8.6 g (0.04 mol) of diethylacetaminomalonate, 2 g (0.04 mol) of a 50% sodium hydride dispersion in mineral oil and 75 ml of dimethylformamide heated at 40 ° C for 30 minutes. slurry. The reaction mixture was then heated in a steam bath for 30 minutes and then partitioned between water and ether. The organic layer was washed with water, dried and evaporated. The residue was chromatographed on silica gel (250 g) and eluted with ethyl acetate. The combined pure fractions were evaporated and the residue was crystallized from a mixture of methylene chloride and ether. Prepare 1-methyl-8-nitro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid ethyl acetate in the form of off-white crystals, m.p. 240-241 ° C. Yield:

1.1 g (14%). An analytical sample of the product was obtained after recrystallization from ethyl acetate.

Example 64

1.95 g (5 mmol) of ethyl 1-methyl-8-nitro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, 50 ml methanol, 0.58 A mixture of potassium hydroxide (0.01 mol) (0.01 mol) and water (2 ml) was heated at reflux under nitrogen for 3 hours. A portion of the solvent was distilled off, the residue was acidified with glacial acetic acid (2 mL) and partitioned between methylene chloride / ethanol (10% v / v) and water. The organic phase is dried and evaporated. The residue was crystallized from a mixture of ethyl acetate and methanol. Straw crystals are obtained in the form of 1-methyl-8-nitro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid. Yield: 1.2 g (66%). An analytical sample of the product, after recrystallization from the above solvent, melts at 240-243 ° C (dec).

Example 65

A suspension of 1.2 g of 1-methyl-8-nitro-6-phenyl-4H-imidazo [1,5-a] - [1,4] benzodiazepine-3-carboxylic acid and 15 ml of hexamethylphosphoric triamide is heated under reflux for 3 minutes. . The cooled solution was partitioned between methylene chloride / ether and aqueous sodium bicarbonate. The organic layer was washed with bicarbonate solution, dried and evaporated. The residue was chromatographed on silica gel (30 kg) and eluted with methylene chloride / ethanol (3% v / v). The residue from the transparent fractions was crystallized from ether / methylene chloride / ethyl acetate. The resulting 1-methyl-8-nitro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, m.p. 168-170 ° C. Yield: 0.27 g (25.5%). The base is converted to maleate. The salt crystallizes from ethyl acetate in 0.5 mol of solvent. 125-128 ° C (dec.).

Example 66

A mixture of 2.45 g (0.07 mol) of 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide, 50 ml of pyridine and 7 g of phosphorus pentoxide Reflux for 15 minutes. The pyridine is distilled off in vacuo and the residue is partitioned between ice, 10% sodium carbonate solution and methylene chloride. The organic layer was separated, dried and evaporated. The residue was chromatographed on silica gel (50 g) and eluted with ethyl acetate-methylene chloride (1: 1). Crystallization from ethyl acetate-hexane gave 8-chloro-3-cyano-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, m.p. 228-229 ° C. Yield: 2g (86%).

Example 67 To a solution of 8-chloro-6- (2-chlorophenyl) -3-hydroxymethyl-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine in 50 ml of methylene chloride, 5 g of activated manganese dioxide We are added. The reaction mixture was stirred at room temperature for 2 hours, the manganese dioxide was filtered off and the filtrate was evaporated. After crystallization of the residue with ethanol, 8-chloro-6- (2-chlorophenyl) -1-methyl-4 H -imidazo [1,5-a] [1,4] is obtained as colorless crystals, m.p. 237-239 ° C. benzodiazepine-3-carboxaldehyde is obtained. Yield: 0.65 g (65%). An analytical sample of the product is obtained after recrystallization from tetrahydrofuran-ethanol.

Example 68

1.4 g (4 mmol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxaldehyde, 2 ml triethylamine A mixture of ethanol (30 ml) and hydroxylamine hydrochloride (0.56 g, 8 mmol) was allowed to stand at room temperature for 1.5 hours. The reaction mixture was diluted with water. The excellent crystals are collected and dried. The resulting 8-chloro-6- (2-fluorophenyl) -1-methylethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxaldoxime m.p. 269-271 ° C. Yield: 1.2 g (82%). After recrystallization from a tetrahydrofuran-ethanol mixture, its analytical grade melts at 272-275 ° C.

Example 69

0.2 g of 3- (benzyloxycarbonylamino) -8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzod

A mixture of -2551 azepine, 10 ml of glacial acetic acid and 2 ml of acetic anhydride was hydrogenated in the presence of 10% palladium on carbon for 1 hour at atmospheric pressure. The catalyst is filtered off and the filtrate is evaporated to an xylene azeotropic end. The residue was chromatographed on silica gel (6 g) and eluted with methylene chloride / ethanol (10% ethanol). The combined pure fractions were evaporated and the residue was crystallized from ethyl acetate / ether. Colorless m.p. 175-178 ° C. Yield: 3-acetamino-8-chloro-6- (2-fluoro- ^10- phenyl) -1-methyl-4H-imidazo [13-a] [1,4] benzodiazepine. Yield: 30 mg (19%).

Example 70 ¹⁵

0.37 g (1 mmol) of 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxaldehyde in 10 ml ethanol and 0.14 g (2 mmol) of hydroxylamine hydrochloride ²⁰ are added to a suspension of 0.5 ml of triethylamine. The reaction mixture was heated on a steam bath until completely dissolved and allowed to stand for 2 hours. The precipitated crystals are filtered off, washed with water, ethanol and ether. The resultant 8-chloro-6- (2-chlorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] ^{benzodiazepine-3-25} karbaldoxim analytical sample from ethanol-tetrahydrofuran mixture after recrystallization, m.p. 290-292 ° C with decomposition. Yield: 0.36 g (93%).

Example 71

8-Chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxaldehyde (0.37 g, 1 mmol) and tetrahydrofuran (10 mL) To this solution was added 5 ml (ca. 35 mol) of a solution of methyl magnesium iodide in ether. The reaction mixture was stirred at room temperature for 15 minutes and quenched with water. The inorganic material was filtered and washed with methylene chloride. The filtrate was dried and evaporated. The residue was crystallized from ⁴⁰ ether and recrystallized from ethyl acetate-hexane. 8-Chloro-6- (2-chlorophenyl) -3- (1-hydroxyethyl) -1-methyl-4H-imidazo [1,5-a] as colorless crystals melting at 197-199 ° C. 1,4] benzodiazepine is obtained. M.p. 197-199 ° C. Yield: 0.1 g ⁴⁵ (26%).

Example 72

0.1 g of 8-chloro-6- (2-chlorophenyl) -3- (1-hydroxyethyl) -1- 50 methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine and A solution of 20 ml of methylene chloride was stirred at room temperature for 3 hours in the presence of 0.5 g of activated manganese dioxide. The magnesium dioxide was filtered off and the filtrate was evaporated. The crystalline residue was recrystallized from ethyl acetate-hexane. 3-Acetyl-8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine as colorless crystals, m.p. 234-236 ° C. we get. Yield: 0.06 g (60%).

Example 73

12.4g (0.03 mol) of 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid

A solution of ethyl ester and methylene chloride (200 mL) was added in one portion at room temperature with m-chloroperoxybenzoic acid (12 g, 0.07 mol). The reaction mixture is stirred for 2.5 hours, the solution is washed with 1N aqueous sodium hydroxide solution, the turbid methylene chloride phase is separated off, diluted with methanol and dried over sodium sulfate, filtered and concentrated in vacuo. Trituration of the gummy residue with ether gave off-white crystals of 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid ethyl ester. oxide is obtained. Yield: 10.3 g (80%). An analytical sample of the product, m.p. 247-249 ° C, is recrystallized from ethanol-methylene chloride (1: 1).

Example 74

Phenylacetaldehyde 2.4 g (0.02 mol) 3.8 g (0.01 mol) of 2- [α-amino-α-methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1 To a solution of 3-dihydro-2H-1,4-benzodiazepine and methylene chloride. Thereafter, 10 g of 5A molecular sieve are added and stirred at room temperature for 15 minutes, then 10 g of activated manganese dioxide are added and stirred for another 15 minutes at room temperature. The inorganic material was filtered through celite, the filtrate was evaporated and the residue was crystallized from ether-hexane. 1-Benzyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid as colorless crystals melting at 155-158 ° C methyl ester. Yield: 3.5 g (73%). An analytical sample of the product melted at 160-162 ° C after recrystallization from ethyl acetate-hexane.

Example 75

2g (4.2 mmol) of methyl 1-benzyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, 1 g potassium hydroxide, 50 ml of methanol and 5 ml of water are refluxed under nitrogen for 4 hours. The solvent was distilled off, the residue was dissolved in water and the solution was acidified with acetic acid. The precipitated crystals are collected, washed with water and dissolved in methylene chloride. The solution was dried and evaporated. After crystallization from methylene chloride-ethyl acetate, 1-benzyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4-a] m.p. ] benzodiazepine-3-carboxylic acid is obtained. Yield: 1.3 g (66%).

Example 76

The product of Example 75 is suspended in 30 ml of methylene chloride. Then 8.0 g of phosphorus pentachloride are added and the mixture is stirred for 30 minutes under ice-water cooling. Ammonia gas was introduced into the reaction mixture until alkaline. The reaction mixture was stirred for 15 minutes at room temperature, aqueous ammonia was added and the biphasic

The -2653 system was stirred for 15 minutes. The methylene chloride phase was separated, dried and evaporated. The crystalline residue was recrystallized from ethyl acetate-methanol. Colorless m.p. 282-284 ° C. 1-Benzyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide is obtained. Yield: 0.85 g (65%). An analytical sample of the product was obtained by chromatography on forty times silica gel eluting with methylene chloride / ethyl acetate (1: 1 v / v). Mp 286-288 ° C.

Example 77

370 mg (1 mmol) of 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxaldehyde, 10 ml ethanol and A mixture of 1,1-dimethylhydrazine (5 ml) was heated to reflux for 15 minutes. The solvent was distilled off and the residue was crystallized from ethanol-water. 8-Chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxaldehyde dimethylhydrazone ethanolate as pale yellow crystals (2/1) we get. Yield: 0.4 g (92%). An analytical sample of the product melts at 238-242 ° C. The crystals contained 0.5 equivalents of ethanol by NMR and analysis.

Example 78

To a suspension of 1.6 g (4 mmol) of 6-2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 100 ml of methylene chloride under ice-cooling, 1.1 g (5.2 mmol) of phosphorus pentachloride were added. The reaction mixture was stirred for 30 minutes, ammonia gas was added until alkaline and stirred at room temperature for a further 1 hour. After adding water, the organic phase was separated, dried and evaporated. The residue was crystallized from methanol-ethyl acetate. 6 <2-Chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide is obtained in the form of yellowish crystals. Mp: 300 ° C. Yield: 1.1 g (69%). An analytical sample of the product is obtained after recrystallization from the above solvent.

Example 79 A mixture of g (0.036 mol) of 1,3-dihydro-5-phenyl-2H-thieno [3,2-e] [1,4] diazepin-2-one, 50 ml of benzene and 300 ml of tetrahydrofuran was stirred in an ice bath. saturated with methylamine. A solution of titanium tetrachloride (9.48 g, 0.05 mol) in benzene (50 ml) was added dropwise. After the addition was complete, the mixture was stirred in an ice bath for 15 minutes, then the ice bath was replaced with a heating jacket and the reaction mixture was refluxed for half an hour. After cooling, 100 g of ice are carefully added, the mixture is filtered and the residue is washed with tetrahydrofuran. The filtrates were combined, dried and evaporated. The product is crystallized from methylene chloride. The resulting 8.6 g of 2-methylamino-5-phenyl-3H-thieno [3,2-e] [1,4] diazepine is melted at 223-227 ° C. Further evaporation of the mother liquors gave a further product, m.p. 222-225 ° C. Total yield: 9.6 g (92.5%). An analytical sample of the product, m.p. 227-229 ° C after recrystallization from methylene chloride.

To a cooled solution of 7.8 g (0.03 mol) of 2-methylamino-5-phenyl-3H-thieno [3,2-e] [1,4] diazepine, 100 ml of methylene chloride and 40 ml of pyridine in ice water is added nitrosyl chloride. The reaction was monitored by TLC, after the disappearance of the starting material, the addition of nitrosyl chloride was discontinued and the reaction mixture was partitioned between methylene chloride and water. The methylene chloride layer was dried and evaporated. The residue was crystallized from methylene chloride-hexane. Yield: 2- (N-Nitrosomethylamino) -5-phenyl-3H-thieno [3,2-e] [1,4] diazepine as yellow crystals, m.p. 156-159 ° C. Yield: 7.9 g (91%). An analytical sample of the product, after recrystallization from ether-hexane, melts at 158-160 ° C.

Example 80

A mixture of 7.7 g (0.278 mol) of 7-chloro-1,3-dihydro-5-phenyl-2H-thieno [2,3-e] [1,4] diazepin-2-one, 50 ml of benzene and 250 mT of tetrahydrofuran in an ice bath while stirring, saturated with methylamine. A solution of titanium tetrachloride (7.38 g, 0.0389 mol) and benzene (50 ml) was added dropwise from a dropping funnel. After the addition was complete, the mixture was stirred in an ice bath for 15 minutes. The ice bath was changed to a heating jacket and the reaction mixture was refluxed for 20 minutes, then cooled and carefully added with 100 g of ice. The mixture was filtered and the residue was washed with tetrahydrofuran. The filtrates were combined, dried and evaporated. The residue was crystallized from a mixture of methylene chloride and ether. The resulting 7-chloro-5-phenyl-2-methylamino-3H-thieno [2,3-d] [1,4] diazepine is melted at 246-249 ° C. Yield:

5.5 g (68.4%). An analytical sample of the product, m.p. 247-250 ° C after crystallization from methylene chloride.

To a solution of 5.8 g (0.02 mol) of 7-chloro-5-phenyl-2-methylamino-3H-thieno [2,3-e] [1,4] diazepine, 100 ml of methylene chloride and 50 ml of pyridine was added nitrosyl chloride, the reaction was complete by TLC. The mixture was partitioned between water and toluene. The organic phase is dried and evaporated. After crystallization from the residual ether-hexane mixture, 7-chloro-2- (N-nitrosomethylamino) -5-phenyl-3H-thieno [2,3-e] [l] as yellow crystals, m.p. 4] diazepine is obtained. 108-110 ° C. Yield: 4.7 g (80%). After recrystallization from ether / hexane, 111-113 ° C.

A melting sample of analytical purity is obtained.

Example 31

50 g (1.161 mol) of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-thieno [2,3-e] [1,4] diazepin-2-one, 900 ml of anhydrous tetrahydrofuran and 300 ml of anhydrous benzene solution are cooled in an ice bath and saturated with methylamine gas,

A solution of titanium tetrachloride (-2755 g, 0.209 mol) in benzene (100 ml) was added dropwise with stirring. After allowing the reaction mixture to stand at room temperature for 4 hours, a few grams of ice were added and the reaction mixture was born. The precipitated product was washed several times with 5 boiling tetrahydrofuran, and the filtrates were combined and evaporated. The residue was partitioned between dichloromethane (250 mL) and water (200 mL). The dichloromethane solution was separated, filtered and evaporated. The residue and the precipitate obtained previously were recrystallized from a mixture of tetrahydrofuran and ethanol. The product obtained is a

7-Chloro-5- (2-chloro-phenyl) -2-methylamino-3H-thieno [2,3-e] - [1,4] diazepine. Yield: 42 g (81%). An analytical sample of the product, after recrystallization from a mixture of tetrahydrofuran and hexane, forms pale yellow prisms melting at 259-262 ° C.

A mixture of 7-chloro-5- (2-chlorophenyl) 2-methylamino-3H-thieno [2,3-e] [1,4] diazepine (0.123 mol), dichloromethane (700 ml) and pyridine (350 ml) was cooled in an ice bath. and stirring with nitrosyl chloride for 20 minutes with stirring. After 1 hour, nitrosyl chloride was bubbled through for an additional 5 minutes and water (600 mL) was added slowly. The dichloromethane is separated off, washed with 25 ml of water, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was dissolved in dichloromethane and filtered through Florisil (400 g). The column was eluted with dichloromethane then ether. The dichloromethane fractions were combined, evaporated and the residue crystallized from ether / petroleum ether. An analytical purity sample of 34-g of 7-chloro-5- (2-chlorophenyl) -2- (N-nitrosomethylamino) -3H-thieno [2,3-e] [1,4] diazepine was obtained in petroleum ether. after recrystallization from a mixture at 35 ° C-104 ° C to form 35 melting yellow prisms. An additional 6 g of product were obtained from the ether fraction with a total yield of 92%.

A mixture of potassium tert-butylate (3.4 g, 0.03 mol), dimethyl malonate (7 ml) and dimethylformamide (20 ml) was stirred under nitrogen for 5 minutes. 7-Chloro-5- (2-chlorophenyl) -2- (N-nitrosomethylamino) -3H-thieno [2,3-e] [1,4] diazepine (3.55 g, 0.01 mol) was added. The reaction mixture was heated on a steam bath for 5 minutes with stirring, acidified with acetic acid (3 ml) and crystallized by slow addition of water. The precipitated material is filtered off, washed with water and methanol and dissolved in methylene chloride. The solution was dried and evaporated. The residue was crystallized from ethanol. 7-Chloro-5- (2-chlorophenyl) -50-1,3-dihydro-2- (bis-carbomethoxymethylidene) -2H-thieno [2,3-e] [1,4] as pink crystals diazepine is obtained. Yield: 3g (70%). An analytical sample of the product melted at 158-160 ° C after recrystallization from ethanol.

2.15 g (5 mmol) of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2- (bis-carbomethoxymethylidene-2H-thieno [2,3-e] [1, 4] A mixture of diazepine, 50 ml of methanol and 0.7 g (1.25 mmol) of potassium hydroxide was heated at reflux for 3 hours under nitrogen, the solvent was partially distilled off and the residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. the organic phase is dried and evaporated to give crude 7-chloro-5- (2-chlorophenyl) -2,3-dihydro-2- (methoxycarbonylmethylene) -2H-

-thieno [2,3-e] [1,4] diazepine is dissolved in 20 ml of glacial acetic acid. Sodium nitrite (0.5 g) was added and the mixture was stirred at room temperature for 15 minutes, diluted with water and extracted with methylene chloride. The extracts were washed with water and sodium bicarbonate solution, dried and evaporated. The residue was crystallized from methylene chloride-ether and recrystallized from tetrahydrofuran-methanol. 7-Chloro-5- (2-chlorophenyl) -a-hydroxyimino-3H-thieno [2,3-e] [1,4] diazepine as yellow crystals (melting point 242-245 ° C). Methyl 2-acetic acid is obtained. Yield: 0.45 g (23%).

Methyl 7-chloro-5- (2-chlorophenyl) -α-hydroxyimino-3H-thieno [3,2-f] [1,4] diazepine-2-acetic acid (0.4 g, 1 mmol) in 30 mL tetrahydrofuran and 20 ml of ethanol. Half a teaspoon of Raney nickel was then added and the mixture was hydrogenated at atmospheric pressure for 45 minutes. The catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 10 ml of methanol and 0.4 ml of orthoacetic triethyl ester and 3 drops of ethanol hydrochloric acid were added. The reaction mixture was refluxed for 10 minutes, evaporated and the residue partitioned between methylene chloride and aqueous sodium bicarbonate. The organic layer was dried and evaporated. The residue was chromatographed on silica gel (10 g), eluting with methylene chloride / ethyl acetate (3: 5). After removal of the eluent and crystallization from ethanol, 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] thieno [3,2- f] [1,4] Diazepine-3-carboxylic acid methyl ester is obtained. Yield: 95 mg (23%).

Example 82 Lithium aluminum hydride (38 mg, 0.001 mol) was added to ether (mL). The mixture was cooled in an ice bath and 0.2 g (0.000493 mol) of 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] thieno [3,2-f] A solution of] [1,4] diazepine-3-carboxylic acid methyl ester and 20 ml of anhydrous tetrahydrofuran are added dropwise. After 1 hour, ethyl acetate (5 mL) was added followed by saturated sodium bicarbonate solution (3 mL). The reaction mixture was filtered through celite, washed with dichloromethane, the combined filtrates evaporated and the residue crystallized from dichloromethane / ether. The resulting 8-chloro-6- (2-chlorophenyl) -3-hydroxymethyl-1-methyl-4H-imidazo [1,5-a] thieno [3,2-f] [1,4] diazepine was obtained as described above. after recrystallization from a solvent mixture, it forms almost white prisms, melting at 100-110 ° C, which once solidified again at 190-194 ° C. Yield: 0.1 g (53%).

Example 83

0.1 g (0.000247 mol) of 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] thieno [3,2-f] [1,4 A solution of diazepine-3-carboxylic acid methyl ester and 0.028 g (0.000493 mol) of potassium hydroxide in 10 ml of methanol / ⁶⁵ ml of water was added. The reaction mixture was refluxed for 2 hours under reflux and evaporated. The residue was dissolved in water (10 ml), washed with ether (10 ml) and acidified with acetic acid. The mixture was extracted with dichloromethane (30 mL), dried over anhydrous sodium sulfate, evaporated, cooled and filtered. The product was recrystallized from dichloromethane / ether. 8-Chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] thieno [3,2-f] [1] in the form of white prisms melting at 242-247 [deg.] C. 4] Diazepine-3-carboxylic acid is obtained. Yield: 40 mg (40%).

Example 84

0.8 g (0.00204 mol) of 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] thieno [3,2-f] [1,4 Phosphorus pentachloride (0.46 g, 0.002 mol) was added to a solution of diazepine-3-carboxylic acid and 100 ml of anhydrous dichloromethane in an ice bath. Ammonia was bubbled through the mixture for 5 minutes with stirring. After 2 hours, water (75 mL) was added and the product filtered. The dichloromethane layer was separated, dried and evaporated. The product is crystallized from ethanol, combined with the first precipitate and recrystallized from chloroform-ethanol. 300 -305 ° C as white rods 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] thieno [3,2-f] [1,4] Diazepine-3-carboxamide is obtained. Yield: 0.65 g (81%).

Example 85

6.8 g (0.0255 mol) of 6,8-dihydro-3-ethyl-1-methyl-4-phenylpyrazolo [3,4-e] [1,4] diazepin-7 (1H) -one, A solution of 125 ml of anhydrous tetrahydrofuran and 50 ml of anhydrous benzene is cooled in an ice bath and saturated with methylamine gas. A solution of titanium tetrachloride (6.3 g, 0.0331 mol) in benzene (20 ml) was added dropwise with stirring, stirred at room temperature for 18 hours and refluxed for 30 minutes. The solution was cooled and treated with 4 g of ice. The reaction mixture was filtered and washed with tetrahydrofuran followed by dichloromethane. The combined filtrates were evaporated to dryness and the residue was crystallized from methanol-ether and recrystallized from dichloromethane-ether. 3-Ethyl-1,6-dihydro-1-methyl-7-methylamino-4-phenylpyrazolo [3,4-e] [1,4] diazepine is obtained in the form of off-white prisms, m.p. 218-221 ° C. . Yield: 5.8 g (81%).

5.6 g (0.0199 mol) of 3-ethyl-1,6-dihydro-1-methyl-7-methylamino-4-phenylpyrazolo [3,4-e] [1,4] diazepine, 100 ml of dichloromethane and A solution of 50 pyridine was stirred in an ice bath and bubbled with nitrosyl chloride for 10 minutes. The reaction mixture was kept at room temperature for 2 hours, and then nitrosyl chloride was bubbled through for a further 5 minutes. After standing for 30 minutes, the mixture was poured into 200 ml of ice water. The organic layer was separated, washed with water (100 mL), dried over anhydrous sodium sulfate and filtered through 100 g of Florisil. Wash Florisil thoroughly with ether and evaporate the combined filtrates to dryness. The intermediate 1-nitroso derivative is not further purified but used in the next step as follows:

A mixture of dimethyl malonate (35 ml) and Ν, Ν-dimethylformamide (35 ml) was treated with potassium tert-butylate (6.5 g, 0.0580 mol) and stirred for 5 minutes and treated with 10 ml of N, N for 10 minutes. -dimethylformamide solution. The resulting mixture was heated on a steam bath for 5 minutes, cooled, and glacial acetic acid (6 mL) was added. The reaction mixture is poured into 300 ml of cold water and after 15 minutes the solution is decanted. The residual oil was dissolved in dichloromethane (75 mL), washed with dilute ammonium hydroxide (50 mL), dried over anhydrous sodium sulfate and chromatographed on Florisile. The column was eluted with dichloromethane followed by ether and finally ethyl acetate. The ether and ethyl acetate fractions were combined and evaporated. The residue was crystallized from methanol and recrystallized. Nearly white rods melting at 145-148 L in a 1 a (3-ethyl-6,8-dihydro-1-methyl-4-phenylpyrazolo [3,4-e] [1,4] diazepine-7) 1H-ylidene) malonic acid dimethyl ester is obtained. Yield: 1.8 g (24%).

1.7 g (0.00445 mol) of (3-ethyl-6,8-dihydro-1-methyl-4-phenylpyrazolo [3,4-e] [1,4] diazepin-7 (1H) -ylidene ) -Malonic acid dimethyl ester and 40 ml of methanol are treated with 0.56 g (3.01 mol) of potassium hydroxide and

Reflux for 2.5 hours. The solvent was distilled off and the residue was partitioned between dichloromethane (50 mL) and water (30 mL).

The aqueous phase was first acidified with hydrochloric acid, then basified with ammonium hydroxide and extracted with dichloromethane (75 mL). The organic layers were combined, dried over anhydrous sodium sulfate and filtered through Florisil. Florisil was eluted with ether and then ethyl acetate. The eluates were combined and evaporated. The crude monoester as an oil was dissolved in glacial acetic acid (10 mL) without further purification, and sodium nitrite (0.35 g, 0.005 mol) was added with stirring. After 45 minutes, the reaction mixture was poured into water (100 mL) and extracted with dichloromethane (75 mL). The organic layer was washed with dilute sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture of ethyl acetate and ether and then recrystallized from dichloromethane / ether. Nearly white, melting at 225-227 ° C

Methyl 3-ethyl-1,6-dihydro-p-hydroxyimino-1-methyl-4-phenylpyrazo [3,4-e] [1,4] diazepine-7-acetic acid is obtained. Yield: 0.4 g (25%).

0.35 g (0.000986 moles) of 3-ethyl-1,6-dihydro-α-hydroxyimino-1-methyl-4-phenylpyrazolo [3,4-e] [1,4] diazepine-7-acetic acid are obtained. To a solution of methyl ester, 20 ml of anhydrous tetrahydrofuran and 25 ml of methanol are added 2 ml (0.0109 mol) of orthoacetic triethyl ester and 1 spatula of Raney nickel. The reaction mixture was hydrogenated at room temperature and atmospheric pressure for 2.5 hours. The catalyst was filtered off and the nickel was washed with methanol. The combined filtrates were evaporated and the residue was dissolved in dichloromethane (40 mL). The solution was washed with dilute ammonium hydroxide (30 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was refluxed for 20 minutes in 50 mL of methanol containing 2 mL (0.109 mol) of triethyl orthoacetic acid and 0.2 mL (0.00114 mol) of 5.7N hydrochloric acid in ethanol. The solvents were evaporated in vacuo and the residue was dissolved in dichloromethane, washed with dilute ammonium hydroxide over anhydrous sodium sulfate.

-2959 dried and evaporated. The oily crude product was applied to three silica gel plates and washed with 5% methanol in ethyl acetate / methanol. The product corresponding to 0.5 Rf is scraped off, washed with methanol and filtered. The solution was evaporated and the ⁵ residue was crystallized from ether. 3-Ethyl-1,1'-dihydro-1,9-dimethyl-4-phenylimidazo [1,5-a] pyrazolo [4,3-f] [1,4] as white prisms melting at 181-184 [deg.] C. ] yields diazepine-7-carboxylic acid methyl ester.

Example 86 7-Chloro-1,3-dihydro-2- (bis-carboxymethoxymethylidene) -5-phenyl-2H-1,4-benzodiazepine-4-g (0.075 mol).

oxide, 4 g (0.095 mol) of sodium hydroxide, 300 ml of methanol and 5 ml of water are heated under reflux for 3 hours. The precipitated crystals were filtered off and recrystallized from methanol. The resulting 7-chloro-1,3-dihydro-2- (methoxycarbonylmethylene) -5-phenyl-20H-1,4-benzodiazepine-4-oxide m.p. 215-216 ° C. Yield: 11 g. 38%).

To a mixture of 6.8 g (0.02 mol) of 7-chloro-1,3-dihydro-2- (methoxycarbonylmethylene) -5-phenyl-2H-1,4-benzodiazepine-4-oxide in 100 ml of glacial acetic acid 1 4 g (0.02 mol) of sodium 25 nitrite were added. The reaction mixture was stirred for 15 minutes at room temperature and then diluted with 100 ml of water. The crystals are filtered off, washed with water and dried. 7.6 g of 7-chloro-α-hydroxyimino-5-phenyl-3H-1,4-benzodiazepine-2-acetic acid methyl ester 4-oxide are obtained in the form of a yellow product, m.p. 237-239 ° C. . An analytical purity sample of the product, after recrystallization from dimethylformamide-methanol, showed a constant melting point.

Example 87 To a solution of 5- (2-fluorophenyl) -1,3-dihydro-7-iodo-2H-1,4-benzodiazepin-2-one (g, 0.0264 mol) in dry tetrahydrofuran (140 mL) g (0.039 mol) of 54% sodium hydride (40%) was added under argon with stirring. The reaction mixture was refluxed for 1 hour, cooled to 0 ° C and

Phosphomodimorpholidochloride (10.8 g, 0.0422 mol) was added. After 18 hours, the solution is filtered, concentrated to a small volume of 45 and ether is added. The solid was filtered and recrystallized from dichloromethane / ether. 5- (2-Fluorophenyl) -7-iodo-2- [bis (morpholino) phosphinyloxy] -3H-1,4-benzodiazepine is obtained in the form of white plates melting at 104-112 ° C. Yield: 6.8 g (43%).

Example 88

To a suspension of 3.35 g (0.075 mol) of a 54% mineral sodium hydride in oil solution and 267 ml of dimethylformamide under argon is added portionwise 17.5 g (0.08 mol) of diethylacetamidomalonate. After stirring at room temperature for 30 minutes, 7-bromo-2- [bis (morpholino) -phosphinyloxy] -5- (2-pyridyl) -3H-1 (26.7 g, 0.05 mol) was added in one portion. 4-benzodiazepine is added. The reaction mixture was stirred at room temperature under argon for 7 hours. The dark mixture was poured into glacial acetic acid 65 and diluted with water. The excellent yellow-green solid is filtered off, washed with water and air-dried on the filter. Yield: 8.3 g (32%). About 7 g of a solid is chromatographed on silica gel and eluted with ethyl acetate. The resulting 4g amorphous solid showed a single spot (R _F 0.5) by TLC. The product is mixed with a small amount of isopropanol to crystallize a solid. Recrystallization from isopropanol afforded acetylamino [7-bromo-5- (2-pyridyl) -3H-1,4-benzodiazepin-2-yl] -malonic acid diethyl ester as a pale tan solid, m.p. 178-180 ° C.

Example 89

0.46 g (2.2 mmol) of phosphorus pentachloride are 0.785 g (2 mmol) of 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo] 1,5-a] thieno [3.2 -f] [1,4] diazepine-3-carboxylic acid and 50 ml of methylene chloride. The mixture was stirred under nitrogen for 30 minutes on an ice bath, then made basic with dimethylamine, stirred for 30 minutes at room temperature, washed with saturated aqueous sodium carbonate, dried and evaporated. The residue was crystallized from ethyl acetate / ether. In the form of off-white crystals, 8-chloro-6- (2-chlorophenyl) -1, N, N-trimethyl-4H-imidazo [1,5-a] thieno [3,2-f] [1,4] Diazepine-3-carboxamide is obtained. An analytical sample of the product melted at 197-200 ° C after recrystallization from ethyl acetate.

Example 90

4.15 g (20.1 mmol) of ethyl 2 -] (phenylmethylene) amino] acetate N-oxide [Buehler E. and Brown G. B. J. Org. Chem. 32, 265 (1967)] and tetrahydrofuran (200 ml) were cooled to -73 ° C and a mixture of 13.2 g (21.2 mmol) of n-butyllithium and hexane was slowly added dropwise. After 15 minutes, the light orange solution was treated with 10.15 g (20 mmol) of 7-chloro-2- (bis-morpholino-phosphinyloxy) -5- (2-fluorophenyl) -3H-1,4-benzodiazepine and 225 A solution of tetrahydrofuran (mL) was added slowly dropwise, and the resulting dark brown suspension was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added water (3 mL) and the solvent was removed. The residue was diluted with water (300 mL) and extracted several times with ether. The combined organic layers were washed twice with water, washed once with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. Light yellow solid crude product is obtained. Yield: 8.7 g (95%). Recrystallization from aqueous acetone afforded 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] diazepine-3-carboxylic acid ethyl acetate as a white solid. . Yield:

5.9 g (65%). Concentration of the mother liquor gave an additional 2.1 g of the final product, 8 g (87%). Mp 228-230 ° C.

Example 91

2- [α-Amino-α-methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazole (375 mg)

A mixture of -3061 pins, 20 ml of toluene and 0.5 ml of benzaldehyde was refluxed for 10 minutes in the presence of 5A molecular sieve. After addition of 1 g of activated manganese dioxide, reflux for a further 10 minutes. The reaction mixture was filtered through Celite and the filtrate was evaporated. The crystalline residue was collected with ether and recrystallized from ethyl acetate-hexane. 8-Chloro-6- (2-chlorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester is obtained in the form of off-white crystals. M.p. 272-275 ° C. Yield: 250 mg (54%).

Example 92

A solution of 94.6 g (0.3 mol) of 5- (2-chlorophenyl) -1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one in 2 liters tetrahydrofuran and 300 ml benzene cooled with ice water and saturated with methylamine. A solution of titanium tetrachloride (40.2 mL, 0.36 mol) and benzene (300 mL) was added via a dropping funnel and the mixture was refluxed for 3 hours. Water (300 mL) was slowly added to the cooled reaction mixture. The precipitated inorganic solid was filtered off and washed thoroughly with tetrahydrofuran. Water was separated from the filtrate and the organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel (500 g) and eluted with methylene chloride-ethanol (10% v / v ethanol). The pure fractions were crystallized from methylene chloride-ethanol. Yellow (5- (2-chlorophenyl) -7-nitro-2-methylamino-3H-1,4-benzodiazepine) is obtained. Yield: 20 g (20%). M.p. 219-221 ° C.

Sodium nitrite (8.63 g, 0.125 mol) was added in 3 portions over 33.9 g (0.1 mol) of 5- (2-chlorophenyl) -7-nitro-2-methylamino-3H-1,4-benzodiazepine and Add 200 ml of glacial acetic acid solution. After the addition was complete, stirring was continued at room temperature for an additional 1.5 hours and the product was precipitated by addition of water. The yellow solid was filtered off with suction, washed with water, suctioned and recrystallized from ethanol. 5- (2-chlorophenyl) -7-nitro-2- (N-nitrosomethylamino) -3H-1,4-benzodiazepine is obtained as yellow crystals, m.p. 164-166 ° C. Yield: 24.6 g (69%). An analytical sample of the product melted at 167-169 ° C after recrystallization from methylene chloride / ethanol.

Example 93

23.6 g (0.10 mol) of 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one and 1 liter of tetrahydrofuran, ca. Contains 20 moles of monomethylamine - the solution is cooled in an ice bath. A solution of titanium tetrachloride (14 ml, 1.73, 0.125 mol) and benzene (200 ml) was added to the reaction mixture. The mixture is stirred at room temperature for 2 days and the titanium complex is decomposed with 20 ml of water. The inorganic salts are filtered off, the filtrate is evaporated and the residue is partitioned between methylene chloride and water. The colorless amorphous solid (10 g) (m.p. 227-229 ° C) was filtered off. An additional 12.5 g of the colorless solid (m.p.

226-228 ° C) by drying the methylene chloride mother liquors over anhydrous sodium sulfate, evaporating to dryness and crystallizing the residue from ethyl acetate. Analytical sample of product after recrystallization from dimethylformamide

Yield: 22.5 g (90%), m.p. 227-229 ° C.

To a cooled (10 ° C) solution of 2-methylamino-5-phenyl-3H-1,4-benzodiazepine (10.0 g, 0.04 mol) in pyridine (100 ml) was added a solution of nitrosyl chloride in saturated acetic anhydride (100 ml). The solution was stirred for 3.5 hours while allowing to warm to room temperature. The solution was poured into ice-water (300 ml) and the aqueous solution was extracted with methylene chloride (5 x 150 ml). The combined organic extracts were washed with water and brine, dried over calcium sulfate and the solvent was evaporated in vacuo. 11.7 g of a dark semi-solid are obtained, which is chromatographed on 500 g of silica gel and eluted with chloroform. The product was 2- (N-nitrosomethylamino) -5-phenyl-3H-1,4-benzodiazepine (m.p. 192-199 ° C dec.). Yield: 10.9 g (98%).

Example 94 g (0.02 mol) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -3-methyl-2H-1,4-benzodiazepin-2-one and 100 ml of anhydrous tetrahydrofuran To this solution was added 1.05 g (0.25 mol) of a 57% sodium hydride dispersion in mineral oil. The mixture was placed under argon and heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and then mixed with 7.4 g (0.03 mol) of dimorpholinophosphinic acid and stirred under argon for a further 2 hours at room temperature. The reaction mixture was filtered and concentrated in vacuo. The gummy residue was stirred with 100 ml of anhydrous ether. The resulting white crystals were collected, washed with a little ether and air dried. The resulting 7-chloro-2- (bis-morpholine-phosphinyloxy) -5- (2-fluorophenyl) -3-methyl-3H-1,4-benzodiazepine, m.p. 90-95 ° C. Yield: 8.5 g (82%).

Example 95

19.3 g (0.06 mol) of 1,3-dihydro-7- (2-methyl-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one and Anhydrous tetrahydrofuran (300 mL) was treated with a solution of 3.1 g (0.075 mol) of a 57% sodium hydride in mineral oil under argon. The reaction mixture was refluxed for 1 hour, then cooled to room temperature and

22.2 g (0.087 mol) of dimorpholine phosphinic acid chloride are added. The reaction mixture was stirred at room temperature for 2 hours and then allowed to stand overnight. The sodium chloride was filtered off and the filtrate was evaporated and the residue was crystallized from ether. 7- (2-Methyl-1,3-dioxolan-2-yl) -2- (bis-morpholino-phosphinyloxy) -5-phenyl-3H-1,4-benzodiazepine is obtained.

-3 163

Example 96

56.4 g (0.20 mol) of 1,3-dihydro-7-ethyl-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one and 2.01 tetrahydrofuran containing 4 mol of monomethylamine Cooling the solution in an ice bath. A solution of titanium tetrachloride (33.0 mL, 0.30 mol) and benzene (360 mL) was added and the mixture was stirred at room temperature for 3 days. The titanium tetrachloride was decomposed with 100 ml of water. The inorganic salts were filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between methylene chloride and water. The methylene chloride phase was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was crystallized from acetonitrile. 7-ethyl-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine is obtained in the form of light yellow prisms. Yield: 40.5 g (70%). 172-174 ° C. An analytical sample of the product was recrystallized from acetonitrile. 172-174 ° C.

To a solution of 29.5 g (0.1 mol) of 7-ethyl-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine and 100 ml of glacial acetic acid in 1.5 portions 8.6 g (0.125 mole) of sodium nitrite was added. The reaction mixture was stirred for an additional 1.5 hours at room temperature, then diluted with ice water and extracted with methylene chloride. The extracts were washed with water and aqueous bicarbonate solution, dried over sodium sulfate and evaporated. Crude 7-ethyl-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1,4-benzodiazepine (21.7 g) was obtained as a yellow oil.

Example 97

The method. Preparation of 3-ethyl-1,6-dihydro-1,9-dimethyl-4-phenylimidazo [1,5-a] pyrazolo [4,3-f] [1,4] diazepine-7-carboxylic acid methyl ester

0.35 g (0.000986 mol) of 3-ethyl-1,6-dihydro-α-hydroxyimino-1-methyl-4-phenylpyrazolo [3,4-e] [1,4] diazepine-7-acetic acid A solution of methyl ester in 20 ml of anhydrous tetrahydrofuran and 25 ml of methanol is treated with 2 ml (0.0109 mol) of triethyl orthoacetate and 1 spatula of Raney nickel. The reaction mixture was hydrogenated at room temperature and atmospheric pressure for 2.5 hours. The catalyst was filtered off and the nickel was washed with methanol. The combined filtrates were evaporated and the residue was dissolved in dichloromethane (50 mL). The solution was washed with dilute ammonium hydroxide solution (40 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was refluxed in methanol containing 50 ml of 2 ml (0.109 mol) of triethylorthoacetate and 0.2 ml (0.00114 mol) of 5.7N hydrochloric acid in ethanol. The solvents were evaporated in vacuo and the residue was dissolved in dichloromethane which was washed with dilute ammonium hydroxide solution, dried over anhydrous sodium sulfate and evaporated. The oily crude product was developed on three silica gel thin-layer plates with 5% methanol in ethyl acetate / methanol. The product corresponding to Rf = 0.5 is scraped off, washed with methanol and natalized. The solution was evaporated and the mara32 crystallized from ether. White pure prisms, m.p. 186-189 ° C.

Method B. Preparation of B-ethyl-1,6-dihydro-1,9-dimethyl-4-phenylimidazo [1,5-a] pyrazolo [4,3-f] [1,4] diazepine-7-carboxylic acid methyl ester

0.2 g (0.000567 mol) of 3-ethyl-1,6-dihydro-α-hydroxyimino-1-methyl-4-phenylpyrazolo [3,4-e] [1,4] diazepine-7-acetic acid A solution of methyl ester, 10 ml of dichloromethane and 0.35 ml of acetic acid was treated with 0.4 g (0.0061 mol) of zinc powder and stirred for 5 minutes. The reaction mixture is filtered and the zinc is washed with dichloromethane and tetrahydrofuran. The combined filtrates were treated with 0.3 mL (0.00164 mol) of triethylorthoacetate. The mixture was concentrated in vacuo and the residue refluxed in ethyl acetate (15 ml, 0.3 ml triethyl orthoacetate) for 1 minute. The solution was concentrated and developed on two silica gel plates with 10% methanol / ethyl acetate / methanol. The portion corresponding to Rf = 0.2-0.4 is scraped off and washed with methanol. The methanolic solution was filtered and evaporated. The residue was crystallized from ethyl acetate and recrystallized from ethyl acetate / ether. The final product is obtained in the form of white bars melting at 186-189 ° C. Yield: 0.1 g (49%).

Example 98

8.5 g (0.02 mol) of 2- [α-amino-α-methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl-1,3-dihydro-2H-1,4-benzodiazepine) ethanolate, 200 ml of toluene, 4 ml of pyridine-2-carboxaldehyde and 15 g of 4A molecular sieve are refluxed for 10 minutes, 20 g of activated manganese dioxide are added and the mixture is refluxed for 10 minutes. The residue was crystallized from ethyl acetate, and the off-white crystals melted at 282 DEG-285 DEG C. After recrystallization from methylene chloride-ethyl acetate, an analytical sample of m.p. methyl chloro-6- (2-chlorophenyl) -1- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, 7.5 g. (81%).

Example 99

4.5 g (0.0107 mol) of 2- [α-amino-α-methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4- benzodiazepine ethanolate, 100 ml methylene chloride, 2 ml butyraldehyde and 5 g 5A molecular sieve are stirred at room temperature for 15 minutes. After addition of 10 g of activated manganese dioxide, stirring was continued for a further 15 minutes. The reaction mixture was filtered through celite and the filtrate was evaporated. The residue was crystallized from ether m.p. 196-198 ^she C 8-chloro-6- (2-chlorophenyl) -l-propyl-4H-imidazo [l, 5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester. Yield: 3.8 g (82%). The product is of analytical purity

A sample of -3265 melts at 197-198 ° C after recrystallization from ethyl acetate-tetrahydrofuran-hexane.

Example 100

The procedure of Example 99 was carried out with the change of using isobutyraldehyde instead of butiraldehyde. The final product was recrystallized from ether (3.2 g, 70%) while its analytically pure sample was recrystallized from ethyl acetate-tetrahydrofuran-hexane. The resulting 8-chloro-6- (2-chlorophenyl) -1-isopropyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester melted at 234-235 ° C.

Example 101 ml of chloroacetaldehyde solution (prepared by boiling a mixture of 50 ml of 2N hydrochloric acid in 50 ml of chloroacetaldehyde dimethylacetal under reflux for 30 minutes) 4.5 g (0.0107 mol) of 2- [α-amino- a-methoxycarbonylmethylene] -

- A solution of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine ethanolate and 200 ml of methylene chloride was added. After stirring for 15 minutes, the reaction mixture was partitioned between methylene chloride and saturated aqueous sodium carbonate. 8-Chloro-1-chloromethyl-6- (2-chloro-

The organic phase containing the phenyl) -1,2-dihydro-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester is dried and 12 g of activated manganese dioxide are added. After stirring for 15 minutes at room temperature, the manganese dioxide was removed by filtration through celite and the filtrate was evaporated. The residue was crystallized from methylene chloride-ether. The product of analytical purity was swallowed by chromatography on 30x silica gel with methylene chloride / ethyl acetate (7: 3). The purified product, after crystallization from ether, m.p. 237-239 ° C (dec). The product is methyl 8-chloro-1-chloromethyl-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid. Yield: 2.5 g (54%).

Example 102 Dimethylamine and 2 ml acrolein 4.5 g (0.0107 mol) of 2- [α-amino-α-methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H The reaction mixture was stirred at room temperature for 10 minutes, then 12 g of activated manganese dioxide was added, after stirring for 15 minutes, the manganese dioxide was removed by filtration through celite and the filtrate was evaporated. After recrystallization from ethanol-ether, the product was recrystallized from ethyl acetate-methanol-hexane (3.7 g, 75%) to give 8-chloro-6- (2-chlorophenyl) -1- (2 -dimethylaminoethyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester, m.p. 203-204 ° C (analytical purity sample).

Example 103

8-Chloro-6- (2-chlorophenyl) -1- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carbon (4.3 g, 0.009 mol). a mixture of the acid methyl ester, 200 ml methanol, 10 ml water and 0.7 g (0.03 ml) potassium hydroxide was refluxed for 4 hours. The solvent was partially distilled off, the residue was acidified with glacial acetic acid and diluted with water. The excellent product is born, washed with water and dried. An analytical sample of crystalline product (yield: 4g, 95%), m.p. 262-265 ° C (recrystallized from methylene chloride / methanol / ethyl acetate). The product obtained is 8-chloro-6- (2-chlorophenyl) -1- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-

carboxylic acid.

Example 104

3g (0.0145 mol) of phosphorus pentachloride 4g (0.0089 mol) of 8-chloro-642-chlorophenyl) -1- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] added benzodiazepine-3-carboxylic acid and 250 ml of methylene chloride suspension under Arctic _x water cooling. The reaction mixture was stirred for 30 minutes under ice-water cooling, and ammonia was added until alkaline. Then, 20 ml of aqueous ammonium hydroxide solution and 200 ml of methylene chloride are added and the mixture is stirred for a further 15 minutes. The organic phase was separated, dried over sodium sulfate and passed through a silica gel plate using a 5% v / v mixture of methylene chloride and ethanol. The solution was evaporated and the residue was crystallized from ethanol-ethyl acetate. The resulting off-white crystals (yield: 3.25 g, 81%) were analytical vol. recrystallize from methylene chloride / ethyl acetate. The resulting 8-chloro-6- (2-chlorophenyl) -1- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide was obtained at 255-257 ° C. melt, then solidify and re-melt at 275-278 ° C.

Example 105

1.5 g (3.5 mmol) of methyl 8-chloro-6- (2-chlorophenyl) -1-propyl 4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid. of methanolic ammonia were treated as in Example 106. The resulting 8-chloro-6- (2-chlorophenyl) -1-propyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide was recrystallized from methylene chloride-ethanol. At 300 ° C. Yield: 1.1 g (75%).

Example 106

Methyl 8-chloro-6- (2-chlorophenyl) -1-isopropyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid (1.3 g, 3 mmol); of methanol containing 20% by weight of ammonia was heated in an autoclave at 130 ° C for 20 hours. The solvent was distilled off and the residue was crystallized from methylene chloride-ethanol. The resultant 8-chloro-6- (2-chlorophenyl) -1 -izopropil4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide melting at 328-330 C. ^u. Yield:

-3 367

1.1 g (87%). An analytical sample of the product is obtained after recrystallization from the above solvent mixture.

Example 107

0.46 g of methyl 8-chloro-6- (2-chlorophenyl) -1- (2-dimethylaminoethyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and a mixture of 10 ml of methanol containing 20% by weight ammonia was heated at 130 ° C for 20 hours in a bomb. The solvent was distilled off and the residue was chromatographed on 7 g of silica gel with 20% ethanol in methylene chloride-ethanol. After crystallization of the pure fractions from 2-propanol, pure 8-chloro-6- (2-chlorophenyl) -1- (2-dimethylaminoethyl) -4H-imidazo [1,5- a] [1,4] Benzo diazepine-3-carboxamide is obtained. Yield: 80 mg (18%).

Example 108 ml of 20% solution of methylamine in tetrahydrofuran 3g (6.9 mmol) of 8-chloro-1-chloromethyl-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1 A solution of 4] benzodiazepine-3-carboxylic acid methyl ester in 50 ml of tetrahydrofuran was added. The reaction mixture was heated at 100 ° C for 18 hours in a closed apparatus. The solvent was distilled off and the residue was crystallized from ethanol. The final product obtained (1.9 g, 64%) was chromatographed on silica gel (50 g) with methylene chloride / ethanol (5 volumes). The combined pure fractions were evaporated. After crystallization from a mixture of methylene chloride and ethanol, 1.5 g of 8-chloro-6- (2-chlorophenyl) -N-methyl-1-methylaminomethyl-4H-imidazo [1,5-a] m.p. [1,4] benzodiazepine-3-carboxamide is obtained.

Example 109

2.4 g (5.4 mmol) of methyl 1-azidomethyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid A solution of 50 ml of tetrahydrofuran and 50 ml of ethanol was hydrogenated at atmospheric pressure for 2 hours in the presence of Raney nickel catalyst. The catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 2-propanol and treated with 5 mmol of ethanol hydrochloric acid. The precipitated hydrochloride was collected and recrystallized from 2-propanol-methanol. The resulting 1-aminomethyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester hydrochloride was obtained at 265-270 ° C. are good. Yield: 1.9 g (77%). An analytical sample of the product, after recrystallization from the above solvent mixture, melts at 270-275 ° C (dec.).

Example 110

0.435 g (1 mmol) of methyl 8-chloro-1-chloromethyl-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, 15 ml of tetrahydrofuran and A mixture of 1.5 ml of dimethylamine was heated in a sealed tube at 100 ° C for 3 hours, the solvent was distilled off and the residue was partitioned between methylene chloride and aqueous sodium bicarbonate solution, the organic phase was dried and evaporated and the residue was crystallized from ether. 35 g (79%) of the product are obtained after recrystallization from ethyl acetate-hexane to give 8-chloro-6- (2-chlorophenyl) -1-dimethylaminomethyl-4H-imidazo [1 5α] [1,4] Benzodiazepine-3-carboxylic acid methyl ester, m.p. 181-183 ° C.

Example 111

2.18 g (5 mmol) of methyl 8-chloro-1-chloromethyl-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, A mixture of 65 g (10 mmol) of sodium azide and 30 ml of dimethylformamide was heated at reflux for 5 minutes. The product is precipitated by addition of water, filtered and dissolved in methylene chloride, and the solution is evaporated after drying. After crystallization from ethyl acetate / ether, 1.7 g of 1-azidomethyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] are obtained as colorless crystals, m.p. 187-189 ° C. ] [1,4] benzodiazepine-3-carboxylic acid methyl ester is obtained. An analytical sample of the product, m.p. 188-190 ° C after recrystallization from ethyl acetate-hexane.

Example 112

0.435 g (1 mmol) of methyl 8-chloro-1-chloromethyl-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, 0.5 A mixture of sodium acetate (g) and dimethylformamide (20 ml) was heated at reflux for 10 minutes under nitrogen. The solvent was evaporated in vacuo and the residue partitioned between water and methylene chloride. The methylene chloride phase was dried and evaporated. The residue was chromatographed on silica gel (7 g) with methylene chloride / ethyl acetate (30% by volume). The combined pure fractions afforded 1-acetoxymethyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester 186- 188 ° C. Yield: 0.25 g (54%). An analytical sample of the product was obtained after recrystallization from methylene chloride-ether-hexane.

Example 113 g (4.65 moles) of 1-azidomethyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide; of tetrahydrofuran and 75 ml of ethanol in the presence of Raney nickel at atmospheric pressure

Hydrogenate for 1.5 hours. The catalyst was filtered off and the filtrate was evaporated. The product obtained after crystallization from ethanol-ether melted at 230-235 ° C. Yield: 1.45 g (77%). The product is converted to the hydrochloride as follows:

1.2 g of this base are dissolved in a mixture of hot ethanol and methanol. Thereafter, 3 mmol of ethanol hydrochloric acid

Adding -3469. The mixture was evaporated and the hydrochloride was precipitated by addition of isopropanol and cooling. The precipitated crystals are collected, washed with 2-propanol and ether. The product melts at 250-260 ° C. Yield: 1.1 g. An analytical sample of the product is prepared by recrystallization from a mixture of methanol and 2-propanol. The crystals consist of 1-aminomethyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide hydrochloride hemihydrate hemiisopropanolate, m.p. Mp: 250-260 ° C.

Example 114

0.44 g (1 mmol) of methyl 8-chloro-6- (2-chlorophenyl) -1-dimethylaminomethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and of methanol containing 20% ammonia was heated in an autoclave at 130 ° C for 16 hours. The solvent was evaporated and the residue was crystallized from methanol-ether. Yield: 0.25 g (58%). An analytical sample of the product was obtained by chromatography on silica gel eluting with methylene chloride / ethyl acetate (1: 1). 8-Chloro-6- (2-chlorophenyl) -1- (dimethylaminomethyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide m.p. 242-245 ° C.

Example 115

4.4 g (0.01 mol) of methyl 1-azidomethyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid , 200 ml methanol, 10 ml water and

A mixture of potassium hydroxide (1.7 g, 0.03 mol) was heated at reflux for 3 hours. The reaction mixture was partially concentrated and the residue was acidified with glacial acetic acid and diluted with water. The precipitated product is filtered off and dissolved in methylene chloride. The solution was dried and evaporated. The residue was crystallized from methylene chloride-ethyl acetate-hexane (4 g, 93%) 1-azidomethyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1 , 4] benzodiazepine-3-carboxylic acid is converted to the amide as follows:

To a suspension of the above product and 200 ml of methylene chloride was added 2.1 g (0.01 mol) of phosphorus pentachloride. The mixture was stirred with ice-water cooling for 20 minutes. Ammonia gas was introduced into the reaction mixture until alkaline. The reaction mixture was stirred for an additional 15 minutes, then aqueous ammonium hydroxide solution was added and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with methylene chloride and washed with a saturated aqueous sodium chloride solution. The organic phase is dried and evaporated. The residue was chromatographed on silica gel (120 g) with methylene chloride / ethanol (2.5% v / v). The pure fractions were combined and evaporated, and the residue was crystallized from ethanol. The resulting 1-azidomethyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] - [1,4] benzodiazepine-3-carboxamide m.p. 258-260 ° C. dec). Yield: 2.4 g (56%). An analytical sample of the product is obtained after recrystallization from methylene chloride / ethyl acetate.

Example 116 g (0.028 mol) of methyl 7-chloro-β-hydroxyimino-5-phenyl-3H-1,4-benzodiazepine-2-acetic acid

To a solution of 200 ml of methanol and 200 ml of tetrahydrofuran was added 2 teaspoons of Raney nickel. The mixture was hydrogenated at atmospheric pressure for 5 hours. The catalyst was filtered off with celite and the filtrate was evaporated to dryness. The residue was dissolved in 100 ml of methanol and 10 ml of triethylorthoformate and 5 ml of ethanol hydrochloric acid were added. After refluxing for 10 minutes, the solvent was evaporated in vacuo and the residue partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic phase is dried and evaporated. The residue was crystallized from ether. Yield: 5 g (50.5%). Ά An analytical purity sample of the obtained 8-chloro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, m.p. 235-236 ° C after recrystallization from methylene chloride / ether.

Example 117 g 2- [α-Amino-α-methoxycarbonylmethylene] -7-chloro-5 (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine ethanolate, 100 ml toluene and The mixture was refluxed for 15 minutes. The solvent was evaporated in vacuo and the crystalline residue was taken up in ether. After recrystallization from ethyl acetate-methanol, 8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, m.p. 206-208 ° C. methyl ester. Yield: 7 g (85%).

H8. Example 8 A mixture of 8-chloro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester and 100 ml of methanol containing 20% ammonia in an autoclave at 130 ° C for 8 hours. overheat. The precipitated crystals are filtered off and recrystallized from tetrahydrofuran-methanol. The resulting 8-chloro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide m.p. 295-296 ° C. Yield: 2.2 g (46%). An analytical sample of the product, after recrystallization from a mixture of dimethylformamide in ether, melted at 296-297 ° C.

Example 119

2.6 g (0.0125 mole) of phosphorus pentachloride 3.55 g (0.01 mole) of 8-chloro-6- (2-fluorophenyl) -4 H -imidazo [1,5-a] [1,4] to a suspension of benzodiazepine-3-carboxylic acid and 200 ml of methylene chloride in ice-water cooled. The reaction mixture was stirred for 30 minutes and then ammonia gas was added until alkaline. After a further 15 minutes, aqueous ammonium hydroxide was added and stirring continued for 30 minutes. The reaction mixture was mixed with water and methylene chloride / ethanol (10% v / v)

-3571 will be shared. The organic phase was dried and passed through a pad of silica gel. The solution was evaporated and the solid residue was recrystallized from ethanol. Yield: 1.6 g (45%). Analytical sample of the resulting 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide after recrystallization from tetrahydrofuran-ethanol 292- - 294 ° C.

Example 120 g (0.013 mol) of methyl 8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and 75 ml. A mixture of methanol containing 1% ammonia was heated in an autoclave at 130 ° C for 18 hours. The reaction mixture, from which the product crystallizes, is heated in methanol / methylene chloride until dissolution is complete. After filtration and concentration, 3.5 g of 8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide, m.p. An analytical sample of the product is obtained after recrystallization from methylene chloride-ethanol.

Example 121

5g (0.014 mol) of methyl 8-chloro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, 2.4 g (0.043 mol) of potassium hydroxide, 10 ml of water and A mixture of 140 ml of methanol is refluxed for 6 hours. The solvent was distilled off and the residue was dissolved in water. The solution was filtered and acidified with glacial acetic acid. The precipitated crystals are filtered off and crystallized from methylene chloride-ethanol. The resulting 8-chloro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid m.p. 268-270 ° C (4.0 g, 83%).

A mixture of the above carboxylic acid (g), phosphorus pentachloride (1.3 g) and methylene chloride (100 ml) was stirred at room temperature for 2 hours. Dimethylamine was bubbled into the mixture under ice-cooling until a clear solution of alkaline pH was obtained. The solution was washed with brine and water, and the methylene chloride layer was dried and evaporated. The residue was crystallized from ether to give 8-chloro-6-phenyl-N, N-dimethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide (0.6 g, 57% yield). ), m.p. 231-233 ° C after recrystallization from methylene chloride / ethyl acetate.

Example 122 g of 8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester, 15 ml of hexamethylphosphoric triamide and 1.5 g of lithium chloride the mixture was heated to 225 ° C. The cooled reaction mixture was partitioned between water and methylene chloride / ether. The organic layer was washed with aqueous sodium bicarbonate solution, dried and evaporated. Crystallization from ether gives 8-chloro-6- (2-chlorophenyl) -N, N-dimethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide (1: 1); 2 g (58%), m.p. 240-242 ° C after recrystallization from ethyl acetate-methanol.

Example 123 g (0.065 mol) of methyl 8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid ¹⁰ vol and 250 ml tetrahydrofuran A solution of lithium aluminum hydride in 200 ml of ether was added at -10 ° C. After the addition was complete, the mixture is stirred at a temperature between -5 ° C and 0 ° for 15 minutes and then 25 ml of water was added to hydrolyze ¹⁵ Juk. The inorganic material was filtered off with celite and the filtrate was dried and evaporated. Crystallization of the remaining methylene chloride from ether / ethyl acetate gave the solvated product. Yield:

18.3 g (78%). Recrystallization of 8-chloro-6- (2-chlorophenyl) -3-hydroxy ²⁰ methyl-4H-imidazo [1,5-a] [1,4] benzodiazepin-isopropanolate of 2-propanol and ether afforded 103- 105 DEG C., decomposes, m.p. 1 M isopropanol, m.p.

Example 124

A mixture of 0.5 g of 8-chloro-6- (2-chlorophenyl) -3-hydroxymethyl-4H30-imidazo [1,5-a] [1,4] benzodiazepine isopropanolate, ml of methylene chloride and 2.5 g of activated manganese dioxide and stirred at room temperature for 2 hours. The manganese dioxide was removed by filtration through celite and the filtrate was evaporated. The residue was crystallized from ether. The resulting 8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxaldehyde m.p. 213-215 ° C. Yield: 0.3 g (70%).

Example 125 g of crude 8-chloro-6- (2-chlorophenyl) -3-hydroxymethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine is slowly added to 30 ml of thionyl chloride. After the addition was complete, the mixture was stirred at room temperature for 15 minutes and then diluted with 100 ml of ethyl acetate. After 5 minutes, the precipitated crystals are filtered and then partitioned between methylene chloride and aqueous sodium bicarbonate solution. The final product is obtained by treatment with methylene chloride in ether. Yield: 3.6 g (66%). An analytical sample of the product was obtained by chromatography on silica gel with methylene chloride / ethyl acetate (10% v / v). After ethereal crystallization, ca. 55-165-C-8-chloro-3-chloromethyl-6- (2-chlorophenyl) -

-4H-imidazo [1,5-a] [1,4] benzodiazepine is obtained. The crystals do not melt at slow heating, but at fast heating they do not melt. Mp 165 ° C.

Example 126

A solution of 2.8 g (7.8 mmol) of 8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5] [1,4] benzodiazepine-3-carboxaldehyde in 65 ml of 150 ml of tetrahydrofuran was added M

Add to -3673 ether methylmagnesium iodide. The reaction mixture was stirred at room temperature for 15 minutes, then hydrolysed by addition of water, diluted with tetrahydrofuran, dried over sodium sulfate and filtered through celite. The filtrate was concentrated and 60 g of silica dekora Remainder ⁵ 5 volume 'in an ethanol-methylene chloride-ethanol mixture kroi.ntografáljuk. The pure fractions containing 8-chloro-6- (2-chlorophenyl) -3- (1-hydroxyethyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine were combined and evaporated. The residue was dissolved in methylene chloride ( ¹⁰ mL, 100 mL) and, after addition of 15 g of activated manganese dioxide, was stirred at room temperature for 2 hours. The manganese dioxide was filtered off with celite and the filtrate was evaporated. 30 g of silica gel with 10% ethyl acetate in purified contain performed ¹⁵ using methylene chloride-ethyl acetate to chromatography. Recrystallization of the combined pure fractions from ethyl acetate-hexane gave 3-acetyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine 214-216. mp ²⁰ ° C -one. Yield: 0.6 g (20%).

Example 127

2.7 g (7.15 mmol) of 8-chloro-3-chloromethyl-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine, 50 ml of methanol and The mixture is refluxed for 20 minutes. The solvent was evaporated and the residue partitioned between ³⁰ metilénklo- anhydride and 10% aqueous sodium carbonate solution. The methylene chloride layer was dried and evaporated. The residue was dissolved in 2-propanol and treated with ethanolic hydrochloric acid. The excellent crystalline dihydrochloride (m.p. 230 DEG C., decomposition) was born and partitioned between ³⁵ methylene chloride and aqueous sodium carbonate solution. The organic phase is dried and evaporated. Crystallization of the residue from ether-hexane gave 8-chloro-6- (2-chlorophenyl) -3-methoxymethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine 126-130 ° C. They are C's. Yield: 1.7 g (64%). An analytical sample of the product is obtained after recrystallization from ether.

Example 128

1.5 g (4.2 mmol) of 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, 1.7 g (8 mmol) a mixture of phosphopentachloride and methylene chloride (100 mL) was stirred under argon for 3 hours. At room temperature, dimethylamine is introduced until an alkaline clear solution is obtained. The solution was washed with water, dried and evaporated. The residue was crystallized from ethyl acetate-hexane. After recrystallization from ether, 8-chloro-6-phenyl-1,1N, N-trimethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide is obtained, m.p. 173-175 ° C. Yield: 0.6 g (37%).

Example 129

Phosphorus pentachloride (1.3 g, 6.25 mmol) 1.9 g (5 mmol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [l , 4] benzodiazepine-3-carboxylic acid and 100 ml of methylene chloride. The reaction mixture was stirred for 30 minutes under ice-water cooling, then 7 ml of aniline was added and stirring was continued at room temperature for 30 minutes. The reaction mixture was partitioned between 10% aqueous sodium chloride solution and methylene chloride. The organic phase is dried and evaporated. The residue was crystallized from ether and recrystallized from methylene chloride-ethanol. Yield: 1.4 g (63%). After recrystallization from tetrahydrofuran-ethanol

8-Chloro-6- (2-fluorophenyl) -1-methyl-N-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3, m.p. 228-288 ° C. -carboxamide is obtained.

Example 130

1.3 g (6.25 mmol) of phosphorus pentachloride are 1.9 g (5.1 mmol) of 8-chloro-6- (3-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [ 1,4] benzodiazepine-3-carboxylic acid and

Add 100 ml of a suspension of methylene chloride. The reaction mixture was stirred under ice-water cooling for 30 minutes, then cyclopropylamine (3 ml) was added and stirred for an additional 10 minutes. The reaction mixture was washed with aqueous sodium carbonate solution, dried and evaporated. The residue was passed through silica gel with methylene chloride / ethanol (10% v / v). After crystallization from ethyl acetate-hexane, 8-chloro-N-cyclopropyl-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] in the form of crystals melting at 196-197 ° C. [1,4] benzodiazepine-3-carboxamide is obtained. Yield: 1.3 g (62%).

Example 131

3.6 g (0.0093 mol) of 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and To a suspension of dichloromethane (mL) was added 2.1 g (0.01 mol) of phosphorus pentachloride in portions with stirring and cooling in an ice bath. The reaction was stirred cold in a flask protected by a drying tube for 30 minutes. With further stirring and cooling, dimethylamine was introduced for 5 minutes and stirring continued for another 30 minutes. The reaction mixture was evaporated to dryness in vacuo. The gum was triturated with water and basified with ammonium hydroxide, dried over methylene chloride and concentrated in vacuo. The tan foamy residue was dissolved in 600 mL of spinning ether and the insoluble material was filtered off. Stir the filtrate on a steam bath for approx. Concentrate to 250 ml and filter again. Then again for approx. It is concentrated to 100 ml and scraped occasionally to initiate crystallization. The heating was discontinued and cooled to room temperature overnight. The excellent nearly white prisms are filtered off, washed with food and air dried. Yield: 1.6 g (42%). Mp 225-230 ° C. The received

After recrystallization from 8-chloro-6- (2-chlorophenyl) -1, N, N-trimethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide from benzene-ether 228 -232 ° C.

-3 775

Example 132

1.2 g (2.9 mmol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid 2 A mixture of 2-dimethylhydrazide, 50 ml methylene chloride, 5 ml glacial acetic acid and 2.5 zinc powder was stirred at room temperature for 2 hours. The inorganic material is separated off and the filtrate is washed with sodium carbonate solution, dried and evaporated. The residue was crystallized from ethyl acetate / ether. Yield: 1.15 g (95%). The resulting 8-chloro-5,6-dihydro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid 2,2 of dimethyl hydrazide, m.p. 218-219 DEG C., recrystallized from ethyl acetate.

Example 133 g (0.018 mol) of 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide and 70 ml of glacial acetic acid 5.6 g (0.087 grams) of zinc powder are added in portions while stirring. The reaction mixture was heated to 110 ° C in an oil bath for 5 hours under argon. The reaction mixture was cooled to room temperature, then filtered and the solid was washed with methylene chloride. Methylene chloride was removed from the filtrate in vacuo at 60 ° C, the residue was poured into cold water and basified with ice-cold ammonia. The precipitated white solid is filtered off, washed with water and partially dried on the filter. The wet solid was stirred in 200 mL of 1N hydrochloric acid for 5 minutes and the unreacted white solid was filtered off (about 3 grams). The filtrate was basified cold with dilute aqueous ammonium hydroxide solution, the resulting white solid was collected, washed with water and air-dried on the filter. Yield: 4g (57%). After recrystallization from ethanol-methylene chloride, 8-chloro-6- (2-chlorophenyl) -5,6-dihydro-1-methyl-4H-imidazo [1,5-d] m.p. -a] [1,4] benzodiazepine-3-carboxamide is obtained.

Example 134

To a suspension of 1.3 g (0.0034 mol) of the base prepared in Example 133 and 75 ml of 95% ethanol were added 10 ml of 5.7 N ethanolic hydrochloric acid and the mixture was stirred on a steam bath to form a clear solution. The solution was filtered and allowed to stand overnight at room temperature. The excellent white needle crystals are collected, washed with ethanol and air dried. 0.4 g of 8-chloro-6- (2-chlorophenyl) -5,6-dihydro-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide was obtained. -hydrochloride-1 1/3 hydrate melts at 310-315 ° C before decomposing to a prismatic crystalline form at about 250 ° C. Evaporation of the mother liquor yielded an additional 0.6 g (decomposition) of product at 305-310 ° C.

Example 135

A solution of 185 mg of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 5 ml of ethylene glycol was added under nitrogen for 1 hour. reflux. The cooled reaction mixture was partitioned between ether-toluene and saturated aqueous sodium bicarbonate. The organic layer was separated, dried and evaporated. The residue was chromatographed on silica gel (7 g) with methylene chloride-ethanol (3% v / v) ethanol. The less polar 8-chloro-6- (2-fluorophenyl) -1-methyl-6H-imidazo [1,5-a] [1 , 4] benzodiazepine (m.p. 177-179 ° C) (12 mg, 7%) and 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5 -a] [1,4] benzodiazepine (m.p. 151-153 ° C) (110 mg, 67%).

Example 136

The following formulation (10 liters) is prepared for parenteral administration:

per ml

8-Chloro-1-methyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine maleate 1.0 mg

Benzyl alcohol 0.15 mL

Tartaric acid buffer containing sodium hydroxide Water for injection q. s. ad 1 ml

In a glass or glass-coated container, 8 liters of water for injection are heated to 90 ° C. The water is cooled to 50-60 [deg.] C., then 1.5 L of benzyl alcohol are added and dissolved with stirring. The solution was allowed to cool to room temperature. Then, under nitrogen atmosphere, 10.0 g of 8-chloro-1-methyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine maleate were added and stirring was continued until complete dissolution. . The pH is adjusted to 3.0 ± 1.0, preferably 3.0 ± 0.5 with a mixture of tartaric acid buffer and sodium hydroxide solution. Then, make up to 10 liters with water for injection and the solution is filtered through a candle filter, filled into ampoules of appropriate size, placed under nitrogen and sealed.

Example 137

Tablets are prepared as follows: per tablet

8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate 10.0 mg

Lactose 113.5 mg

Corn starch 70.5mg

Pre-gelatinized corn starch 8,0mg

Calcium stearate 3.0 mg total weight: 205.0 mg

-3 877

8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate is mixed with lactose, corn starch and pregelatinised corn starch in a suitable mixer. , then grind it. The mixture was moistened with water in the mixer and the dense paste mass was transferred to a grinding machine, and the wet granules were dried in a paper-coated tray at 45 ° C. The dried granules are then mixed with calcium stearate in a blender and compressed into tablets weighing 200 mg.

Example 140

We make the following capsules:

Each capsule contains:

chloro-6- (2-fluorophenyl) -1-methyl-

-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate 50mg

Lactose 125mg

Corn starch 30mg

Talc 5mg total weight: 210 mg

Example 138

We make tablets of the following composition:

Each tablet contains:

8-Chloro-6- (2-fluorophenyl) -1-methyl-

-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate 25.00 mg

Lactose 64.50mg

Corn starch 10,00mg

Magnesium Stearate 0.50mg Total Weight: 100.00mg

3-Chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] - [1,4] benzodiazepine maleate is mixed with lactose, corn starch and magnesium stearate in a suitable mixing apparatus. The mixture was ground and then compressed into 100 mg tablets.

Example 139

We make the following capsules:

Each capsule contains:

8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate 25mg

Lactose 158mg

Corn starch 37mg

Talc 5mg total weight: 225 mg

8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate is mixed with lactose and corn starch in a suitable mixer. The mixture is ground, then thoroughly mixed with talc and filled into hard gelatine capsules on an encapsulating machine.

8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine is mixed with lactose and corn starch in a suitable mixer. The mixture is ground and then thoroughly mixed with talc. The mixture is filled into hard gelatine capsules on an encapsulating machine.

Example 141

We make the following capsules:

Each capsule contains:

8-Chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine maleate 50mg

Lactose 125mg

Corn starch 30mg

Talc 5mg total weight: 210 mg

The 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine maleate is mixed with the lactose and corn starch in a suitable mixing apparatus. The mixture is ground, thoroughly mixed with talcum and filled into hard gelatin capsules on an encapsulating machine.

Example 142

We make the following capsules:

Each capsule contains:

8-Chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine maleate 25mg

Lactose 158mg

Corn starch 37mg

Talc 5mg total weight: 225 mg

The active ingredient is mixed with lactose and corn starch in a suitable mixer. The mixture is ground, then the talc is mixed and, after thorough mixing, filled into hard gelatin capsules on an encapsulating machine.

-3 979

Example 143

We make tablets of the following composition:

per tablet: 5

8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -

-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate 25 mg

Lactose 64.50 mg10

Corn starch 10,00mg

Magnesium Stearate 0.50mg Total: 100.00mg

The active ingredient is mixed with lactose, corn starch and magnesium stearate in a suitable blender. The mixture is ground and then compressed into tablets with a suitable particle size of 100 mg. 20

Example 144

In accordance with methods known in the art of pharmaceutical manufacture, tablets are prepared in the following compositions:

Each tablet contains:

8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -30

-4H-imidazo [1,5-a] J [1,4] benzodiazepine maleate 10.0 mg

Lactose 113.5 mg

Corn starch 70.5mg

Pre-gelatinized corn starch 8.0 mg35

Calcium stearate 3.0 mg total weight: 205.0 mg

The active ingredient is mixed with lactose, corn starch and pre-gelatinized corn starch in a suitable mixer and then ground. The mixture is then moistened with water in a mixer to form a thick paste, then ground and the wet granules dried on paper-lined trays at 45-45 ° C. The dried granules are thoroughly mixed with the calcium stearate in the blender and compressed into 200 mg tablets.

Example 145

Preparations suitable for parenteral administration in the following compositions are prepared by known pharmaceutical preparation methods:

8-Chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine maleate

Be Nil Alcohol Tartaric acid buffer containing sodium hydroxide

Water for injection q. s. give

LO mg ₆₀

0.15 mL niu 65

In a glass or glass-lined container, 8 liters of water for injection is heated to 90 ° C, then cooled to 50-60 ° C, 1.5 liters of benzyl alcohol is added and dissolved with stirring. The solution is allowed to warm to room temperature and then, under nitrogen atmosphere, 10.0 g of the active ingredient are added and thoroughly mixed until the pH is 3.0 ± 1.0, preferably 3.0 ± 0.5 with a mixture of tartaric acid buffer and sodium hydroxide solution. and make up to 10 liters with water for injection. The solution is filtered through a candle filter, filled into ampoules of appropriate size, placed under an atmosphere of hydrogen and sealed.

Claims (20)

Free ” ¹ · ™ claims: A process for the preparation of the imidazo [1,5-a] [1,4] diazepine compounds of formula (Γ) wherein A is -C (R ₆ ) = N-, wherein R ₆ represents phenyl, mono- or dihalo-phenyl or pyridyl radical, R 1 is hydrogen, lower alkyl, alpha-hydroxy-lower alkyl, alpha-lower alkanoyloxy-lower alkyl, phenyl, alpha-halo- lower alkyl, a-amino (lower) alkyl, lower alkyl-substituted a- or 0-amino (lower) alkyl, pyridyl, phenyl- lower) - alkyl or -CHO, R ₂ is chlorine, bromine, iodine, a-hydroxy (lower) alkyl, a- (lower) -alkanoyloxy (lower) alkyl a-lower (lower) -alkoxy (lower) -alkyl, a-halo (lower) -alkyl, a-amino (lower) -alkyl, cyano, -cyano (lower) alkyl, lower alkanoylamino, lower alkoxycarbonylamino, phenyl (lower) (mu) -alkoxycarbonylamino, lower alkyl-substituted-amino (lower) alkyl, -COOR10 (wherein R10 is hydrogen or lower alkyl), -COR10 (wherein R _{10 is} hydrogen or lower alkyl), -CH = NR ₁ j (wherein R 1 is hydroxy, lower alkoxy or di (lower) alkylamino), -CONR ₁₂ R ₁₃ (wherein R _{2 is} hydrogen, lower alkyl, phenyl, or - (CH ₂ ) _n NR 14 ₄ R ₅ and R 14 is lower alkyl; represents a group while n is an integer from 1 to 4; R 13 is hydrogen, lower alkyl or phenyl, or R ₂ and R 3 together with the nitrogen atom to which they are attached represent a pyrrolidino group 40 -4081) or -CONH-NR ₁₇ R ₁₈ (wherein R ₁₇ and R _{18 are} hydrogen or lower alkyl) or when R _{1 is} hydrogen; formyl or hydroxymethyl, R 'may also be hydrogen, R ₃ is hydrogen or lower-C 1 -C 4 alkyl, and is a group of formula (a), (b) or (d) wherein X is chlorine, bromine or iodine, T and Y are lower alkyl, and R _{4 is} hydrogen, halogen, nitro, cyano, trifluoromethyl or lower alkyl, and (I * N-oxides of formula (I ') and 5,6-dihydro derivatives of formula (I') - wherein in the latter formulas (Z2 (a) or (b) R ₄ and X are as defined above, R _{2, with} the exception of hydrogen, is as defined above for R ', and R 1, R ₃ and R _{6 for} the preparation of the pharmaceutically acceptable salts of the above compounds - and the compounds of formula (I), (Γ ”) and R - other than hydrogen, as listed above, characterized in that: A) for the preparation of compounds of formula F wherein R 1 _is hydrogen or lower alkyl, R _{2 is} -CO ₆ R ₁₀ wherein R _{0 is} lower alkyl, while R _{0 is} lower alkyl. A and R ₃ are as defined above, (VII) a compound of formula - wherein R is a lower alkyl group, and @ 3 and R @ ₃ are as defined above -, or an N-oxide, optionally an acidic catalyst in the presence of room temperature or above with an alkanoic acid orthoester of R1C (OR) ₃ wherein R is as defined above and R1 is hydrogen or lower alkyl, or B) for the preparation of compounds of formula F wherein R1 is -COOR10 and is a Rinkis alkyl group, while (O2, A, R1 and R3 ₎ are as defined in the general formula (XIII); treating a compound of the formula wherein A, R 1 and R ₃ are as defined above, R is as defined in Process A) with an oxidizing agent, preferably manganese dioxide, air or oxygen; obsession C) for the preparation of compounds of formula I 'in which R 1 is hydrogen, lower alkyl or phenyl, R' -COOR ₁₀ and wherein R _{10 is} lower alkyl, while A and R ₃ denotes a compound of formula XI wherein R 'is hydrogen, lower alkyl or phenyl, and A and R ₃ are within the scope and R is Or N-oxide as defined in process A), optionally in the presence of a solvent, a catalyst and / or a water binder, is heated to 100-300 ° C and subjected to dehydration and ring closure; obsession D) for the preparation of compounds of formula I 'wherein R 1 is phenyl or pyridyl, ^{5 is} a compound of formula (a), R "is a -COOR 1 or -CONR ₂ R ₃ group (wherein R 1, R represents ₂ and R ₃ a lower alkyl group) and A and ₁₀ R ₃ are as defined above, (IX ') reacting a compound of formula wherein R ₃ , R ₄ and R ₆ are as defined herein, with a nitrone of formula XLVI wherein R _{23 is} phenyl or pyridyl and R ₂₄ is lower alkoxy or di- ( lower alkyl) amino; and optionally following procedure A), B), C) or D) 20 a) for the preparation of compounds of formula I 'wherein R1 is other than α (lower) alkanoyloxy (lower) alkyl and alpha-halo (lower) alkyl as defined herein. meaning R '-COORj ₀ general Is a group and, Ri ₀ is hydrogen of formula 25, and A and R ₃ have the above mentioned meanings, a compound of formula for preparing a compound of formula (I '), (XII) - where R "is hydrogen, lower 30 alkyl, a-hydroxy (lower) alkyl, phenyl, a-halo (lower) alkyl, a-amino (lower) alkyl, lower a-alkyl or -N-amino-lower alkyl, pyridyl, phenyl-lower alkyl or -CHO substituted with alkyl, and R ₃ , A and © have the meanings and R is subjected to the process as defined in A) to hydrolysis, preferably an alkali metal hydride ⁴⁰ in the presence of oxides; and if desired aa) for the preparation of compounds of formula I 'wherein R 1 is one of the substituents R ¹¹ defined below, R' is a group of formula ^{45 -} CONR 12 R 13 (wherein R 12 and R 3 are as defined herein), and A, R and are as defined above, a compound of formula for preparing a compound of formula (F) (XVIIF) - wherein ⁵⁰ R, ¹¹ is hydrogen, a lower alkyl group, a phenyl group, the alkylamino (lower It represents lower) alkyl group, a substituted lower alkyl group, a- or / 3-amino (lower) alkyl group, a pyridyl group, a phenyl (lower -C ⁵⁵⁾ alkyl group or a group -CHO , and A, R 3 and (§ £) are reacted with an amino compound of the formula HNRi ₂ Ri ₃ where R ₂ and R ₃ are as defined herein. ⁶⁰ and, if desired, a compound of formula (XXVIII) which is a narrow group of compounds of formula (F) wherein R 1 'is as defined above for R ¹¹ , A, R ₃ and is -4183, the corresponding carbamoyl compound is subjected to dehydration; or (b) for the preparation of compounds of formula (Γ) wherein R 1 is R ^{11 as} defined in process aa, R 'is -CONH- -NR 17 R 18 (wherein R 17 and R 18 are as defined in the scope) and A, R 3 and is a compound of formula (XVIII ') of the general formula (Γ), wherein RY ¹¹ is as defined above, A, R3 and (Z1) are the acid chloride of the parent compound represented by H. ₂ ) with a hydrazine of the formula N-NR ₁₇ R ₁₈ - wherein R ₁₇ and R ₁₈ are as defined in the preceding claims - or ac) for the preparation of compounds of formula (Γ) wherein R _r is a substituent Rf ¹ as defined below; "Represents a chlorine atom, a bromine atom or an iodine atom, and A, R3 and denotes a compound of the general formula (XVIII ') ), wherein RY ¹¹ is a substituent Rf ¹ as defined below, and A, R3 and (^ are as defined herein) are decarboxylated and the resulting compound of formula XXX where Rf ^{1 is} lower alkyl, a phenyl, lower alkyl-substituted α- or O-amino (lower) alkyl, pyridyl, phenyl (lower) alkyl, or -CHO group, and A, R ₃ and (£ £ is as defined in the disclosure) with a chlorinating carbon, brominating agent or iodinating agent, preferably N-chlorosuccinimide, bromine or N-bromosuccinimide; or d) for the preparation of (I ') are compounds of formula I, wherein R _t represents ¹ substituent, R Y is as defined below, R' represents a lower alkoxycarbonylamino group or a phenyl (lower) -alkoxikarbonilamino group, and A, R3 and ( § £ denotes an azide of a carboxylic acid of formula (Γ) as defined herein, that is, a compound of formula (XXIV): wherein R 11 and R Y ^{111 are} hydrogen, lower alkyl, phenyl, pyridyl, phenyl- C 1 -C 4 alkyl, or -CHO, and A, R 3 and C 1 -C 6 are heated with a lower alkanol or a phenyl (C 1 -C 4) alkanol and optionally to prepare compounds of formula (Γ) in which R1 represents the substituent RY ⁿⁱ as defined in process (d), R 'represents a lower alkanoylamino group , A and R3 are as defined in the parent ring and in the parent ring, with the proviso that R4 in the formula (a) can be only a substituent other than nitro and cyano, as defined above. resulting compound within the scope of formula (I ') A compound of formula (XXV) - wherein Ri9 benzyl radical, R Y ¹¹¹ are the same as defined above, A and R3 are as defined above, and is as defined above - are hydrogenated, and reacting the resulting free amine with a lower alkane carboxylic anhydride or halide; obsession b) for the preparation of a compound of formula XIV which is a narrower group of compounds of formula (Γ), wherein A and R ₃ are as defined in the foregoing, R "'is as defined in process a) except for the formyl group; with the proviso that R _{4 in} the group represented by formula (a) may only be a substituent other than nitro and cyano in a group represented by the formula (XII); where A and R ₃ are as defined in the present invention, R '' is as defined in Process a) (2 C as defined above and R is as defined in Process A), and preferably the lithium aluminum hydride is used as the reducing agent. compound optionally ba) forming a narrower group of the compounds (I ⁵⁾ of formula (XIX) s thereof, wherein R ^{v is hydrogen, lower alkyl group, a phenyl group, the-halo (lower) alkyl group, or a- 0- [di (lower) alkylamino) - (lower) alkyl, pyridyl, or phenyl (lower) alkyl, A and R ₃ are as defined herein, R is The groups defined in process A) and as defined herein are provided that R _{4 in} formula (a) can only be a substituent other than nitro and cyano, a compound of formula XIV - wherein a and R ₃ are as defined above, with the same R "'is R \ ^v report, and are as defined above - optionally acylated with a lower fatty acid anhydride or chloride in the presence of 3avmegkötőszer; or bb) for the preparation of compounds of the general formula (XX) which are a narrow group of compounds of formula I ', wherein RY is hydrogen, lower alkyl, phenyl, α-amino-lower alkyl, a-or 0-amino (lower) alkyl, pyridyl, or phenyl (lower) alkyl substituted with C 1-4 alkyl, X 'is halogen, A and R ₃ are as defined above. with the proviso that R _{4 in} the group (a) may only be a substituent other than nitro and cyano, a compound of the formula (XIV) wherein A and R ₃ has the same meaning as defined in the preamble, R "'has the same meaning as RY and ^ Z''has the above meaning - a halogenating agent, preferably a phosphorus halide or with thionyl chloride; and then optionally preparing a compound of formula (Γ) wherein R 1 is a RY substituent in the present process, R 'is a lower alkoxymethyl group, an aminomethyl group, a cyanomethyl group, or a lower alkyl group. is aminomethyl, A and R ₃ -4285 is intended to mean the groups defined in the present specification and those in the scope of the disclosure, provided that in the group R4 in the formula (a), only a substituent other than nitro and cyano can be substituted by a compound of the formula (XX) compound - wherein Y and X 'is in the present process, given a and R ₃ are as defined above, and is as defined above - with ammonia, substituted with a lower alkyl group, a primary or secondary amine with a lower alkoxide or with a cyanide ; or be) for the preparation of compounds of formula I * wherein R hydrogen, lower alkyl, phenyl, a-halo-lower alkyl, a-amino (lower) alkyl, lower alkyl-substituted α- or β-amino - is (lower) alkyl, pyridyl or phenyl (lower) alkyl, R 'is formyl, A and R ₃ are as defined in the present specification and ^are listed in ^{the present} specification. with the proviso that R4 in the formula (a) may only be a substituent other than nitro and cyano, a compound of the formula (XIV) wherein A, R3, R'1 and ), preferably with chromium trioxide or manganese dioxide, and then the 3-aldehyde group of the compound of formula (XV) wherein R n is R 3, A and the above, if desired with alkyl Grignard or lithium reagent; and, if desired, preparing compounds of formula (I) wherein R 1 is hydrogen, lower alkyl, phenyl, a-halo-lower alkyl, a-amino-lower alkyl, is a lower alkyl substituent α- or (3-amino (lower) alkyl), pyridyl or phenyl (lower) alkyl, R '-COR10 ( wherein R10 is lower alkyl, and R3 and A are as defined in the parent ring, and the groups listed in the parent ring are provided with the proviso that R4 in the group of formula (a) is selected from nitro and cyano only. a different substituent may be an alcohol of formula XXII obtained in one of the above compounds of formula (I ') - wherein R ¹ is R ¹ above A and R3 are as defined in the present specification, R10 is lower alkyl and is reacted with an oxidizing agent of the above meaning, preferably chromium trioxide or manganese dioxide or, if desired, to produce compounds of formula (I *). wherein R 1 is hydrogen, lower alkyl, phenyl, a-amino-lower alkyl, lower-alkyl or 0-amino-lower alkyl, pyridyl-; is a group or a phenyl (lower) alkyl, R 'is -CH = N-R 1 group of formula (where R _t! are as defined above) and R _3, A and (^ are as defined above, optionally in the presence of 5 above proviso into any of the (XV) with a compound from the group of compounds of formula (XXXIV) - wherein A, R ₃ and represents a hydrogen atom as defined above, R 0 is and R Y ¹ is as last defined Ri report of ⁰ at - hydroxylamine, is reacted with a lower alkoxy-amine or of an H ₂ NR ₂₀ of a hydrazine of formula - wherein R _{2 O} di- ( lower alkyl) amino, if desired 5 for the preparation of compounds of formula (Σ '), wherein R 1 is an Rf substituent, R' is an aminomethyl group, and A, R ₃ and (2JT) are as defined above for a compound of formula (XXXV) wherein Rf is hydrogen, lower alkyl, phenyl, a-amino (lower) alkyl, lower alkyl or 0-amino (lower) alkyl, pyridyl or phenyl (lower) alkyl ⁵ , R 10 is hydrogen, R 23 is hydroxy or lower alkoxy, A and R 3 are as defined in the present specification, and (§ £) is with the proviso that the substituent R4 can only ciano. and nitro-groups (a) is generally ⁰ nos group X may be - hydrogen reducing agent, preferably in the presence of Raney nickel or c) (I ') are compounds of formula előállí- ⁵ TUSAN wherein R is hydrogen, a lower alkyl group, a phenyl group, the hydroxy (lower) alkyl group, a lower alkyl group substituted by a- is 0 or hydroxy (lower) alkyl group, a pyridyl group or ^3-phenyl (lower) alkyl group, R "is -CONRj ₂ R ₁₃ group of formula (wherein R ₃ is hydrogen and R ₃₂ and R ₃ , A and a compound of formula (XII) of the formula (Γ), wherein R ₃ , A and (ΖΓ) are as defined herein and R 1 'denotes the groups enumerated in process a), except for the α-halo and α-hydroxy (lower) alkyl group and the -CHO group - an H _{2 by} NR ₁₂ ammoniolating the amino compound of formula nos wherein R ₁₂ is as defined in the disclosure; obsession . d) reacting a (Γ) compounds of the formula wherein represents substituents listed process R c) R "-CONHNRi ₇ R ₈ group of formula (wherein R? ₇ and R ₈ are as defined above), and A, R ₃ and (HRC are as defined above, a, within the scope of formula (I ') A compound of formula, Ooi) a compound of formula - wherein R _3, A and (g £ have the meanings, R is a) in the process and R "'has the same meaning as R 1 above - with a compound of formula H ₂ N-NR ₁₇ R ₁₈ -4 387 - wherein R 17 and R 17 are as defined in the instant disclosure - subject to direct hydrazinolysis; obsession e) for the preparation of compounds of formula (I *) wherein R j is the substituent R [ ^x ] defined below, R '-COOR ₁₀ ! It refers to a group in which _R10 represents a lower alkyl group, R ₃ a lower alkyl group, and A and @ 2 are as defined above, a covered by (I *) of compounds of formula general ¹⁰ formula (XII ') the compound of formula - wherein R is as defined in method A), A and are as defined above, and R ^x is hydrogen, lower alkyl group, a phenyl group, a substituted lower alkyl group, a- or ^0-amino-15 - (lower) alkyl, pyridyl, phenyl (lower) alkyl or -CHO - is alkylated at the 4-position with a lower alkyl halide; obsession (For the preparation of compounds from the group ^{of 20} selected number of compounds of formula Γ), (XLII) - wherein _R10 is H, A, R ₃ and (Z% have the meanings as defined above - formula (XLI), E) a compound of formula - wherein Ac is a lower alkanoyl group, ²⁵ R, o are as defined above, A, R ₃ and (Zj [^ have the meanings as defined above - an alkali metal alkoxide or hydroxide, and then adding, if desired, (Γ) compounds of formula narrower compounds forming range (XXXIX) wherein front ³⁰ thereof, - wherein R ₀ is hydrogen, A, R ₃ and (ZjT frequency is obtained as defined above, with an above (XLII) of the compound of formula - wherein R ₀ is as defined above , A, and R ₃ have the meanings as defined above -, oxidizing agent preferably are treated with chromium trioxide or manganese dioxide; and thereafter for the preparation of 5,6-dihydro compounds of the formula (I '') wherein R 1, R ₂ , R ₃ , R _{6 4} θ and are as defined in the scope of the formula A, B), A compound of formula (I) prepared by any one of processes C) or D) - wherein R, R _2, R _3, A and Z 'have the meanings, (I') or (I '') wherein optionally with MEG ₄₅ except reducible groups under the conditions used - reducing agent, preferably platinum treatment with hydrogen in the presence of an oxide catalyst or with zinc in the presence of acetic acid; or N-oxides of formula (I) - wherein R 1, R ₂ , R ₃ , R ₆ and (Z 1 C) are as defined in the preceding claims - a compound of formula (I) obtained by any of the above processes A, B, C) or D) wherein R 1, R ₂ , R ₃ , A and (zT are as defined in the parent compounds (I ') and (I'') 55) - an organic persaw, preferably peracetic acid, perpropionic acid or m-chloroperbenzoic acid, and / or, if desired, converting a compound of formula (Ip, (1 ") or (I '") wherein R' is a group other than hydrogen, prepared according to any of the above processes, into a pharmaceutically acceptable salt. 04) A process for the preparation of process A), B), C) or D) according to claim 1 for the preparation of compounds of formula (I '), (I ") and (Γ") 65 and pharmaceutically acceptable salts thereof which are: (Γ) -C (R 1) = N-, where R e is phenyl, mono- or dihalophenyl or pyridyl, R 1 is hydrogen, lower alkyl, a-hydroxy- lower alkyl, a- (lower) alkanoyloxy-lower alkyl, phenyl, a-halo-lower alkyl, a-amino (lower) alkyl, lower alkyl-substituted or / 3-alkylamino (lower number of new-alkyl, pyridyl, phenyl (lower) alkyl or -CHO formula, R ₂ represents chlorine , bromine, iodine, α-hydroxy (lower) alkyl, lower alkanoyloxymethyl, lower alkoxymethyl, halomethyl, α-amino (lower) alkyl , cyano, cyanomethyl, lower alkanoylamino, small lower alkoxycarbonylamino group, a benzyloxycarbonylamino group, a substituted lower alkyl group, aminomethyl group, a -COOR ₀ group of the formula (wherein R _J0 is hydrogen or a lower alkyl group), -COR ₀ group of the formula (wherein Rio is as defined above), -CH = NR]! a group of formula (wherein R R 1 hydroxy group, a lower alkoxy group or di (lower) alkylamino group), -CONR ₂ Ri3 group of formula (in which R _J3 is hydrogen, lower alkyl group or is a phenyl group, and R _j2 a hydrogen atom, a lower alkyl group, a phenyl group or a - (CH _{2) n} NR ₄ R, represents a 5 group of formula, and in the latter group R _J4 and R ₅ lower alkyl is a group and n is an integer from 1 to 4; or R _t form a pyrrolidino group ₂ and R ₃ together with the nitrogen atom), or -CONH-NR ₇ R ₈ of the group (wherein R _t7 and R ₈ represents a hydrogen atom or formula lower alkyl), R ₃ is hydrogen or lower alkyl and (Z 2 is a), (b) or (d) wherein X is chlorine, bromine or iodine, T and Y are lower alkyl and R4 is hydrogen, halogen, nitro, cyano, trifluoromethyl or lower alkyl, and (I ') and (I') "), R ₁ , R ₃ and R ₆ are as defined above, R ₂ is as defined above for R _{2 with} the exception of chlorine, bromine, iodine, lower alkanoylamino, lower alkoxycarbonylamino and benzyloxycarbonylamino; -4489 (Z1) denotes a group of formula (a) or (b) wherein X and R4 are as defined above, characterized in that the appropriate starting materials are used and the desired subsequent steps are carried out. .) The method of carrying out the processes A), B), C), a), aa), ab), ac), ad), b), c) and d) according to claim 2, wherein (Γ), (I) ") or (Γ") compounds of the formula: and s pharmaceutically acceptable salts thereof, wherein R is hydrogen or lower alkyl; R ₃ hidrogénatornot, _E (which is (Γ R) compound of formula A csoportr ^ represents sec) phenyl or halophenyl group, an (Ζ1Γ either (a) a group of formula which R4 is nitro csoportqt halogen cane sugar, and the meaning of R ₂ and R ₂ is 3 in claim 2, wherein characterized by using the appropriate starting materials (Priority VIII, 07, 1975). The dental prodrug of process A), B), C) or D) according to claim 1 for the preparation of a compound of formula (I), (I ") or (I '") and pharmaceutically acceptable salts thereof, wherein: _R8 (which is part of group (I ') is obtained. compounds) is _2-halophenyl group, or (a) group and R 4 represents a halogen atom at the 8-position, & IRU formula. ^R ? The process of claim 1 wherein the appropriate starting materials are used and the desired subsequent steps are carried out. (Priority: 7/8/1975) A process for the preparation of process A), B), C) or D) according to claim 1 for the preparation of compounds of formula (I ⁵ ), (1 ") or (I '") and pharmaceutically acceptable salts thereof, wherein: R6 (which is part of Group A in the compounds of Formula ())) represents 2-chlorophenyl or 2-fluorophenyl, (Z) E, or @ 1 ( ^a ) wherein R4 is R ₂ , R ₂ and R ₃ are the same Claim 1, characterized in that the appropriate starting materials are used and the desired subsequent steps are carried out. (Priority: VIII, 07, 1975.) 6. The Ϊ. Process for the preparation of process A), B) or C) according to claim 1, for the preparation of compounds of formula (Γ), (I ") or (I '") and pharmaceutically acceptable salts thereof, wherein R 1 is methyl; , R ₂ , R ₆ , R ₂ , R ₃ , (and as defined in claim 1, characterized in that the appropriate starting materials are used. (Priority VHI 1975, 07). 7, in any method according to claim 1 foganatqsjtási rnodE, a (Γ), (I '), (Γ or' formula) compounds and their pharmaceutically acceptable salts _v thereof, wherein R ₃ methyl csoportpt, and A, R ₆ , R ₂ R ₂ , R _1; (Zj £ and (2V are as defined in claim 1, characterized in that the appropriate starting materials are used. (Priority: 07.07.1975)) A process for the preparation of process E according to claim 1, for the preparation of compounds of formula I ⁵ wherein R _{2 is} hydrogen and A, R 1, R ₃ and are as defined in claim 1, process E), to use the appropriate starting materials. (Priority: ⁵ April 1976) The aa), ab), b), be), c) of claim 1, d) or D process embodiment, a (Γ), (I ") or (I '') wherein the compounds and their pharmaceutically acceptable salts thereof, ⁰ wherein R ₂ and R ₂ a-hydroxy (lower formula ) alkyl, or carboxamido group karbonsavhidrazido- means, and A, _R6, R, and R _3s are as defined in claim, characterized in that the appropriate starting materials, ⁵ al parafin (Priority:. 1975 VIII 07th ) Aa), ab), b), c) or claim 1 according to claim 1 d) a process for the preparation of a compound of formula (I), (I ") or (Γ") or a pharmaceutically acceptable salt thereof, wherein R ₂ and R "are hydroxymethyl or -CONH- NH? or - CONH ₂ , and R ₁ , R ₁ , R ₃ , (21Q or, respectively, as defined in claim 1, characterized in that the appropriate starting materials are used. (Priority 1975, Vili, 07). Embodiment 11. A method according Aj Claim 1 aa), in) or c), is (Γ), (I '), (Γ or' formula) compounds and their gyógyászá- ¹⁰ tihg acceptable salts thereof, wherein (Zj means £ or 8-chloro-8-chloro-benzo- or thieno [3,2-f] groups, R is hydrogen or methyl, R ₂ and R 'is acetyl, or dimethyl karboxarnido- a carboxamido group (which in the compounds of formula (F) is a substituent} 2'-fluoro or 2'-chlorophenyl and R ₃ is hydrogen, characterized in that the appropriate starting materials are θ (Priority: 07-07-1975) 12. Process for the preparation of process b) according to claim 1 for the preparation of 8-chloro-6- (2-fluorophenyl) -3-hydroxymethyl-1-methyl-4H-imidazo [1,5-a] (1,4-benzodiazepine). characterized in that an 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid (lower) alkyl- the ester is reduced (Priority: Vililla 07, 1975). 13. A process according to claim 1 for the preparation of process b) or d) of 8-chloro-6- (2-fluoro-phenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine. For the preparation of 3-carboxylic acid hydrazide, characterized in that one 8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] beisodiazepine-3-carboxylic acid (lower) alkyl ester or chloride is reacted with hydrazine . ₅ (Priority: 7/8/1975) 14. The process of claim 1 a) or c) according to claim 1, which is 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine. For the preparation of 3-carboxamide, characterized in that an 8-chloro-6- (2) -fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid - (lower alkyl ester or chloride is reacted with ammonia. (Priority 19-5, VIII. 07) 1.5 ... The process of process aa or c according to claim 1, 8-chloro-6- (2-chlorophenyl) -1-methyl- -4 591 For the preparation of -4H-imidazo [1,5-a] thieno [3,2-f] [1,4] diazepine-3-carboxamide, characterized in that 8-Chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] thieno [3,2-f] [1,4] diazepine-3-carboxylic acid (lower carbon) (mu) alkyl ester or chloride was reacted with ammonia. (Priority: 7/8/1975) 16. A process according to claim 1 for the preparation of 8-chloro-6- (2-chlorophenyl) -1, N, N-trimethyl-4Himidazo [1,5-a] thieno [3,2-f] ] [1,4] diazepine-3-carboxamide, characterized in that 8-chloro-6- (2-> 0-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] thieno [ 3,2-f] [1,4] Diazepine-3-carboxylic acid chloride is reacted with dimethylamine. (Priority: 7/8/1975) 17 according to claim 1, in) ¹⁵ Process variant embodiment of 3-acetyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine preparation, wherein characterized in that 8-chloro-6- (2-chlorophenyl) -3- (a-hydroxyethyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine is oxidized. (Priority: 04.3.1976) 18. A process according to claim 1 for the preparation of 8-chloro-6- (2-chlorophenyl) -N, N-dimethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3. carboxamide, characterized in that 8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid chloride is reacted with dimethylamine. (Priority: 04.3.1976) 19. A process for the preparation of process aa) according to claim 1, 8-chloro-6- (2-chlorophenyl) -1, N, N-trimethyl-4Himidazo [1,5-a] [1.41] benzodiazepine-3-carboxamide characterized in that 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid chloride is reacted with dimethylamine. (Priority: 04.3.1976) 20. A process according to claim 1 for the preparation of 8-chloro-6- (2-fluorophenyl) -4 H -imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide. characterized in that a lower alkyl ester of 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid or chloride is reacted with ammonia. (Priority: 1976. III. 04.) 21. A process for the preparation of a pharmaceutical composition having muscle relaxant, sedative and anticonvulsant properties, wherein the compound of formula (Γ), (I ”) or (Γ”) is prepared by any one of the methods of claim 1 wherein A, R ₆ , R _n R ₂ , R ₂ , R ₃ , (Z ₂ and R ₁₎ , or a pharmaceutically acceptable acid addition salt thereof, as an active ingredient, into a pharmaceutical composition using an inert, non-toxic, pharmaceutically acceptable carrier. . III. 04)