Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/06—Peri-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
  • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
  • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines

Definitions

• the present invention is concerned with tetrahydroimidazo[1,4]benzodiazepines having the formula :
• R 1 is C 1-6 alkyl optionally substituted with aryl; C 3-6 alkynyl; C 3-6 cycloalkyl; or a radical of formula :
• Alk is C 1-6 alkanediyl
• R 8 and R 9 each independently are hydrogen, halo, C 3-6 cycloalkyl, trifluoromethyl, 2,2,2- trifluoroethyl, C 1-4 alkyl optionally substituted with C 1-4 alkyloxy;
• R 10 is hydrogen, halo or C 1-4 alkyl
• each R 11 independently is hydrogen or C 1-4 alkyl; or both R 11 taken together may form a C 1-6 alkanediyl radical;
• R 12 is hydrogen, halo or C 1-4 alkyl
• n 2, 3, 4, 5 or 6;
• each R 13 independently is hydrogen or C 1-4 alkyl; or both R 13 taken together may form a C 1-6 alkanediyl radical;
• R 14 is hydrogen or C 2-6 alkenyl
• n 0, 1 or 2;
• R 15 is C 1-6 alkyl, aryl, arylmethyl, C 3-6 cycloalkyl or (C 3-6 cycloalkyl) C 1-4 alkyl;
• R 2 is hydrogen or C 1-6 alkyl
• R 3 is hydrogen or C 1-6 alkyl
• R 4 and R 5 each independently are hydrogen, C 1-6 alkyl, halo, cyano, nitro,
• R 6 is C 1-6 alkyl
• R 7 is hydrogen or C 1-6 alkyl
• X is OH, SH or NR 16 R 17 ;
• R 16 is hydrogen, C 1-6 alkyl, aryl, cyano, hydroxy, amino, nitro, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl or arylsulfonyl;
• R 17 is hydrogen, C 1-6 alkyl or aryl; and each aryl is phenyl optionally substituted with from 1 to 3 substituents independently selected from C 1-6 alkyl, halo, hydroxy, C 1-6 alkyloxy, amino, nitro and trifluoromethyl.
• the compounds of formula (I) may also exist in their tautomeric form. Said tautomeric form, although not explicitly indicated in the above formula, is intended to be included within the .scope of the present invention.
• halo is generic to fluoro, chloro, bromo and iodo
• C 1-4 alkyl defines straight and branch chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl and the like
• C 1-6 alkyl defines C 1 -4 alkyl radicals as defined hereinabove and the higher homologs thereof having from 5 to 6 carbon atoms
• C 1-6 alkanediyl defines bivalent straight or branch chained hydrocarbon radicals containing 1 to 6 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof
• C 3-6 cycloalkyl defines cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• R 11 , R 13 and R 14 in the radicals of formula (a-2) and (a-3), when being as defined hereinbefore but other than hydrogen, is meant to replace a hydrogen atom of the -(CH 2 ) n - or the "CH" moiety in said radicals.
• the compounds of formula (I) may have several asymmetric carbon atoms .
• the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure.
• the absolute configuration of each chiral center may be indicated by the stereochemical descriptors R and S, this R and S notation corresponding to the rules described in Pure Appl. Chem. 1976, 45, 11-30.
• Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of the invention. Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures.
• Diastereoisomers may be separated by physical separation methods such as .selective crystallization and chromatographic techniques, e.g., counter current distribution, liquid chromatography and the like; and enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids.
• Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
• the compounds of formula (I) have basic properties and, consequently, they may be converted to their therapeutically active non-toxic acid addition salt forms by treatment with appropriate acids, such as, for example, inorganic acids, e.g. hydrochloric, hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, prop.anoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy- 1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesul
• salt form can be converted by treatment with alkali into the free base form.
• pharmaceutically acceptable acid addition salts also comprises the solvates which the compounds of formula (I) may form and said solvates are intended to be included within the scope of the present invention. Examples of such solvates are e.g. the hydrates, alcoholates and the like.
• R 1 is C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl or C 1-6 alkyl substituted with aryl or C 3-6 cycloalkyl
• R 4 and R 5 each independently are hydrogen, C 1-6 alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, C 1 -6 alkyloxy, amino or mono- or di(C 1-6 alkyl)amino
• R 7 is hydrogen
• R 2 , R 3 , X, R 16 , R 17 a nd aryl are as defined under formula (I).
• Particular compounds are those compounds of formula (I) or those compounds comprised within the abovementioned interesting group, wherein R 1 is C 1-6 alkyl optionally substituted with aryl, C 3-6 alkynyl or a radical of formula (a-1), (a-2) or (a-3); and/or R 4 and R 5 each independently are hydrogen, C 1-6 alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy or C 1-6 alkyloxy. More particular compounds are those particular compounds wherein R 1 is C 3-6 alkyl or a radical of formula (a-1) or (a-3); and/or R 5 is hydrogen; and/or R 6 is C 1-4 alkyl; and/or R 7 is hydrogen.
• a first particular subgroup comprises those more particular compounds wherein
• R 2 and R 3 each independently are hydrogen or methyl; and/or X is OH or SH.
• a second particular subgroup comprises those more particular compounds wherein R 2 and R 3 each independently are hydrogen or methyl; and/or X is NR 16 R 17 and R 17 is hydrogen.
• R 1 is C 3-6 alkyl or a radical of formula (a-1) wherein R 8 and R 9 each independently are C 3-6 cycloalkyl, trifluoromethyl or C 1-4 alkyl; or a radical of formula (a-2) wherein R 12 is hydrogen or C 1-4 alkyl; or a radical of formula (a-3) wherein n is 2 or 3.
• Particularly interesting compounds are tho.se interesting compounds wherein R 1 is propyl; methylcyclopropyl optionally substituted with one or two methyl groups and/or one 2-methylpropenyl group; methylcyclobutyl; 2-propenyl; 2-butenyl; 2-methyl-2-butenyl; 3-methyl-2-butenyl, 2,3-dimethyl-2-butenyl or 3-ethyl-2-pentenyl; and/or R 4 is hydrogen, methyl or chloro; and/or R 6 is methyl.
• the compounds of formula (I) can generally be prepared by reacting a
• L is a reactive leaving group such as, for example, halo, e.g. chloro, bromo.
• Appropriate reagents of formula B-X (III) are, for example, water, thiourea, an alkali metal thiosulfate, e.g. sodium thiosulfate, ammonia, mono- and di(C 1-6 alkyl)amines, mono- and di(aryl)amines, (C 1-6 alkyl)(aryl)amines, hydroxylamine, hydrazine and the like reagents.
• Said reaction can conveniently be conducted by stirring and optionally heating the reactants in a reaction-inert solvent such as, for example, water, an alkanol, e.g., methanol, ethanol, 1-propanol, 2-propanol, butanol, 1,2-ethanediol and the like; or an aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene and the like; a halogenated hydrocarbon, e.g. trichloromethane, tetrachloromethane, chlorobenzene and the like; an ether, e.g.
• a reaction-inert solvent such as, for example, water, an alkanol, e.g., methanol, ethanol, 1-propanol, 2-propanol, butanol, 1,2-ethanediol and the like
• an aromatic hydrocarbon e.g. benzene, methylbenzene, dimethylbenzene
• a dipolar aprotic solvent e.g. N,N dimethylformamide, N ,N-dimethylacetamide, dimethyl sulfoxide, 1-methyl-2-pyrrolidinone, pyridine, methylpyridine, dimethylpyridine, tetrahydrothiophene 1,1-dioxide and the like; or a mixture of such solvents.
• reaction-inert solvent as defined above.
• the reaction may be conducted at an elevated temperature, more particularly the reflux temperature of the reaction mixture.
• a base such as, for example, an amine, e.g. N,N-diethylethanamine, H-ethyl-N-(1-methylethyl)-2-propanamine, 4-methylmorpholine and the like amines.
• the compounds of formula (I) may also be obtained by M-alkylating an intermediate of formula (V) with a reagent of formula R 1 -W (IV) wherein W represents an appropriate reactive leaving group such as, for example, halo, e.g. chloro, bromo or iodo; or a sulfonyloxy group, e.g. benzenesulfonyloxy, 4-methylbenzenesulfonyloxy, methanesulfonyloxy and the like.
• W represents an appropriate reactive leaving group such as, for example, halo, e.g. chloro, bromo or iodo; or a sulfonyloxy group, e.g. benzenesulfonyloxy, 4-methylbenzenesulfonyloxy, methanesulfonyloxy and the like.
• Said N-alkylation reaction may conveniently be conducted in a reaction-inert solvent such as, for example, an aromatic hydrocarbon, e.g., benzene, methylbenzene, dimethylbenzene and the like; a lower alkanol, e.g., methanol, ethanol, 1-butanol and the like; a ketone, e.g., 2-propanone, 4-methyl-2-pentanone and the like; an ether, e.g., 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like; a dipolar aprotic solvent, e.g.
• a reaction-inert solvent such as, for example, an aromatic hydrocarbon, e.g., benzene, methylbenzene, dimethylbenzene and the like; a lower alkanol, e.g., methanol, ethanol, 1-butanol and the like; a ketone
• an appropriate base such as, for example, an alkali metal carbonate or hydrogen carbonate, e.g. sodium carbonate, sodium hydrogen carbonate ; sodium hydride or an organic base such as, for example, N,N-diethylethanamine or
• N-(1-methylethyl)-2-propanamine and the like may be utilized to pick up the acid which is liberated during the course of the reaction.
• an iodide salt preferably an alkali metal iodide, e.g. potassium iodide, is appropriate.
• Said reductive N-alkylation reaction may conveniently be carried out by
• Suitable solvents are, for example, water, C 1-6 alkanols, e.g. methanol, ethanol, 2-pr ⁇ panol and the like; ethers, e.g. 1,4-dioxane and the like; halogenated hydrocarbons, e.g. trichloromethane and the like; dipolar aprotic solvents, e.g. N,N-dimethylformamide, dimethyl sulfoxide and the like; esters, e.g.
• catalytic hydrogenation procedures means that the reaction is carried out under a hydrogen atmosphere and in the presence of an appropriate catalyst such as, for example, palladium-on-charcoal, platinum-on-charcoal and the like.
• an appropriate catalyst such as, for example, palladium-on-charcoal, platinum-on-charcoal and the like.
• an appropriate catalyst-poison to the reaction mixture, e.g., thiophene and the like.
• said reductive N-alkylation may alr ⁇ be performed following art-known reduction procedures by treating a stirred and, if desired, heated mixture of the reactants with a reducing agent such as, for example, sodium borohydride, sodium cyanoborohydride, formic acid or a salt thereof, in particular the ammonium salt thereof.
• a reducing agent such as, for example, sodium borohydride, sodium cyanoborohydride, formic acid or a salt thereof, in particular the ammonium salt thereof.
• Appropriate agents of formula (VIII) are for example urea, di(C 1-6 alkyl)carbonate, carbonoic dichloride, trichloromethyl chloroformate, 1,1'-carbonylbis[1H-imidazole], alkali metal, alkaline earth metal or ammonium isocyanates, phenyl isocyanate, benzoyl isoyocyanate, thiourea, carbonothioic dichloride, carbon disulfide, 1,1'-carbonothioyl-bis[1H-imidazole], xanthogenates, alkali metal, alkaline earth metal or ammonium isothiocyanates, phenyl isothiocyanate, benzoyl isothiocyanate, 1,3-dithiolane-2-thione, a guanidine salt, e.g., guanidine carbonate, hydrochlonde, nitrate and the like salts of guanidine, N-cyan
• Said condensation reaction may conveniently be conducted by stirring and optionally heating the reactants in a reaction-inert solvent, such as, for example, an aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene and the like; a halogenated hydrocarbon, e.g. trichloromethane, tetrachloromethane, chlorobenzene and the like; an ether, e.g. tetrahydrofuran, 1,4-dioxane, 1,1'-oxybisbutane, 1,1'-oxybis(2-methoxyethane), 1,2-bis(2-methoxyethoxy)ethane and the like; a dipolar aprotic solvent, e.g.
• a reaction-inert solvent such as, for example, an aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene and the like; a halogenated hydrocarbon, e.g. trichlorome
• a base such as, for example, a tertiary amine, e.g. N,N-diethylethanamine, N-ethyl-N-(1-methylethyl)-2-propanamine, 4-methylmorpholine and the like amines.
• the reaction can also be conducted conveniently in an alkanol such as, for example, methanol, ethanol, propanol and the like, in the presence of a base such as sodium or potassium hydroxide and the like or in carbon disulfide as solvent and in the presence of a suitable base such as, for example, an alkyl magnesium halide, e.g. ethyl magnesium bromide, an alkyl lithium, e.g. butyllithium, an amine, e.g., N,N-diethylethanamine, a carbodiimide, e.g.
• an alkanol such as, for example, methanol, ethanol, propanol and the like
• a base such as sodium or potassium hydroxide and the like or in carbon disulfide as solvent
• a suitable base such as, for example, an alkyl magnesium halide, e.g. ethyl magnesium bromide, an alkyl lithium, e.g. butyllith
• N,N-di- cyclohexylcarbodiimide and the like reagents may also be conducted in basic solvent such as, for example, pyridine and the like, in the presence of a phosphite such as, for example, diphenylphosphite.
• the compounds of formula (I-b) wherein X 1 is SH, said compounds being represented herebelow in their equivalent tautomeric form in formula (I-b-2), can be prepared by thionation of the compounds of formula (I-b) wherein ⁇ l is OH, said compounds represented by formula (I-b-1), with 2,4-bis(4-methoxyphenyl)-1,3-dithia2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) in an appropriate reaction-inert solvent
• solvents are for example, aromatic hydrocarbons, e.g. benzene, methylbenzene, dimethylbenzene, dipolar aprotic solvents, e.g. hexamethylphosphoric triamide (HMPA) and the like solvents.
• the compounds of formula (I-b-2) may also be obtained by thionation of the compounds of formula (I-b-1) with phosphorus pentasulfide.
• the compounds of formula (I-b-2) may also be obtained by direct thiation of a tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepine of formula (IX) with elemental sulfur at an elevated temperature.
• Said reaction may conveniently be conducted without a solvent at a temperature above 200°C, more particularly a temperature in the range of 230 to 250°C.
• the compounds of formula (I-b-2) may also be prepared by the combined reduction-thiocarbonylation of a 9-nitrobenzodiazepine of formula (X) in the presence of an alkali metal sulfide or hydrogen sulfide, and carbon disulfide.
• Said reduction-thiocarbonylation reaction may conveniently be conducted by stirring the reactants in a reaction-inert solvent, optionally at an elevated temperature.
• the compounds of formula (I) may also be prepared by cyclizing a benzimidazole of formula (XI) in a suitable reaction-inert solvent, optionally in the presence of a base and optionally at an elevated temperature.
• W represents a reactive leaving group as defined hereinbefore.
• Said cyclization reaction may conveniently be conducted by stirring, and, if desired, heating the starting material.
• Suitable solvents are, for example, aromatic hydrocarbons, e.g. benzene, methylbenzene, dimethylbenzene and the like, halogenated hydrocarbons, e.g. trichloromethane, tetrachloromethane, chlorobenzene and the like, ethers, e.g. tetrahydrofuran, 1,4-dioxane and the like, dipolar aprotic solvents e.g.
• Bases which may conveniently be employed in said cyclization reaction are, for example, alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, oxides, amides, hydrides and the like.
• a iodide salt preferably an alkali metal iodide, e.g. potassium iodide, may be advantageous.
• the compounds of formula (I) may also be converted into each other following artknown functional group transformation reactions.
• the compounds wherein R 16 and/or R 17 are C 1 -6 alkyl may be prepared by N-alkylating the compounds of formula (I) wherein R 16 and/or R 17 are hydrogen with a reagent (C 1-6 alkyl)-W, wherein W is a leaving group as defined hereinabove.
• R 16 is C 1-6 alkylcarbonyl or C 1-6 alkyloxycarbonyl
• R 16 is hydrogen with an appropriate acyl halide, e.g., acetyl chloride, propanoyl chloride and the like, a carboxylic acid anhydride, e.g., acetic anhydride, propanoic anhydride and the like, a C 1-6 alkylcarbonochloridate, e.g.,
• reaction products may be isolated from the reaction mixture and, if necessary, further purified according to methodologies generally known in the art.
• the intermediates of formula (II) can generally be prepared from the compounds of formula (I-b-1) by reaction with a halogenating reagent such as, for example, phosphoryl chloride, phosphorous trichloride, phosphorous tribromide, thionyl chloride, oxalyl chloride and the like reagents, optionally at an elevated temperature, in particular the reflux temperature of the reaction mixture, and optionally in the presence of a base such as, for example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate and the like.
• the reaction can be conducted in an excess of the halogenating reagent as solvent, optionally in admixture with a reaction-inert solvent such as, for example, an aromatic hydrocarbon or an ether.
• the benzodiazepin-7-ones of formula (XII) can be reduced to benzodiazepines of formula (XIII) with a complex metal hydride, e.g. lithium aluminum hydride and the like in a suitable reaction-inert solvent such as, for example, 1,2-dimethoxyethane, 1,1'-oxybis(2-methoxyethane), 2,5,8, 11-tetraoxadodecane, methoxybenzene and the like solvents.
• a complex metal hydride e.g. lithium aluminum hydride and the like
• suitable reaction-inert solvent such as, for example, 1,2-dimethoxyethane, 1,1'-oxybis(2-methoxyethane), 2,5,8, 11-tetraoxadodecane, methoxybenzene and the like solvents.
• a complex metal hydride e.g. lithium aluminum hydride and the like
• a suitable reaction-inert solvent such as, for example, 1,2-
• benzodiazepines of formula (XIII) can be dehydrogenated to intermediates of formula (XIV).
• Said dehydrogenation can be carried out by oxidation of (XIII) with permanganate or with manganese(IV)oxide.
• Said dehydrogenation reaction can be carried out in a suitable reaction-inert solvent such as, for example, water, an alcohol, e.g. methanol, ethanol and the like, an ether, e.g. 1,1'-oxybisethane, tetrahydrofuran and the like or a mixture of such solvents.
• the imine (XIV) may be obtained by reaction with nickel, platinum or chromium catalysts or in the presence of easily reducible substances such as sulfur, amyldisulfide, selenium or sodium amide in liquid ammonia.
• the benzodiazepines of formula (V) wherein R 7 is hydrogen, said intermediates being represented by formula (V-a), can be prepared from intermediates of formula (XIV) by reaction with organometallic compounds of formula R 6 -M, wherein M represents a metal group such as, for example, lithium, halo magnesium, copper lithium and the like, in a reaction-inert solvent such as, for example, an ether, e.g.
• tetrahydrofuran 1,1'-oxybisethane, 1,2-dimethoxyethane and the like
• a hydrocarbon e.g. hexane, benzene, methylbenzene and the like, or a mixture thereof.
• the benzodiazepines of formula (V), wherein R 4 is C 1-6 alkyl, said intermediates being represented by formula (V-b) and .said radical by R 7-a , can be obtained in a similar way.
• Dehydrogenation of (V-a) yields an imine, which can be converted to the 7-dialkylbenzodiazepine (V-b) with organometallic compounds of formula R 7-a -M, following the same procedures as described hereinabove for the preparation of (V-a) from (XIII).
• the intermediates of formula (V) can also be obtained from a benzylated compound of formula (I-c) following art-known hydrogenolysis procedures.
• Said debenzylation reaction can be accomplished by stirring a compound of formula (I-c) in an appropriate reaction-inert .solvent in the presence of a suitable metal catalyst and under a hydrogen atmosphere.
• suitable metal catalyst e.g. aluminum, magnesium, calcium, magnesium, calcium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium
• carboxylic acids e.g. acetic acid, propanoic acid and the like.
• suitable metal catalysts there may be mentioned palladium-on-charcoal, platinum-on-charcoal and the like catalysts.
• a catalyst-poison to the reaction mixture such as, for example thiophene.
• intermediates of formula (V) wherein X is SH may also be prepared by thionation of intermediates of formula (V-c-1) following the procedures described hereinabove for the preparation of the compounds of formula (I-b-2) from the compounds of formula (I-b-1).
• the intermediates of formula (VH) can generally be prepared from a 9-aminobenzodiazepine of formula (Vll-a) following N-alkylation reaction procedures such as described hereinabove for the preparation of the compounds of formula (I) and (I-a) from an intermediate of formula (V) with an alkylating reagent (IV) or with an aldehyde or ketone of formula (VI) as defined hereinabove.
• the aniline derivatives in the reaction scheme may conveniently be prepared by reduction of the corresponding nitrobenzene derivatives following art-known nitro-to- amine reduction procedures (reaction step A). Said reduction may conveniently be conducted by treatment of .said nitrobenzenes with a reducing agent such as, for example, a complex metal hydride, e.g. lithium aluminum hydride, sodium bis(2-methoxyethoxy)- aluminum hydride; a hydride, e.g. diborane, aluminum hydride and the like, in a reaction-inert solvent such as, for example, 1,1'-oxybisethane, tetrahydrofuran,
• a complex metal hydride e.g. lithium aluminum hydride, sodium bis(2-methoxyethoxy)- aluminum hydride
• a hydride e.g. diborane, aluminum hydride and the like
• a reaction-inert solvent such as, for example, 1,1'-oxybisethane
• 1,4-dioxane, 1,2-dimethoxyethane and the like optionally in the presence of a cosolvent such as an aromatic hydrocarbon, e.g. benzene, methylbenzene and the like, and, if desired, at an elevated temperature.
• a cosolvent such as an aromatic hydrocarbon, e.g. benzene, methylbenzene and the like, and, if desired, at an elevated temperature.
• said reduction may also be accomplished by treatment of said nitrobenzene derivatives with sodium dithionite, sodium sulfide, sodium hydrogen sulfide, titanium(III) chloride and the like reducing agents in a suitable solvent, in particular water.
• Said nitro-to-amine reduction may alr ⁇ be conducted following art-known catalytic hydrogenation procedures.
• said reduction may be carried out by stirring the reactants under a hydrogen atmosphere and in the presence of an appropriate catalyst such as, for example, palladium-on-charcoal, platinum-on-charcoal, Raney nickel and the like catalysts.
• Suitable solvents are, for example, water, alkanols, e.g. methanol, ethanol and the like, esters, e.g. ethyl acetate and the like.
• Raney nickel is used as reductant, it may be advantageous to add to the reaction mixture an adjuvant, in particular hydrazine.
• reaction mixture In order to enhance the rate of .said reduction reaction it may be advantageous to elevate the temperature and/or the pressure of the reaction mixture. Undesired further hydrogenation of certain functional groups in the reactants and the reaction products may be prevented by the addition of a catalyst poison such as, for example, thiophene and the like, to the reaction mixture.
• a catalyst poison such as, for example, thiophene and the like
• the nitrobenzene derivatives in the above reaction scheme 1 can be prepared from benzenamine derivatives following art-known nitration procedures (reaction step B).
• the starting materials may be nitrated by treatment with concentrated or fuming nitric acid in the presence of concentrated sulfuric acid and optionally in the presence of a cosolvent such as, for example, a halogenated hydrocarbon, e.g. dichloromethane, trichloromethane, tetrachloromethane and the like solvents.
• a cosolvent such as, for example, a halogenated hydrocarbon, e.g. dichloromethane, trichloromethane, tetrachloromethane and the like solvents.
• said nitration can in some instances also be accomplished conveniently by adding the nitrate salt of the starting material to concentrated sulfuric acid.
• the benzodiazepine derivatives (VII-H), (XV) and (XVI) may be obtained from the corresponding aniline derivatives (XVII), (XVIII) and (XIX) following the cyclization procedures such as described hereinabove for the preparation of the compounds of formula (I) from intermediates of formula (XI) (Reaction step C).
• Said aniline derivatives in turn, wherein W is a reactive leaving group as defined hereinbefore can be prepared from the corresponding alkanols by treatment with a halogenating reagent such as, for example, thionyl chloride, phosphoryl chloride, phosphorous trichloride and the like; or by treatment with a sulfonylating reagent, e.g. methanesulfonyl chloride, 4-methylbenzenesulfonyl chloride and the like (Reaction step D).
• a halogenating reagent such as, for example, thionyl chloride, phosphoryl chloride, phosphorous trichloride and the like
• a sulfonylating reagent e.g. methanesulfonyl chloride, 4-methylbenzenesulfonyl chloride and the like
• Said alkanols may be prepared by N.-alkylating appropriately substituted benzene derivatives of formulae (XXIII), (XXV) or (XXVI) with an aminoethanol derivative of formula R 1H NH-CH(R 2 )-CH(R 3 )OH (XXIV) following art-known N-alkylation procedures such as described hereinabove (Reaction step E).
• the intermediates of formula (XV) wherein R 1H and R 7 are both hydrogen, said intermediates being represented by (XV-a) can also be obtained by reacting an appropriately substituted nitrobenzene (XXVII) and a diamino reagent of formula (XXVIII).
• Y either hydrogen or a removable protective group such as, for example, C 1-6 alkylcarbonyl, e.g. acetyl, trichloroacetyl and the like, a benzyl group, a C 1-6 alkyloxycarbonylgroup, e.g. 1,1-dimethylethyloxycarbonyl, and the like groups commonly used to protect an amino group.
• Said reaction may conveniently be conducted by condensing the diamino reagent of formula (XXVIII) with the nitrobenzene of formula (XXVII), optionally removing the protective group by alkaline or acid hydrolysis or by catalytic hydrogenation and reducting the thus obtained intermediate (XXIX).
• Said condensation reaction can conveniently be conducted in a suitable reaction-inert solvent such as, for example, an alkanol, e.g. methanol, ethanol, 2-propanol, 1-butanol and the like; an aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene and the like; a halogenated hydrocarbon, e.g.
• trichloromethane tetrachloromethane and the like
• an ether e.g. tetrahydofuran, 1,4-dioxane, 1,1'-oxybisbutane, 1,1'-oxy(2-methoxyethane) and the like
• a ketone e.g. 2-propanone, 4-methyl-2-pentanone and the like
• a dipolar aprotic .solvent e.g. N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and the like; or a mixture of such solvents.
• a base such as an alkali metal or earth alkaline metal carbonate, e.g. sodium carbonate, sodium hydrogen carbonate and the like
• Said condensation reaction can conveniently be conducted at an elevated temperature, in particular at the reflux temperature of the reaction mixture.
• Said reductions in the above procedure may conveniently be conducted by reacting the intermediate imines with a suitable reductive reagent such as, for example, sodium borohydride, sodium cyanoborohydride and the like reductive reagents.
• the preparation of the intermediates of formula (VII-H) wherein R 3 is hydrogen, said intermediates being represented by formula (VII-H- ⁇ ) can be prepared following the reaction pathways described in scheme 2 hereinbelow. Reaction steps designated A through D are intended to refer back to the analogous reaction steps described in reaction scheme 1. In all of the following schemes, those compounds wherein R 3 is hydrogen, are designated by appending the suffix - ⁇ to their numerical reference.
• the intermediates of formula (VII-H- ⁇ ) can be prepared by reduction of a benzodiazepinone of formula (XXX) or (XXXI) with a complex metal hydride, e.g. lithium aluminum hydride; a hydride, e.g.
• reaction-inert solvent such as, for example, and ether, e.g. 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; optionally in the presence of a co-solvent such as an aromatic hydrocarbon, e.g. benzene, methylbenzene and the like; and optionally at an elevated temperature (reaction steps F and G).
• reaction steps F and G optionally at an elevated temperature
• the benzodiazepinones in scheme 2 can be obtained by cyclizing (reaction step H) the corresponding acyclic intermediates of formula (XXXIII), (XXXIV) and (XXXV), wherein R represents a group such as C 1-6 alkyl or aryl,
• a bifunctional catalyst such as, for example, acetic acid
• 2-hydroxypyridine, pyrazole, 1,2,4-triazole and the like in a reaction-inert solvent such as, for example, an aromatic hydrocarbon, e.g. methylbenzene, dimethylbenzene and the like; optionally at an elevated temperature; or
• halogenating reagent such as, for example, thionyl chloride and the like.
• the amide derivatives (XLVI), (XLVII) and (XLVIII) in reaction scheme 3 can conveniently be prepared by N-acylating an ethanolamine of formula (XXIV) wherein R 1H is H, said formula being represented by NH 2 -CH(R 2 )-CH(R 3 )-OH
• N-acylation reaction may be carried out by stirring the reactants in a reaction-inert solvent, optionally at an elevated temperature.
• said N-acylation reaction may also be carried out by treating the reactants with reagents capable of forming amides such as, for example, N,N-dicyclohexylcarbod ⁇ mide (DCC) optionally in the presence of a catalyst such as hydroxybenzotriazole (HOBT) or 4-dimethylaminopyridine (DMAP); 2-chloro-1-methylpyridinium iodide, 1,1'-carbonylbis[1H-imidazole], 1,1'-sulfonylbis[1H-imidazole] and the like reagents.
• DCC N,N-dicyclohexylcarbod ⁇ mide
• HOBT hydroxybenzotriazole
• DMAP 4-dimethylaminopyridine
• Suitable solvents are halogenated hydrocarbons, e.g. dichloromethane, trichloromethane and the like, ethers, e.g. tetrahydrofuran, 1,4-dioxane and the like, dipolar aprotic solvents, e.g. N,N-dimethylformamide, N,N-dimethylacetamide, pyridine and the like; or mixtures of such solvents.
• halogenated hydrocarbons e.g. dichloromethane, trichloromethane and the like
• ethers e.g. tetrahydrofuran, 1,4-dioxane and the like
• dipolar aprotic solvents e.g. N,N-dimethylformamide, N,N-dimethylacetamide, pyridine and the like; or mixtures of such solvents.
• stereochemically isomeric forms such as, for example, diastereomeric mixtures, enantiomeric mixtures, e.g. racemates and enriched
• Stereochemically isomeric forms of the intermediates described in the foregoing reaction schemes and of the compounds of formula (I) may be obtained by the application of art-known procedures.
• diastereoisomers may be separated by physical separation methods such as destination, selective crystallization, chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like techniques.
• Enantiomerically pure intermediates can conveniently be obtained from the enantiomerically pure isomeric forms of the appropriate starting materials, provided that the subsequent reactions occur stereospecifically.
• Particularly interesting enantiomerically pure starting materials for use in the foregoing reaction schemes are aminoacids and/or substituted derivatives thereof, having the formula R 1H NH-CHR 2 -COOR (XXXIX), and the corresponding aminoalkanols and/or substituted derivatives thereof, having the formula R 1H NH-CH(R 2 )-CH(R 3 )OH (XXIV) or (XXIV-a) (wherein R 1H is hydrogen).
• enantiomerically pure intermediates may also be obtained by separating the corresponding racemates for example, by the .selective crystallization of their diastereomeric salts with optically active resolving agents, chromatography of diastereomeric derivates, chromatography of the racemate over a chiral stationary phase and the like techniques.
• the compounds of formula (I) show antiviral and in particular antiretroviral properties.
• retroviruses were considered to be the pathogenic agents in a number of non-human warm-blooded animal diseases only, unlike viruses which have been known for quite some time to be the cause of a large number of diseases in warmblooded animals and humans alike.
• HAV Human Immunodeficiency Virus
• ARV ARV
• retroviral infections and the treatment of subjects suffering therefrom have received the utmost attention.
• the HIV virus preferentially infects human T-4 cells and destroys them or changes their normal function, particularly the coordination of the immune system. As a result, an infected patient has an everdecreasing number of T-4 cells, which moreover behave abnormally.
• the immunological defense system is unable to combat infections and neoplasms and the HIV infected subject usually dies by opportunistic infections such as pneumonia, or by cancers, rather than as a direct result of HIV infections.
• Other conditions associated with HIV infection include thrombocytopaenia, Kaposi's sarcoma and infection of the central nervous system characterized by progressive demyelination, resulting in dementia and symptoms such as, progressive dysarthria, ataxia and disorientation.
• HIV infection further has also been associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL) and AIDS-related complex (ARC).
• PDL progressive generalized lymphadenopathy
• ARC AIDS-related complex
• the compounds of formula (I), their pharmaceutically acceptable salts and the stereochemically isomeric forms thereof are useful in the treatment of warm-blooded animals infected with viruses, in particular retroviruses or for the prophylaxis of said warm-blooded animals.
• the compounds of die present invention may be useful in the treatment of warmblooded animals infected with viruses whose existence is mediated by, or depends upon, the enzyme reverse transcriptase.
• human retroviral infections include HTV and HTLV-I (human T-lymphotropic virus type I), causing leukemia and lymphoma.
• FeLV feline leukemia virus
• Conditions which may be prevented or treated with the compounds of the present invention, especially conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as, for example HTV mediated dementia and multiple sclerosis.
• the subject compounds may be formulated into various pharmaceutical forms for administration purposes.
• an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
• a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
• These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection.
• any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
• the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
• Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
• Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
• the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
• compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment
• Acid addition salts of (I) due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage.
• Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
• the present invention is also related with a method of treating viral diseases in warm-blooded animals suffering from said viral diseases by administering an effective antiviral amount of a compound of formula (I), a pharmaceutically acceptable acid addition salt or a stereoisomeric form thereof.
• an effective antiviral amount would be from 0.1 mg/kg to 200 mg/kg body weight, and in particular from 1 mg/kg to 50 mg/kg body weight It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day.
• Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
• unit dosage forms for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
• the 50% cytotoxic dose (CD 50 in ⁇ g/ml) was defined as the concentration of compound that rcduced the absorbance of the mock-infected control sample by 50%.
• the percent protection achieved by the compound in HIV-infected cells was calculated by the following formula :
• (OD T )HIV is the optical density measured with a given concentration of the test compound in HIV-infected cells
• (OD C ) HIV is the optical density measured for the control untreated HIV-infected cells
• (OD C ) MOCK is the optical density measured for the control untreated mock-infected cells; all optical density values were determined at 540 nm.
• the dose achieving 50% protection according to the above formula was defined as the 50% effective dow (ED 50 in ⁇ g/ml).
• the ratio of CD 50 to ED 50 was defined as the selectivity index (SI).
• the wet powder mixture was sieved, dried and sieved again.
• the whole was mixed well and compressed into tablets, giving 10.000 tablets, each containing 10 mg of the active ingredient.

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