IE41844L - Imidazodiazepines - Google Patents

Imidazodiazepines

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Publication number
IE41844L
IE41844L IE751973A IE197375A IE41844L IE 41844 L IE41844 L IE 41844L IE 751973 A IE751973 A IE 751973A IE 197375 A IE197375 A IE 197375A IE 41844 L IE41844 L IE 41844L
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formula
compound
hydrogen
lower alkyl
mixture
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IE751973A
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IE41844B1 (en
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Hoffmann La Roche
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Priority to IE222/79A priority Critical patent/IE41847B1/en
Priority to IE221/79A priority patent/IE41846B1/en
Priority to IE220/79A priority patent/IE41845B1/en
Publication of IE41844L publication Critical patent/IE41844L/en
Publication of IE41844B1 publication Critical patent/IE41844B1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02Muscle relaxants, e.g. for tetanus or cramps
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/20Hypnotics; Sedatives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic 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
    • C07D487/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12Heterocyclic 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 three hetero rings
    • C07D487/14Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Neurosurgery (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Imidazo[1,5-a][1,4]diazepine compounds of the formula <IMAGE> in which the symbols <IMAGE>, A, R1, R2 and R3 have the meaning given in Claim 1, analogues thereof as are defined in Claims 2 to 4, and pharmaceutical utilisable acid addition salts of these compounds have useful muscle-relaxant, sedative and anti-convulsive properties. They are particularly suitable for the preparation of injection solutions on account of the good water solubility of their acid addition salts. The compounds are prepared by dehydrogenation of the corresponding 3a,4-dihydro derivatives and optional N-oxidation, reduction or reaction with ethylene oxide or propylene oxide. [GB1527131A]

Description

io 41844 This invention relates to pharmacologically active imidazo[l,5-a3 Cl,43 diazepines. The chemical structure of these compounds may be depicted by the following formula: / wherein A is -C=N; R^ is hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, substituted phenyl, pyridyl or ar&lkyl; is hydrogen or lower alkyl; R^ is hydrogen or lower alkyl; is hydrogen, alkanoyloxy or hydroxy? Rg is phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl; and is selected from the group consisting of c (d) T i and^J or 15 20 wherein R4 is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, hydroxy lower alkyl or lower alkanoyl; X is hydrogen, chlorine, bromine or iodine; and T is hydrogen or lower alkyl; and the pharmaceutically acceptable salts thereof. - 2 - 4 18 4 4 Various analogous compounds derived from the above compounds, together with various novel intermediates leading to the above compounds, exhibit pharmacological activity per se are useful intermediates to pharmacologically active compounds. Certain of these compounds and intermediates are the subjects of Patent Specification Nos. t, / 2C k> >^4^29 7 / ' / Analogs of the above compounds which form a part of this invention include compounds of the formula 7Vr, ZA A lO wherein A is selected from the group consisting of (e) H <*> I ^ \ C » and C = N 20 R6 R6 \ « H wherein V = hydrogen or lower alkyl, vaJL is selected from the group consisting of formulae (a), (b) and (c) above, and , R2, R^ and Rg are as in Formula I above 15 except that in formula IA with A being structure (f) R4 is not nitro and Rg is not nitro-substituted, and the pharmaceutically acceptable salts thereof.
A particular group of compounds whith which the invention is concerned comprises compounds of formula I where /JJ is I *6 R is hydrogen or lower alkyl; R2 and are independently hydrogen or lower alkyl; R5 is hydrogen, alkanoyloxy or hydroxy; R4 is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, amino, hydroxy lower alkyl and lower alkanoyl; and Rg is selected from the group consisting of phenyl, mono- substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl, and analogs thereof corresponding to formula I but wherein A Is the group - 3 - 20 41844 H I / / C— N or -C=N I ^ I \ K " A. 0 and Rg is hydrogen.
As used in this disclosure, the term "lower alkyl* comprehends both straight and branched chain (C^-C^) carbon-hydrogen radicals, preferably C^-C^ carbon-hydrogen radicals such as methyl, ethyl, propyl, isopropyl and butyl.
By the term "lower alkanoyl" or "acyl" as utilized herein, an acyl moiety of a Cj-C7, preferably a Cj-C^, alkanoic acid is intended, e.g. acetyl, proplonyl, butyryl, i.e. moieties of the wherein R20 is Cj-Cg aliphatic hydrocarbyl or hydrogen. Also as utilized herein, the term "lower alkanoyl" comprehends a protected aldehyde or ketone such as an acetal or ketal having 2 to 7 carbon atoms, e.g. a group of the formula if 10 formula R20 *•' "20 15 wherein R20 is aliphatic hydrocarbyl or hydrogen. The ketal or acetal is utilized to prevent conversion of the contained ketone or aldehyde (R20 -C-) in r oxidation, reduction and condensation reactions.
The term "halogen" is used to include all four forms thereof, i.e., chlorine, bromine, fluorine and iodine.
The terms "aromatic and aliphatic sulfonyl group" comprehend compounds of the formula S02X' wherein X* is a branched or straight chain C1~C7, prefer;\bly Cj-C4, aliphatic hydrocarbyl group, e.g., methyl, or a substituted or un-25 substituted aromatic group such as a phenyl or substituted phenyl group, e.g. tolyl. - 4 - • 41844 The phenyl moiety Rg may be mono- or di-substituted provided that such di-substitution occurs in the 2,3; 2,5; or, most preferably, in the 2,6 position of the phenyl moiety. When the phenyl ring is mono-substituted the 5 substituent is preferably halogen or nitro and preferably the substituent is in the 2-position of the phenyl moiety.
When the phenyl ring is di-substituted the substltuents are preferably 2,6 or 2,5 di-halogen or 2,6 or 2,5 halogen-nitro. In the case of mono-substituted pyridyl, the preferred IO substltuents are halogen and nitro.
In the case of compounds of formula I in which substltuents Rj and R,. are not identical, optical isomerism will occur and such optical antipodes and racemates are within the ambit of this invention. 15 By the term "aryl" is meant a substituted or unsubstituted monocyclic aromatic moiety such as phenyl, chlorophenyl and tolyl.
By the term "alkoxy" is meant straight or branched chain saturated hydrocarbyloxy groups containing from 1 to 7 carbon 20 atoms, preferably from 1 to 4 carbon atoms, such as methoxy, ethoxy and propoxy.
By the term "substituted amino" herein is meant an -NH^ group which may be mono or disubstituted by lower alkyl, e.g. methylamino or dimethylamino groups, and an acyl amino group 25 e.g., acetylamino which may also be substituted on the nitrogen atom by lower alkyl or aryl e.g., methyl, phenyl or tolyl groups. 41844 By the term "aralkyl" is meant a hydrocarbon group having both aromatic and aliphatic structures, that is, a hydrocarbon group in which a lower alkyl H atom is substituted by a monocyclic aryl group, e.g., phenyl or tolyl.
Preferred compounds are those wherein R^ is hydrogen or lower alkyl, preferably methyl R-j and R,. are hydrogen; is "€X 10 15 20 wherein R^ is located preferably in the 8-position of the imidazobensodlazepine molecule and is hydrogen, nitro or halogen, preferably chlorine; A is -C=N^ I R6 wherein Rg is phenyl or halo, nitro, or lower alkyl substituted phenyl, preferably halo e.g., fluoro, with the fluoro substituted in the 2-position of the phenyl moiety e.g., IB wherein Rj^ and R2 are as defined in formula IB' below.
Thus an especially preferred genus included within the preview of the present invention comprises compounds of the formula - 6 - 41844 wherein R^' is hydrogen or lower alkyl preferably methyl, R^ is hydrogen, nitro or halogen, most preferably chlorine, and in a most preferred embodiment R4 is 5 positioned in the 8-position of the imidazobenzodiazepinc, Rg0 is phenyl or halo; nitro, or lower alkyl-substituted phenyl, preferably halo - substituted phenyl, with fluorine being the preferred halogen. Preferably the substituted fluoro is positioned in the 2-position 10 of the phenyl moiety. R2 is hydrogen or lower alkyl. - 7 - 41844 Another preferred class of compounds falling within the scopc of formula I are those wherein R^ •, R2» R^, R,., Rg and A are as in Formula IB' above and R^ is lower alkyl. preferably methyl, e.g., compounds of the formula Compounds of formula IC and their pharmaceutically acceptable salts exhibit optical isomerism. Such compounds have been resolved into their optical enantiomers by a procedure similar to the one generally outlined in Advanced 10 Organic Chemistry, L. Pieser and M. Fieser, 1961 pp. 85-88, Reinholt Publishing Co. Both the optical isomers and the racemic forms of compounds IC exhibit pharmacological activity. For example, in the case of the tartrate salt of compounds of formula IC the (+) isomer is considerably more 15 active than the (-) isomer. The less active (-) isomer may, if desired, be converted to the active racemic form thereof such as by treatment with a non-aqueous base, e.g., sodium tertiary bu-toxide in the presence of an organic solvent in which the isomer is soluble. - 8 - 41844 The expression"pharmaceutically acceptable Baits", Is used to Include salts with both inorganic and organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, 5 citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid and para toluene-sulfonic acid. Such salts can be formed quite readily by those skilled in the art, with the prior art and the nature of the compound to be placed in salt form, in view. 10 The roost preferred pharmaceutically acceptable acid addition salts of the compounds of formula IC and ID respectively are: 15 8-chloro-6-(2-fluorophenyl)-l-raethyl-4H-imidazo [i. 5-al [l, 4] benzodiazepine maleate; 8-chloro-l,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a^ Ql»benzodiazepine maleate.
It has been found that certain compounds of formula I in solution open to compounds of formula ID, ID R, 6 - 9 - 41844 wherein Y~ is the anion of an organic or inorganic acid, and R^, Rj, R^» and R( are as in formula I.
Such open compounds exist in a pH-dependent equilibrium In solution with compounds of Formula I i.e., their 5 corresponding ring closed compounds. The compounds of Formula ID can be isolated as acid addition salts by treatment of thei* corresponding closed ring compounds with an aqueous mineral acid followed by evaporation of solvent. When isolated, these salts, 10 which are also pa-t of the invention, exhibit pharma cological activity comparable to their corresponding closed ring parents.
The imidazo £l,5-a3£l,4j diazepine compounds of the formula I, their analogs of formula IA find the pharmaceutically 15 acceptable acid addition salts of these compounds can be prepared by the various process embodiments defined in Claim 1, hereinbelow. - 10 - 41844 Compounds of the formula IA whoro A is / -C=N I R 0 6 are formed by the conversion of corresponding formula I compounds into the N-oxides thereof. This conversion may 5 be effected for example by oxidising a formula I compound with an organic peracid. A conventional organic peracid, such as peracetic acid, perpropionic acid or m-chloroperbenzoic acid can be utilized in carrying out this reaction. The oxidation can be effected at room temperature, XO or above or below room temperature.
Compounds of the Formula IA where A is / -C=»N I >> 6 may be then utilized to produce compounds of Formula I wherein R^ is alkanoyloxy or hydroxy by methods known in 15 the art, such as, for example, a Polonvski rearrangement utilizing an acid anhydride to form the alkanoyloxy radical which may be converted to the hydroxy radical by treatment with an alkali metal hydroxide such as sodium hydroxide. An example of such a Polonovski rearrangement is found in 20 U.S. Patent No. 3,296,249 issued January 3, 1967 to S.C. Bell.
Compounds of the formula IA where A is i1 / -C -N I \ r6 h are formed by the reduction of corresponding formula I 25 compounds to compounds of the formula IA' - 11 - wherein RjyRj, R3 and 0C are as in Formula X and R4 is as in Formula X but is not nitro and Rg is as in Formula I but not nitro substituted phenyl or nitro substituted pyridyl (since nitro substltuents may be reduced to amino under the reaction conditions) which may then be converted to other compounds of the The reduction of formula X compounds to XA' compounds is accomplished by any suitable reducing agent but most preferably accomplished by hydrogen in the presence of a platinum oxide catalyst or zinc in the presence of acetic acid. These compounds (IA') may be converted to IA" compounds having an R^radical other than hydroxy by reaction with an alkyl or aryl sulfonyl halide, e.g. tosyl chloride, mesyl chloride, or lower alkanoyl group providing agent, e.g. acetyl chloride.
This process is conveniently effected in the presence of an inert organic solvent such as an alkanol, e.g., ethanol and methanol, an ether such as diethyl ether and tetrahydrofuran or dimethylformamide. Suitably, an acid acceptor is provided to accept the hydrogen halide formed when utilizing a halide, e.g., an aryl sulfonyl (e.g. tosyl) halide or am alkyl sulfonyl (e.g. mesyl) halide, with a compound of the formula XA' formula IA" H 7 wherein R^, R2, R^, R^ and Rg are as in formula XA' and R^ is hydroxy, acyl or an aromatic or aliphatic sulfonyl group. These compounds of formula XA" form the subject of Patent Specification No. ^ / - 12 - 41844 above. Preferred acid acceptors are tertiary amines, e.g., triethylamine and pyridine.
Temperature and pressure are not critical aspects of the first stage of the process involving the conversion of the compound of the formula I above to the corresponding compound of the formula IA. However, the reaction is most preferably effected at about room temperature and atmospheric pressure for the preparation of compounds ZA* and at room temperature and above for the conversion of compounds IA' to IA" bearing an R^ radical other than hydrogen Reduction of IA compounds wherein A is / -ON I \ R6 with hydrogen in the presence of platinum catalyst and acetic acid leads to IA" compounds wherein R7 is hydroxy.
Compounds of formula IA" wherein R^ is hydroxy, may be converted to the corresponding formula I unsaturated imine by treatment of the IA" compound with an acetic anhydride/pyridine mixture. No solvent is necessary for this reaction and temperature is not critical although the reaction is best effected at room temperature.
Compounds of formula IA" above wherein R^ is acetyl, mesyl or tosyl may be converted to the corresponding formula I unsaturated imine by treatment of the IA" compound with a non-aqueous base, e.g., potassium tertiary butoxide, in the presence of an inert solvent e.g., THF or DMF.
Such a reaction and the conditions at which it is run are well known in the art, see, for example U.S. Patent No. 3,625,957 issued December 7, 1971 to Fryer et al. 41844 Compounds of Formula IA* above may be converted to the analogous formula I unsaturated compounds by oxidation of the secondary amine at the 5-position. Such a selective oxidation may be accomplished by known 5 oxidants and reaction schemes see> for example, U.S. Patent No. 3,322/753 issued May 30, 1967 to Fryer et al.
Conversion of compounds of formula 1 wherein is amino to compounds wherein R^ is nitro may be suitably effected by, for example, the Sandmeyer Reaction wherein 10 the amino group is replaced by a nitro group. The treatment of a formula I compound wherein i8 amlnophenyl with excess sodium nitrite in the presence of a copper sulfate/ sodium sulfite mixture and utilizing as a solvent dilute sulfuric acid may result in an intermediate of the formula wherein R^, R2, R^ and Rg are as in Formula I, which may then be converted to an anlogous formula I compound. This process may be effected in a two-step sequence without isolation of the intermediate formed by treatment of the above formula XXIIZ' compound with phosphorus tribromide in an inert organic solvent e.g., dichloromethane at about -10° to 25°C (although temperature is not critical) and then subsequent treatment in 3itu with ammonia, preferably liquid ammonia which is allowed to warm to room temperature. - 14 - 41844 The Sandmeyer reaction has been found to also be applicable in producing compounds which contain a cyano, chloro or bromo group in place of a nitro group. Corresponding compounds of formula XXIII can be converted to their 5 ring closed analogs in the same manner as described above for nitro confounds.
It is obvious to one skilled in the art that certain other substltuents may also be attacked during the above reactions, but such vulnerable groups may be blocked b> a 10 suitable protecting group or modified before the above reaction sequence is carried out. Such methods of modifying or protecting groups subject to attack are well known in the art.
Compounds of the formula IA where A is C—N'C 6 v may be formed by the direct reaction of formula I compounds with ethylene oxide or propylene oxide in the presence of a Lewis acid catalyst (yielding a compound wherein V is hydrogen or methyl) or by the reaction of a compound of the 20 formula - 15 - 41844 R :hoh 3 2 XXIII c=o R, '6 wherein R^, R^. R3 eind Rc are as in Formula I (except that R^ is not amino or substantial amino) with phosphorus tribromide and subsequent treatment of the Intermediate (xxiv) with ethanolamlne, a 1-alkyl substituted ethanolamlne or a 2-alkyl substituted ethanolamlne as shown in the following reaction scheme: 16 41844 Trie ^p'-X"' r^"T" (DC ,d2C».f ? ° PBr, | . " "C-—W K K y> 6 v XXIII xxrv nh2 ch •v ia"* V is hydrogen or lower alkyl The compounds of formula xxiii may be formed by tho ro&o;ion of a compound of the formula Id with sodium nitrite in the prescnco of a compatible 5 'solvent such as water or dilute mineral acid. The temperature of the reaction may bo -10°c to room temperature. The reaction of Formula XX1I1 compounds with phosphorus tribromide is effected as illustrated above, preferably in an inert organic solvent such as dichloromethane at about room temperature although such temperature is hot critical. 10 The reaction of the compound of formula XXIV with ethanolamine or 1-alkyl or 2-alkyl substituted ethanolamine is effected in situ, in the presence of an inert solvent such as dichloromethane, at a temperature in the range -10°C to reflux, preferably about room temperature. - 17 - 41844 Tho diroct reaction of formula X compounds with ethylene oxido or propylene oxide is preferably catalyzed by a Lewis acid, e.g. titanium tetrachloride or boron trifluoride.
Za compounds of formula I and their analogs wherein the is present as a 8-posltlon substituent in an imidazobenzodiazepine, such ketal group nay be converted to an 8-position ketone by subjecting the ketal group to a mild aold hydrolysis. The 8-ketone can then 10 be converted to a 8-position secondary or tertiary alcohol which is racemic in nature. The reaction conditions for the above two steps, are found in U.S. Patent No. 3,846,410 issued November 5, 1974. 15 with ethylene oxide or propylene oxide to produce formula IA"' compounds i.e.* oxazolo type compounds. Reaction parameters and. conditions to effect such a reaction are known in the art, see for example U.S. Patent No. 3(868,362 Issued February 25, 1975 to Fryer et al. 5 ketal group e.g.
As stated above compounds of formula X may be directly reacted - 18 - 41844 Tbi comDounds of 'formula I above can be prepared according to the following novel process aspects which form a part of the present invention.
In one of the aforenentioned novel process aspects of this 5 invention, the compound* of formula X above may be prepared by the nitrosation of a conpound of the formula wherein A is -ON R, or -C=N I \ »6 ° d and R3 is hydrogen or lower alkyl and lO Rg are as described in formula I, to produce a compound of the formula ?*3 wherein A, R^ and in Formula II.
Ill <1 are as described 19 - 41844 Such a nitrosatlon may be affected by "in situ formed" nitrous acid.
Reagents which may be employed include (1) alkali metal nitrites, e.g^,sodium nitrite , in the presence of organio or inorganic acids, e.g., glacial acetic acid, and aqueous or non-aqueous solvents; (2) alkyl nitrites,e.g., methyl nitrite, 5 in the presence of an inert solvent such as an alcohol or a chlorinated hydro-or, for exanple, diinethylfannanide; and (3) a nitrosyl chloride solution in an inert solvent and in the presence of an acid acceptor such as pyridine. Such a nitrosatlon reaction should be affected at around or below room temperature, i.e., in the rang* of -20°C. to 25°C. f3 10 The 2-positlon nitroeoalXylamine, e.g., —H—NO, represents a "leaving group." Equivalent leaving groups which may be utilised as 2-positlon substltuents include groups such as alkoxide, e.g., -OCH_; alkylthio, e.g., -SCH^; halo, e.g., chloro; cyano, i.e., -CN, and phosphate.e.g. 15 alkoxide and alkylthio 2-positlon substltuents are well known in the art; see, for example, G. A. Archer and L. H. Sternbach, Journal of Organic Chemistry, 29, 231 0964) and U.S. Patent No. 3,681,341, issued August 1, 1972 to Fryer et al. 2 Reactions which form the - 20 - 418 4 4 Compounds of formula III may then be condensed with a nitroalkane to form a novel intermediate of the formula wherein is hydrogen or lower alkyl, and A, and The condensation reaction is effected with a nitroalkane, (Rj-CI^-NC^), e.5. nltromethane or nitroethane, in the presence of a base which is strong enough to generate the nitroalkane anion. Suitable bases include the alkali metal or alkaline earth metal alkoxides, e.g., potassium tertiary butoxide, amides, e.g., lithium amide or hydrides, e.g. sodium hydride. The reaction is preferably carried out in an inert solvent, such as dimethylformamide, dimethylsulfoxide, or an ether, e.g. THF, at temperatures below or above room temperature, i.e., in the range of -50°C. to 150°C., preferably at about room temperature.
The novel compounds of formula IV and formula V below, besides being major intermediates in the synthesis of compounds of formula I, also exhibit activity as central nervous system depressants.
Compounds of formula IV may then be catalytically hydrogenated, for example, with Raney nickel in the presence of hydrogen or by other reductants such as lithium aluminium hydride (with limitation that A is not N-oxide) to - 21 - 41844 producc o compound of tho formula 3 V wherein A is -C= , and R. are as 9 R e in Formula II, except that R4 is not nitro or cyano, and R is not nitro substituted> and R-, is hydrogen or lower alkyl. o The exclusion of nitro and cyano from the substituent groups present results from the conversion of nitro into amino and cyano into methylamino under the reaction conditions employed in the step IV—? V.
Solvents suitable for hydrogenatlon with Raney nickel include alcohols. ®.g., ethanol, ethers, e.g., THF and diethylether, hydrocarbon solvents, e.g. toluene and dimethylformamide. The reaction temperature may be above or below room temperature (i.e., -50°C. to 150°C.) and the reaction may be carried out with or without pressure, i.e. at a pressure of one atmosphere or higher.
Solvents suitable for hydrogenatlon employing a reductant such as lithium aluminum hydride Include ethers, o.g, THF, dioxane, diethylether and mixtures of ethers and hydrocarbon solvents, e.g., THF and benzene. The reaction may be carried out from below room temperature to reflux temperature, i.e., preferably in the range of - 50°C. to 60°C. - 22 - 41844 Tho compounds of formula V may then bo acyluted with un ucylotlng Oi;ent auch oa an acid halide or add anhydride, i.e., a group of tho formula RjCTCl or (RjCO) 20 wherein is as defined In formula I, e.^. ace tic anhydride and acetyl chloride, to produce a oenpound of the^ fomnia wherein A, R^, Rjarcl MX are aa described in Formula V, R^ ia aa in formula I and Y la hydrogen or -COR1.
In acylating the compounds of formula V to compounds of formula VI. there may be obtained a mixture consisting predominantly of the ncnoacylated product, i.e., wherein the NHg group of V (poaition2) Is converted to NHCOR^. and the diacylated product wherein both the NH^ of V (position 2) and 1-position nitrogen are acylated. The yield of diacylated product may be increased by subjecting the compounds of formula V to more rigorous conditions, i.e., excess of acylating agent and increased reaction time.
The acylation is preferably carried out in the prcscnce of an aqueous or non-aqucous solvent e.g., water, methylene chloride, benzene or chloroform, and preferably with an acid acceptor such as on organic or inorganic base such as trlcthylamine, pyridine or an alkali metal carbonate. The compounds of formula VI may then be cyclized to novel compounds of the formula - 23 - 41844 R 3 VII wherein A, R^, R2» R3 and 10 are as described in Formula VI.
The cyclization reaction is effected with a dehydrating agent such as phosphorus pentoxide, polyphosphoric acid or other acid catalysts, i.e., organic or inorganic acids e.g., conc. I^SO^. A solvent is not essential but a solvent such as an aromatic hydrocarbon solvent, e.g, toluene, xylene, may be employed. The reaction is carried out at a temperature in the range of from about 100°C to 200°C.
These compounds of formula VII form the subject of Patent Specification No. Ills'!?.
The compounds of formula V may also be reacted with an acylating agent such as an orthoester, e.g., triethylorthoacetate, an orthoamide, e.g., the dimethylacetal of N,N-dimethylformamide, or a compound of the formula P N-CH3 CH3 CH N -CH 3 N-CH 3 CH 3 24 41844 optionally in the presence of an acid catalyst, e.g., an organic or inorganic acid, e.g., £-toluene sulfonic acid or phosphoric acid, and at room temperature or above, i.e., 25°C. to 150°C., in which instance the cyclization to compound VII occurs spontaneously. Other useful acylating agents include esters, e.g., methyl acetate; amidines, e.g., acetamidine; nitriles, e.g., acetonitrile and ester imidates, e.g., a compound of the formula Ws CH3-C=NH 20 The compounds of formula VII may then be dehydrogenated to yield compounds of the formula IF 15 wherein A, R1# R2, r3 and are as described in formula VI. - 25 41344 Preferred reactants for the dehydrogenatlon include manganese dioxide and palladium on carbon although potassium permanganate may also be utilized. Solvents which may be utilized include chlorinated hydrocarbon solvents, aromatic S hydrocarbons and dimethylformamide. The dehydrogenatlon is carried out at room temperature or above, i.e., in the range of about 25°C. to 200°C.
The novel compounds of formula VII also exhibit activity as central nervous depressants. 10 The above novel process may proceed, if desired, from intermediate compounds IV or V to conpounds of formula IF without the requirement of isolating any formed intermediate compounds before proceeding to the next process step.
It should be noted that, in acylating the compounds 15 of formula V to the compounds of Formula VI when R^ is amino, the amino substituted R^ may also be acylated to acylamino. The acylamino may be converted back to amino by subjecting the compounds of Formula VII or Formula I to a mild hydrolysis. 26 41844 Also it has been found that conpounds of the formulas IV, V, VI and VII may exhibit both optical and geometric isomerism.
The reaction of a compound of the formula V with acctic acid and zinc or any other suitable reductants e.g., hydrogen in the presence of a catalyst e.g., platinum in dilute acetic acid solution, produces a compound of the formula Depending on the above method of reduction chosen, formula V' when Rj Is hydrogen can be Isolated as a racemic mixture of either of the two possible diastereomers. - 27 - 41844 A compound of the formula V' may be converted to the dihydroimidazo derivative of the formula VI1» *3 a wherein (zJ^,A, B2 and R3 are as in formula V' and R^ is hydro-5 gen or lower alkyl/ with retention of stereochemistry, by utilizing the direct reaction set forth above i.e. tho reaction of formula V compounds with an acylating agent such as an orthoester e.g., triethylorthoacetate and .maintaining the reaction parameters set forth above for such a reaction. 10 Compounds of formula VIZ' can also be prepared by reduction of a compound of formula VII by utilizing reductantB as mentioned above e.g., acetic acid and zinc or H^/platinum catalyst in dilute acetic acid, with the particular stereoisomer produced dependent on the reductant chosen. 15 Compounds of the formula VII' can, if desired, be oxidized directly to analogous compounds of the formula I using an oxidant such as manganese dioxide in toluene or benzene solution. Reaction conditions utilized and various alternate useful oxidants are found in U.S. Patent No. 3,322,753 issued May 30, 1967 to Fryer 20 et al. - 28 - 41844 Another process to produce tho novel intermediates of formula V where and Rg are other than nitro or cyano and is hydrogen consists of the reduction of conpounds of the formula wherein A is —C»N and R,, 8,1(1 R' L / *6 are as described in formula II except that R^ is not nitro or cyano and R^ is not nitro-substituted.
The reduction comprises the reaction of the compounds of formula X with a Known reductant such as Raney nickel in the presence of hydrogen or by other reductants such as lithium aluminum hydride. Solvents suitable for 10 hydrogenatlon with Raney nickel include alcohols e.g., ethanol, others e.g..
THF, hydrocarbon solvents e.g., toluene, and dimethylformamide. The reaction temperature may be above or below room temperature (i.e., -50°C. to 150°C.) and the reaction may be carried out with or without pressure, i.e., at a pressure of one atmosphere or higher. - 29 - 41844 Solvents suitable for hydrogenatlon employing a reductont^auch as lithium aluminum hydride include ethers, such as dioxane, diethyl other and THF. The reaction may be carried out from below room temperature to reflux temperature, - preferably in the rang* of -50°C to 60°C.
A variation of the above process comprises a mild add hydrolysis of the compounds of formula X to produce compounds of the formula The mild acid hydrolysis is suitably affected by a dilute mineral add. e.g., aqueous H^SO^ in aqueous alcohol. The reaction temperature may range from room temperature, i.e., about 25°C., to aboe* roan temperature, i.e., etoot 60"C.
The compounds of formula XI may then be reduced to the novel intermediates of fbmiia v.
Another process, although it does not form a part of the present invention, is useAil in produdng novel Intermediates of formulas IV and V. The following process is included in this specification for the sake of unity.
XI are as in formula X. 30 41844 Compounds of formula IV abovo may be produced by tfyu successive reaction of the compounds of the formula XII wherein A,- IZ|| and R3 are as in formula II, except that R4 is not amino or substituted amino, with dimorpholinophosphinic chloride to produce compounds of the formula XIII wherein A, ( « || and R3 are as in formula XII ; - 31 - 41844 which imlno phosphates are then (Unplaced by the anion of a nitroalkane to produce the novel intermediates IV.
The displacement reaction is effected with a nitroalkane, e.g.nitrontethane or nitroethane, in the presence of a base 5 which is strong enough to generate the nitroalkane anion. Suitably baseo incltide the alkali metal or alkaline earth metal alkoxides, hydrides, amides or hydroxides. The reaction is preferably carried out in an inert solvent, such as dimethylformamide, dimethylsulfoxide, or an ether, at temperatures below or above 10 room temperature, i.e., in the range of -50°C. to 150°C. - 32 - 41844 Another process to produce intermediates of formula IV wherein is hydrogen and a is an N-oxide comprises the ring expansion of compounds of the formulae aci or / wherein A is -C=N i.\ ««• a and R.^ are as described in formula II except that R4 is not amino.
The ring e*r>!ir.;icn comprises the reaction of the compounds of formulae VIII or IX with nltromethane in the presence of a base strong enough to generate the nltromethane anion. Suitable bases Include the alkali metal and alkaline earth metal alkoxldcs e.g., potassium tertiary butoxide, amides e.g., lithium amide or hydrides e.g.. sodium hydride. The reaction may preferably be carried out in an inert solvent such as anhydrous ether e.g. , TH F, dimethylformamide or dimethylsulfoxide, and at a temperature in the range of about -20°c. to 25°C. - 33 - - 41844 \ Compounds of the formulae I, IA and ID and their pharmaceutically acceptable acid addition salts are useful as muscle relaxants, sedatives and anticonvulsants and many are particularly useful when utilized in intravenous and 5 intramuscular preparations because of the acid addition salts' solubility in aqueous solution. As contemplated by this invention, the novel compounds of the formula I and their acid addition salts can be embodied in pharmaceutical dosage formulations containing from about 0.1 to about 40 mgs. most 10 preferably 1-40 mg with dosage adjusted to species and individual requirements. The novel conpounds of Formulae I, IA and ID and their pharmaceutically acceptable salts can be administered internally, for example, parenterally or enterally, in conventional pharmaceutical dosage forms. For example, they 15 can be incorporated in conventional liquid or solid vehicles such as water, gelatin, starch, magnesium stearate, talc and vegetable oils to provide tablets,^alixirs, capsules, solutions and emulsions according to acceptable pharmaceutical practices; and according to another aspect of the invention 20 a process for the manufacture of preparations having muscle relaxant, sedative and anti-convulsant properties comprises mixing a compound of formula I or an analog thereof or a pharmaceutically acceptable acid addition salt, as active substance, with a non-toxic, inert, therapeutically compatible 25 solid or liquid carrier commonly used in such preparations, and/or an excipient.
The following examples are illustrative but not limitative of the present invention. All temperatures are stated in degrees Centigrade. — J - 34 - 41844 Example 1 A solution of 200 g (0.695 m) of 7-chloro-l,3-dlhydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one in 2 1 of tetra-hydrofuran and 250 ml of benzene was saturated with methylamina 5 with cooling in an ice bath. A solution of 190 g (1 m) of titanium tetrachloride In 250 ml of benzene was added through a dropping funnel within 15 minutes. After addition the mixture was stirred and refluxed for 3 hours. Water (GOO ml) wac added slowly to the cooled reaction mixture. The inorganic TO material was separated by filtration and was washed well witn tetrahydrofuran. The water layer was separated and the organic phase was dried over sodium sulfate and evaporated. The crystalline residue of 7-chloro-5-(2-fluorophenyl)-2-methy1-amino-3H-l,4-benzodiazepine was collected, m.p. 204-206°. The 15 analytical sample was recrystalllzed from methylene chloride/ ethanol, m.p. 204-206°.
Sodium nitrite, 8.63 g (0.125 m), was added in three portions over a 15 minute period to a solution of 30.15 g (0.1 m) of 7-chloro-5-(2-fluorophenyl)-2-methylamino-3H-l,4-20 benzodiazepine in 150 ml of glacial acetic acid. After stirring for 1 hour at room temperature the reaction mixture was diluted with water and extracted with methylene chloride. The extracts were washed with saturated sodium bicarbonate solution, were dried over sodium sulfate and evaporated, at 25 the (Mid azootropicully with toluene to yield 29 g of crude - 35 - 41844 7-chloro-5-(2-fluorophenyl)-2-(N-nitrooomethylamino )-3H-l, 4-benaodiazepine as a yellow oil.
This material was dissolved In 100 ml of diaethylfor-aamide and added to a mixture of 200 ml of dimethylforaaaide, 5 50 ml of nltromethane and U.l g (0.1 m) of potassium t-buto-xlde which had been stirred under nitrogen for 15 minutes.
After stirring for 1 hour at room temperature, the reaction mixture was aoldlfled by addition of glaolal acetic acid, was diluted with water and extracted with methylene 10 chloride. The extracts were washed with water, dried over sodium sulfate and evaporated.
Crystallisation of the residue from ether yielded 7-chloro-l, 3-dihydro-5- (2-fluorophenyl )-2-nitromethy lene-2H-1,4-benzodiazepine, m.p. 170-172°. The analytical sample 15 was reorystallized from methylene chloride/ethanol, m.p. 174-176°.
A solution of 16.5 g (0.05 m) of 7-chloro-l,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-l,4-benzodiazepine in 500 ml of tetrahydrofuran and 250 ml of methanol was 20 hydrogenated with 5 teaspoons of fianey nickel for 2 1/2 hours at atmospherio pressure. Separation of the catalyst and evaporation of the solvent left crude 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine. - 36 - 41844 10 15 20 Propionic anhydride (20 ml) was added to a solution of 12 g of the above material in 300 ml of methylene chloride. The solution was added to 300 ml of 10% aqueous sodium carbonato and the two phase mixture was stirred at room tcmpo-raturo for 30 minutes. Tho orgnnic layer w/m :;oparntod, wash'.d with sodium carbonate solution and dried over sodium sulfate. Evaporation yielded crude 7-chloro-2,3-dihydro-5-(2-fluoro-phenyl)-2-propionylaminomethyl-lH-l,4-benzodiazepine.
This material was heated in 50 g of polyphosphoric acid at 150-170° for 10 minutes. The reaction mixture was cooled, dissolved in water and made alkaline with concentrated ammonia and Ice. The base was extracted with methylene chloride and the extracts were dried over sodium sulfate and evaporated. The residue was chromatographed over 300 g of silica gel using 20# methanol in methylene chloride. The clear fractions were combined, evaporated and the residue was crystallized from ether to yield 8-chloro-3a,4-dihydro-l-ethyL-6-(2-fluorophenyl)-3H-imidazo[l,5-a][l,4]benzodiazepine m.p. 131-133°.
A mixture of 3.4 g of 8-chloro-3a,4-dihydro-l-ethyl-6-(2-fluorophenyl)-4H-imidazo[l,5-a][l,4]benzodiazepine, 400 ml toluene and 30 g activated manganese dioxide was refluxed with separation of water in a Dean-Stark trap for 2 hours. The manganese dioxide was separated by filtration over Celite(trade mark) and the filtrate was evaporated. Crystallization of the residue from ether yielded 8-chloro-l-ethyl-6-(2-fluorophenyl)-4H- 37 41844 lmidazo[l,5-a][1,4]benzodiazepine, m.p. 140-143°. For analysis it was reorystalllzed from ether, m.p. 143-145°.
Bxamole 2 Aoetio anhydride (7 ml) was added to a solution of t 5 6.16 g of orude 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluoro-phenyl)-IH-1,4-benzodiazepine in 200 ml of methylene chloride. The solution was added to 200 ml of saturated aqueous sodium bicarbonate aad the mixture was stirred for 20 minutes. The organio layer was separated, washed with sodium bicarbonate, 10 dried over sodium sulfate and evaporated to leave resinous 2-acetylaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H- 1,4-benzodiazeplne. This material was heated with 40 g of polyphosphorlo acid at 150° for 10 minutes. The cooled reaction mixture was dissolved in water, made alkaline with ammonia 15 and ice and extraoted with methylene chloride. The extraots were dried and evaporated and the residue was chromatographed over 120 g of silica gel using 20 % methanol in methylene chloride. The olean fractions were combined and evaporated to yield resinous 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-l-20 methyl-4H-imidazo[l,5-a][l,4]benzodiazepine. A mixture of this material with 500 ml of toluene and 30 g of manganese dioxide was heated to reflux for 11/2 hours. The manganese dioxide was separated by filtration over Celite. The filtrate was evaporated and the residue was crystallized from ether to 25 yield 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidaao[l,5-a]-[1,4]benzodiazepine, m.p. 152-154°. The analytical sample was - 38 41844 recrystallized from methylene chloride/hexane.
Bxample 3 Reaction as in the first paragraph of Example 1 of 152.5 g (0.5 mi of 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-5 2H-l,4-benzodiazepin-2-one saturated with methylamine with 133 g (0.7 a) of titanium tetrachloride in 2 1 of tetrahydro-furan and 400 ml of benzene yielded 7-chloro-5-(2-chloro-phenyl)-2-methylamino-3H-l,4-benzodiazepine, m.p. 216-219°. The analytical sample was recryatallized from methylene 10 chloride/ethanol and had m.p. 217-219°.
Sodium nitrite (10 g, 0.145 m) was added in portions over 45 minutes to a solution of 22.4 g (0.07 m) of 7-chloro-5-(2-chlorophenyl)-2-methylamino-3H-l,4-benzodiazepine in 150 ml of glacial acetic acid. After addition stirring was continued 15 for 20 minutes under nitrogen. The product was precipitated by addition of ice-water, collected and dissolved in toluene. The solution was washed with saturated aqueous sodium bicarbonate, dried and evaporated under reduced pressure. The yellow viscous oil consisted according to thin layer chromatogram 20 mainly of the desired nitrosoamine. This material was dissolved in 100 ml of dimethylformamide and was added to a mixture of 30 ml of nltromethane, 100 ml of dimethylformamide and 10 g of potassium t-butoxide. The reaction mixture was 3lowly heated up to 85° with stirring under a nitrogen 25 stream. After 5 minutes, the reaction mixture was cooled, and then - 39 - 41844 acidified by addition of 10 ml of glacial acetic acid. The product was crystallized by gradual addition of water with seeding (seeda were obtained by chromatography over silica gel using 10$ ethyl noetate in methylene ohloridc). The separated 5 crystals vere colleoted, washed with water and reorystallized from methylene chloride/ethanol to yield 7-chloro-5-(2-chlorophenyl )-1,3-dihydro-2-ni tromethylene-2H-l,4-benzodiazepine, m.p. 182-185°.
Hydrogenatlon of 7 g of 7-chloro-5-(2-chlorophenyl)-10 1,3-dihydro-2-nitromethylene-2H-l,4-benzodiazepine in 300 ml of tetrahydrofuran and 1^0 ml of methanol in the presence of Raney nickel (5 teaspoonsful) for 1 hour yielded crude 2-aminomethyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-lH-l,4-benzodiazepine. This material was acetylated in the usual 15 fashion to produce oily 2-acetylanvinomethyl-7-chloro-5-(2-chlorophenyl) -2,3-dihydro-lH-l,4-benzodiazepine which was heated in 15 g of polyphosphoric acid for 10 minutes at 140-150°. The usual workup afforded a yellow resin which was chromato-graphed over 250 g of silica gel using 20# methanol in 20 methylene chloride.
The clean fractions left resinous 8-chloro-6-(2-chlorophenyl) -3a, 4-dihydro-l-methyl-4H-imidazo[ 1 ,5-a][1,4]benzodiazepine. This material was oxidized with 10 g of manganese dioxide in 200 ml of toluene. After heating to reflux for 25 1 1/2 hour, the manganese dioxide was separated and the filtrate was evaporated. Crystallization of the residue from _ 40- 41844 ether yiolded 8-chloro-6-(2-chlorophcnyl)-l-mt Sodium nitrite (8.63 g, 0.125 m) was add^d in three portions over a 15 minute period to a solution of 33.9 a (0.1 m) of 5-(2-chlorophenyl)-7-nitro-2-methylamino-3H- 1.4-benzodiazepine in 200 ml of glacial acetic acid. After - 41 - 41844 addition stirring waq continued for 1 1/2 hours at room temperature and the product was precipitated by addition of water. The yellow solids were collected, washed with water, sucked dry and recrystallized from ethanol to 5 yield 5-(2-chlorophenyl)-7-nltro-2-(N-nitrOBomethylamino)- 3H-1,4-benzodiazepine as yellow crystals with m.p. 164-166°. The analytical sample was recryBtallized from methylene chloride/ethanol, m.p. 167-169°.
A mixture of 3.58 g (0.01 m) of 5-(2-chlorophenyl)-10 7-nitro-2-(N-nitro80methylamino)-3H-l,4-benzodiazepine, 20 ml of dimethylformamide, 5 ml of nltromethane and 1.3 g (0.0115 m) of potassium t-butoxide was stirred at room temperature for 15 minutes under nitrogen. After addition of 2 ml of glacial acetic acid the reaction mixture was partitioned between 15 methylene chloride and water. The organic phase was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed over 80 g of silica gel using 10# (v/v) ethyl acetate in methylene chloride. Crystallization of the clean fractions from methylene chloride/ethanol 20 yielded straw colored crystals of 5-(2-chlorophenyl)-l,3-di-hydro-7-nitro-2-nitromethylene-2H-l,4-benzodiazepine with m.p. 240-243° (dec.).
Example 5 A solution of 33 g (0.1 m) of 7-chloro-2-(N-nitroso-25 methylamino)-5-phenyl-3H-l,4-benzodiazepine 4-oxide in 100 ml - 42 41844 of dimethylformamide was added to a mixture of 50 ml of nltromethane, 12.5 g (0.11 m) of potassium t-butoxide and 100 ml of dimethylformamide. The reaction mixture was stirred under a stream of nitrogen for 1 hour. After addition of 10 ml 5 of glaoial acetic acid, the product was crystallized by gradual addition of 250 ml of water. The precipitated yellow material was colleoted, washed with water, methanol and ether to leave 7-chloro-l, 3-dihydro-2-nitromethylene-5-phenyl-2H-l, 4-benzodiazepine 4-oxJ.de, m.p. 253-255° (deo.).The analytical sample was recryatal-10 lized from methylene chloride and shoved the same melting point.
Raney nickel (5 'oaapoons) was added to a solution of 16.5 g (0.05 m) of 7-chloro-l,3-dihydro-2-nitromethylene- 5-phenyl-2H-l,4-benzodiazepine 4-oxide in 500 ml of tetrahydrofuran and 250 ml of methanol. The mixture waa hydrogena- 15 tod for 5 hours at atmospheric proaaure. The catalyst waa removed by filtration and the filtrate was evaporated. The reaidue was diaaolved in 2-propanol and the solution was made atrongly acidic with ethanolic hydrogen chloride. The dihydrochloride of the product cryatallized upon evaporation 20 of part of the solvent. The orange crystals were collected to leave 2-aminomethyl-7-chloro-2,3-dihydro-5-phenyl-lH-l,4-benzodiazepine dihydrochloride, m.p. 230-240°.
Acetic anhydride (10 ml) was added to a solution of 10 g of the above dihydrochloride in 50 ml of water and 50 ml 25 of methanol. A 10# aqueous solution of sodium carbonate (100 ml) was added with stirring over a period of 5 minutes. After - 43 - 41844 addition the mixture was atirred for an additional ton minutes and was then extracted with methylene chloride. The extracts were washed with sodium carbonate solution, dried over sodium sulfate and evaporated, at the end 5 azeotropically with toluene. 2-Acetamidomethyl-7-chloro-2,3-dihydro-5-pheny 1-1H-1,4-benzodiazepine was obtained as a y«Uow resin.
The above material was heated in 50 g of polyphosphoric acid to 135-140° for 10 minutes. The initially orange color of 10 the reaction mixture faded to a light yellow. The cooled reaction mixture was dissolved in water, made alkaline with concentrated ammonia and ice and extracted with methylene chloride. The extracts were dried and evaporated. The yellow resin was dissolved in 2-propanol and treated with ethanolic hydTXjgen 15 chloride whereupon the colorless dihydrochloride of the product crystallized. Melting point was 240-245°.
This hydrochloride was partitioned between methylene chloride and aqueous ammonia. The organic phase was dried and evaporated. Crystallization of the residue from ether 20 yielded 8-chloro-3a,4-dlhydro-l-methyl-6-phenyl-3H-imidazo [l,5-a][1,4]benzodiazepine as a colorless product with m.p. 116-118°.
A mixture of 3.1 g (0.01 m) of 8-chloro-3a,4-dihydro-l-methyl-6-phenyl-3H-imidazo[l,5-a][l,4]benzodiazepine, 20 g 25 of activated manganese dioxide and 150 ml of toluene was - 44 - 41644 refluxed for 1 hour. The manganese dioxide was removed by filtration over Celite and was washed well with methylene chloride. The filtrate was evaporated and the residue was crystallized from other to yield 8-chloro-l-methyl-6-phenyl-5 4H-imidazo[l,5-a][l,4]benzodiazepine as colorleso crystals with m.p. 187-188®.
Example 6 A mixture of 11.2 g (0.1 m) of potassium tert.butoxide, 50 ml of nitroethane and 200 ml of dimethylformamide was 10 stirred at room tomper^urc for 15 min. A solution of 29 g (0.088 m) of crude 7-chloro-5-(2-fluorophenyl)-2-(N-nitroso-methylamino)-3H-l,4-benzodiazepine in 100 ml of dimethylformamide was then added and stirring under nitrogen was continued for 6 hrs. The reaction mixture was neutralized by 15 addition of glacial acetic acid and diluted with water. The product was extracted with ether. The extracts were washed with saturated aqueous sodiumbicarbonate solution, dried over sodium sulfate and evaporated. Crystallization from ether yielded 7-chloro-l,3-dihydro-5-(2-fluoropheny2)-2-(1-nitro-20 ethylene)-2H-l,4-benzodiazepine as yellow crystals with m.p. 136-142°.
Raney nickel (5 teaspoonsful) was added to a solution of 17.3 g (0.05 m) of 7-chloro-l,3-dihydro-5-(2-fluorophenyl)-2-(l-nitroethylene)-2H-l,4-benzodiazepine in 750 ml of tetra-25 hydrofuran. The mixture was hydrogenated at atmospheric pressure - 45 - 41844 for 4 hrs. The catalyst was removed by filtration over Celite and was washed well with methanol. The filtrate was evaporated to leave crude 2-(1-aminoethy1)-7-ohloro-2,3-dihydro-5-(2-fluorophenyl)-lH-l,4-benzodiazepine as a 5 reddish oil.
Thia material was dissolved in 300 ml of methylene chloride. Pollovlng the addition of 14 ml of acetic anhydride, 300 ml of saturated aqueous sodium bicarbonate solution was added and the two-phase mixture was stirred at 10 room temperature for 1 hr. The methylene chloride layer was separated, washed with bicarbonate, dried over sodium sulfate and evaporated. The residue was heated with 40 g of polyphosphoric acid for 10 minutes at 160-170°. The cool reaction mixture was diluted with water, made alkaline with 15 ammonia and extracted with methylene chloride. The extracts were washed with water, dried and evaporated to leave a brown residue which was chromatographed on 250 g of silica gel using 20# (v/v) methanol in methylene chloride. The thin layer chromatographically homogeneous fractions were combined 20 to yield a resin which was subjected to the following oxidation.
A mixture of the above material, 20 g of activated manganese dioxide and 300 ml of toluene was heated to reflux for 3 hrs using a Dean-Stark trap to remove the water. The manganese dioxide was separated by filtration over Celite 25 and was washed well with methylene chloride. The flltrato was evaporated and the residue was chromatographed with pressure - 46 - 41844 over 150 g of ailica gel H using 3# ethanol in methylene chloride. The first eluted major component was 8-chloro-l,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine.
It wae oonverted to a crystalline dihydrochloride by 5 treatment with ethanolic hydrogen chloride in ether, Mp. 247-250° (dec.).
The more polar component could be crystallized from methylene chloride/ether/hexane to yield 8-chloro-l,3-dimethy1-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine with 10 mp. 178-180e.
Example 7 A mixture of 3.1 g (0.01 m) of 8-chloro-l-methyl-6-phenyl-4H-imidazo[l,5-a][l,4]benzodiazepine, 2.15 g (0.0125 m) of m-chloroperbenzoic acid and 100 ml of methylene chloride 15 was stirred for 48 hrs. at room temperature. It was then washed with 10# aqueous sodium carbonate solution and water. The residue was chromatographed over 80 g of silica gel uBin^ 10# (v/v) of ethanol in methylene chloride. Tho Tlc-homogoncou:j fractions were combined and evaporated. Crystallization of the 20 residue from methylene chloride/ether yielded 8-chloro-l- methy1-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine 5-oxide, mp. 260-261°. - 47 - 41844 Example 8 A. solution of 1 g of 8-chloro-l-methyl-6-phenyl-4H-imidazo[l-5-a][l,4]benzodiazepine 5-oxide in 20 ml of acetic anhydride was heated on the steam bath for 24 hrs. The reagent 5 was evaporated undor reduced pressure the residue was crystallized from ether to yield 4-acetoxy-8-chloro-l-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine, mp. 200-201°.
Example 9 Sodium methexide (0.54 g) was added to a solution of 10 0.73 g (2 mmol) of 4-acetoxy-8-chloro-l-methyl-6-phenyl-4H- imidazo[l,5-a][l,4]benzodiazepine in 20 ml of methanol. After sitting at room temperature for 30 min, the solvent was evaporated under reduced pressure after neutralization with acetic acid. The residue was partitioned between methylene 15 chloride and sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. Crystallization of the residue from ether yielded 8-chloro-4~hydroxy-l-methyl-6-phenyl-4H-lmidazo[l,5-a][l,4]benzodiazepine, mp. 173-174°.
Example 10 20 A warm solution of 6.5 g (0.02 m) of 8-chloro-6-(2-fluo rophenyl) -l-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 30 ml of ethanol was combined with a warm solution of 2.6 g (0.022 m) of maleic acid in 20 ml of ethanol. The mixture was - 48 - 41844 diluted with 150 ml of ether and heated on the stcsm bath for 3 min. After cooling, the crystals were collected, waahed with ether and dried in vacuo to yield 8-chloro-6—(2-fluorophenyl)-l-methyl-4H-lmidazo[l,5-a][l,4]benzodiazepine maleate, op. 5 148-151®.
Bxamole 11 A mixture of 17.4 g (0.05 m) of 7-chloro-l,3-dihydro- 5- (2-fluorophenyl )-2- (1-nitromethylene )-2H-l, 4-benzodiazepine 4-oxide, 500 ml of tetrahydrofuran, 200 ml of methanol and 5 10 tcaspoonsful of Raney nickel was hydrogenated at atmospheric proanurc for 5 hrs. The catalyst was removod by filtratLon and the filtrate was evaporated,at the end azeotropically with xylene to leave crude 2-aalnomethyl-7-chloro-5-(2-fluorophenyl)-2,3-dihydro-lH-l,4-benzodiazepine. 15 This material was dissolved in 200 ml of ethanol and the solution was heated to reflux for 2 hrs. after addition of 14 ml of trlethylorthoacetate and 2.8 g of p-toluenesulfo-nic acid. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride 20 and 10# aqueous sodium carbonate solution. The organic layer was dried and evaporated to yield oily 8-chloro-3a,4-dihydro- 6-(2-fluorophenyl)-1-methyl-3H-imldazo[1,5-a][1,4]benzodiazepine. This crude product was dissolved in 500 ml of xylene.
After addition of 50 g of activated manganese dioxide, the ?.'> mixture was stirred and heated to reflux for 1 1/2 hrs with - 49 - 41844 separation of water in a Dean-3tark trap. Tho inorganic material was removed by filtration and the filtrate waa evaporated to leave 10 g of brown oil.
A warm solution of 4.65 g (0.04 m) of maleic acid in 5 50 ml of ethanol was added to this residue. After the solution was complete, the product was orystallized by addition of ether. It was collected and washed with ether to leave 8-ohloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [ 1,5-a] [1,4]-benzodlazeplne maleate, mp. 112-115°. Heating under vacuum 10 at 90° to 100° converts this product to the higher melting form with mp. 148°-lSl1-.
Example 12 A solution of 0.32 g (1 mmol) of 8-chloro-6-(2-fluoro-phenyl)-l-methyl-4H-imidaao[l,5-a][l,4]benzodiazepine in 5 ml 15 of ethanol was treated with excess ethanolic hydrogen chloride. The salt was crystallized by addition of 2-propanol and ether. The colorless crystals were collected, washed with ether and dried to leave 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imi-dazo[l,5-a][l,4]benzodiazeplne dihydrochloride, mp. 290-295°. 20 Example 13 A solution of 0.325 g (1 mmol) of 8-chloro-6-(2-fluorophenyl )-l-methyl-4H-imldazo[l,5-a][l,4]benzodiazepine in 3 ml of ethanol was combined with a suspension of 0.4 g (1 mmol) of - 50 - 41844 tho dihydrochloridc of tho sane compound in 5 ml of ethanol After filtration, the solution was treated with ether and heated on the eteaa bath for 5 min to crystallize. The crystals were oollected, washed with ether and dried to leave 8-chloro-5 6-(2-fluorophenyl)-l-oethyl-4H-imidazo[l»5-a][l,4]benzodiazepine hydrochloride, mp. 295-297°.
Example 14 A solution of 23.6 g (0.10 mole) of l,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 1 liter of tetrahydrofuran 10 containing about 20 moles of monomethylamine was chilled in an ice bath. To this mixture waB added 14 ml. (d=1.73, 0.125 mole) of titanium tetrachloride in 200 ml of benzene.
This mixture was stirred at room temperature for two dayB. The titanium complex was destroyed with 20 ml of water. 15 The inorganic salts that precipitated were removed by filtration, the solvent was evaporated in vacuo, and the residue partitioned between methylene chloride and water. A colorlcss amorphous solid mp. 227-229° was removed by filtration. An additional sample, mp. 226-229° of the.colorless solid was obtai-20 ned from the methylene chloride mother liquors after drying over anhydrous sodium sulfate, evaporation to dryness, and crystallization from ethyl acetate.
An analytical sample was prepared by recryBtallization from dimethylforaamide to yield colorless pri^ans, mp. 227-229°C. - 51 - 41844 To a coolcd (10°), stirred solution of 10.0 g (0.04 m) of the product, 2-mothylamino-5-phenyl-3H-l,4-benzodiazepine,in lOO ml of pyridine was added 100 ml of a saturated solution of nitrosyl chloride in acetio anhydride. The solution was stirred for 5 3.5 hr. during which time it was allowed to wars to ambient temperature. The solution was poured into 300 ml of ice-water, and the aqueous solution was extraoted with five 150 ml portions of methylene chloride. The combined organic extracts were washed with water and brine, dried (CaSO^), and the 10 solvent removed under reduced pressure affording a dark semi-solid. Chromatography on 500 g of silica gel (chloroform elution) afforded the r-(N-nitrosomethylamino)-5-phenyl-3H-1,4-benzodiazepine, mp 192-199° (dec.). This material waa used in the following step: 15 The conjugate base of nltromethane was prepared by treatment of 50 ml of nltromethane in 200 ml of dimethylformamide with 5.7 5 (0.05 m) of potassium tert-butoxide. The resultant stirred yellow suspension was treated with 10.9 g of crude 2-(N-nitrosomethylamino)-5-phenyl-3H-l,4-benzodia-20 zepine in 100 ml of dimethylformamide. The dark mixture thus obtained was Btirred for 2 hrs. at 25° and for 1 hr at 85° and then cooled to 25° and poured onto 1 1 of water. After acidification with acetic acid, the aqueous solution was extracted with four 250 ml portions of methylene chloride, 25 and the combined organic extracts were then washed with water and brine, dried (CaSO^), and concentrated in vucuo to givr. ?i dark oil which wan purified by chromatography over 1 kg of - 52 - 4 1844 nllica gol (CHClj elutlon) to afford crud». i, ;5-di^lydro-2-nitromothylcne-5-phe^yl-2H-l,4-benzodiazepine, mp. 131-142°.
An analytical sample, mp 141-142°, was prepared by recxystalllzation from ethanol. 5 A mixture of 8.4 g (0.03 a) of l,3-dihydro-2-nitrome- thylene-5-phenyl-2H-l,4-benzodiazepine, 75 ml of tetrahydro-furan, 75 ml of methanol and 2 teaspoonsful of Raney nickel was hydrogonated at atmospheric pressure for 6 hro. Tho catalyst was removed by filtration and tho filtrate wao 10 evaporated to leave crude 2-aminomethyl-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine.
This material was dissolved in 50 ml of methylene chloride and was treated with 6 ml of acetic anhydride and 200 ml of saturated aqueous sodium bicarbonate solution for 15 15 min. with stirring. The methylene chloride layer was separated, washed with bicarbonate solution, dried and evaporated. The residue was treated with 25 g of polyphosphoric acid to 130-150° for 15 min. The cooled Reaction mixture was partitioned between water and ether. The aqueous phase was 20 made alkaline with ammonia and was extracted with methylene chloride. The extracts were dried and evaporated. Chromatography of the residue over 70 g of silica gel with 20# (v/v) ethanol in methylene chloride yielded 3a,4-dihydro-l-methyl-6-phenyl-3H-imidazo[l,5-a][l,4]benzodiazepine as a light 2'> yellow reoin. - 53 - 41844 Thia material waa heated in 50 ml of toluene with 7 g of activated manganese dioxide to reflux for 1 1/2 hra. The inorganic material was filtered off and the filtrate was evaporated. The reaidue waa purified by chromatography over 30 g of ailica gel using 10# ethanol in methylene chloride. The clean fractions were combined and evaporated. Crystallization of the residue from ether yielded l-methyl-6-phenyl-4H-imidnzo[l,5-a][l,4]-benzodiazepine.
Example 15 To a stirred solution of 6 g (0.02 m) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -3-methy 1- 2H-1,4-benzodiazepin- 2-one in 100 ml of dry tetrahydrofuran was added 1.05 g (0.25 m) of 57# sodium hydride dispersion in mineral oil. The mixture was placed under argon and refluxed for 1 hr.
After cooling to room temperature, the mixture was treated with 7.4 g (0.03 m) of dimorpholinophosphinlc chloride and stirring under argon was continued at room temperature for 2 hrs. The mixture was filtered and evaporated at reduced pressure to give a gummy residue. Stirring the gum with 100 ml of anhydrous ether gave white crystals which were collected by filtration, washed with a little ether and air dried. 7-Chloro-2-di- (morpholino) -phosphiny loxy-5 - (2-fluorophenyl) - 3-methyl-3H-l,4-benzodiazepine thus obtained had a mp. of 90-95°.
A stirred solution of 2.4 g (0.04 m) of nltromethane in 50 ml of dry dimethylformamide was treated with 1 g (0.024 m) - 54 - 41844 of 571/* sodium hydride dispersion in mineral oil at room temperature under argon. After stirring for 1 hr. at room temperature, the mixture waa treated with 5.2 g (0.01 m) of 7-chloro-2-di(-morpholino)-phosphinyloxy-5-(2-fluorophenyl)-3-methy 1-5 3H-1,4-benzodiazepine in one portion and stirring under argon waa continued at room temperature for 24 hrs. The dark mixture waa poured over a mixture of ice and glacial acetic acid with stirring to give a yellow solid. Stirring wa3 continued until the ice had melted. The solid was filtered, washed with water 10 and air dried on the funnel to yield 7-chloro-l,3-dihydro-5-(2-fluorophenyl)-3-methy1-2-nitromethylene-2H-l,4-benzodiazepine having mp of ?15° (dec.). Recrystallization of a sample from 1:1 methanol/methylene chloride gave yellow needles, mp. 219-221° (dec.). 15 A solution of 5.2 g (0.015 m) of 7-chloro-l,3-dihydro- 5-(2-fluorophenyl)-3-methy1-2-nitromethylene-2H-l,4-benzodiazepine in 450 ml of 2:1 tetrahydrofuran-methanol was hydroge-natcd for 3 hrs. using a Parr apparatus, Raney nickel catalyst (3 teaspoonsful) and an initial pressure of 18 psi. The mixture 20 was filtered and evaporated at reduced pressure to give crude 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-3-methy1-1H-1,4-benzodiazepine as a yellow oil.
The crude aminomethyl compound was mixed with 5 ml of triethyl orthoacetate and 0.5 g of p-toluenesulfonic acid 25 monohydrate in 100 ml of ethanol. After heating under reflux for 2 hrs, the solution was evaporated at reduced pressure. - 55 - 41844 The residue was cooled to room temperature, treated with a mixture of ioe and concentrated ammonium hydroxide and extracted with methyleneohloride. Evaporation of the dried extracts in vacuo gave crude 8-chloro-3a,4-dihydro-l,4-dimethyl-6-(2-5 fluorophenyl)-3H-imldazo[l,5-a][l,4]benzodiazepine as a gum.
The crude dlhydroimidazobenzodiazepine was mixed with 20 g of aotivated manganese dioxide and 200 ml of toluene and heated under reflux for 2 hrs. The mixture was filtered and the manganese dioxide waa washed with methylene chloride. Evapora-10 tion of the combined filtrate and washings at reduced pressure gave a brown gum. The d*tydrochloride of 8-chloro-l,4-dimethy1-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]-benzodiazepine was obtained as a white powder by stirring the gum with ethanolic hydrogen chloride for a few minutes. The salt melted at 247-250°. 15 Example 16 Zinc duct, 3 g» va3 added to a solution of 2.8 g of b-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[1,5-a] [ 1,4 ] -benzodiazepine in 75 mi of methylene chloride and 75 ml of glacial acetic aoid. After stirring at room temperature for ?0 2 hrs, the inorganic material was filtered off and washed with methylene chloride and water.
The filtrate was diluted with 100 ml of methylene chloride and 200 ml of water and was made nlkuline with ammonia. The methylene chloride layer was separated, dried - 56 - 4 1844 and evaporated. Crystallization of the residue from ether/ hexane yielded 8-chloro-5,6-dihydro-6-(2-fluorophenyl)-l-methyl-4H-iaidazo[l,5-a][l,^benzodiazepine, mp. 200-203°.
Example 17 5 A mixture of 100 g (0.8 m) of chloroacetaldehyde dimethylaoetal and 100 ml of 1.5 N hydrochloric acid was heated under reflux for 15 min. and then coolcd and added to a solution of 130 g (0.5 a) of 2-aaino-2,-fluoro-5-nitro-benzophenone and 46 g (0.28 o) of hydroxylamine sulfate «nii 10 1 1 of ethanol. The mixture was stirred at room temperature for 2 hr. and then heated to reflux for 1.5 hr. The mixture was cooled and the product obtained by filtration. Recrystal-lization from a mixture of chloroform and methanol gave pure 2-chloromethyl-4-(2-fluor? phenyl)-6-nitro-l,2-dihyaroquina-15 zollne 3-oxide as yellow prisms, mp. 220-224°.
A solution of 142 g (0.423 m) of 2-chloromethyl-4-(2-fluorophenyl)-6-nitro-l,2-dihydroquinazoline 3-oxide in 2.3 1 of dichloromethane was treated with 400 g of manganese dioxide, and after stirring for 18 hr. the solution was filte-20 red. The manganese dioxide was washed with 600 ml of tetrahydrofuran and 800 ml of dichloromethane. The combined filtrates were concentrated to 400 ml and 1 1 of ether was added. This was cooled and filtered to give 2-chloromethyl-4-(2-fluorophenyl)-6-nitroquinazoline 3-oxide. A sample was 25 recrystallized from a mixture of dichloromethane and methanol - 57 - 41844 to give the pure product as pale yellow prisms, mp. 127-130°.
To 500 ml of dlmethylsulfoxlde and 75 ml (1.4 m) of nltromethane waa added with stirring under nitrogen 15.6 g (0.678 a) of lithium amide. After 30 minutea the solution 5 waa oooled to 5° and 104 g (0.31 m) of 3-chloromethyl- 4-(2-fluorophenyl)-6-nitroqulnazoline 3-oxide waa added alowly, keeping the temperature below 8°. After 68 hr. at room temperature the reaction mixture was poured into a mixture of 2.5 1 of ice and water and 25 al of acetic acid, and the solution waa filtered. 10 The gummy precipitate was dissolved in 1 1 of dichloromethane which was washed with aixute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated. The residue waa crystallized from ethyl acetate to give l,3-dihydro-5-(2-fluorophenyl)-7-nitro-2-nitromethylene-2H-l,4-benzodiazepine 15 4-oxide, and the filtrates were evaporated, disnolved in dichloromethane and filtered through a Bintorod glaao funnel containing 200 g of Plorisil (trade mark).The Florisil was eluted with dichloromethane (600 ml), ether (600 ml) and ethyl acetate (1.2 1). The ether and ethyl acetate fractions were combined 20 suid concentrated to give additional final product. A sample waa recrystallized from a mixture of tetrahydrofuran and hexane to give the pure product as yellow prisms, mp. 216-220°.
A suapenaion of 25 g (0.0698 m) of l,3-dihydro-5-(2-fluorophenyl)-7-nitro-2-nltromethylene-2H-l,4-benzodiazepine 25 4-oxide in 1.3 1 of abaolute ethanol waa treated with 10 teaapoona of Raney nickel and hydrogenated at atmospheric - 58 - 41844 pressure and room temperature for 9 hr. The mixturo waa filtered through Celite and the filtrate was evaporated to dryneou. A sample of the oil was crystallized from tetrahydrofuran to give the intermediate 7-amino-2-aminomethyl-l,3-dihydro-5-5 (2-fluorophenyl)-2H-1,4-benzodiazepine aa yellow prisms which melted with decomposition at 185-192°.
Without further purification, the oil obtained from the reduotion was heated under reflux for 2 hr. in a solution of 300 ml of absolute ethanol, containing 4.5 ml (0.0257 a) of 10 ethanolic hydrogen chloride and 50 g (0.309 m) of triethyl- orthoaoetate. The mixture was then evaporated to dryness and the residue was disBolveu in 150 ml of dichloromethane which was washed with 100 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness. 15 The reaidual oil, which waa crude 8-acetylamino-3a,4- dihydro-6-(2-fluorophenyl)-1-methyl-3H-imidazo[1,5-a][1,4]-benzodiazepine, was diasolved in 500 ml of benzene and treated with 100 g of activated manganese dioxide. The mixture was refluxed and stirred for 9 hr. using a Dean Stark trap. An 20 additional 25 g of activated manganese dioxide was added and after 4 hr. of refluxing the manganese dioxide was removed by filtration and was washed with 500 ml of tetrahydrofuran. The filtratea were combined and evaporated to dryness. The reaidual oil, whioh was 8-acetylamino-6-(2-fluorophenyl)-1-25 mothyl-4H-imidazo-[l,5-a][l,4]benzodiazepine, waa dleoolvcd in 75 ml of methanol and an excess of ethanolic hydrogen chloride waa added. After 10 min, 100 ml of water was added, - 59 - 41844 and after an additional 20 min, during which time tho 8-acetyl group was hydro ly zed, a mixture of ice and dilute ammonium hydroxide was added until the solution was basic. The reaction was filtered and the precipitate and filtrates 5 were extracted separately with dichloromethane. The extraots were dried, and evaporated. The extract from the filtrates were crystallized from isopropanol to give 8-amino-6-(2-fluorophenyl) -l-oethyl-4H-iaidazo-[1,5-a][1.4]benzod iazepine isopropanol and the *xtraot from the precipitate was chromato- 10 graphed through Florisil, first with dichloromethane and then with ether and ethyl acetate containing 10# (v/v) of methanol gave, after evaporation and crystallization from Isopropanol, additional product. Recrystallization of the combined products from isopropanol gave the product as white rods, m.p. 135-145°. 15 Example 18 A mixture of 17 g (0.05 m) of racemic 8-chloro-l,4-d imethy1-6-(2-fluorophenyl)-4H-imidaeo[1,5-a][1,4]benzodiazepine which had been obtained from its dihydrochloride by partitioning between methylene chloride and aqueous ammonia, 2o 18,8 g (0.05 m) of 0,0'-dibenzoyl-d-tartaric acid hydrate and 170 ml of ethanol was boiled until solution was complete. For crystallization the solution was allowed to sit overnight. The separated crystals were collected, washed with ethanol and ether to yield the 0,0'-dibenzoyl-d-tartrate with ra.p. 140-142°. 2s Rocryatallization from ethanol/ether yielded a product with m.p. 141-142° and [o]p^ - 43.39 (c = 1# in methanol).
- GO - 41844 A solution of 1.6 g (0.0106 m) of 1-tartaric acid in 11 ml of ethanol was added to a solution of 3.5 g of the levo-rotatory base liberated from the above 0,0*-dibenzoyl-d-tartrate in 11 ml of ethanol. The crystals obtained were collected and 5 washed with ethanol and other to yield (+)-8-chloro-l,4- dimothyl-6-(2-fluorophenyl)-4H-lmidazo[1,5-a][1,4]benzodiazopi-ne 1-tartrate, m.p. 178-180°. Recrystallization from ethanol gave product with m.p. 183-185° and [a+25.69° (c = 1.012# in methanol). The amorphous base liberated from this salt showed 10 a rotation of [«]^ -36.74° (c = 0.939# in methylene chloride).
Example 19 The mother liquor left after separation of the crystalline salt with 0,0'-dibenzoyl-d-tartaric acid described In the preceding example was evaporated and tecoaverted to the base by 15 partitioning between aqueous ammonia and methylene chloride.
The methylene ohloride solution was dried over sodium sulfate and evaporated to yield partly resolved base.
A solution of 9.7 g (0.029 m) of this material in 15 ml of ethanol was treated with a solution of 4-4 g of d-tartaric 20 acid in 14 ml of ethanol. The crystals which separated after several hours were collected to yield (-)-8-chloro-l,4-dimethyl-6—(2 -fluorophenyl)-4H-imidazo[l,5-a][lf4]benzodiazepine d-tartrate, m.p. 176-178®. Recrystallization from ethanol gave a product with m.p. 182-184° and [a]^° -24.96° (0.9616# in methanol). The 25 amorphous base liberated from this salt showed a rotation of [a]^5° +37.6° (c = 1.0# in methylene chloride). - 61 - . 41844 Example 20 A solution of 19-5 g (0.06 m) of 1,3-dihydro-7-(2-methyl-1,3-dioxolan-2-yl)-5-pheny 1-2H-1,4-benzodiazepin-2-one in 300ml of dry tetrahydrofuran was treated under an atmosphere of argon 5 with 3-1 g (0.075 a) of a 57$ suspension of sodium hydride in mineral oil. She mixture was heated under reflux for 1 hr., cooled to room temperature when 22.2 g (0.087 m) of dimorpho-llnophosphlnlc chloride was added. The mixture was allowed to stir at room temperature for 2 hr. and then stand overnight. 10 Sodium chloride was removed by filtration and the crude 7-(2-mothyl-1,3-dioxolan-2-yl)-2-[bis(morpholino)phosphinyloxy]-5-phenyl-3H-l,4-benzodiazepine was obtained by removal of the solvent and crystallization of the residue from ether.
A mixture of 100 ml of dry N,N-dimethylformeaide and 15 6.8 g of nltromethane was treated under an atmosphere of argon with 2.8 g (0.066 m) of a 57£ suspension of sodium hydride in mineral oil. The mixture was 3tirred for 1 hr. at room temperature when a solution of 18 g (0.033 m) of crude 7-(2-methyl-l,3-dioxolan-2-yl)-2[bis(morpholino)phoaphinyloxy] 5-phenyl-20 3H-1,4-benzodiazepine in 50 ml of dry N,N-dLmethylfonnamide was added. The reaction mixture was allowed to stand at room temperature for 15 hrs. when the dark viscous liquid was poured over a mixture of ice and dilute acetic acid. The bright yellow precipitate was removed by filtration, dissolved in dichloro-25 methane which was washed with dilute ammonium hydroxide and' water, dried over anhydrous sodium sulfate and evaporated. The - 62 - 41844 original filtrate was extraoted with dichloromethane which waa washed, dried and evaporated as above. The two crude residues were combined and chromatographed over Plorisil, Using dichloromethane, IO56 (v/v) other as the eluent and 5 monitoring the fractions by tic, several fractions containing the product vere collected and evaporated. Crystallization and reorystallization from a mixture of dichloromethane «nH hexane gave the pure 2,3-dihydro-7-(2-oethyl-l,3-dioxolan-2-yl)-2-nitromethylene-5-phenyl-lH-l,4-benzodiazepine as pale 10 yellow prlsmB, m.p. 158-161°.
Hydrogenatlon cf 5 g (0.0137 m) of 2,3-dihydro-7-(1-methyl-l,3-dioxolan-2-yl)-2-nitromethylene-5-phenyl-lH-1,4-benzodiazepine in 250 ml of absolute ethanol in the presence of 1 teaspoon of Raney nickel for 3-5 hours yielded 15 crude 2-aminomethy 1-2,3-dihydro-7-( 1-methyl-l,3-dioxolan-2-yl)-5-phenyl-lH-l,4-benzodiazepine. To a solution of 4 g (0.0119 m) of this compound in 75 ml of absolute ethanol was added 0.7 g (0.0037 m) of p-toluene sulfonic acid and 6 g (0.037 m) of triethyl orthoacetate. The mixture was 20 refluxed for 2 hours, evaporated to dryness and the residue waa dissolved in 50 ml of dichloromethane. This was washed with 25 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to give crude 3a,4-dihydro-l-me thy 1-8- (1-methyl-1,3-dioxo lan-2-yl) -6-phenyl-3H-±midazo [ 1,5-a] 25 [l,4]benzodiazepine as an oil.
A solution containing 3.8 g (0.0105 m) of this crude oil, - 63 - 41844 and 18 g of activated manganese dioxide in 100 ml of toluene was refluxed and stirred for 2 hours using a Dean Stark trap. The mixture was filtered and washed with a mixture of 250 ml of dichloromethane and 250 ml of tetrahydrofuran. The filtrates wore evaporated and diaoolvod in a small amount of isopropanol and treated with 1.4 g (0.0121 m) of maloic acid in ethanol. Ether was added and the precipitate was filtered and recrystallized from a mixture of methanol and ether to give l-methyl-8-(2-mothyl-l,3-dioxolan-2-yl)-6-phenyl-4H-imidaao[ 1,5-a] [1,4]-benzodiazeplne maleate methanol (2/1) as off white prisms, m.p. 179-182°.
Example 21 a solution of 0.3 g (0.1000607 m) of l-methyl-8-(2-methy 1-1,3-d ioxolan-2-yl) -o-phenyl-4H-imidaz o[l,5-aJ[l,4] benzodiazepine maleate methanol (2/1) in 10 ml (0.01 m) of IN hydrochloric acid was allowed to stand for 18 hours. A small amount of charcoal was added and the reaction mixture was filtered. The solution was made basic with ammonium hydroxide, extracted with 25 ml of dichloromethane, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in isopropanol and 0.35 g (0.10015 m) of ploric acid in 5 ml of ethanol was added. The solution was evaporated and the residue was crystallized from methanol. Reorystallization from a mixture of tetrahydrofuran and isopropanol gave 8-acetyl-l-methy 1-6-phenyl-4H-imidazo[l,5-a][l,4]benzodiazepine dipicrate as yellow prisms - 64 - 41844 m.p. 225-230°.
Example 22 A solution of 1 g (0.00317 m) of 8-acetyl-l-methyl-6-phenyl-4H-imldaz o[1,5-a][1,4]benzodiazepine dipicrate in 5 75 ml of absolute ethanol was treated with 0.78 g (0.0205 m) of sodium borohydride and after 18 hours the solution was evaporated to drynesB. The residue was acidified with dilute acetic acid, made basic with ammonium hydroxide and the mixture was extracted with 75 ml of dichloromethane. The 10 organic layers were combined, dried over anhydrous sodium sulfate and evaporated to dryness. The oil thus obtained was dissolved in isopropanol and 1.6 g (0.007 m) of picric acid in 20 ml of ethanol was added. The precipitated salt was filtered and recrystallized twice from methanol to give 15 8-(1-hydroxyethyl)-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]-benzodiazepine dipicrate as yellow rods, m.p. 223-225°.
Example 23 The filtrates from the reaction of Example 22 were concentrated and the crude product was filtered off. Re-20 crystallization twice from a mixture of tetrahydrofuran and methanol gave pure 8-(1-hydroxyethyl)-1-methy1-6-phenyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine dipicrate aa yellow rods, m.p. 143-145°. - 65 - 41344 Example 24 A solution of 56.4 g (0.20 mole) of l,3-dihydro-7-ethyl-5-(2-fluorophenyl)-2H-1,4-benzodlazepln-2-one in 2.0 1 of tetrahydrofuran containing 4 moles of monoaethyl-5 amine was chilled in an ice bath. To this was added 33.0 ml (0.30 mole) of titanium tetrachloride in 350 ml of benzene. The mixture was stirred at room temperature for three days.
The titanium tetrachloride was decomposed with 100 ml of water. The inorganic salts were removed by filtra-10 tion. The filtrate was evaporated to dryness in vacuo. The residue was partitioned between methylene chloride and water. The methylene chloride layer was dried over anhydrous sodium sulfate, evaporated to dryness in vacuo. The residue on crystallization from acetonltrile yielded 7-ethyl-5-(2-fluoro-15 phenyl)-2-methylamino-3H-l,4-benzodiazepine as light yellow prisms, m.p. 172-174°.
An analytical sample was prepared by recrystallization from acetonltrile to give light yellow prisms, m.p. 172-174°.
Sodium nitrite (8.6 g, 0.125 m) was added in three 20 portions over a 1/2 hour period to a solution of 29.5 g (0.1 m) of 7-ethy1-5-(2-fluorophenyl)-2-methylamino-3H-l,4-benzodiazepine in 100 ml of glacial acetic acid. After stirring for another 1/2 hour at room temperature, the mixture was diluted with ice-water and extracted with methylene - 66 - 41844 ohloride. The extracts were washed with water and aqueous bicarbonate, dried over 'sodium sulfate and evaporated to leave orude 7-ethy1-5-(2-fluorophenyl)-2-(N-nitrosomethy1-amlno)-3H-1,4-henzodiazepine aa a yellow oil.
The material prepared above was dissolved in 100 ml of dlxnethylformamide and the solution was added to a mixture of 100 ml of dimethylformamide, 35 ml of nltromethane and 9.9 g of potassium t-butoxide which had been stirred for 1/2 hour at room temperature. After completion of the addition,the reaction mixture was stirred for 1 hour at room temperature and for 30 minutes on the steam bath. The oooled solution was .. acidified with glacial acetic acid, diluted with water extracted with methylene chloride. The extracts were washed with water, dried and evaporated. The residue wa3 dissolved in 50 ml of ethanol and Wbo allowed to crystallize in the refrigerator overnight after seeding. The yellow crystals were collected and recrystallized from ethanol yielding 1.3-dihydro-7-ethy 1-5-(2-fluorophenyl)-?-nitromethy lene-2H- 1.4-benzodiazepine, m.p. 138-140°. Seed crystals were obtained by chromatography of the crude product over 40-fold amount of Bilica gel using 5# (v/v) of ethylacetate in methylene chloride. The analytical sample was recrystallized from ether/hexane, m.p. 138-141°. 1,3-Dihydro-7-ethy1-5-(2-fluorophenyl)-2-nitromethylonc-2H-1,4-benzodiazepine (2.6 g) waB hydrogenated for 4 hours with Raney nickel (1 teaspoonful) in 30 ml of ethanol. The catalyst - 67 _ 41844 wiiu Mtipnral'jd by f| Lt.ruti.ori mul the riil.ml.it w;i:i ovn|K>mti-ii. Tho residue wan dissolved In ether and the amine was extracted with 10^ aqueous acetic acid. The extracts were washed with ether and made alkaline with ammonia. The precipitated amine 5 waa extracted with methylene chloride. The extraots were dried and evaporated to leave 1.5 g of orude 2-aminomethyl-2,3-dihydro-7-ethyl-5-(2-fluorophenyl)-lH-lf4-benzodiazepine. This material was dissolved in 50 ml of xylene. The solution was then heated to reflux for 2 hours after addition of 3 ml of triethyl-10 orthoacetate. The residue obtained after evaporation under reduced pressure was chromatographed over 50 g of silica gel using 20f> methanol in methylene chloride. The homogenous fractions were combined and evaporated to yield 3a,4-dihydro-8-ethyl-6-(2-fluorophenyl)-1-methyl-3H-imidazo[1,5-a][1,4]-15 benzodiazepine. This material was dissolved in 50 ml of toluene and the solution was heated to reflux for 1 hour after addition of 5 g of activated manganese dioxide. The inorganic material was separated by filtration and the filtrate waa evaporated. The residue was dissolved in ether and treated with ethanolic 20 hydrogen chloride and acetone. The crystalline dihydrochloride (m.p. 248-255°) was collected and reconverted to the base by partitioning between methylene chloride and aqueous ammonia. The methylene chloride layer was dried and evaporated. Crystallization of the residue from ether/hexane yielded 8-ethyl-25 6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazc— pine, m.p. 152-154°. - 68 - 41844 Example 25 Sodium nitrite (27.6 g, 0.4 m) was added in portions over a period of 30 minutes to a solution of 90.45 g (0.3 m) of 7-chloro-5-(2-fluorophenyl)-2-methy1amino-3H-1,4-benzodiazepine in 400 ml of glacial acetic acid. Following Cv^aple-tlon of the addition, the mixture was stirred at room temperature for 1 hour and was then diluted with 1 1 of water and extracted with methylene chloride. The extracts were washed twice with water and then with 10% aqueous sodium carbonate solution. The solution was dried and evaporated to yield crude 7-chloro-5-(2-fluorophenyl)-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepine as a yellow oil. - 69 - 41844 Example 26 To 5 ml of aoetlc anhydride was added 0.3 g (0.00082 m) of 8-amino-6-(2-fluorophenyl)-1-methyl-4H-imidazo[l,5-a][1,4]-benzodiaaeplne Isopropanol and the reaot ion mixture was heated on the ate Jim bath for 1 hour, and then evaporated to dryness. The reaidue was dissolved in 25 ml of dichloromethane which was washed with 15 ml of 5 potassium oarbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness. The product was recrystallized twice from a mixture of methanol 10 and ethyl acetate to give 8-acetamido-6-(2-fluorophenyl)-l-mothyl-4H-imidazo[l,5-e]rl,4]benzodiazepine as white rods, m.p. 326-331°.
BTample 27 A solution of 0.8 g (0.0024 m) of 8-acetamido-6-(2-fluo-^5 rophenyl)-l-methyl-4H-imidazo[l,5-a][l,4]benzodiazepine in 10 ml of dry N,N-dimethylformamide under nitrogen was treated with 0.13 g (0.003 m) of 55# sodium hydride in mineral oil and after 30 minutes the reaction mixture was oooled in an ice bath. To the stirred reaction mixture o.43 g (0.003 m) of methyl iodide was 2o added and after 18 hours at room temperature the reaction mixture was poured into water. Filtration afforded the crude product which was recrystallized from a mixture of ethyl acetate and ether to give 6-(2-fluorophenyl)-1-methy1-8-(N-methy lacetamido) -4H-imidazo [ 1,5-a] [ 1,4 ] benzodiazepine 25 as off white prisms, m.p. 217-223°. - 70 - 41844 Example 28 A solution of 0.3 g (0.000828 m) of 6-(2-fluorophenyl)-1-methy 1-8- (JJ-methylacetamido) -4H-imidazo[ 1,5-a] [ 1, ^benzodiazepine in 10 ml of methanol was treated vith 3 ml of concentra-5 ted hydrochloric aoid and refluxed for 1 hour. The solution was made basic with ammonium hydroxide and then partitioned between 50 ml of dichloromethane and 50 ml of water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was dissolved in 10 ml of dichloro-10 methane and filtered though Plorisil. It was eluted with «ther/ ethyl acetate and finally ethyl acetate containing 5# methanol. This last mixture was evep.rated and the residue crystallized from a mixture of ethyl acetate and ether to give 6-(2-fluorophenyl)-1-methy1-8-methylamino-4H-imidazo[l,5-a][l,^benzodiazepine as off white 15 prisms, m.p. 255-259°.
Example 29 A solution of 0.3 g (0.00082 m) of 8-amino-6-(2-fluoro-phenyl)-1-methyl-4H-imidazo[l,5-a][l,4]benzodiazepine isopropanol in 0.5 ml of sulfuric acid was treated with 4 g of ice 20 followed by 0.2 g (0.0029 m) of sodium nitrite. After 5 minutes this was added to a fresh solution prepared by adding 1 g (0.00625 m) of copper sulfate in 10 ml of water to 1 g (0.00794 m) of sodium sulfite in 5 ml of water and then adding this to 8 g (0.116 m) of sodium nitrite in 40 ml of water. 25 After 15 minutes the reaction mixture was wanned to 35° for 5 minutes 41844 made basic with 10# potassium carbonate solution and extracted with 100 ml of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated and applied to a silica gel thick layer plate. This was developed 5 in a mixture of othyl acetate and ethanol (10/1), and the spot having an Rf of 0.5 was scraped off. Crystallization from methanol and reorystallisation from a mixture of dichloromethane and ether gave (2-fluorophenyl)-[2-(5-hydroxymethy1-2-methy 1-1-imldazoly 1)-5-nitrophenyl]methanone as off white 10 prisms, m.p. 188-192°.
Bxamr?.e 30 A solution of 0.5 g (0.00137 m) of 8-amino-6-(2-fluorophenyl)-! -methyl-4H-imidazo[l,5-a][l,4]benzodiazepine isopropanol in 20 ml of formic acid and 5 ml (0.062 m) of 37# formal-15 dehyde waB heated on the steam bath for 3 hours, and then evaporated to dryness. The residue was dissolved in 50 ml of dichloromethane, which was washed with 15 ml of 10# potassium carbonate solution, dried over anhydrous sodium sulfate and concentrated. The residual oil was applied to and developed on 20 2 silica gel thick layer plates in a mixture of ethyl acetato and ethanol (7/1). The material having an Rf of 0.4 was scraped off, washed with methanol, filtered and evaporated. The oil wa3 dissolved in ether and 5 ml of'a 10# ethanolic solution of picric acid was added. The precipitate wao filtered 25 and recrystallized from a mixture of tetrahydrofuran and isopropanol to give (2-fluorophenyl)[2-(2-oethyl-5-dimethylamino- - 72 - 41844 methy l-l-iraidazolyl)-5-dlmethylamino phenylImuthanone dipicrate as yellow prisma, m.p. 228-230°. i Bxamnle 31 A) A solution of 3 g (0.00920 a) of 9-chloro-6-(2-fluoro-5 ph.enyl)-l-oethyl-4H-imidazo[l,5-a][1,4]benzodiazepine in 50 ml of water and 0.5 ml (0.4092 m) of concentrated sulfuric acid was treated with 1.5 g (0.0217 m) of sodium nitrite. After 18 hours an additional 0.5 ml of sulfuric acid and 1.5 g of sodium nitrite Was added, and after 10 minutes the reaction was made 10 basic with ION Bodium hydroxide. The reaction mixture was extracted with 75 ml of dichloromethane, which was dried ov«r anhydrous sodium sulfate and evaporated to dryness. Crystallization of tho residue from a mixture of ethyl acetate and ether gave (2-fluoropheoyl)-[2 (5-hydroxymethyl-2-methyl-l-imidazolyl)-15 5-chlorophenyl]methanone as white prisms, m.p. 165-168°.
B) A solution of 1 g (0.00240 m) of 5-aminomethyl-l-[4-chloro-2-(2-fluorobenzoyl)-phenyl]-2-methylimidazole dihydrochloride was dissolved in 20 ml of water and 1 g (0.0145 m) of sodium nitrite was added slowly with stirring in an ioe bath. 20 After 3 hours the reaction was made basic with ION sodium hydroxide and extracted with 50 ml of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from ethyl acetate gave (2-fluorophenyl)x[ 2- (5-hydroxymethyl-2-methy1-1-imidazoly1)-5-25 chlorophenyl]methanone as white prisms, m.p. and mop with a - 73 - 41844 sample prepared as above 163-166°.
To a mixture of 0.1 g (0.000273 m) of 8-amino-6-(2-fluo- 1 • rophenyl)-1-oethyl-4H-imidazo[1.5-a][1.4]benzodiazepine Isopropanol and 5 ml of water waa added 1 oil of concentrated hydro-5 chlorio add. The reaotlon was cooled In on Ice bath anil 0.15 g (0.00217 a) of sodium nitrite was added slowly with stirring. After 1 hour the reaotlon mixture was poured into a solution of 0.2 g (0.00202 o) of cuprous chloride in 50 ml of water whloh had been heated to 70°. After 18 hours the reaotlon 10 was made basio with sodium hydroxide, extracted with dichloromethane (2 x 50 ml) drle<) over anhydrous sodium sulfate and evaporated to dryness. The residue was developed on a silica gel thick layer plate in a mixture of ethyl acetate and methanol (10/1). The produot which had an Rf or 0.7 waa scraped off the 15 plate, stirred with methanol and filtered. Evaporation and crystallization of the crude product from a mixture of ethyl acetate and ether gave (2-fluorophenyl)-[2-(5-hydroxymethy1-2-methy1-1-1mldazoly 1)-5-chlorophenyl]methanone as white prisma, m.p. and mmp with an authentic sample 159-166°. 20 Example 32 A solution of 0.5 g (0.00145 m) of (2-fluorophenyl)-[2-(5-hydroxymethyl-2-oethy1-1-imidazoly1)-5-chloropheny1]-methanone in 25 ml of dichloromethane. was treated with 0.15 ml (0.00155 m) of phosphorous 25 tribromide in an ice bath and after 1 hour at room tempera - 71 - 41844 ture was poured into 50 ml of liquid ammonia. After the ammonia had evaporated the reaction was partitioned between 50 ml of dichloromethane and water. The organic phase was separated and dried over anhydrous sodium sulfate. The solution was concentrated and the residue was applied to 2 silica gel thick layer plates which were developed in a mixture of ethyl acetate/10% methanol.
The compound which had an Rf of 0.6 was scraped off, stirred with methanol and filtered. The solution was treated with 0.1 g (0.000962 m) of maleic acid and evaporated. The residual salt was crystallized from a mixture of Isopropanol and ether to give the maleate of 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo [l,5-aj (1,43 benzodiazepine as white prisms, m.p. and mmp with an authentic sample 112-115° (melting point of solvated product). The base was obtained by partitioning the salt between dichloromethane and water, adjusting the pH, separating the layers and evaporating the organic phase. Crystallization of the product from ether gave white prisms, m.p. and mmp with an authentic sample 154-157°.
Example 33 A mixture of 9.75 g (0.03 m) of 8-chloro-6-(2-fluorophenyl) -l-methyl-4H-imidazo [1,5-aJ [l,4j benzodiazepine, 200 ml of methylene chloride and 12 g (0.07 m) of m-chloroperbenzoic acid was stirred for 1 1/2 hours. The solution was then extracted with 3 x 150 ml of IN hydrochloric acid. The extracts were washed with ether, made alkaline with ammonia and extracted with methylene chloride. The methylene chloride extracts were dried and evaporated and the residue was crystallized from ethyl - 75 - 41844 Qcotato to loavo a product which was further purified by chromatography over 100 g of silica gel using 5# (v/v) of ethanol in methylene chloride. The dean fractions were combined and evaporated. Crystallization of the residue 5 froa ethyl acetate/ether yielded 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-laldai»io[ 1,5-e.] [1,4] benzodiazepine 5-oxide as colorless crystals, m.p. 245-246° (deo.).
Example 34 A solution of 4 g of 8-chloro-6-(2-fluorophenyl)-l-10 methyl-4H-laldazo[ L,5-u][l,4]bonzodlazepine 5-oxide in 100 ml of acetic anhydride was heated on the steam bath for 24 hours. The reagont was evaporated under reduced pressure, at the end azeotroplcally with xylene. The residue was chromatographed over 80 g of silica gel using 20# (v/v) methylene ohloride in 15 ethyl acetate. Crystallization of the clean fractions from methylene ohlorlde/ether yielded 4-acetoxy-8-chloro-6-(2-fluorophenyl ) -1-methyl-4H-imldazo[ 1,5-a] [1,4] benzodiazepine as colorless crystals, m.p. 201-202°.
Example 35 20 4-Acetoxy-8-chloro-6- (2-fluorophenyl) -1-methy 1-4H- lmldazo[l,5-a][ 1,4]benzodiazepine (0.5 g, 1.3 mmol) was added to 40 ml of methanol containing 4 mmol of sodium methoxlde. After stirring under nitrogen for 1/2 hour at room temperature, the solvent was evaporated under reduced pressure. The residue - 76 - 41844 was dissolved In water and the solution was acidified with acetic acid. The precipitated crystals were collected and dissolved in methylene chloride. The solution was dried and evaporated and the residue was crystallized from methylene chloride/ether to yield 8-chloro-6-(2-fluorophenyl)-4-hydroxy-l-methyl-4H-imidazo [l,5-a][l,4j benzodiazepine as colorless crystals, m.p. 185-186°.
Example 36 A solution of 10 g (0.0358 m) of 7-cyano-2,3-dihydro-5-(2-fluorophenyl)-lH-l,4-benzodiazepin-2-one in 150 ml of dry tetrahydrofuran under argon was treated with 2.4 g (O.OS37 m) of 54% sodium hydride and the reaction was stirred and refluxed for 1 hour. This was cooled to 0° and 13.7 g (0.0537 m) of phosphorodimorpholidic chloride was added. After 18 hours the reaction mixture was filtered, concentrated to a small volume and ether was added. The precipitate was filtered and recrystallized from a mixture of dichloromethane and ether to give 7-cyano-5-(2-fluorophenyl)-2-bis-(morpholino) phosphinyloxy-3H-l,4-benzodiazepine as white rods, m.p. 194-197°.
Example 37.
To a solution of 1.6 g (5 mmoles) of 8-chloro-5,6-dlhy-dro-6- (2-fluorophenyl)-1-methyl-4H-imidazo [1,5-aJ[l,4] benzodiazepine in 10 ml of pyridine was added 1.2 g (6 mmoles) of £-toluenesulfonyl chloride. After standing at room temperature for 19 hours, the reaction mixture was diluted with water and - 77 - 41844 extracted with methylene chloride. The organic extract was dried and concentrated in vacuo to dryness. The residue was crystallized from a mixture of methylene chloride, ether and gave 8-chloro-6-(2-fluorophenyl)-5,6-dihydro-l-methyl-5-(4-methyl-5 phenylsulfonyl)-4H-imidazo£L,5-a)(l,43 benzodiazepine melting at 252-253°. After recrystallization from tetrahydrofuran the pure product formed yellow prisms with the same melting point.
To a stirred solution of 2.4 g (5 mmoles) of 8-chloro-6-(2-fluorophenyl)-5,6-dihydro-l-methyl-5-(4-methylphenylsul-10 fonyl)-4H-imidazo£l,5-al[l,4lbenzodiazepine in 120 ml of dry tetrahydrofuran was added 1.1 g of potassium tert-butoxide.
After stirring at room temperature for 2 hours the reaction mixture was poured into ice water and extracted with a 50% mixture of ether and petroleum ether. The organic extract was dried 15 and concentrated in vacuo to dryness. The residue was crystallized from a mixture of ether, petroleum ether and gave 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo [1,5-a][l,4]-benzodiazepine melting at 152-153°. The mixed melting point with an authentic sample gave no depression. 2o Example 38 To a stirred solution of 1.2 g (3.5 mmoles) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-aJ &, 4] benzodiazepine 5-oxide in 120 ml of ethanol was added slowly 1.2 g (31 mmoles) - 78 - 41844 of sodium borohydride. After stirring for 4.5 hours at room temperature the reaction mixture was diluted with about 175 ml of water and produot melting at 246-248° was separated by filtration. After recrystallization from a mixture of methylene 5 chloride/ether, the pure 8-chloro-6-(2-fluorophenyl)-5,6-di-hydro-5-hydroxy-l-methyl-4H-imidazo[ 1,5-a] [ 1,4] benzodiazepine formed colorless needles melting at 251-252°.
A solution of 0.3 g of 8-chloro-6-(2-fluorophenyl)-5•6-dihydro-5-hydroxy-l-methyl-4H-imidazo[1,5-a][1,4]ben»n-10 diazepine in a mixture of 10 ml of pyridine and 2 ml of acetic anhydride was left at room temperature for 19 hours. The reaction mixture was concentrated in vacuo to dryness. The residue was dissolved in 20 ml of methanol and 0.2 g of sodium methoxi-de added. After standing at room temperature for 45 minutes, 15 the reaction mixture was concentrated in vacuo to dryness. The residue wao partitioned between methylene chloride and water. The organic layer waa separated, dried and concentratod in vacuo to dryness. Tho residue was orystallized from a methylene chloride/ether mixture and gave starting material melting at 20 255-256°. Concentration of the filtrate and crystallization of the residue from ether gave 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine melting at 158-160°. The mixed melting point with an authentic sample gave no depression. - 79 - 41844 Example 39 A solution of 1.5 g of 8-chloro-5»6-dihydro-6-(2-fluoro-phenyl)-l-aethyl-4H-lmldazo[l,5-a][l»4]benzodiazeplne in a mixture of 10 ml pyridine and 5 ml of acetic anhydride was left at room temperature for 18 hours. The reaotlon mixture was conoentrated In vaouo to dryness. The residue was dissolved in methylene ohloride and washed with dilute potassium hydroxide. The organic layer was separated, dried and concentrated in vacuo to dryness. The residue was crystallized from a mixture of methylene chloride, ether, petroleum ether and gave 5-acetyl-8-chloro-6-(2-fluorophenyl)-5,6-dihydro-l-methyl-4H-imldazo[l,5-a][1,4]benzodiazepine melting at 185-186°. After recrystallization from methylene chloride the pure product formed colorless prisms melting at 186-187°.
Example 40 To a stirred solution of 27.8 g (92 mmoles) of DL-2-amino-methyl-7-chloro-2,3-dlhydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine in a mixture of 450 ml of methylene chloride and 300 ml of acetic acid was added slowly 27.8 g of zinc dust. After stirring at room temperature for 4 hours the reaction mixture was filtered over Celite. The filtrate was diluted with ice - 80 - 41844 water, made alkaline with 50# potassium hydroxide solution and extraoted with methylene chloride. The organio extract was separated, dried and concentrated in vacuo to dryness. The residue was crystallized from ether and gave 2-aminomethyl-7-ohloro-2,3,4,5-tetrahydro-5-(2-fluorophenyl)-1II-1,4-benzodiazepine melting at 119-120°. After recrystallization from ether the pure produot formed slightly yellow prisms melting at 127-128°.
The hydrochloride was prepared by treating a solution of the base in isopropanol with an excess of concentrated hydrochloric acid. After recrystallization of the salt from a mixture of water and isopropanol the pure product formed Blightly yellow needles melting at 268-271°.
A) A solution of 3 g (10 mmoles) of rac.2-aminomethy1-7-ohloro-2,3,4,5-tetrahydro - 5- (2-fluorophenyl)-1H-1,4-benzo-zodiazepine in a mixture of 30 ml of xylene and 10 ml of tri-ethylorthoacetate (97#) was refluxed for 4 hours. The reaction mixture was diluted with ether and extracted with dilute ice cold hydrochloric acid. The acid extract was made alkaline with dilute potassium hydroxide and extracted with methylene chloride. The organic layer was separated, dried and concentrated in vacuo to dryness. The residue was crystallized from ether and gave 8-chloro-6-(2-fluorophenyl)-3a,4,5,6-tetrahydro-l-methyl-3H-imidazo[l,5-a][l,4]benzodiazepine (Isomer A) melting at 187-189°. After recrystallization from a mixture of methylene chloride and ether the pure product farmed slightly - 81 - 41844 yellow priaoa melting at 189-190°.
B) To a stirred solution of 2.5 g of 8-chloro-3a,4-dihydro-6- (2-fluorophenyl) -1-methy l-3H-imidazo [ 1,5-a] [l,4]benzodiazcpine in a mixture of 100 ml methylene ohloride and 25 ml of acetio 5 acid vaa added slowly 2.5 g of zinc dust. After stirring at room temperature for 4 hours, the reaction mixture was filtered over Celite. The filtrate was diluted with ice water, made alkaline with 50# potassium hydroxide and extracted with methylene chloride. The organio extract was separated, dried and concentrated 10 in vaouo to dryness. The residue wae crystallized from ether and gave 8-chloro-6-(2-fluor&tLenyl)-3a,4,5,6-tetrahydro-l-methy1-3H-imidazo[l,5-a][1,4]benzodiazepine (Isomer A) which waa identical with the product prepared above, m.p. and mmp 189-190°.
C) A solution of 3.2 g (10 mmoles) of 8-chloro-3a,4-dihydro-15 6- (2-f luoro phenyl) -1-methy l-3H-imldazo[ 1,5-a ] [ 1,4] benzod iaz epine in 50 ml acetic acid and 10 ml of water was hydrogenated at room temperature and atmospheric pressure in the presence of 0.4 g of prehydrogenated platinum oxide. After 15 minutes, 10 mmoles of hydrogen were absorbed. The catalyst was separated by fil-20 tration and the filtrate concentrated in vacuo to dryness. The residue was dissolved in methylene chloride and washed with an excess of ice cold dilute sodium carbonate. The organio layer was separated, dried and concentrated in vacuo to dryness. The residue was crystallized from a mixture of ether/petroleum 25 ether and gave 8-chloro-6-(2-fluorophenyl)-3a,4,5»6-tetrahydro-l-methyl-3H-imidazo[l,5-a][1,4]benzodiazepine (Isomer B) - 02 - 41844 melting at 108-110°. After recrystallization from ether the pure product formed colorless prisms melting at 110-112°.
A mixture of 2.9 g of 8-chloro-6-(2-fluorophenyl)-3a, 4,5,6-tetrahydro-l-methyl-3H-imidazo Ql, 5-cQQ., 4} benzodiazepine, 90 ml of toluene and 15 g of activated manganese dioxide was stirred and refluxed for 2 hours. The reaction was filtered over Hyflo and the filtrate concentrated in vacuo to dryness. The residue was crystallized from ether and gave 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo Q. ,5-a](l,4j-benzodiazepine which gave no melting point depression with an authentic sample.
Example 41 A suspension of 17 g (0.05 m) of 7-chloro-l,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-l,4-benzodiazepine-4-oxide in 200 ml of tetrahydrofuran and 100 ml of methanol was hydrogenated in the presence of 17 g of Raney nickel at an initial pressure of 155 psi for 24 hrs. The catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in 50 ml of 2-propanol and warmed on the steambath. A warm solution of 17 g of maleic acid in 60 mi of ethanol was added and the salt was allowed to crystallize by cooling in the ice bath. The 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine dimaleate consisted of yellow - 83 - 41844 crystals with mp. 196-198°. 2-Aminomethyl-7~chloro-2,3-dihydro-5- (2-fluorophenyl) -IH-1,4-benzodiazepine dioaleate (8.0 g, 0.015 m) waa partitioned between methylene chloride and aqueous ammonia. The methylene 5 chloride solution was washed with water, dried over sodium sulfate and evaporated. The residue was dissolved in 50 ml of pyridine* After addition of 10 ml of acetic anhydride the mixture was heated on the steam bath for 4 hours. The reagents were evaporated under reduced pressure and the residue was 10 partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organio layer was dried and evaporated. Crystallization of the residue from methylene chloride/ ether with seoding yielded l-acetyl-2-acetylaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-IH-1,4-benzodiazepine, 15 mp. 213-215°. Seeds were obtained by chromatography over silica gel (40 fold amount) using 10# (v/v) ethanol in methylene chloride for elution. The analytical sample was recrystallized from ethylacetate/hexane and had a melting point of 215-217°.
A mixture of 0.5 g of l-acetyl-2-acetylaminomethyl-7-20 chloro-2,3-dihydro-5-(2-fluorophenyl)-IH-1,4-benzodiazepine and 10 g of polyphosphorio acid was heated to 150-170° for 10 min. The cool reaction mixture was dissolved in ice-water and the solution was made alkaline with ammonia. The precipitated base was extracted with methylene chloride. The extracts 25 were washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed over 10 g of silica gel - 84 - 41844 using 20# methanol in methylene chloride. The clean fractions were combined and evaporated. The residue was crystallized from ether to yield 8-ohloro-3a,4-dihydro-6-(2-fluorophenyl)-l-mothyl-3H-imidazo[1,5-a][1,^benzodiazepine, mp. 142-144°. 5 Example 42 A solution of 2.9 g (0.00927 m) of 2,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-lH-l,4-benzodiazepine-4-oiide in a mixture of 1 teaspoon of Raney nickel, 90 ml of tetrahydrofuran and 45 ml of methanol was hydrogenated at atmospherio 10 pressure and at room temperature for 2.3 hr. The mixture was filtcrod, and the nickel was washed with dichloromethane. The combined filtrates were evaporated and the resulting oil was dissolved in 50 ml of dichloromethane which was waehed with 50 ml of dilute ammonium hydroxide, dried over anhydrous aodium 15 sulfate and evaporated to dryness. A solution of 2.2 g (0.019 m) of maleio acid in 15 ml of ethanol was added to the oil and after ether was added 2-aminomethy1-2,3-dihydro-5-(2-fluorophenyl)-lH-l,4-benzodiazepine dimaleate hemihydrate crystallized. Recrystallization from a mixture of methanol 20 and ether gave a product as yellow rods, m.p. 147-150°.
A solution of 4.0 g (0.0149 m) of the tase of 2-aminomethy 1-2 ,3-dihydro-5-(2-fluorophenyl)-IH-1,4-benzodiazepine dimaleate hemihydrate in 125 ml of absolute ethanol was treated with 4 g (0.0247 m) of triethylorthoacetate and 0.5 g (0.00263 m) 25 of p-toluone sulfonic acid. After refluxing the mixture for - 85 - 41844 2 hr. the reaction mixture was evaporated to dryness. The resulting oil waa diBSOlved in 50 ml of dichloromethane, which waa washed with 50 ml of dilute ammonium hydroxide, dried over anhydrous □odium sulfate and evaporated to dryness to yield the crude 5 3a, 4-dihydro-6-(2-fluorophenyl) -l-methyl-3H-imida*o[l, 5-a] -[l,4]henzodiazeplne aa an oil.
A) The crude product from the previous paragraph was dissolved in 100 ml of toulene, treated with 18 g of activated manganese dioxide and the mixture was stirred and reflu- 10 xed for 3>5 hr. using a Dean Stark trap. The reaotlon mixture was filtered through halite and the precipitate was washed with 100 ml of tetrahydrofuran and then 100 ml of dichloromethane. The combined filtrates were evaporated and the residue was dissolved in 25 ml of dichloromethane. This solution was 15 chromatographed through a Plorisil column with dichloromethane, and then eluted with ether. Elutlon with ethyl acetate and then a 10# (v/v) solution of methanol in ethyl acetate gave the crude product, which was crystallized from ether and then recrystallized from ethyl acetate to give 6-(2-fluorophenyl)-20 l-methyl-4H-imidazo[l,5-a][l,4]benzodiazepine as white prisms, m.p. 164-168°.
B) A solution of 1.2 g (0.0041 m) of 3a,4-dihydro-6-(2-fluo-rophenyl)-l-oethyl-3H-imidazo[1,5-a][1,4]benzodiazepine in 50 ml of mesitylene and 0.5 g of 10# palladium on charcoal 25 was stirred and refluxed for 28 hr., and then it was filtered and evaporated to dryness. Crystallization from ethyl acetate - 86 - 41844 gave 6-(2-fluorophenyl)-l-methyl-4H-imidazo[1,5-a][1,4]benzo-diazepine as white prisms, m.p. 162-167°, and a fixture with authentic product melted at 162-168°.
Example 43 5 A solution of 0.3 g (0.00103 m) of 6-(2-fluorophenyl )- l-oethyl-4H-imidazo[l,5-a][l,4]henzodiazepine in 2 ml of concentrated sulfuric acid was cooled to 0°, and a solution of 0.11 g (0.0011 m) of potassium nitrate in 1.5 ml of concentrated sulfuric acid was added dropwise. After 18 hr. at room 10 temperature an additional 20 mg (0.0002 m) of potassium nitrate was added and the reaction was stirred for 5 hr. and then poured into a beaker containing ice. The mixture was made baoic with ammonium hydroxide, and extracted with 50 ml of dichloromethane which was separated, dried over anhydrous sodium 15 sulfate, and evaporated to dryness. The oil was dissolved in 3 ml of dichloromethane and applied to a silica gel thick layer plate which was developed in a mixture of ethyl acetate and ethanol (3:1). The nitrated product was scraped off the plate and stirred with a 1:1 (v/v) mixture of methanol and 20 dichloromethane and filtered. The filtrate® were evaporated and the residue was crystallized from methanol. Recrystallization from a mixture of dichloromethane and petroleum ether gave 6-(2-fluoro-5-nitrophenyl)-l-methyl-4H-imidazo[l,5-a] [l,4jbenzodiazepine as white prisms, m.p. 199-203°. - 87 - 41844 Example 44 41.3 g of 8-ohloro-l, 4-dimethy 1-6- (2-fluorophenyl)-4H-imidazo[l,5-a][l,4]benzodiazepine dihydrochloride was partitioned between methylene ohloride and aqueous ammonia. The 5 methylene chloride solution was washed with water, dried over sodium sulfate and evaporated to leave the free base. This material was dissolved in 50 ml of 2-propanol and the solution was treated with a solution of 12 g of maleic aoid in 40 ml of 2-propanol. The solution was gradually diluted with 300 ml 10 of ether. The precipitated crystals were collected and dried to leave 8-chloro-l,4-di^3thy1-6-(2-fluorophenyl)-4H-imidaao-[l,5-a][l,4]benzodiazepine maleate,m.p. 130-132° after recrystallization from ethanol/ether.
Example 45 15 A solution of 5 g (0.00153 o) of 8-chloro-6-(2-fluoro phenyl )-l-methyl-4H-lmidazo[1,5-a][1,4]benzodiazepine in 75 ml of dry ethylene dichloride was cooled in an ice bath and 5 g (0.0352 m) of boron trifluoride etherate was added. After 10 minutes a solution of 4 g (0.091 m) of ethylene oxide 20 in 5 ml of ethylene dichloride was added with Btirring. After 1 hour at room temperature the mixture was made basic with a solution of potassium carbonate in water. The organic layer was separated, dried over anhydrous sodium sulfate, and evaporated. Thu roaiduc was dissolved in 50 ml of dichloromethane and fll— 25 tored through 150 g of Florisil. The Florisil was eluted with - 88 - 41844 750 ml of dichloromethane and then with 750 ml of ether.
The dichloromethane solution waa evaporated and partitioned between 100 ml of ether and 100 ml of 0.5N hydrochloric acid. The acid layer was separated, made basic with ammonium hydroxide and extracted with 100 ml of dichloromethane which was dried and evaporated. The oil was dissolved in 15 ml of isopropanol and 0.8 g (0.0069 m) of maleic aoid was added. The solution was warmed on the steam bath for 5 minutes, cooled and ether was added. The precipitate was filtered, and recrystallized from a mixture of methanol and ether to give 2-chloro-13a-(2-fluorophenyl)-12,1* a-dihydro-6-methyl-9H-llH-imidazo[1,5-a]-oxazolo[3,2-d][1,4]benzodiazepine maleate as white prisms, m.p. 195-200°.
The ether solution from the Plorisil was concentrated, filtered and recrystallized from ether to give the base aa white prisms, m.p. 178-180°.
Bxample 46 A 3tirred solution of 29.9 g (0.1 m) of l,3-dlhydro-5-(2-fluorophenyl)-7-nitro-2H-l,4-benzodiazepin-2-one in 500 ml of dry tetrahydrofuran was treated portionwise under argon with 5.5 g (0.125 m) of a 54# mineral "oil dispersion of sodium hydride and stirring was continued for 1 hour longer. Dimorpholino-phosphine chloride (38 g, 0.15 m) was added to the dark solution in one portion and stirring under argon was continued for - 89 - 41844 8 hours. The resultant dark mixture was filtered over filter aid and concentrated In vacuo at 50° to give a dark gum. When the dark gum was stirred at room temperature in 75 ml of ethyl acetate, crystallization occurred to give a paste. After cooling 5 in an ice bath for 30 minutes the mixture was filtered and the light tan solid was washed 3 times with 35 ml portions of 2tl ether/ethyl acetate and finally with ether. Air drying on the funnel yielded nearly pure 5-(2-fluorophenyl)-2-[bis(morpholino) phosphinyloxy3-7-nitro-3H-l,4-benzodiazepine. Recrystal-10 lizatlon from 15 fold amount of ethyl acetate gave off-white needles, m.p. 169-172°.
Example 47 Fifty-four percent sodium hydride in mineral oil dispersion (11 g, 0.25 m) was added in portions to a stirred 15 solution of 63.2 g (0.2 m) of 7-bromo-l,3-dihydro-5-(2-pyridyl)-2H-l,4-benzodlazepln-2-one in 1 1 of tetrahydrofuran under argon. After refluxing on a steam bath for 1 hour, the solution was cooled to room temperature and treated with 76.2 g (0.3 m) of dimorpholinophosphinic chloride portionwise. 2o Stirring at room temperature was continued for 5 hours. The dark mixture was filtered through Celite. Concentration of the filtrate in vacuo and boiling the dark residue with ether gave tan crystals of 7-bromo-2- Qjis(morpholino)phosphinyloxyj-5-(2-pyridyl)-3H-l,4-benzodiazspine. A sample was recrystalli-25 zed by dissolving it in 2 ml of methylene chloride, filtering, diluting with 10 ml of ethyl acetate and cooling in an ice bath to give light tan plates, m.p. 180-182° (dec.).
Example 48 6 g (0.125 m) of sodium hydride dispersion (50% in 30 mineral oil), was added to a solution of 28.1 g (0.1 m) of 1,3-dihydro-7-nitro-5-phenyl-2H-l,4-benzodiazepln-2-one in 300 ml of dry tetrahydrofuran. After stirring for 1 hour at - 90 - 41844 room temperature 30.2 g (0.12 m) of dlmorphollnophosphinic chloride was added and stirring was continued for 4 hours. The product was crystallized by addition of water and ether. The procipitato was collectcd and dissolved in methylene chloride. The solution was dried and evaporated and the residue was crystallized from ethyl acetate to yield crude 7-nitro-2-Q>is(morpholino)phosphinyloxy]-5-phenyl-3H-l,4-benzodiazepine, m.p. 208-209°.
Example 49 A solution of 25 g of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-iraidazo[l,5-aJ[l, 4] benzodiazepine in 50 ml of water and 50 ml of concentrated hydrochloric acid was allowed to stand at room temperature for 3 hours. Following addition of 250 ml of 2-propanol the mixture was evaporated pa^cially under reduced pressure without heating. Additional 200 ml of 2-propanol were added and partial evaporation was resumed. The precipitated crystals were collected and washed well with 2-propanol and ether to yield 5-aminomethyl-l-(4-chloro-2-(2-fluorobenzoyl)phenyl]-2-methyllmidazole dihydrochloride, m.p. 302-307° (dec.). The analytical sample was recrystallized from methanol/2-propanol without heating.
Example 50 A mixture of 49.9 (0.2 moles) of 2-amino-5-chloro-2'-fluorobenzophenone, 38.0 g (0.3 moles) of 2,2-dichloro propa-nal; 18.O g (0.11 moles) of hydroxylamine sulfate and 500 ml of ethanol was stirred at room temperature for 2 days.
The mixture was diluted with 200 ml of 10% aqueous sodium carbonate solution with vigorous agitation. A gummy material precipitated from solution and the solution was diluted with 1.0 1 of ice-water. The solution was extracted with 3 x 300 ml of dichloromethane. The extracts were combined, dried over sodium sulfate, filtered and concentrated to dryness - 91 - 41844 in vacuo. The residue was crystallized from dichloromethane and petroleum ether giving 6-chlorj-2-(l,l-dichloroethyl)-l»2-dihydro-4-(2-fluorophenyl)-quinazoline 3-oxide as yellow prisms, m.p. 195-8° (dec.), 3.8 ml of nltromethane was added to 50.O ml of dimethylformamide with stirring and under an atmosphere of nitrogen. The solution was chilled to 0° and 1.3 g (0.012 moles) of potassium tertiary butoxida was added In portions. The temperature was maintained at 0 to 10° by means of an ice water bath. The mixture was stirred at room temperature for 1 hour.
The mixture was chilled to 5° with stirring and 2.2 g (0.006 moles) of the quinazoline prepared above was added at 5° to 9° in portions. After the addition had been completed, the mixture was stirred at room temperature for 17 hours.
The reaction mixture was poured into ice water and dichloromethane neutralizing with glacial acetic acid. The dichloromethane was washed with water; brine and dried over sodium sulfate. After filtration and concentration an amber residue was obtained which was crystallized with ethyl acetate. The crystals were collected and dried giving orange 7-chloro-l,3-dihydro=5-(2-fluorophenyl)-3-methy1-2-nitromethylene-2H-l,4-benzodiazepine-4-oxide as prisms, m.p. 198-200°. Recrystallization from dichloromethane/ethyl acetate gave pure material m.p. 216-218° (dec.).
Example 51.
A solution of 0.7 g (0.00203 m) of (2-fluorophenyl)-p-(5-hydroxymethyl-2-methyl-l-imidazolyl)-5-chloropheny l] -methanone in 40 ml of dry dichloromethane was cooled in an ice bath and 0.22 ml (0.00227 m) of phosphorus tribromide was added with stirring. After 1 hr. at room temperature the mixture was cooled in an ice bath and 2 ml (0.0328 m) of ethanolamlne - 92 - 41844 was added. The solution was stirred for 2 hrs. at room temperature, refluxed for 1 hr. and then poured into 50 ml of water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to a small volume. The residue was 5 developed on 4 silica g°l thick layer plates in a solution of 5% methanol in ethyl acetate (v/v). The material corresponding to an Rf of 0.5 was removed from the plate and treated with methanol. The solution was filtered and the filtrates were evaporated. The residue was crystallized from ether yielding 10 2-chloro-13a-(2-fluorophenyl)-12,13a-dihydro-6-methyl-9H,11H-imldazo [l,5-a] oxazolo- [3,2-d)(i,4jbenzodiazepine. Recrystallization from a mixture of methanol and ether gave pure product as white prisms, mp and mmp with an authentic sample 176-181° - 93 - 41844 Example 52 9«5 ml of nltromethane was dissolved in 100 ml of dimethylfonnamide under nitrogen and with stirring 5.0 g (0.045 moles) of potassium tertiary butoxide was added at 5 0-10° aad the mixture was stirred at room teoporaturo for 1 hour. The mixture waa then chilled on ice and 5.1 g (0.015 moles) of 6-ohloro-2-dichloBomethyl-l,2-dihydro-4-phenyl-quinazoline 3—oxide was added slowly at a temperature below 9° • The reaotlon mixture was stirred at room temperature f6r 10 17 hours.
The mixture was poured onto ice-vater dichloromethane and made slightly aold with glacial acetic acid. The aqueous phase was re—extracted three t^'nes with dichloromethane. The organios were combined; washed consecutively with water and 15 brine, dried over sodium sulfate; filtered and concentrated to dryness in vaouo giving an amber residue. Crystallization from boiling ethanol afforded 7-chloro-l,3-dihydro-2-nitromethylene-5-phenyl-2H-l,4-benzodiazepine-4-oxlde as yellow prisms, mp. 245-248° (dec.). Admixture with authentic material gave 20 no depression in melting point.
Bxample si Potassium tert. butoxide (3.37 g, 0.03 m), was added to a stirred suspension of 3.5 g (0.01 m) of 7-chloro-l,3-dihydro-5-(2-fluorophenyl)-2-nltromethylene-2H-l,4-benzodia- - 94 - 41844 zeplne 4-oxide in 100 ml of dimethylfonnamide cooled to -20°. After stirring under nitrogen for 10 min at this temperature 2*13 g (0.015 m) of methyl iodide was added and stirring was continued for 10 min. The reaotlon mixture was neutralized 5 by addition of glaoial acetio acid and was partitioned between water and methylene ohloride. The organic phase was separated, dried over sodium sulfate and evaporated. The residue waa orystallized from methylene chloride/ethyl acetate to yield 7-chloro-l,3-d ihydro-5-(2-fluorophenyl)-3-methvl-2-nitromethy1-10 ene-2H-l,4-benzodiazepine 4-oxide as yellow crystals, mp. 215-218°. The analytical sample was recrystallized from the same solvents, mp. 216-218°.
Bxample 54 A mixture of 7-chloro-l,3-dihydro-5-(2-fluorophenyl)-15 2H-l,4-benzodiazepine-2-carboxamide (64 mg, 0.2 mmole) and lithium aluminum hydride (15 og, 0.4 mmole) in dry THF (3 ml) was boiled for 15 min. The cooled reaotlon mixture was quenched by addition of saturated aqueous sodium sulfate solution. Tic analysis of the resulting solution showed the presence of 20 starting material as the major, more mobile component and the free base 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine as the minor component. The solution 2 waa transferred directly to a 20 x 20 cm preparative tic plate (silica gel) and the plate was developed with ethanol. 25 The lower yellow band was removed and extracted twice with methanol/methylene chloride (2:1). Evaporation of the filtered - 95 - 41844 cxtract left a clear, colorless oil. This wao taken up in ethanol (1 ml), treated vlth excess maleic acid (50 mg), scratched and stored overnight in the freezer. Tho yellow crystals were collected, washed with ether and air-dried. 1 5 The product was identified as 2-aalnomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine dimaleate by comparison of its infrared spectrum in NuJoKtrade mark) and of its melting point 185-166.5° with those of an authentic sample (mp. 168°). The mixture melting point was 134-7°. 10 Bxample 55 A mixture of 10 g (0.036 m) of l,3-dihydro-5-phenyl-2H-thieno-[3,2-e][l,4]diazepine-2-one in 50 ml of benzene and 300 ml of tetrahydrof"T-an was stirred on an ice bath and saturated with methylamine gas. To this mixture was added 15 dropwise a solution of titanium tetrachloride (9.48 g, 0.05 m) in 50 ml of benzene. After the addition was complete, the mixture was stirred on the ice bath for 15 minutes. The ice bath was then replaced with a heating mantle and the mixture refluxed for 1/2 hour. The mixture was cooled and 100 g of 20 ice carefully added. The mixture was filtered and tho residue washed with tetrahydrofuran. Tho filtrates were combined, dried and evaporated. The product was crystallised from methylene chloride to yield 2-methylamino-5-phenyl-3H-thieno-[3»2-e] [l,4]diazepine, m.p. 223-227°. Prom the concentrated mother 25 liquors waa obtained additional product, m.p. 222-22The •uuiJytical sample wa3 rccryatulllzed from motliylene chloride, - 96 - 412 4 4 a.p. 222-229°.
Nitrosyl chloride was introduced into a solution of 7.8 g (0.03 o) of 2-aethylamino-5-phenyl-3H-thieno[3»2-e]-[l,4]diazepine in 100 al of methylene ohloridc- and 40 ml 5 of pyridine cooled in ice water. The reaction was monitored by thin layer chromatography and when the starting material had disappeared the nitrosyl chloride addition was terminated and the reaction mixture was partitioned between methylene chloride and water. The methylene chloride solution was dried 10 and evaporated. Crystallization of the residue from methylene chloride/hexane yielded 2-(N-nitrosomethylamino)-5-phenyl-3H-thieno[3,2-e][l,4]diazepine as yellow crystals, m.p. 156-159°. The analytical sample was recrystallized from ether/hexane, m.p. 158-160°.
IS 2-(N-nitrosomethylamino)-5-phenyl-3H-thieno[3»2-e]l1,4)— diazepine (5.7 g, 0.02 m) was added to a mixture of lr> ml of nltromethane, 4.5 g of potassium t-butoxide and 60 ml of dimethylformamide which had been stirred for 10 minute3 at room temperature. Following addition, the reaction mixture 20 waB stirred under nitrogen and heated on the steam bath for 10 minutes. After acidification with 4 ml of glacial acetic acid the mixture was partitioned between methylene chloride/ toluene and saturated sodium bicarbonate solution. The organic layer was washed with water, dried and evaporated. Crystalli-25 zation of the residue from methanol with seeding yielded 1,2-dihydro-2-nitromethylene-5-phenyl-3H-thieno[3,2-e][1,4]- - 97 - 41844 dlacepine as yellow crystals, m.p. 160-163°• Seeds wero obtained by chromatographic purification over 30 fold amount of silica g«l using 10# (v/v) of ethyl acetate in methylene chloride. The analytical sample was reorystallized from 5 methanol, m.p. 163-164°.
A solution of 1.42 g (5 mmol) of l,2-dihydro-2-nitro-methylene-5-phenyl-3H-thieno[3,2-e][l,4]diazepine in 200 ml of ethanol was hydrogenated over Raney nickel (2 teaspoonofal) for 1 hour at atmospheric pressure. The catalyst was removed 10 by filtration and the filtrate was evaporated. The residue was treated with 1.2 g of maleic acid in 10 ml of 2-propanol. The salt was crystallized by addition of ether to yield 2-amino-methyl-2,3-dihydro-5-phenyl-lH-thieno[3,2-e][1,4]diazepinc dimaleate as yellow crystals, m.p. 170-173°. The analytical lr.> sample was recrystallized from methanol/2-propanol, m.p. 107-189°• 2-Aminomethyl-2,3-dihydro-5-phenyl-lH-thieno[ 3,2-e|-[l,4]diazepine dimaleate (1 g, 2 mmol), was partitioned between methylene chloride and aqueous ammonia. The methyicno 20 chloride layer was dried and evaporated. The residue was heated to reflux for 1 hour with 1 ml of triethyl orthoacctato in 20 ml of xylene. The solvent was evaporated under reduced pressure and the residue was crystallized from 2-propanol/ether to yield 1-methyl-3a,4-dihydro-6-phenyl-3H-imidazo[l,5-a]thieno-25 [2,3-f]diazepine, m.p. 150-152°. This material waa heated to reflux in 30 ml of toluene with 2 g of activated manganese - 98 - 41844 dioxide for 2 hours. The manganese dioxide was filtered off and washed veil with methylene chloride. The filtrate was evaporated and the residue was chrooatographed oyer 7 g of silica gel using 3# (v/v) of ethanol in methylene chloride. 5 The fraotiona containing pure product were combined and evaporated. Crystalligation from methylene chloride/ether and recrystallization from ethyl acetate/hexane yielded l-methyl-6-phenyl-4H-imidazo[l,5-a]thieno[2,3-f]diazepine, m.p. 223-225®. 10 Example 56 A mixture of 7.7 g (0.278 m) of 7-chloro-l,3-dihydro-r>-phenyl-2H-thieno[2,3-e][l,4]diazepin-2-one, 50 ml of benzene and 250 ml of tetrahydrofuran waa stirred on an ice bath and saturated with methylamine gas. To this mixture was added a 15 solution of titanium tetrachloride (7.38 g, 0.0389 m) in 50 ml of benzene from a dropping funnel. After the addition was complete, the mixture was stirred on the ice bath for 15 minutes. The ice bath was then replaced by a heating mantle and the reaction mixture was refluxed for 20 minutes. The mixture was 20 cooled and 100 g of ice were carefully added. The mixture was then filtered, and the residue washed with tetrahydrofuran. The filtrate were combined, dried and evaporated. The reBidue was crystallised from methylene chloride/ether yielding 7-chloro-5-phenyl-2-methylamino~3H-thieno-[2,3-e][1,4 Jdiazcpinc, 25 m.p. 246-249°. The analytical sample was recrystallized from methylene chloride, m.p. 247-250°. - 99 - - 41844 Nitrosyl chloride was introduced into a solution of 5.8 g (0.02 a) of 7-chloro-5-phenyl-2-methylamino-3H-thlcno-[2,3-e][l,4]diazepine in 100 ml of methylene chloride and 50 ml of pyridine until the reaction waa complete according to thin 5 layer ohromatograa. The mixture was partitioned between water and toluene. The organic phase was dried and evaporated. Crystallization of the residue from ether/hexane yielded 7-chloro-2-(N-nitro8omethylamino)-5-phenyl-3H-thiono[2,3-e][1,4]diazepi-ne aa yellow crystals, m.p. 108-110°. For analysis it was 10 recrystallized from ether/hexane, m.p. 111-113°. 7-Chloro-2-(N-nitrosomethylamino)-5-phenyl-3H-thieno-[2,3-e][l,4]diazepine (3-2 g, 0.01 m) waa added to a mixture of 10 ml of nltromethane, 35 ml of dimethylformamide and 2.2b g (0.02 m) of potassium t-butoxide which had been stirred und B) A solution of 320 mg (1 mmol) of 7-chloro-2,'-dihydro-15 2-nitromethylene-5-phenyl-lH-thieno[2,3-o][l,4]diazcpine in 3 ml of tetrahydrofuran was added to a suspension of 0.8 g of lithium aluminum hydride in 20 ml of tetrahydrofuran. After heating to reflux for 5 minutes, the reaction mixture was cooled and hydrolyzed by addition of 5 ml of water. The inorga-20 nic material was separated by filtration and the filtrate was evaporated. The residue was chromatographed as described above and the pure product was converted to the maleate to give 2-aminomethyl-7-chloro-2,3-dihydro-5-phenyl-IH-thieno[2,3-e]-ll,4]diazepine dimaleate as, m.p. 176-178°. 25 2-Aminomethyl-7-chloro-2,3-dihydro-5-phenyl-liI-thieno- [2,3-e][l,4]diazepine dimaleate (0.52 g, 1 mmol) waB partitioned - 101 - 41844 between methylene ohlorlde and aqueous ammonia. The mothylene chloride solution was dried and evaporated. The residue wao heated to reflux for 1 hour with 0.5 tal of triethyl ortho-acetate in 10 ml of xylene. The orude product obtained after 5 evaporation under reduced pressuru was dissolved in 25 ml of toluene and the solution was heated to reflux for 1 1/2 hours after addition of 2.5 g of activated manganese dioxide. The manganese dioxide was then filtered off and the filtrate wao evaporated. The residue web ohromatographed over 6 g of silica 10 gel using 4# (v/v) of ethanol in methylene chloride, fractions containing the pure compound were oombined and evaporated. Crystallization of the residue from ether/hexane yielded 8-chloro-l-methyl-6-phenyl-k4H-imidazo[ 1,5-a J thieno [ 3,2-f ] -ll,4]diazeplne, m.p. 168-170°. 15 Bxample 57 A solution of 50 g (0.161 m) of 7-chloro-5-(2-chlorophenyl )-l,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one in 900 ml of dry tetrahydrofuran and 300 ml of dry benzene wua cooled in an ice bath, methylamine was bubbled in until the 20 solution was saturated and a solution of 40 g (0.209 m) of titanium tetrachloride in 100 ml of benzene wa3 added dropwiae with stirring. After 4 hours at room temperature a few gram:- of ice were added and the reaction was filtered. The precipitate was washed several times with hot tetrahydrofuran, and the 25 combined filtrates were evaporated. The residue was partitioned between .'.'50 ml of dichloromethane and 2oo uiL of water and l'il- - 102 - 41844 tered. The dichloromethane solution was separated, dried and evaporated* This residue the preolpitate wore recrystallized from a mixture of tetrahydrofuran and ethanol to give 7-chloro-5-(2-chlorophenyl)-2-methy lamino-3H-thieno[ 2,3-e]-5 [l,4]diazepine. A sample was recrystallized for analysis from a mixture of tetrahydrofuran and hexane to give pale yellow prisma, m.p. 259-262°.
A mixture of 40 g (0.123 m) of 7-chloro-5-(2-chloro-phenyl)-2-methylaaino-3H-thieno[2,3-e][1,4ldiazepine, 10 700 ml of dichloromethane and 350 ml of pyridine was cooled in an ioe bath and nitrot>yl chloride was bubbled in for 20 minutes with stirring. After 1 hour it was bubbled in for 5 minutes more and then 600 ml of water was added slowly. The dichloromethane layer was separated, washed with 200 ml of water, dried over 15 anhydrous bodium sulfate and evaporated to dryness. The oil was dissolved in dichloromethane and filtered through 400 g of Plorisil. This was eluted with dichloromethane, and then ethor. Crystallization of the dichloromethane fraction from a mixturo of ether and petroleum ether gave 7-chloro-5-(2-chloro-20 phenyl)-2-(N-nitrosomethylamino)-3H-thieno[2,3-el[l,4]d ias.e pi no and moro product wao obtained from the ether fraction. A r.umple was recrystallized for analysis from a mixture of ether and petroleum ether to give yellow prisms, m.p. 104-107°. - 103 - 41844 Example 58 A aolution of 6.8 g (0.0255 m) of 6,8-4ihydro-3-ethyl-l-nethyl-4-phenylpyraaolo[3,4-«][l,4]diazepin-7(lH)-one in 125 ml of dry tetrahydrofuran and 50 ml of dry benzene waa cooled in 5 an loe bath and methylamine was bubbled In until the solution was saturated. A solution of 6.3 g (0.0331 m) of titanium tetrachloride in 20 ml of benzene was then added dropvise with stirring and after 18 hr at room temperature the mixture was rcfluxed for 30 minutes. The solution was cooled, and treated 10 with 4 g of ice. The reaction mixture was filtered and the precipitate was washed with tetrahydrofuran and then with dichloromethane. The combined filtrates were evaporated to dryness and the residue was crystallized from a mixture of methanol and ether, and recrystallized from a mixture of dichlo-15 romethane and ether to give 3-ethyl-l,6-dihydro-l-methyl-7- methylamino-4-phenylpyrazolo[3,4-e][1,4]diazepino as off-white prisms, mp." 218-221®.
A solution of 5.6 g (0.0199 m) of 3-ethyl-l,6-dihydro-1-methy 1-7-methy lamino-4-phenylpyrazolo [3,4-e][1,4]d iazepine 20 in 100 ml of dichloromethane and 50 ml of pyridine was stirred in an ice bath and nitrosyl chloride was bubbled in for 10 min. - 104 - 41844 After 2 hr at room temperature, nitrosyl chloride was bubbled in for an additional 5 min. The mixture was allowed to stand for 30 min when it was poured into 200 ml of ice water. The organic layer was separated, washed with 100 ml of water, dried over anhydrous sodium sulfate, and filtered through 100 g of Florisil. The Florisil was thoroughly washed with ether, and the combined filtrates were evaporated to dryness. The intermediate N-nitroso derivative was not further purified but was used in the next step. - 105 - 41844 Example 50 t A mixture of 3.3 g (0.01 m) of 7-chloro-l,3-dihydro-2-nitrooethyleno-5-phei>yl-2H-l,4-benzodiazepine 4-oxide, 3>3 ml of phosphorus trichloride and 300 ml of methylene 5 chloride was stirred at room temperature for 4 hours. Tho solution was washed with 10# aqueous sodium carbonate solution, was dried over sodium sulfate and evaporated. The orude product was purified by chromatography over 100 g of silica gel using 10# (v/v) ethyl aoetate in methylene ohloride. The combined 10 clean fraotions were crystallized from methylene chloride/ hexane to yield 7-chloro-l,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine as light yellcv crystals, m.p. 104-186°.
Bxampl: eo A mixture of 3.6 g (0.01 m) of 7-bromo-2-(N-nitroaomethyl-15 amino)-5-(2-pyridyl)-3H-1,4-benzodiazepine, 30 ml of dimethylformamide, 5 ml of nltromethane and 2 g (0.018 m) of potassium t-butoxide was stirred at room temperature for 15 minutes and then heated up slowly. When the temperature reached 100° the mixture was cooled and neutralized by addition of glacial 20 acetic acid. The product was precipitated by addition of saturated aqueous sodium bicarbonate and was collected, washed with water and dissolved in methylene chloride. The solution was dried over sodium sulfate and evaporated. Crystallization of the residue from methylene chloride/ethanol yielded 7-bromo-2\> l,3-dihydro-2-nitromethylene-5-(2-pyridyl)-2H-l,4-benzodiazepine - 106 - 41844 5 10 15 - 107 - as a light yellow product, m.p. 232-235 (dec.). For analysis It was recrystallized from tetrahydrofuran/ethanol, m.p. 240-245° (dec.).
Example 61 A solution of 2.8 g (0.00932 m) of DL.-2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-IH-1^-benzodiazepine in 40 ml of dichloromethane was treated with 2.5 g (O.OH9 m) of trifluoroacetic acid anhydride and after 5 minutes the reaction mixture was washed with 15 ml of a 10% potassium carbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from dichloromethane and was recrystallized from a mixture of dichloromethane and hexane to give 7-chloro-2,3-dihydro-5-(2-fluorophenyl)-2-trifluoroacetamid omethyl-lH-1,4-benzodiazepine as pale yellow prisms, m.p. 140-143°. 41844 Example 62 To a solution of 10 g (0.0264 m) of 5-(2-fluorophenyl)-l,3-dihydro-7-lodo-2H-l,4-benzodiazepln-2-one in 140 ml of dry tetrahydrofuran was added 1.8 g (0.039 m) of 54# of sodium 5 hydride under argon with stirring. The reaction was refluxed for 1 hour, cooled to 0®, and 10.8 g (0.0422 m) of phosphoro-dimorpholidio chloride waa added. After 18 hours the solution was filtered, conoentrated to a small, volume and ether was added. The solid was filtered and reoxystallized from a mixture of 10 dichloromethane and ethsr to give 5-(2-fluorophenyl)-7-iodo-2-bis (morpholino )-phosph±nyloxy-3H-l,4-benzodiazepino as white plates, m.p. 104-112°.
A solution of 27 g (0.443 m) of nltromethane in 450 ml of dry dimethyl sulfoxide was cooled to 0° under argon and 15 then 5.4 g (0.119 m) of 54# sodium hydride waa added with stirring. After 2 hours at room temperature the mixture was cooled to 0° and 39.5 g (0.066 m) of 5-(2-fluorophenyl)-7-iodo-2-bis- (morpholino) -phosphinyloxy-3H-l, 4-benzodiazepinc wel3 added all at onoe. The reaction was stirred for 18 hours 20 and then poured into 3 1 of ice and water, which contained 15 ml of acetiC' acid. The mixture was filtered, the precipitate was dissolvred in 700 ml of dichloromethane which was then washed with 300 ml of water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized and 25 recrystallized from a mixture of dichloromethane and ether to give 2,5-dihydro-5-( 2-f luorophenyl)-7-iodo-2-nitromethy lene-1h_1>4-benzodiazepine as yellow prisms; m.p. 214-216°c. - 108 - 418 4 4 Example A A parenteral formulation containing the following ingredients: per ml 5 8-Chloro-1-methy1-6-(2-fluorophenyl)-4H-imidazo- Cl»5-a][l,4jbenzodiazepine maleate 1.0 mg Benzyl Alcohol O.IS mg Tartaric Acid Buffer containing Sodium hydroxide Water for Injection q.s.ad 1 ml was prepared as follows (for 10 liters).
In a clean glass or glass-lined vessel, 8 1 of water for injection were heateu to 90°. It was then cooled to 50-60°, and 1.5 1 of benzyl alcohol was added and dissolved with stirring. The solution was then allowed to cool to room 15 temperature. The 10.0 g of 8-chloro-l-methyl-6-(2-fluorophenyl)-4H-imida2ofjL,5-a}{l,4j benzodiazepine maleate were added under an atmosphere of nitrogen and stirred until completely dissolved. The pH was now adjusted to 3.0 - 1.0, preferably 3.0 - 0.5 - 109 - 41844 with a combination of tartaric acid biiffer and sodium hydroxide solution. Sufficient water for injeotion was then added to make a total volume of 10 liters. This solution vas then filtered through candle,, filled into suitable size ampoules, gassed with nitrogen and sealed.
Example B A tablet formulation containing the following ingredients: per tablet 8-Chloro-6-(2-fluorophenyl)-1-methy1- 4H-imidazo[l,5-a][l,4]benzodiazepine maleate 10.0 mg lactose 113.5 mg Corn Starch 70.5 mg Progelatinized Corn Starch 8.0 mg Culcium Stearate 3.0 mg Total Weight 205.0 mg 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[ 1,5-a] [1,4jbenzodiazepine maleate was mixed with the lactose, corn starch and pregelatinized corn starch in a suitable size mixer and pass?d through a comminuting machine. The mixture was returned to the mixer and moistened with water to a thick paste . The moist mass was passed through a comminuting machine and the moist tpranules were dried on paper lined tray3 at 45°C. The dried granules were returned to the mixer, the calcium stearate was added and mixed well. The granules were compressed at a tablet weight of 200 mg. - 110 - 418 4 4 Example 0 A tablet formulation containing the following ingredients: per tablot 8-Chloro-6- (2-fluorophenyl) -l-oothyl-4H-lmidaeo[1,5-a][1,4]benzodiazepine maleate Laotoae Corn Starch Magnesium Stearate 10.00 mg 25.00 mg 64.50 mg 0.:0 mg Total weight 100.00 mg waa prepared aa follows: 8-Chloro-6- (2-fluorophenyl) -4H-lmidazo[ l,5-a][l,4]-benzodiasepine maleate waa mixed with the lactose, corn starch and magnesium stearate in a suitable mixer. The mixture waa further blended by passing through a comminuting machine. Tho mixed powders were slugged on a tablet compressing machine and the slugs were comminuted to a suitable mesh size and mixed well. The tablets were compressed at a tablet weight of 100 mg.
Ill 41844 R-rnmpIn T> A oapsule formulation containing the following ingredients : per capsule 8-0hloro-6-(2-fluorophenyl)-l-oethyl-4H- 1 n»1 rtazo[ 1,5-a] [ 1,4]benzodiazepine maleate 25 mg Laotose 158 mg Corn Starch 37 mg Talc 5 mg Total Weight 225 mg was prepared a3 follows: O-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a ] -[1,4]benzodiazepine maleate was mixed with the laotoae and corn starch in a suitable mixer. The mixture was further blended by passing through a comminuting machine. The blended powder waa returned to the mixer, the talc added and blended thoroughly. The mixture was then filled into hard-shell gelatin capsules on a capsulating machine. - 112 - 41844 Example B k oapsule formulation containing the following ingredients: per capaulc 5 8-Chloro-6-(2-fluorophenyl)-1-methy1-4H- inidazo[l,5-a][l,^benzodiazepine maleate 50 mg laotoae 125 mg Corn 3taroh 30 mg Talc 5 mg 10 Total Weight 210 mg was prepared as follows: 8-Chloro-6-(2-fluorophenyl)-l-oethyl-4H-imidazo[1,5-a]-[lf4]benzodiazepine maleate was mixed with lactose and corn starch in a suitable mixer. The mixture was further blended by 15 pasoing through a oommlnuting machine. The blended powder war. returned to the mixer, the talc added and blended thoroughJy. The mixture was filled into hard-shell gelatin capsulca on a capsulating machine. - 113 - 41844 Example p A capsule formulation containing the following ingredients t per capsule 8—Chloro—1,4—dime thy-»6—( 2-fluoro phenyl) -4 K-imidazo[l,5-a][l»4]benzodiazepine maleate Lactose Corn Starch Talc 125 mg 30 mg 50 mg 5 ny* Total Weight 210 mg was prepared as follows: 8-Chloro-rl, 4-dime thy 1-6— (2-fluorophenyl) -4H-imidazo-[l,5-a][1,4]benzodiazepine maleate was mixed with lactose and corn starch in a suitable mixer. The mixture was further blended by passing through a comminuting machine. The blended powder wa3 returned to the mixer, the talc added and blended thoroughly. The mixture was filled into hard-shell gelatin capsules on a capsulating machine. 114 41844 Biamole Q A capsule formulation containing the following Ingredients: por capsule 8—Chloro-1,4—dimethy 1-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine maleate lactose 158 mg 25 mg Corn Starch 37 mg Talo 5 mg Total Weight 225 mg was prepared as follows: 8-Chloro-l,4-dimethy 1-6-(2-fluorophenyl)-4H-imidazo-[l,5-a][l»4]benzodiazepine maleate was mixed with the lactose and corn starch in a suitable mixer. The mixture was further blended by passing through a comminuting machine. The blended powder was returned to the mixer, the talc added and blended thoroughly. The mixture was then filled into hard-shell gelatin capsules on a capsulating machine. 115 - 41844 K Example H A tablet formulation containing the following Ingredients per tablet 8-Chloro-l,4-dimethy1-6-(2-fluorophenyl)-4H- 5 imidazo[l,5-n][l»4]benzodiazepinb maleate 25.00 mg Lactoso 64.50 mg Corn Starch 10.00 mg Nugnesium Stearate O.'jO mg Total Weight 100.00 m^ 10 wa3 prepared as follows: 8-Chloro-l,4-dimethy1-6-(2-fluorophenyl)-4H-imidazo-[l,5-a][l,4]benzodiazepine maleate was mixed with the lactose, corn starch and magnesium stearate in a suitable mixer. Th ; mixture was further blended by passing through a comminuting 15 machine. The mixed powders were slugged on a tablet compre ;sing machine and the 3lugs were comminuted to a suitable mesh size mixed well. The tablets were compressed at a tablet weight of 100 mg. - 116 - 41844 R-rnraplfl T A tablet formulation containing the following ingredients: per tablet 5 8-Chloro-l, 4-dimethy 1-6- (2-f luoromethy 1) -4H- imidazo[1,5-a][1,4]benzodiazepine maleate 10.0 mg lactose 113.5 mg Corn Starch 70.5 mg Pregelatinized Corn Starch 8.0 mg 10 Calcium Stearate 3.0 mg Total Weight 205.0 mg was prepared as follows: 8-Chloro-l, 4-dimethy 1-6- (2,-f luorophenyl) -4H-imidazo[ 1 ,r>-a]-[1,4]benzodiazepine maleate was mixed with the lactose, corn 15 starch and pregelatinized corn starch in a suitable size mixer and passed through a comminuting machine. The mixture was returned to the mixer and moistened with water to a thick paste. The moist mass was passed througi a comminuting machine and moist granules were dried on paper lined trays at 45°C. The dried 20 granules were returned to the mixer, the calcium stearate was added and mixed well. The granules were compressed at a tablet weight of 200 mg. - 117 - 41844 Example J A parenteral formulation containing the following ingredients: per ml 8-Chloro-l,4-dimethy1-6-(2-fluorophenyl)-4H-imidazo[l,5-a][1,4]benzodiazepine maleate 1.0 mg Benzyl Alcohol 0.15 ml Tartario Acid Buffer containing Sodium Hydroxide Water for Injection (^■8. ad« 1 ml waa prepared aa follows (for 10 liters): In a clean glass or glass-lined vessel, 8 1 of water for injection were heated to 90°. It was then cooled to 50-60°, and l.S 1 of benzyl alcohol was added and dissolved with stirring. The solution was then allowed to cool to room temperature. The 10.0 g of 8-ohloro-l,4-dimethy1-6-(2-fluorophenyl)-4H-imida20-[l,5-a][l,4]benzodiazepine maleate were added under an atmosphere of nitrogen and stirred until completely dissolved. The pH was now adjusted to 3.0 i 1.0, preferably 3.0 - 0.5 with a combination of tartaric acid buffer and sodium hydroxide solution. Sufficient water for injection wat; then added to make a total volume of 10 liters. This solution was then filtered through a candle, filled into suitable siae ampoules, gassed with nitrogen and sealed. 118

Claims (14)

CLAIMS: 41844
1. A process for the preparation of imidazo[i,5-a][l,4j dLazepine compounds of the general formula wherein A is -■-^3 -C°N; 10 R^ is hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, substituted phenyl, pyridyl or aralkyl; R2 is hydrogen or lower alkyl; R^ is hydrogen or lower alkyl; Rg is hydrogen, alkanoyloxy or hydroxy; R^ is phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl, and is selected from the group consisting of (a) (b) X, ») (c) 'iy."QC (d) and 15 wherein R4 is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, hydroxy lower alkyl or lower alkanoyl; X is hydrogen, chlorine, bromine or iodine; and T is hydrogen or lower alkyl; analogs thereof corresponding to formula I but wherein A is selected from the 20 group consisting of - 119 - - 41844 (c) \ / \ "2 (IA) wherein A is -C=N | V • n 15 R^, R2, R^ and Rg are as in Formula I above and - 120 - 41844 is selected from the group consisting of formulae (a), (b) and ( above converting a corresponding compound of formula I into the N-oxide thereof, or (b) converting a compound of formula IA into a corresponding compound of formula I wherein R5 is alkanoyloxy by methods known In the art, or (c) converting a compound of formula I wherein Rs is alkanoyloxy into a corresponding compound of formula I wherein Rg represents hydroxy by methods known in the art, or (d) for preparing a compound of formula are as in Formula IA but is not nitro and Rg is not nitro substituted, reducing a corresponding compound of Formula I, or (e) dehydrating a compound of formula IA wherein A is H wherein R^, R2, R^, R^and to the corresponding compound of formula I, or - 121 - 41844 (f) converting a compound of formula IA wherein A is H I / -C-N I V *6 7 wherein R*^ is acetyl, mesyl or tosyl, to the corresponding compound of formula I by treatment with a non-aqueous 5 base in the presence of an inert solvent, or (g) converting a compound of formula IA wherein A is H I ^ -C-NH I *6 to the corresponding compound of formula I by oxidation of the secondary amine of the 5-posltion,or lO (h) cyclizing a compound of formula 15 wherein R^, R2» R^, R^ and Rg are as in formula I, to a corresponding compound of formula I, or (i) for preparing a compound of formula IA wherein A is — C N—. /\_?C wherein V is hydrogen or lower alkyl, reacting a corresponding compound of formula I with ethylene oxide or propylene oxide in the presence of a Lewis acid catalyst or reacting a corresponding compound of formula - 122 - 418 4 4 (XXIV) wherein R^, R2, R3, Rg and are aa in formula I, except that R4 is not amino or substituted 5 amino, with a compound selected from the group consisting of ethanol-amine, a 1-alkyl substituted ethanolamlne and a 2-alkyl substituted ethanol-amine, or (j) converting a ketal group present as R^ substituted in an imidazobenzodiazepine to the corresponding ketone 10 substituent, or (k) converting a ketone group present as R^ substituent in an imidazobenzodiazepine to a secondary or tertiary alcohol substituent, or (1) dehydrogenating a compound of formula - 123 - 41844 oc are as in formula I but R4 is not nitro and Rg is not nitro substituted, to a corresponding compound of formula I, or (m) converting a compound of formula I, wherein represents an aminophenyl group, into the corresponding nitro-, cyano-, chloro or bromo-substituted compound, or (n) subjecting a compound of formula I wherein R4 is 10 acylamino to a mild hydrolysis so as to obtain a corresponding compound of formula I wherein R^ is amino, or (o) oxidizing a compound of formula - 124 - 41844 (p) resolving a racemic compound into its optical enantiomers, or (q) converting a compound of formula I or an analog thereof corresponding to formula X but wherein A is selected from the group consisting of (e) (f) H (g) ^ r Vc—vT and /\ I \ | *0 R« 0 ' I V 6 wherein V-hydrogen or lower alkyl, lO 15 is selected from the group consisting of formula (a), (b) and (c) above, , Rj, R^ and Rg are as in Formula I above, and Rg is hydrogen or lower alkyl, except that in formula I with A being structure (f) R4 is not nitro and Rg is not nitro-substituted, into a pharmaceutically acceptable acid addition salt.
2. A process as claimed in Claim 1, wherein there are prepared compounds of formula I wherein 0L is A is -C=N; - 125 - 41844 la hydrogen or lower alkyl; R2 and R3 are independently hydrogen or lower alkyl; r5 is hydrogen, alkanoyloxy or hydroxy; R^ is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, amino, substituted amino, hydroxy lower alkyl 5 or lower alkanoylr and Rg is phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl, analogs thereof corresponding to formula I but wherein A is the group H I ^ / C — N or —ON I v IV " «6 ° lO and Rj is hydrogen, or pharmaceutically acceptable acid addition salts thereof and wherein at least one of the process embodiments (a), (b), (c), (d), (1), (o) and (p) of Claim I is performed.
3. A process as claimed in Claim 1, wherein there is 15 prepared a compound of formula I wherein R^ is hydrogen or lower alkyl, is R4 is hydrogen, nitro or halogen, is phenyl or halo, nitro or lower alkyl substituted phenyl, R2 is hydrogen 2o or lower alkyl, and R^ and R^ are hydrogen.
4. A process as claimed in Claim 3, wherein R^ is lower alkyl and is hydrogen.
5. A process as claimed in any one of claims 2 to 4, wherein R^ is 8-halo and Rg is 2-halophenyl. 25
6. A process corresponding to that claimed in any one of claims 3 to 5 but wherein R3 is lower alkyl.
7. A process as claimed in Claim 6, wherein R^ is methyl. - 126 - 41844
8. A process as claimed in claim 5, wherein 8-chloro-6-(2- f luorophenyl) -l-methyl-4H-lmldazo Q., 5-jTJQ. , 4j benzodiazepine or tho maleate thereof is prepared.
9. A process as claimed in claim 7, wherein 8-chloro- 5 6-(2-fluorophenyl)-l,4-dimethyl-4H-imidazo £l, 5-a] [l, 4] benzodia zepine or the maleate thereof is prepared.
10. A process as claimed in claim 1, wherein 2-chloro- 13a-(2-fluorophenyl)-12,13a-dihydro-6-methyl-9H«llH-imidazo- £l»S-aJoxazolo[3,2-dJQ.,4] benzodiazepine is prepared. 10
11. A process for the preparation of an imidaao £,5-jk7ll»47 diazepina confound of th* formula I given aad described in Claim 1 substantially as hereinbefore particularly described, especially with reference to any one of the foregoing Examples 1-62.
12. A process for the manufacture of preparations havir.g IS muscle relaxant/ sedative and anti-convulsant properties, wherein a compound of formula I as defined in claim 1 or an analog thereof as defined in claim 1 or a pharmaceutically acceptable acid addition salt of such compound is mixed, as active substance, with nontoxic, inert, therapeutically compatible 20 solid or liquid carriers, commonly used in such preparations, and/or excipients.
13. Compositions having muscle relaxant, sedative and anti-convulsant properties, containing a compound of formula I as defined in claim 1 or an analog thereof as defined in claim 1 or a pharmaceutically acceptable acid addition salt of such compound and a carrier.
14. Imidazo|[i,5-a]diazepine compounds of the general formula R, - ^ / R-, 25 ■n <■ wherein A is io / -C=N; I R, - 127 - • 41844 R^ is hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, subs ltuted phenyl, pyridyl or aralkyl, R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl; Rg is hydrogen, alkanoyloxy or hydroxy; Rg is phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl; and GT is selected from the group consisting of (a) (b)
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HU174752B (en) 1980-03-28
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DD121640A5 (en) 1976-08-12
NL171060C (en) 1983-02-01
CU34346A (en) 1982-08-24
DK157615B (en) 1990-01-29
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CA1067491A (en) 1979-12-04
MY8200214A (en) 1982-12-31
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BR7505864A (en) 1976-08-03
FR2285890A1 (en) 1976-04-23
NO147109B (en) 1982-10-25
YU40267B (en) 1985-12-31
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IL48069A (en) 1980-09-16
NO146573B (en) 1982-07-19
FR2285890B1 (en) 1981-12-31
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HK63381A (en) 1981-12-24
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KE3173A (en) 1982-01-08
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NO148188B (en) 1983-05-16
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SE7902667L (en) 1979-03-23
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