United States Patent 119) Liepmann et al. [54] ISOMERIC 2-CHLOROMETHYL-1,4- BENZODIAZEPINE OR 3-CHLORO-1,5-BENZODIAZOCINE ‘COMPOUND {75] Inventors: Hans Liepmann; Michael Ruhland, both of Hanover; Herbert Muesch, ‘Wennigsen; Werner Benson, Hanover; Henning Heinemann, Hanover, Horst Zeugner, Hanover, all of Fed. Rep. of Germany Kali-Chemie Pharma GmbH, Hanover, Fed. Rep. of Germany [21] Appl. No. 707,037 (22) Filed: Mar. 1, 1985 [73] Assignee: Related U.S. Application Data [62] Division of Ser. No. 453,785, Dec. 27,1982, Pat No 4,308,716. {30} Foreign Application Priority Data Dec. 2%, 1981 [DE] Fed. Rep. of Germany ... 3151557 (51) Ime. cus ComD 319/08; Co7D 487/04; OTD 498/04; AGIK 31/495 [2] US. a... 549/359; 260/239.3 D; 260/243 3; 260/244. 4; 260/245.7; 260/330. 260/330.9; 514/219; 514/220; $14/250; 514/339; 514/422; 914/453; 514/461; 514/463; 544/343; 544/346, 546/271; 548/518; 549/59; 549/433; 549/472 [58] Field of Search 260/244.4, 245.7, 330.3, 260/330.9; 549/59, 472, 359, 433 (56) References Cited US. PATENT DOCUMENTS 3403161 9/1968 Fryer 260/239 BD 3846463 11/1974 Moffett 260/239 BD 39nR816 1/1976. Somuszkovice 260/249.5 3,998,809 12/1976. Mikowski eta. 260/238 BD 4073784 2/1978 Moffet enron 260/243.3 4,096,161 6/1978 Milkowski etal ann. 260/239 BD 4,098,786 7/1978 Milkowski etal... 260/239 BD 4328957 4/1982 Zeugnor ct al 260/248.4 4338314 7/1982 Liepmann et a. 260/239 R $508,716 4/1985. Liepmann etal 360/239.3 D 11) Patent Number: #5] Date of Patent: 4,594,436 Jun, 10, 1986 FOREIGN PATENT DOCUMENTS 8045 2/1980 European Pat. Off. 2314993 10/1978 Fed. Rep. of Germany OTHER PUBLICATIONS ‘Smith et al, J. Med. Chem. 1980, 23, 952-955. Primary Examiner—Donald G. Daus ‘Assistant Examiner—Cecilia Shen ‘Attorney, Agent, or Firm—Schwartz, Jeffrey, Schwaab, Mack, Blumenthal & Evans (1 ABSTRACT [1,2}-fused 1,4-benzodiazepine compounds are disclosed corresponding to the general formula I C x 1 a Ry Ry Boy ‘wherein X is an oxygen or sulfur atom or an optionally substituted imino group, Ry is a hydrogen or halogen atom, lower alkyl radical, a lower alkoxy radical or a nitro group and R2 is a hydrogen or halogen atom, a lower alkyl radical, a lower alkoxy radical or a nitro group, or if Ry is a hydrogen atom, Ryimay also be a lower alkylthio radical, or, if Ris a hydrogen atom and Xisa sulfur atom or an imino group, Ramay be a triflu- ‘oromethy! radical; or Ry and Rzare bonded to adjacent ‘carbon atoms and together denote a methylenedioxy or cethylenedioxy radical; R3 is an optionally substituted fury, thienyl, pyrrolyl or pyridyl radical and n is zero or, if Rais furyl or thienyl, n may be 0 or 1. The com- pounds may be in the form of their optical isomers or acid addition salts. The compounds exhibit neuroleptic properties. Processes for preparing the compounds and pharmaceutical compositions containing them are also disclosed. 1 Claim, No Drawings4,594,436 1 ISOMERIC 2-CHLOROMETHYL-1,4-BENZODIAZEPINE OR 3-CHLORO-1,5-BENZODIAZOCINE COMPOUND This isa division of application Ser. No. 453,785 filed Dec. 27, 1982, now U.S. Pat. No. 4,508,716. BACKGROUND OF THE INVENTION This invention relates to new [1,2}-fused 7-heteroaryl- 1 4-benzodiazepine compounds and salts thereof, phar- rmaceutical compositions containing these compounds, and processes for the preparation of these compounds. USS. Pat. No. 4,338,314 discloses [1,2}-fused 7-phenyl- 1A-benzodiazepine derivatives which have a pro- nounced ulcer-inhibiting action and at the same time display only relatively little activity on the central ner- ‘vous system. It is the object of the invention to provide new [1,2}- fused 1,4-benzodiazepine compounds. ‘Another object of the invention is to provide new [1,2}fused 1,4-benzodiazepine compounds which ex- hibit neuroleptic activity. It is also an object of the present invention to provide new [1,2}fused 1,4-benzodiazepine compounds which do not show strong central nervous system sedating, activity, ‘A further object of the present invention is to provide new [1,2}fused 1,4-benzodiazepine compounds which exhibit @ good therapeutic range. Yet another object of the present invention is to pro- vide new [1,2}fused 14-benzodiazepine compounds which exhibit low toxicity A still further object of the present invention is to provide pharmaceutical compositions comprising new [1,2}fused 1,4-benzodiazepine compounds. SUMMARY OF THE INVENTION These and other objects are achieved according to cone aspect of the present invention by providing a [1,2]- fused 1,4-benzodiazepine compound corresponding to the general formula I C x N Ry RY & ‘oy wherein X represents an oxygen or sulfur atom or an imino group =N—Ry in which Rg represents a hydrogen atom, a C)-Cralkyl radical, a C2-Cs-alkyl radical ‘which is terminally substituted by a methoxy radical or a hydroxyl group, a Cs-Cs-alkenyl radical or a cyclo- propylmethyl radical; Ri represents a hydrogen or halogen atom, a lower alkyl radical, a lower alkoxy radical or a nitro group, and Ry represets a hydrogen or halogen atom, a lower alky] radical, a lower alkoxy radical or a nitro group, or, if Ry is a hydrogen atom, R; may be a lower akylthio radical or, if Ry is a hydrogen atom and X is a sulfur 25 3 0 4 55 6s 2 atom or an =N—Re group, Re may also be a trifluoro- ‘methyl radical; or Rj and R2 are bonded to adjacent carbon atoms and together denote a methylenedioxy or ethylenedioxy radical; Rj represents a radical selected from the group con- sisting of radicals corresponding to the formulas a, b, € ord t 5 Rs ; Rs 2 in which Rs represents # hydrogen, fluorine, chlorine, ‘or bromine atom, a lower alkyl radical or a nitro group and Re represents a hydrogen atom, a C1-Cs-alkyl radi- cal, a C2-Csalkyl radical which is terminally substi tuted by a hydroxyl group or methoxy radical, a C3-Cs- alkenyl radical or a cyclopropylmethyl radical; and n is zet0 oF, if Rs is the radical a or b, m is 0 or 1; and the ‘optical isomers and acid addition salts of said com- pound, If the substituents Ry and Ro in the compound of formula I represent or contain a lower aikyl group, this ‘may be @ straight-chain or branched alkyl group with peferably | to 4 carbon atoms, in particular @ methyl or ethyl radical. Thus, preferred lower alkyl substituents are methyl radicals and preferred lower alkoxy or alkyl- thio substituents are methoxy or methylthio radicals, respectively. Suitable halogen atoms for the substituents Ry and Ro are, in particular, fluorine, chlorine and bro- mine atoms. The substituents R; and Rz are preferably located in the 9- and/or 10-position, or, if they are nitro ‘groups or trifluoromethyl radicals, in the 9-position, and are preferably selected from hydrogen, chlorine, bromine or fluorine atoms and methoxy and methyl radicals. If X represents an =N—Ry group and Re is an op- tionally substituted alkyl radical, this is preferably a straight-chain alkyl radical with 1'to 5, more preferably 1 to 3, carbon atoms. Re is preferably a methyl, ethyl, ‘methoxyethyl or hydroxyethyl radical. If Rs is a lower alkyl radical, this can be straight- ‘chain or branched and may contain | to 4 carbon atoms, and is preferably a methyl or ethyl radical If Rais a furyl group a, Rs is preferably a hydrogen ‘atom, a lower alkyl radical or a nitro group, more pref- erably a hydrogen atom or methyl radical. IfRsisa thienyl group b, Rsis preferably a hydrogen atom or a lower alkyl radical, mote preferably a methyl radical, a fluorine, chlorine or bromine atom or a nitro group. IER3 represents a pyrrolyl group c, Rsis preferably a hydrogen atom or methyl radical. If Reis an optionally substituted alkyl radical, this is preferably straight-chai and contains I to 5, preferably 1 to 3, carbon atoms, an4,594,436 3 4 is more preferably a methyl, ethyl, methoxyethyl or hydroxyethyl radical, Rs most preferably being a ‘methyl radical. IFX is an =N-R, group, Rg and Recan ls advantageously be identical. 5 If Rsis a pyridyl group d, this is preferably bonded in the 2-position to the benzodiazepine skeleton Ri ‘According to another aspect of the present invention, the objects are achieved by providing a process for the 1° Ry preparation of a new [1,2]-fused benzodiazepine com- pound corresponding to the general formula Iand opti- where Ry, Rz, R' and X' have the above defined mean- cal isomers and acid addition salts thereof, wherein ings; or (@)a compound corresponding to the general formula _(c) a compound of the formula Td Wor lll 6 M20 N Rr Rr =n = 8 yw \ Ry wo oo Oh» where Ri, Rs, Ry’ and X have the above defined mean- im i885, is reduced to form a compound of the formula Te oy x0 * a eS ke ® * C \ Boy, ci ‘wherein R;, Rz, Rsand n have the above defined mean- ings and Y isa halogen atom, a lower alkanesulfonyloxy radical, a benzenesulfonyloxy radical, or a benzenesul- Where Ri, Ra, Rs’ and X have the above defined mean- fonyloxy radical in which the benzene ring is substi- 4, INES OF tuted by one or more lower alkyl radicals and/or halo- (@) a compound of the formula IV ‘gen atoms, is reacted with an alkali metal hydroxide, an alkali metal sulfide or an amine of the formula Ry—NHb, wherein Ry has the above defined meaning; 59 or (©) a compound of the formula Tb v C 7 55 nN R: © where Ri, Reand Rshave the above defined meansings, on Z has the meanings given above for Y and Z’ is a chlo- Rr Bs rine atom, or Z and Z' together denote an oxygen or sulfur atom or an =N—Ry group, is reacted with an where R, and Re have the above defined meanings, X’ © amine of the formula R¢-—NHb, where Re has the above is an oxygen or sulfur atom and Ry is an a or b radical, defined meaning, to form a compound of the formula Te is oxidized to form a compound of the formula Ia