United States Patent (19) 11 4,094,984 Weber et al. 45) June 13, 1978 (54) 6-PHENYL-8BROMO-4H-STRAZOLO. 3,952,006 4/1976 Tahara et al..................... 260/308 R 3,4CTHENO-2,3E-1,4-DIAZEPINES AND SALTS THEREOF FOREIGN PATENT DOCUMENTS 75 Inventors: Karl-Heinz Weber, Gau-Algesheim; 2,405,682 8/1974 Germany ......................... 260/308 R Adolf Baier, Ingelheim am Rhein; OTHER PUBLICATIONS Peter Danneberg, Ockenheim; Franz Araki et al., Chen. Abstracts, vol. 82, Abstract No. Josef Kihn, Bingen, all of Germany 171102(g), (1975). 73) Assignee: Boehringer Ingelheim GmbH, Primary Examiner-Alton D. Rollins Ingelheim am Rhein, Germany Attorney, Agent, or Firm-Hammond & Littell (21) Appl. No.: 839,792 57 ABSTRACT 22 Filed: Oct. 6, 1977 Compounds of the formula Related U.S. Application Data 63 Continuation of Ser. No. 672,280, Mar. 31, 1976, abandoned, which is a continuation-in-part of Ser. No. 554,309, Feb. 28, 1975, abandoned. 30 Foreign Application Priority Data Mar. 2, 1974 Germany ............................. 2410030 Jul. 20, 1974 Germany ...... ... 2435041 Sep. 24, 1974 Germany ...... ... 2445430 Dec. 21, 1974 Germany ............................. 246O776 51) Int. C.’.................... A61K 31/55; CO7D 495/04; CO7D 495/14 (52) U.S. C. ............................. 424/269; 260/239.3 B; wherein R1 is hydrogen, fluorine, chlorine, bromine, 260/308 R; 260/332.2 R; 260/332.3 R; nitro or trifluoromethyl; and 260/332.3 P; 260/332.5 Rishydrogen, alkyl of 1 to 4 carbon atoms or hydroxy 58 Field of Search..................... 260/308 R; 424/269 alkyl of 1 to 4 carbon atoms; and non-toxic, pharmaco logically acceptable acid addition salts thereof; the 56 References Cited compounds as well as their salts are useful as tranquiliz U.S. PATENT DOCUMENTS ers, muscle-relaxants and anticonvulsants. 3,681,343 8/1972 Hester .............................. 260/308 R 3,904,641 9/1975 Nakanishi et al. ............... 260/308 R 8 Claims, No Drawings 4,094,984 1. 2 wherein R has the meanings previously defined, with 6-PHENYL-8-BROMO-4H-STRIAZOLO-34C an acid of the formula THIENO-(2,3E)-1,4-DIAZEPINES AND SALTS THEREOF R -COOH (V) This is a continuation of Ser. No. 672,280, filed Mar. 5 31, 1976, now abandoned, which is a continuation-in wherein R has the meanings defined above, or with a part of copending application Ser. No. 554,309 filed functional derivative of this acid. Feb. 28, 1975, now abandoned. The reaction described under method A may be car This invention relates to novel 6-phenyl-8-bromo-4H ried out attemperatures between 100 and 250' C with s-triazolo-3,4c-thieno-2,3e-1,4-diazepines and non- 10 out a solvent as well as with a solvent, such as methanol, toxic acid addition salts thereof, as well as to methods of ethanol, dioxane, chloroform, tetrahydrofuran, ben preparing these compounds. zene, toluene, xylene or mixtures of any two or more of More particularly, the present application relates to a these, and in the presence or absence of an acid catalyst, novel class of compounds represented by the formula such as hydrochloric acid, sulfuric acid, phosphoric . 15 acid, polyphosphoric acid, acetic acid, propionic acid, (I) benzenesulfonic acid or toluene-sulfonic acid; it is gen erally allowed to proceed to the end product without isolating the intermediate product of the formula 20 NH-NH-COR (VI) 25 wherein R is hydrogen, fluorine, chlorine, bromine, nitro or trifluoromethyl; and R is hydrogen, alkyl of 1 to 4 carbon atoms or hy- 30 droxyalkyl of 1 to 4 carbon atoms; and non-toxic, phar wherein R1 and R2 have the meanings previously de macologically acceptable acid addition salts thereof. fined, but under milder reaction conditions (for in The compounds embraced by formula I above may stance, at room temperature) it is possible to isolate the be prepared by the following methods: intermediate product without difficulties, METHODA 35 The reaction described under method B proceeds with the free acid of the formula V or with a suitable By reacting a compound of the formula functional derivative of this acid. Examples of suitable functional derivatives of the acid of the formula V are (II) an orthoester of the formula RC(OR); an iminoether 40 of the formula R-C(=NH)-OR; an amidine of the formula R-C-(-NH)-NH; an amide of the for mula R2-CONH2; a thioamide of the formula R-CSNH; an ester of the formula R-COOR" (for 45 example, a methyl, ethyl or nitrophenyl ester); an acid anhydride of the formula R-CO),O; an acid halide of the formula R-COHal; or a nitrile of the formula R-CN; in these formulas R has the meanings previ wherein Rhas the meanings previously defined, and X is ously defined, R is lower alkyl, and R' is aliphatic, SH-, NH-, lower alkoxy, lower alkylmercapto- or araliphatic or aromatic hydrocarbyl. The iminoethers halogen, with a compound of the formula 50 and amidines are used in the form of their salts formed R-CO-NH-NH. w (III) with mineral acids, e.g. as their chlorohydrates, as con ventional. wherein Rhas the meanings previously defined. 55 The reaction conditions may be chosen pursuant to the particular acid derivative which is used. Generally, METHODB the reaction may be carried out without a solvent or By reacting a compound of the formula with a solvent, (such as in methanol, ethanol, chloro form, tetrahydrofuran, benzene, toluene or mixtures of NH-NH. (IV) 60 any two or more of these, without or in the presence of an acid catalyst, such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, acetic acid, propionic acid, benzenesulfonic acid or toluenesulfonic acid. The presence of a base, such as 2-methylimidazole, R 65 as catalyst is useful as well. The reaction temperature lies between 0 and 300 C, preferably 20 to 180° C. The following further describe the particular variants of this method: 4,094,984 3 4. VARIANT I toxic, pharmacologically acceptable acid addition salts In this case the functional derivative of the acid of the are those formed with hydrohalic acids, sulfuric acid, formula V is an orthoester of the formula RC(OR), phosphoric acid, nitric acid, cyclohexylsulfaminic acid, where R2 and R' have the meanings defined above. citric acid, tartaric acid, ascorbic acid, maleic acid, Usually, the reaction proceeds in the presence of an formic acid, salicylic acid, methane- or toluene-sulfonic excess of the orthoester which serves simultaneously as the solvent medium, at temperatures between 90 and acid, 8-chlorotheophylline or the like. 100C; or one of the aforementioned solvents, option The starting compounds of the formulas III and Vare ally in the presence of one of the aforementioned cata O described in the literature, and the preparation of the lysts, at temperatures between room temperature and compounds of the formulas VI and VII is described the reflux temperature of the reaction mixture. above. VARIANT II The hydrazine derivatives of the formula IV may be In this case the functional derivative of the acid of the 15 prepared by reacting a compound of the formula II with formula V is an iminoether of the formula R-C(=N- hydrazine. This reaction may be performed in one of the H)-OR", where Rand R' have the previously defined meanings. It is advantageous to perform the reaction in above-mentioned solvents and, if desired, in the pres one of the previously mentioned solvents at a tempera ence of one of the previously mentioned acid catalysts, ture between room temperature and the reflux tempera 20 advantageously at a temperature between room temper ture of the reaction mixture. ature and the reflux temperature of the reaction mix VARIANT III ture. In this case the functional derivative of acid of the The compounds of the formula II, which may be formula V is an amidine of the formula R-C(-N- 25 reacted either directly with compounds of the formula H)-NH2, where R has the meaning previously de III to form compounds of the formula I, or else may be fined. It is advantageous to perform reaction in the presence of a basic catalyst, such as 2-methylimidazole, reacted with hydrazine to form compounds of the for at elevated temperatures, for example between 150' and mula IV, are prepared starting from known (see Ger 250 C. In case the reaction temperature is lower, for 30 man Offenlegungsschrift No. 2,217,157) compounds of example if the reaction is carried out at room tempera the formula ture, an intermediate product of the formula R II (VIII) NH-N=CC 2 (VII) 35 NH where R and R2 have the previously defined meanings, wherein R1 has the previously defined meanings, by is first formed. This intermediate product may be iso 45 brominating them in conventional manner, and reacting lated and subsequently subjected to a cyclization reac the resulting compounds of the formula tion by heating it at 150' to 250° C. However, isolation is not required by any means. VARIANT IV H (IX) 50 Br S N In this case the functional derivative of the acid of the formula V is an amide or thioamide of the formula R2 CONH, or R-CSNH, where R has the meanings de fined above. The reaction may be performed with or without a solvent, and without or with catalyst, at tem 55 peratures between 0 and 300° C. VARIANT V Here, the functional derivative of acid of the formula V is an ester of the formula R2-COOR', an anhydride of 60 wherein R1 has the previously defined meanings, in a the formula (RCO),O, an acid halide of the formula Solvent, such as pyridine, dimethylformamide or tetra R-COHal, or a nitrile of the formula R2-CN, where hydrofuran or mixtures thereof.