PYRAZINO-BENZOXAZEPINE AND -BENZTHIAZEPINE DERIVATIVES, PROCESSES FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: Compounds of formula I, wherein R₁ is hydrogen, alkyl of 1 to 4 carbon atoms, hydroxyalkyl with a maximum of 4 carbon atoms, which may be acylated by an alkanoyl group of 2 to 18 carbon atoms, alkoxyalkyl with a maximum of 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 7 carbon atoms or a group of formula II, wherein R₅ is hydrogen, halogen, alkyl or alkoxy of 1 to 4 carbon atoms, and either i) X is -CH₂- and n is 0, 1, 2 or 3 or ii) X is -CO- and n is 1, 2 or 3 or iii) X is -O- and n is 2 or 3 and R₂ and R₃ are independently hydrogen, halogen, trifluoromethyl or alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, each of 1 to 4 carbon atoms and R₄ is hydrogen, alkyl or alkoxy of 1 to 4 carbon atoms, Z is -O- or -S-, with the proviso that, when R₃ is trifluoromethyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, R₄ is other than alkoxy, are useful for inducing sleep and treating psychotic disturbances and depressions.

Description: PYRAZINOBENZOXAZEPINE DERIVATIVES, PROCESSES FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM The present invention relates to pyrazinobenzoxazepines, processes for their production and pharmaceutica compositions containing them. The present invention provides compounds of formula I, EMI1.1 wherein R1 is hydrogen, alkyl of 1 to 4 carbon atoms, hydroxyalkyl with a maximum of 4 carbon atoms, which may be acylated by an alkanoyl group of 2 to 18 carbon atoms, alkoxyalkyl with a maximum of 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 7 carbon atoms or a group of formula II, EMI2.1 wherein R5 is hydrogen, halogen, alkyl or al koxy of 1 to 4 carbon atoms, and either i) X is -CH2- and n is 0, 1, 2 or 3 or ii) X is -CO- and n is 1, 2 or 3 or iii) X is -O- and n is 2 or 3 and R2 and R3 are independently hydrogen, halogen, trifluoromethyl or aikyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, each of 1 to 4 carbon atoms and R4 is hydrogen, alkyl or alkoxy of 1 to 4 carbon atoms, Z is -O- or -S-, with the proviso that, when R3 is trifluoro methyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, R4 is other than alkoxy. Any alkyl, alkoxy or alkylthio radical of 1 to 4 carbon atoms is preferably of 1 to 3 carbon atoms, especially 1 and 2 carbon atoms. Hydroxyalkyl has preferably 2 or 3 carbon atoms. Preferably the hydroxy group is attached to a carbon atom other than the carbon atom adjacent to the nitrogen atom. The alkoxy moiety in alkoxyalkyl is preferably located in the terminal position of the alkylene chain which preferably has 2 or 3, especially 2 carbon atoms. The alkoxy radical in alkoxyalkyl is preferably methoxy. Cycloalkyl or the cycloalkyl moiety of cycloalkylalkyl is conveniently cyclopropyl or cyclopentyl. The alkyl moiety of cycloalkylalkyl is conveniently methyl. Halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, especially chlorine. R1 is preferably hydrogen, alkyl or a group of formula II, R5 is preferably hydrogen or fluorine. X is preferably -CH2- or -CO-, n is preferably 1 or 3. R2 is preferably hydrogen, halogen or alkoxy. R3 is preferably hydrogen, halogen or alkyl. R4 is preferably hydrogen. When R2 and R3 are other than hydrogen, Rq is preferably in position 8. Z is preferably -0-. The present invention also provides a process for the production of a compound of formula I as defined above, which comprises reacting a compound of formula III, EMI4.1 wherein R2, R3, R and Zare as defined above and y is a leaving group, with a compound of formula IV, EMI4.2 wherein R1 is as defined above. The reaction may be effected in conventional manner for the production of similar compounds. Y is preferably chlorine. The process may be conveniently effected at a tem perature Ct fran 20 to 170 C in an inert organic solvent such as toluene, methylenchloride or dioxane. When R1 is hydrogen conveniently a compound of formula III is added to a solution of a compound af formula IV. The starting material of formula III may be prepared in known manner, e.g. as described herein, for example via the corresponding lactam, e.g. by reaction with phosphoroxychloride. Insofar as the production of starting materials is not particularl described these compounds are known or may be produced in analogous manner to known compounds. Free base forms of the compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids are e.g. maleic acid, oxalic acid, methanesulphonic acid, hydrochloric acid and hydrobromic acid. In the following Examples the temperatures given are in degrees Centigrade and are uncorrected. In the table the following abbreviations are used: *) monomÅaleate **) monooxalate EXAMPLE 1: 11- (4-thyl-l-piperazinyl) -pyrazino [2,3-b) [1,5]benaxazepine 3.6 g 1-methylpiperazine are added to a stirred suspension of 4.2 g 11-chloro-pyrazino[2,3-b[l,5]benz- oxazepine in 50 ml as. toluene. Stirring is maintained for four hours at room temperature. 100 ml water and 100 ml ethyl acetate are added and the mixture well shaken. The organic phase is filtered, dried over anhydrous magnesium sulphate and evaporated. The residue is dissolved in ethanol and 1 equivalent of maleic acid in ethanol is added, to yield the heading compound in monomaleate salt form, m.p. 190-191 . The starting material 11-chloro-pyrazino[2,3-b7 tl,5]benzoxazepine may be obtained as follows: a) pyrazino [2,3-b] benzoxazepin=11(10H)-one OH)-one A solution of 51 g 3-bromo-pyrazine-2-carboxylic acid in 130 ml hexamethylphosphorotriamide is cooled to -10 and treated under stirring dropwise with 18 ml of thionyl chloride4 After 5 minutes there are added in one portion 27.3 g of owmnophenol and the reaction mixture i8 stirred 'for 2 honri at room temperature. The mixture is poured on tce and extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid, 2N sodium carbonate and finally with water, dried over anhydrous magnesium sulphate, filtered and evaporated. The residue is treated with 2.2 1 of 0.1 N sodium hydroxide and stirred at 700 for 15 hours. The resulting solid is filtered, washed with water and dried in vacuo at 800 to yield the heading compound, m.p. 269-2720. b) ll-chloro-pyrazino[2z3-b][l-5]benzoxazepine 16 g of pyrazino[2,3-b][1,5]benzoxazepine- -11(10H)-one, 140 ml of phosphoroxychloride and 5.6 ml of N,N-dimethylaniline are refluxed for 15 hours. Residual phosphoroxychloride is removed by distillation. The residue is dissolved in methylene chloride and poured on ice. The methylene chloride layer is washed with 4N hydrochloric acid and water, dried over anhydrous magnesium sulphate and evaporated to give the heading compound, m.p. 123-1i60, In analogous manner to that described in Example 1, the following compounds of formula I are obtained, wherein Z is -0-: : EMI8.1 <tb> Example <SEP> R1 <SEP> R <SEP> Ra <SEP> R4 <SEP> m.p. <tb> <SEP> 2 <tb> <SEP> 2 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 223-224** <tb> <SEP> 3 <SEP> CH2CH2OH <SEP> H <SEP> H <SEP> H <SEP> 218-220** <SEP> (dec.) <tb> <SEP> 4 <SEP> H <SEP> 8-C1 <SEP> H <SEP> H <SEP> 197-199* <SEP> (dec.) <tb> <SEP> 5 <SEP> CH3 <SEP> 8-C1 <SEP> H <SEP> H <SEP> 118-119 <tb> <SEP> 6 <SEP> CH2CH2OH <SEP> 8-C1 <SEP> H <SEP> H <SEP> 230-232** <SEP> (dec.) <tb> <SEP> 7 <SEP> CH3 <SEP> H <SEP> CH3 <SEP> H <SEP> 171-173 <SEP> * <tb> <SEP> 8 <SEP> CH3 <SEP> H <SEP> CH3 <SEP> CH3 <SEP> 175-177 <SEP> * <tb> <SEP> 9 <SEP> CH3 <SEP> H <SEP> C1 <SEP> H <SEP> 134-135 <SEP> F <tb> <SEP> 10 <SEP> H <SEP> H <SEP> H <SEP> CH3 <SEP> 197-198 <SEP> * <tb> <SEP> 11 <SEP> H <SEP> H <SEP> CH3 <SEP> H <SEP> 178-180 <SEP> * <tb> <SEP> 12 <SEP> H <SEP> H <SEP> C1 <SEP> H <SEP> 184-186 <SEP> * <tb> <SEP> 13 <SEP> 02H5 <SEP> H <SEP> H <SEP> H <SEP> 170-171 <SEP> * <tb> <SEP> 14 <SEP> OH <SEP> (OH3)2 <SEP> H <SEP> H <SEP> H <SEP> II <SEP> 145-148 <SEP> * <tb> <SEP> 15 <SEP> CH2CH2OCH3 <SEP> H <SEP> H <SEP> H <SEP> 157-158 <SEP> * <tb> <SEP> 16 <SEP> H <SEP> 8-CH3 <SEP> H <SEP> H <SEP> 196-197 <SEP> * <tb> <SEP> 17 <SEP> CH3 <SEP> 8-OH3 <SEP> H <SEP> H <SEP> 171-172 <SEP> * <tb> <SEP> 18 <SEP> H <SEP> 7-CH3 <SEP> H <SEP> H <SEP> 215-216 <SEP> * <tb> <SEP> 19 <SEP> CH3 <SEP> 7-CH3 <SEP> H <SEP> H <SEP> 160-162 <SEP> * <tb> <SEP> 20 <SEP> H <SEP> 8-OCH3 <SEP> H <SEP> H <SEP> 178-180 <SEP> * <tb> <SEP> 21 <SEP> CH3 <SEP> 8-OCH3 <SEP> H <SEP> H <SEP> 159-161 <SEP> * <tb> <SEP> 22 <SEP> H <SEP> 8-F <SEP> H <SEP> H <SEP> 181-182 <SEP> * <tb> <SEP> 23 <SEP> CH3 <SEP> 8-F <SEP> H <SEP> H <SEP> 170 <SEP> * <tb> <SEP> 24 <SEP> CH3 <SEP> H <SEP> H <SEP> CH3 <SEP> 178-179 <tb> <SEP> 25 <SEP> CH2CH2 <SEP> < <SEP> H <SEP> H <SEP> H <SEP> 140-141 <tb> <SEP> 26 <SEP> CH2CH2 <SEP> e <SEP> 8-OCH3 <SEP> H <SEP> H <SEP> 215-216** <tb> <SEP> - <SEP> (dec.) <tb> <SEP> 27 <SEP> CH,CH, <SEP> H <SEP> H <SEP> CH3 <SEP> 201-203 <tb> <SEP> 27a <SEP> CH2CH2 <SEP> t <SEP> H <SEP> C1 <SEP> CH3 <SEP> 204-208 <SEP> * <tb> EMI9.1 <tb> Example <SEP> R1 <SEP> 2 <SEP> R3 <SEP> R4 <SEP> m.p. <tb> 28 <SEP> CH2CH2 <SEP> t <SEP> H <SEP> CH3 <SEP> H <SEP> 136-138 <tb> <SEP> (OH2)2O\ <SEP> H <SEP> H <SEP> H <SEP> 160-162** <tb> <SEP> 2 <SEP> 2 <SEP> (dex.) <tb> <SEP> 30 <SEP> (CH2)3CO <SEP> e <SEP> F <SEP> H <SEP> H <SEP> H <SEP> 130-131 <tb> <SEP> 31 <SEP> CH2CH2 <SEP> t <SEP> H <SEP> C1 <SEP> H <SEP> 135-137 <SEP> F <tb> <SEP> OH <SEP> 2 <SEP> e <SEP> H <SEP> H <SEP> H <SEP> 137-138* <tb> .33 <SEP> 2 <SEP> 2 <SEP> 9 <SEP> H <SEP> H <SEP> H <SEP> 119-121 <tb> <SEP> C1 <tb> <SEP> 34 <SEP> (CH2)2CH2 <SEP> H <SEP> H <SEP> H <SEP> 133-135"" <tb> <SEP> r <SEP> ) <tb> <SEP> 35 <SEP> H <SEP> H <SEP> CH3 <SEP> CH3 <SEP> 200-202* <tb> <SEP> 36 <SEP> OH2CH2 <SEP> H <SEP> CH3 <SEP> CH3 <SEP> 182-183 <tb> <SEP> 37 <SEP> H <SEP> 8-C1 <SEP> CH3 <SEP> H <SEP> 192-193* <tb> <SEP> 38 <SEP> CH3 <SEP> 8-C1 <SEP> CH3 <SEP> H <SEP> 189-192* <tb> <SEP> 39 <SEP> 2 <SEP> t <SEP> 8-Cl <SEP> CH3 <SEP> H <SEP> 212-213** <tb> <SEP> - <SEP> (dec0) <tb> <SEP> 40 <SEP> CH3 <SEP> 8-C1 <SEP> C1 <SEP> H <SEP> 207-209 <tb> <SEP> 41 <SEP> H <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> 42 <SEP> CH2CH2 <SEP> e <SEP> 8-Cl <SEP> H <SEP> H <tb> EMI10.1 <tb> <SEP> Example <SEP> R1 <SEP> b <SEP> R2 <SEP> 3 <SEP> R4 <SEP> m.p. <tb> <SEP> 43 <SEP> CH2 <SEP> < <SEP> H <SEP> H <SEP> H <tb> <SEP> 44 <SEP> CH2 <SEP> < <SEP> H <SEP> C1 <SEP> H <tb> <SEP> 45 <SEP> CH2 <SEP> < <SEP> 8-C1 <SEP> H <SEP> H <tb> <SEP> 46 <SEP> < <SEP> H <SEP> H <tb> <SEP> 47 <SEP> H <SEP> H <SEP> H <tb> <SEP> 48 <SEP> CH3 <SEP> H <SEP> OCH3 <SEP> H <tb> ¯ <SEP> 2 <SEP> 2 <SEP> e <SEP> H <SEP> OCH3 <SEP> H <tb> <SEP> 50 <SEP> H <SEP> H <SEP> C1 <SEP> CH3 <tb> 51 <SEP> CH3 <SEP> H <SEP> C1 <SEP> CH3 <SEP> 121-123* <tb> <SEP> 52 <SEP> CH3 <SEP> H <SEP> SOH3 <SEP> H <tb> <SEP> 53 <SEP> CH3 <SEP> H <SEP> SOCH3 <SEP> H <tb> <SEP> 54 <SEP> H <SEP> CH3 <SEP> H <tb> In analogous manner to that described in Example 1, the following compounds of formula I are obtained, wherein Z is -S-: Example R1 R2 R3 R4 m. p. 55 H H H H 158-161 56 CH3 H H H 171-173* 57 H 8-C1 H H 191-192* (dec.) 58 CH3 8-C1 H H 148-149 59 CH CH OH 8-C1 H H 235-237** (dec.) 60 CH2CH2OH H H H 253-256 naphthalene 1,5-disulpho- nate (aec.) 61 CH3 7-C1 H H 169-170 62 H 7-C1 H H 209-211* 63 CH3 8-F H H 64 H 8-F H H 65 CH3 8-F CH3 H 66 CH3 8-F Cl H 67 CH3 H CH3 H 68 CH3 H C1 H 69 CH3 H SCH3 H 70 CH3 H SOCH3 H 71 CH3 H SO2CH3 H 72 CH3 8-Cl' CH3 H 73 H 8-C1 CH3 H 74 CH3 8-C1 C1 H The starting material ll-chloro-pyrazinot2,3-b] [1,5]benzothiazepine for Example 55 may be prepared as follows: a) 3-(2-amino-henylthio)-pyrazine-2-carboxylic acid methyl eser A mixture of 18 g 3-bromopyrazine-2-carboxylic acid methyl' ester, 13.4 g 2-amino-thiophenolhydrochloride and 250 ml triethylamine is refluxed for 3 hours. Thereafter the solvent is evaporated and the residue treated with methylene chloride and water. The organic phase is dried over sodium sulphate and evaporated, whereby there is obtained the heading compound, which after recrystallisation from ethyl acetate has a m.p. of 155-1560. b) pyrazino [2-3-bltlL5lbenzothia2eEin-ll(lOH)-one Freshly prepared sodium methylate (from 1.8 g of sodium) in 200 ml abs. toluene and 16.8 g 3-(2-aminophenylthio)-pyrazine-2-carboxylic acid methyl ester are stirred together at room temperature for 15 hours. The mixture is poured on ice and the resulting precipitate filtered, whereby there is obtained the heading coMpound, which after recrystallisation from ethyl acetate has a m,p. of 280-2820, c) ll-chloro-pyrazinof2z3-b? rlL51benzothiazesinn In analogous manner to that described in Example lb) there is obtained the heading compound. The compounds of formula T exhibit pharmacolo- gical activity. In particular, they exhibit sleep inducing activity, as indicated in standard tests. For example in one test according to the principles of A.O. Sayers and G. Stille, Electroenceph. Clin. Neurophysiol. 27, 87-89 (1969), the sleep inducing activity in rats is observed after a single peroral administration of from about 0,5 to about 80 mg/kg animal body weight. The compounds are therefore indicated for use as sleep inducing agents. For this use an indicated daily dose is from about 1 to about 100 mg conveniently given shortly before retiring to sleep. Additionally, the compounds of formula I exhibit neuroleptic activity, as indicated in standard tests. For example, in one standard test an inhibition of spontaneous motor activity is observed in mice on p.o. administration of from 1 to 50 mg/kg anir,al body weight cf the compounds in accordance with the principles of Caviezel and Baillod [Pharm. Acta Helv. (195E), 33, 465 484) The compounds are therefore indicated for use as neuroleptic agents. For this use an indicated daily dose is from about 50 to about 500 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing from about 12.5 to about 250 mg, or in sustained release form. Additionally, the compounds of formula I exhibit antidepressant activity, as indicated in standard tests, for example, by an inhibition of tetrabenazine-induced catalepsy and ptosis in rats on intraperitoneal administration of from 5 to 15 mg/kg animal body weight in accordance with the method described by Stille (Arznei mittel-Forsch. 1964, 14, 534). The compounds are therefore indicated for use as antidepressant agents. For this use an indicated daily dose is from about 5 to about 150 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing ftom about 1.25 to 75 mg, or in-sustained release form. The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms exhibit the sane order of activity as the frec base forms. The present inven tion also provides a pharmaceutical ccmposition com prising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet. The sleep inducing activity and the neuro leptic activity is the preferred utility for compounds of formula I. The compounds of formula I wherein Z is -o- , especially those of Examples 1 and 25 are especially indicated as sleep inducing agents. The compounds of Examples 5, 7, 9, 31, 38, 58and 68 are especially indicated as neuroleptic agents. In one group of compounds R1 is hydrogen, alkyl of 1 to 4 carbon atoms, hydroxyalkyl with a maximum of 4 carbon atoms or alkoxyalkyl with a maximum of 6 carbon atoms, R2 is hydrogen, halogen, alkyl or alkoxy of 1 to 4 carbon atoms, R3 and R4 are hydrogen and Z is -O-. In another group of compounds R1 is hydrogen, alkyl of 1 to 4 carbon atoms, hydroxyalkyl with a maximum 0±- 4 carbon atoms, alkoxyalkyl with a maximum of 6 carbon atoms or a group of formula II, wherein R5 is hydrogen, halogen, alkyl or alkoxy of 1 to 4 carbon atoms, and either i) X is -CIS2- and n is O, 1, 2 or 3 or ii) X is -CO- and n is 1, 2 or 3 or iii) X is -O- and n is 2 or 3, R2 is hydrogen, halogen, alkyl or alkoxy of 1 to 4 carbon atoms, R3 is hydrogen, halogen, trifluoromethyl or alkyl, alkoxy or alkylthio, each of 1 to 4 carbon atoms, R4 is hydrogen, alkyl or alkoxy of 1 to 4 carbon atoms and Z is -O-.

Claims: WHAT WE CLAIM IS: 1. A compound of formula I, EMI17.1 wherein R1 is hydrogen, alkyl of 1 to 4 carbon atoms, hydroxyalkyl with a maximum of 4 carbon atoms, which may be acylated by an alkanoyl group of 2 to 18 carbon atome, alkoxyalkyl with a maximum of .6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 7 carbon atoms or a group of formula II, EMI17.2 wherein R5 is hydrogen, halogen, alkyl or al koxy of 1 to 4 carbon atoms, and either i) X is -CH2- and n is 0, 1, 2 or 3 or ii) X is -CO- and n is 1, 2 or 3 or iii) X is -0- and n is 2 or 3 and R2 and R3 are independently hydrogen, halogen, trifluorpmethyl or alkyl, alkoxy, 'alkylthiO alkylsulfinyl or alkylsulfonyl, each of 1 to 4 carbon atoms and R4 is hydrogen, alkyl or alkoxy of 1 to 4 carbon atoms, Z is -O- or -S-, with the proviso that, when R3 is trifluoro methyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, R4 is other than alkoxyor an acid addition salt thereof. 2. A process for the production of a compound of formula I, as defined in claim 1, which comprises reacting a compound of formula III, EMI19.1 wherein R21 R3, R4 and Z are as defined in claim 1. and y is a leaving group, with a compound of formula IV, EMI19.2 wherein R1 is as defined in claim 1. 3. A compound of claim 1, wherein R1 is hydrogen, alkyl of 1 to 4 carbon atoms, hydroxyalkyl with a maximum of 4 carbon atoms or alkoxyalkyl with a maximum of 6 carbon atoms, R2 is hydrogen, halogen, alkyl or alkoxy of 1 to 4 carbon atoms, R3 and R4 are hydrogen and Z is -O-. 4. A compound of claim I, wherein R1 is hydrogen, alkyl of 1 to 4 carbon atoms, hydroxyalkyl with a maximum of 4 carbon atoms, alkoxyalkyl with a maximum of 6 carbon atoms or a group of formula II, wherein R5 is hydrogen, halogen, alkyl or alkoxy of 1 to 4 carbon atoms, and either i) X is -OH2- and n is O, 1, 2 or 3 or ii) Xis -CO- and n is 1, 2 or 3 or iii) Xis -O- and n is 2 or 3, R2 is hydrogen, halogen, alkyl or alkoxy of 1 to 4 carbon atoms, R3 is hydrogen, halogen, trifluoromethyl or alkyl, alkoxy or alkylthio, each of 1 to 4 carbon atoms, R4 is hydrogen, alkyl or alkoxy of 1 to 4 carbon atoms and Z is -O-. 5. A compound of claim 1, which is 11-(4-methyl-l- piperazinyl)-pyrazino[2,3-b) [l,5)benzoxazepine. 6. A pharmaceutical composition comprising a compound of claim 1 in free base form or in pharmaceuti cally acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.

Inventors: LEUTWILER, ALBERT, DR., SORG, DIETER, DR.
Applicants: SANDOZ AG
Application year: 1978
Main classification: C07D498
IPC codes: A61K31, C07D241, A61P25, C07D513, C07D498