3,3-DISUBSTITUTED BENZODIOXEPINS

摘要

1,274,690. Benzodioxepins. CHARLES E. FROSST & CO. 21 Aug., 1969 [26 Aug., 1968; 9 June, 1969], No. 41840/69. Heading C2C. Novel compounds of Formula I and acid-addition salts thereof, in which R is a hydrogen atom or a hydroxy, C 1-5 alkyl or C 1-3 alkoxy radical; R1 is a hydrogen, chlorine or bromine atom or a C 1-5 alkyl, nitro, amino, C 1-5 alkylamino, di-(C 1-5 alkyl) amino, C 2-4 alkanamido, C 1-3 alkylsulfonylamino, (C 1-5 alkoxy) carbonylamino, hydroxy or C 1-5 alkoxy radical; each of X and X1 is a hydrogen or halogen atom or a C 1-5 alkyl radical; R2 is a hydrogen atom or a C 1-5 alkyl, phenyl, phenyl-(C 1-3 alkyl), C 3-6 cycloalkyl, pyridyl or pyridyl-(C 1-3 alkyl) radical; R3 is a hydrogen atom or a C 1-5 alkyl, phenyl or phenyl-(C 1-3 alkyl) radical; R4 is a hydrogen atom or a C 1-4 alkyl radical; R6 is a hydrogen atom or a C 1-5 alkyl or 2-phenyl-2- hydroxyethyl radical and R6 is a hydrogen atom or a C 1-10 alkyl, C 1-10 aminoalkyl, (C 1-5 alkyl)- amino-(C 1-10 alkyl), di-(C 1-5 alkyl)-amino-(C 1-10 alkyl), (C 3-6 cycloalkyl)-(C 1-10 alkyl), (C 1-3 alkoxy)-(C 1-10 alkyl), (C 1-3 hydroxyalkoxy)- (C 1-10 alkyl), C 1-10 hydroxyalkyl, phenyl-(C 1-10 hydroxyalkyl), phenyl - (C 1-10 alkyl), (halophenyl) - (C 1-10 alkyl), (hydroxyphenyl)- (C 1-10 alkyl), [(C 1-3 alkoxy)-phenyl]-(C 1-10 alkyl), methylenedioxyphenyl-(C 1-10 alkyl), indolyl- (C 1-10 alkyl), morpholino-(C 1-10 ) alkyl), (1,2,5- thiadiazolyloxy) - (C 1-10 alkyl), phenyl - (C 3-6 cycloalkyl), C 3-5 alkenyl, C 3-5 alkynyl, phenyl, halophenyl, (C 1-3 alkyl) phenyl, (C 1-3 alkoxy) phenyl or 2-pyridyl radical, a cycloaliphatic hydrocarbon radical, a radical of Formula II or III where R‹ is C 1-10 alkylene and X, R and R1 are as defined above, or a radical of formula -C(: NH).NHR7, where R7 is a hydrogen atom or a C 1-5 alkyl, benzyl, phenyl, halophenyl, (C 1-3 alkyl) phenyl or (C 1-3 alkoxy) phenyl radical, or R5 and R6 are linked to form with the nitrogen atom to which they are attached a morpholino, 1-piperazinyl, 4-alkyl-1-pi,.erazinyl, 4 - phenyl - 1 - piperazinyl, 1 - aziridinyl or 3-(2-iminothiazolidinyl) radical, are prepared from 3 - oxo - benzodioxepins (A) via 3- hydroxy - 3 - cyanobenzodioxepins (C), 3- hydroxy - 3 - nitroalkylbenzodioxepins (B) and 3 - spiro - 21- oxirane - benzodioxepins (E) as shown in the following reaction scheme I: Certain substituents in compounds I may be converted to other substituents, e.g. amino to guanidino, 1-aziridinyl to 3 - (2 - iminothiazolidinyl), hydroxy to alkoxy. alkoxy to hydroxy, amino to acylamino, nitro to amino and amino to another amino (e.g. via an amide or imine). In certain cases it may be necessary to protect the amino and hydroxy groups in the 3-position, e.g. by acetylation, before such conversions and then to remove the protecting groups. Alternatively, a 3 - hydroxy - 3- (R6NHCH 2 -) benzodioxepin may be converted to a 1,5 - benzodioxepin - 3 - spiro - 51 - oxazolidine (e.g. by treatment with phosgene, an aldehyde or dibutyl carbonate), the spiro compound nitrated in the 7-position, the nitro group converted to an amino group and a primary amino group in turn converted to an acylamino or hydroxy group. The resulting substituted spiro compound then converted to. the desired compound I. by hydrolysis. 3 - Hydroxy - 3 - hydroxymethyl - 3,4 - dihydro- 2H-1,5-benzodioxepins are produced as byproducts in the production of compounds E from compounds A (see reaction scheme I). 7 - Nitro - 3,4 - dihydro - 2H - 1,5 - benzodioxepin - 3 - spiro - 21 - oxirane is prepared by reacting 3,4 - dihydro - 2H - 1,5 - benzodioxepin- 3-spiro-21-oxirane with nitronium tetrafluoroborate. 2-Methyl-3-oxo-3,4 dihydro-2H-1,5 benzodioxepin is prepared by reacting 3-oxo-3,4 dihydro - 2H-1,5 benzodioxepin with morpholine to form 3 - hydroxy-3-morpholino - 3,4 - dihydro - 2H - 1,5 - benzodioxepin, dehydrating this to form 3 -mor- 'pholino-2H-1,5-benzcdioxepin, and treating this with methyl iodide followed by hydrolysing the product. Pharmaceutical compositions having bronchodilating activity comprise a compound of Formula I, or a pharmacologically acceptable acid addition salt thereof, together with a pharmaceutical carrier. The compositions may be in a form suitable for sublingual, oral, rectal, topical or parenteral administration.