2,6-METHANO-3-BENZAZOCINES AND PREPARATION THEREOF

摘要

1323491 2,6-Methano-4-benzazocines STERLING DRUG INC 3 June 1971 [4 June 1970] 18897/71 Heading C2C Novel 2,6-methano-3-benzazocines of the general formula wherein (a) Y1 is a hydroxy, C 1- 22 alkanoyloxy, C 4-22 alkenoyloxy (one or two double bonds), Ar-C m H 2m -CO-O- (where m is 0, 1 or 2 and Ar is a phenyl group optionally substituted by 1-3 substituents selected from C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, C 2-8 dialkylamino, halogen and C 1-6 alkanoylamino substituents), phenoxyacetoxy, naphthalenecarbonyloxy, pyridinecarbonyloxy, cycloalkyl- or fluorocycloalkyl-C m H 2m -CO-O- (optionally having one or more alkyl substituents on the ring and having a total of 4-10 C atoms, 3-7 of which are ring C atoms, m being 0, 1 or 2), C 2-7 alkylcarbonato, carboamoyloxy or C 2-9 monoordialkyl-carbamoyloxy group; Y2 is a hydrogen atom or a C 1-6 alkyl or Ar1-C n H 2n -group (where n is 0, 1, 2, 3 or 4 and Ar1 is a phenyl group optionally substituted by 1-3 substituents selected from C 1-4 alkyl, C 1-4 alkoxy and C 2-8 dialkylamino groups; or Y1 and Y2 together form an oxo group; Q is a C 3-8 alkyl, C 3-6 alkenyl, C 3-6 haloalkenyl (having 1-3 Cl, F and/or Br atoms attached to ethylenic C), C 2-6 cyanoalkyl, C 4-8 mono- or di-cyano-alkenyl, C 4-8 2,2-dialkoxyethyl, C 3-6 alkynyl, cycloalkyl- or fluoro-cycloalkyl- C n H 2n optionally having one or more alkyl substituents on the ring (where n is 0, 1, 2, 3 or 4 and there is a total of 3-10 C atoms, 3-7 of which are ring atoms), 2- or 3-cycloalkenyl optionally having one or more alkyl substituents on the ring (having 5 or 6 ring carbon atoms and a total of 5-8 carbon atoms) cycloalkenyl-C p H 2p - optionally having one or more alkyl substituents on the ring (where p is 1, 2, 3 or 4 and there is a total of 6-11 C atoms, 5 or 6 or them being in the ring) or Ar2-C p H 2p group (where p is 1, 2, 3 or 4 and Ar2 is a phenyl group optionally substituted by amino, nitro, C 1-6 alkanoylamino, C 1-4 alkoxy, C 1-4 alkyl, halogen or trifluoromethyl substituents, provided that Q has no tertiary alpha-C atom; Z is a hydrogen atom or a hydroxy group or an acyloxy group as in the definition of Y1, and R1 and R2 are each a hydrogen atom or C 1-4 alkyl group; (b) Y1 and Y2 together form an oxo group, Z is a C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, benzyloxy or C 3-6 alkenyloxy group and Q, R1 and R2 are as defined under (a); (c) Q is a methyl or ethyl group, R2 is a C 1-4 alkyl group; Z is a hydrogen atom or a hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, benzyloxy or C 3-6 alkenyloxy group or an acyloxy group as in the definition of Y1 under (a), and Y1, Y2 and R1 are as defined under (a); (d) Q is a C 2-7 carbalkoxy, carbobenzyloxy or, when Y1 and Y2 together form an oxo group, a C 4-9 N-carbalkoxyaminoacetyl or N-carbobenzyloxyaminoacetyl group, Y1, Y2, R1 and R2 are as defined under (a) and Z is as defined under (c); (e) Q is a hydrogen atom, Z is as defined under (c) and Y1, Y2, R1 and R2 are as defined under (a); and (f) Q is a Q1-CO-group, where Q1 is a C 1-7 alkyl, C 2-5 alkenyl, C 2-5 halo alkenyl (having 1-3 halogen atoms selected from Cl, F and Br attached to ethylenic C), C 2-5 alkynyl, cycloalkyl-C q H 2q - optionally having one or more alkyl substituents on the ring (where q is 0, 1, 2, or 3 and there is a total of 3-10 C atoms, 3-7 of which are in the ring) or Ar2-C q H 2q -group (where q is 0, 1, 2 or 3 and Ar2 is a phenyl group optionally substituted by amino, nitro, C 1-6 alkanoylamino, C 1-4 alkoxy, C 1-4 alkyl, halogen or trifluoromethyl substituents, R1 and R2 are defined as under (a), Y1 and Y2 are defined as under (a) or, when an oxo group, may be in the form of the corresponding ketal, and Z is as defined under (c); and acid addition salts thereof are prepared (i) when Q is an optionally substituted alkyl, alkenyl, alkynyl or acyl group, by N-alkylation, -alkenylation, -alkynylation or -acylation of the corresponding compound in which Q is a hydrogen atom, (ii) when Y1 and Y2 together form an oxo group, by oxidation of the corresponding compound in which Y1 and Y2 are each a hydrogen atom; (iii) when Y1 is a hydroxyl group and Y2 is a hydrogen atom, by reduction of the product of (ii); (iv) when Y1 is a hydroxyl group and Y2 is other than a hydrogen atom, by reaction of the product of (ii) with a suitable Grignard reagent; and (v) by interconversions of substituents by esterification, hydrolysis or reduction; followed optionally by salification of the product. Novel 3,5-ethanonaphth[2,1-d]oxazol-2(3H)- ones of the general formula wherein Y2, R1 and R2 are as defined under (a) above and Z2 is defined as Z under (c) above, and acid addition salts thereof are prepared by reaction of a corresponding 2,6-methano-3- benzazocine of the first general formula above wherein Y1 is a 1(eq)-hydroxy group and Q is a hydrogen atom with phosgene, or by heating the said 2,6-methano-3-benzazocine wherein Y1 is a 1(eq)-hydroxy group and Q is a carbalkoxy group in the presence of an alkoxide, followed optionally by salification of the product. 2,6 - Methano - 3 - benzazocines of the first general formula above wherein Y1 and Y2 are each a hydrogen atom and the other symbols are as defined under (f) above are prepared by N-acylation of the corresponding compound in which Q is a hydrogen atom. Pharmaceutical compositions having central nervous system depressant activity comprise, as active ingedient, a 2,6-methano-3-benzazocine of the first general formula above wherein the symbols are defined as under (a), (b), (c) or (e), or an acid addition salt thereof, together with a suitable carrier and may be administered orally or parenterally.