Patent GB-1323491-A (GB)
Title: 2,6-methano-3-benzazocines and preparation thereof
IPC: C07D498/08
Filed: 1971-06-03
Abstract: 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) Y<SP>1</SP> 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; Y<SP>2</SP> is a hydrogen atom or a C 1-6  alkyl or Ar<SP>1</SP>-C n H 2n -group (where n is 0, 1, 2, 3 or 4 and Ar<SP>1</SP> 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 Y<SP>1</SP> and Y<SP>2</SP> 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 Ar<SP>2</SP>-C p H 2p  group (where p is 1, 2, 3 or 4 and Ar<SP>2</SP> 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 Y<SP>1</SP>, and R<SP>1</SP> and R<SP>2</SP> are each a hydrogen atom or C 1-4  alkyl group; (b) Y<SP>1</SP> and Y<SP>2</SP> together form an oxo group, Z is a C 1-6  alkoxy, difluoromethoxy, trifluoromethoxy, benzyloxy or C 3-6  alkenyloxy group and Q, R<SP>1</SP> and R<SP>2</SP> are as defined under (a); (c) Q is a methyl or ethyl group, R<SP>2</SP> 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 Y<SP>1</SP> under (a), and Y<SP>1</SP>, Y<SP>2</SP> and R<SP>1</SP> are as defined under (a); (d) Q is a C 2-7  carbalkoxy, carbobenzyloxy or, when Y<SP>1</SP> and Y<SP>2</SP> together form an oxo group, a C 4-9  N-carbalkoxyaminoacetyl or N-carbobenzyloxyaminoacetyl group, Y<SP>1</SP>, Y<SP>2</SP>, R<SP>1</SP> and R<SP>2</SP> 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 Y<SP>1</SP>, Y<SP>2</SP>, R<SP>1</SP> and R<SP>2</SP> are as defined under (a); and (f) Q is a Q<SP>1</SP>-CO-group, where Q<SP>1</SP> 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 Ar<SP>2</SP>-C q H 2q -group (where q is 0, 1, 2 or 3 and Ar<SP>2</SP> 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, R<SP>1</SP> and R<SP>2</SP> are defined as under (a), Y<SP>1</SP> and Y<SP>2</SP> 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 Y<SP>1</SP> and Y<SP>2</SP> together form an oxo group, by oxidation of the corresponding compound in which Y<SP>1</SP> and Y<SP>2</SP> are each a hydrogen atom; (iii) when Y<SP>1</SP> is a hydroxyl group and Y<SP>2</SP> is a hydrogen atom, by reduction of the product of (ii); (iv) when Y<SP>1</SP> is a hydroxyl group and Y<SP>2</SP> 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 Y<SP>2</SP>, R<SP>1</SP> and R<SP>2</SP> are as defined under (a) above and Z<SP>2</SP> 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 Y<SP>1</SP> 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 Y<SP>1</SP> 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 Y<SP>1</SP> and Y<SP>2</SP> 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.