Canadian Patents Database / Patent 1248540 Summary

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(12) Patent: (11) CA 1248540
(21) Application Number: 441289
(54) English Title: PHENETHYLAMINE DERIVATIVES AND INTERMEDIATES THEREFOR
(54) French Title: DERIVES DE PHENETHYLAMINE, ET INTERMEDIAIRES CONNEXES
(52) Canadian Patent Classification (CPC):
  • 260/353
  • 260/557
  • 260/492.1
  • 260/603.6
  • 260/598.7
(51) International Patent Classification (IPC):
  • A61K 31/135 (2006.01)
(72) Inventors (Country):
  • HUSBANDS, GEORGE E.M. (United States of America)
  • YARDLEY, JOHN P. (United States of America)
  • MUTH, ERIC A. (United States of America)
(73) Owners (Country):
  • WYETH (United States of America)
(71) Applicants (Country):
(74) Agent: MARKS & CLERK
(45) Issued: 1989-01-10
(22) Filed Date: 1983-11-16
(30) Availability of licence: N/A
(30) Language of filing: English

(30) Application Priority Data:
Application No. Country Date
545,701 United States of America 1983-10-26
83/16646 United Kingdom 1983-06-18
449,032 United States of America 1982-12-13

English Abstract




PHENETHYLAMINE DERIVATIVES



Abstract of the Disclosure
This invention provides a group of hydroxycycloalkanephenethyl amine
antidepressant derivatives of the following structural formula:
Image
in which A is a moiety of the formula
Image
where the dotted line represents optional unsaturation;
R1 is hydrogen or alkyl;
R2 is alkyl;
R4 is hydrogen, alkyl, formyl or alkanoyl;
R5 and R6 are, independently, hydrogen, hydroxyl, alkyl, alkoxy,
alkanoyloxy, cyano, nitro, alkylmercapto, amino, alkylamino,
dialkylamino, alkanamido, halo, trifluoromethyl or, taken together,
methylenedioxy;
R7 is hydrogen or alkyl; and
n is 0, 1, 2, 3 or 4;

or a pharmaceutically acceptable salt thereof.


Note: Claims are shown in the official language in which they were submitted.


THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A compound of the formula:
Image
wherein the dotted line represents optional olefinic unsatura-
tion, and R1 is hydrogen or alkyl of 1 to 6 carbon atoms; R2 is
alkyl of 1 to 6 carbon atoms; R4 is hydrogen, alkyl of 1 to 6
carbon atoms, formyl, or alkanoyl of 2 to 7 carbon atoms; R5 and
R6 are independently hydrogen, hydroxyl, alkyl of 1 to 6 carbon
atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 7 car-
bon atoms, nitro, alkylmercapto of 1 to 6 carbon atoms, amino,
alkylamino of 1 to 6 carbon atoms, dialkylamino in which each
alkyl group is of 1 to 6 carbon atoms, alkanamido of 2 to 7 car-
bon atoms, halo, trifluoromethyl, or, when taken together, methy-
lene dioxy; R7 is hydrogen or alkyl of 1 to 6 carbon atoms; and n
is one of the integers 0, 1, 2, 3 or 4; or a pharmaceutically
acceptable salt thereof.

2. A compound of Claim 1, in which R1 is hydrogen or
alkyl of 1 to 3 carbon atoms; R2 is alkyl of 1 to 3 carbon atoms;
R4 is hydrogen, alkyl of 1 to 6 carbon atoms, formyl, or alkanoyl
of 2 to 7 carbon atoms; R5 is hydrogen, hydroxy, alkoxy of 1 to 3
carbon atoms, chloro, bromo, trifluoromethyl or alkyl of 1 to 3
carbon atoms; R6 is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to
3 carbon atoms, chloro, bromo, trifluoromethyl or alkanoyloxy of
2 to 3 carbon atoms; R7 is hydrogen or alkyl of 1 to 3 carbon


atoms; and n is one of the integers 0, 1, 2, 3 or 4; or a phar-
maceutically acceptable salt thereof.

3. A compound of formula
Image
or a pharmaceutically acceptable salt thereof where R1, R2, R4,
R6 and R7 are as in claim 2 and R5 and R6 are in the meta posi-
tion and n is 2.

4. 1-[2-(dimethylamino(4-
methoxyphenyl)ethyl]cyclohexanol or a pharmaceutically acceptable
salt thereof.

5. 1-[?-[(dimethylamino)methyl]-benzyl]cyclohexanol
or a pharmaceutically acceptable salt thereof.

6. 1-[?-[methylaminomethyl]-benzyl]cyclohexanol or a
pharmaceutically acceptable salt thereof.

7. 1-[1-(4-chlorophenyl)-2-(dimethylamino)ethyl]cyclo-
hexanol or a pharmaceutically acceptable salt thereof.

8. 1-[1-(4-methoxyphenyl)-2-(methylamino)ethyl]cyclo-
hexanol or a pharmaceutically acceptable salt thereof.

46


9. 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclo-
hexanol or a pharmaceutically acceptable salt thereof.

10. 1-[1-(3-bromophenyl)-2-(dimethylamino)ethyl]cyclo-
hexanol or a pharmaceutically acceptable salt thereof.

11. 1-[1-(3-chlorophenyl)-2-(dimethylamino)ethyl]-
cyclohexanol or a pharmaceutically acceptable salt thereof.

12. 1-[1-(2-chlorophenyl)-2-(dimethylamino)ethyl]-
cyclohexanol or a pharmaceutically acceptable salt thereof.

13. 1-[1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl]-
cyclohexanol or a pharmaceutically acceptable salt thereof.

14. 1-[1-(3,4-dimethylphenyl)-2-(dimethylamino)ethyl]-
cyclohexanol or a pharmaceutically acceptable salt thereof.

15. 1-[1-(4-trifluoromethylphenyl)-2-(dimethylamino)-
ethyl]cyclohexanol or a pharmaceutically acceptable salt thereof.

16. 1-[1-(3-trifluoromethylphenyl)-2-(dimethylamino)-
ethyl]cyclohexanol or a pharmaceutically acceptable salt thereof.

17. 1-[1-(4-methylphenyl)-2-(dimethylamino)ethyl]-
cyclohexanol or a pharmaceutically acceptable salt thereof.

18. 1-[2-dimethylamino)-1-(4-methoxyphenyl)ethyl]-
cyclohex-2-en-1-ol or a pharmaceutically acceptable salt thereof.

19. 1-[2-dimethylamino)-1-(3-bromo-4-methoxyphenyl)-
ethyl]cyclohexanol or a pharmaceutically acceptable salt thereof.

20. 1-[2-(dimethylamino)-1-(3-methoxyphenyl)ethyl]-
cyclohexanol or a pharmaceutically acceptable salt thereof.

47

21. 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]-
cyclohexanol or a pharmaceutically acceptable salt thereof.

22. 1-[2-dimethylamino)-1-(3-hydroxyphenyl)ethyl]-
cyclohexanol or a pharmaceutically acceptable salt thereof.

23. 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]-
cyclobutanol or a pharmaceutically acceptable salt thereof.

24. 1-[1-(4-methoxyphenyl)-2-(dimethylamino)ethyl]-
cyclopenantol or a pharmaceutically acceptable salt thereof.

25. 1-[1-(4-methoxyphenyl)-2-(dimethylamino)ethyl]-
cycloheptanol or a pharmaceutically acceptable salt thereof.

26. 1-[1-(4-methoxyphenyl-2-(dimethylamino)ethyl]-
cyclooctanol or a pharmaceutically acceptable salt thereof.

27. 1-[1-(4-aminophenyl)-2-(dimethylamino)ethyl]cyclo-
hexanol or a pharmaceutically acceptable salt thereof.

28. 1-[1-(4-nitrophenyl)-2-(dimethylamino)ethyl]cyclo-
hexanol or a pharmaceutically acceptable salt thereof.

29. 1-[1-dimethylamino)-2-(4-methoxyphenyl)prop-2-
yl]cyclohexanol or a pharmaceutically acceptable salt thereof.

30. A process for the production of a compound of the
formula:

48


Image
wherein the dotted line represents optional olefinic unsaturation, and R1 is hydrogen
or alkyl of 1 to 6 carbon atoms; R2 is alkyl of 1 to 6 carbon atoms; R4 is hydrogen,
alkyl of 1 to 6 carbon atoms, formyl, or alkanoyl of 2 to 7 carbon atoms; R5 and R6
are independently hydrogen, hydroxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6
carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, nitro, alkylmercapto of 1 to 6
carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino in which each
alkyl group is of 1 to 6 carbon atoms, alkanamido of 2 to 7 carbon atoms, halo,
trifluoromethyl, or, when taken together, methylene dioxy; R7 is hydroxy of alkyl of
1 to 6 carbon atoms; and n is one of the integers 0, 1, 2, 3 or 4; or a pharmaceutically
acceptable salt thereof, which comprises (a) reducing an amide of the formula
Image
in which R1, R2, R7 and n are defined, supra, the dotted line

49


represents optional unsaturation, R4 is hydrogen or alkyl of 1 to
6 carbon atoms and R5 and R6 are, independently, hydrogen,
hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon
atoms, aralkoxy of 7 to 9 carbon atoms, alkanoyloxy of 2 to 7
carbon atoms, alkylmercapto of 1 to 6 carbon atoms, N-protected
amino, halo, trifluoromethyl, or when taken together, methylene-
dioxy, with the proviso that said reduction is selectively per-
formed with aluminum hydride when the dotted lines represent ring
unsaturation; or (b) reducing a nitrile of the formula
Image
in which R4, R5, R6, R7, n and the dotted lines are defined under
(a), supra, with the exception that R5 and R6 are not methylene-
dioxy, to produce an amine, followed by N-mono- or -di-alkylation
and optionally (1) acylating the product with an active deriva-
tive of formic acid or an alkanoic acid containing from 2 to 7
carbon atoms to introduce the R4 group or an R1 and/or R2 acyl
group which Is subsequently reduced to afford an R1 and/or R2
alkyl group; (2) deprotecting said N-protected amino substituent
to obtain the free amine, mono-or di-alkylating or acylating the
amine or diazotizing the amino group and displacing the diazotate
salt with a nitrite or a nitrile; (3) displacing a halo sub-
stituent with a nitrile; or (c) subjecting an aldehyde of the
formula



Image
in which R4, R5, R6, R7, n and the dotted lines are defined under
(a), supra, (1) to amination with hydroxylamine, ammonia, a pri-
mary alkylamine or a secondary alkylamine followed by reduction
or (2) to reductive amination with an amine of the formula HNR1R2
and a reducing agent; or (d) subjecting a compound of the formula
Image
in which R4, R5, R6, R7 n and the dotted lines are defined under
(a), supra, and Z is a leaving group to reaction with ammonia or
HNR1R2 wherein R1 and R2 are defined in (a), supra, followed by
alkylation of the product obtained in the reaction with ammonia.

31. The process of Claim 30, in which 1-[cyano(4-
methoxyphenyl)methyl]-cyclohexanol is catalytically hydrogenated
to afford 1-[2-amino-1-(4-methoxyphenyl)-ethyl]cyclohexanol which
is reacted with a mixture of formaldehyde and formic acid to pro-
duce 1-[2-(dilmethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol.

32. The process of Claim 30, in which 1-[?-
(aminoethyl)benzyl]cyclohexanol is treated with a mixture of

51

formaldehyde and formic acid to produce 1-[?-[(dimethyl-
amino)methyl]benzyl]cyclohexanol.

33. The process of Claim 30, in which 1-[?-(tri-
fluoroacetylaminomethyl)-benzyl]cyclohexanol is treated with
methyl iodide and deprotected to produce 1-[?-[methylamino-
methyl]benzylcyclohexanol.

34. The process of Claim 30, in which 1-[2-amino-1-(4-
chlorophenyl)ethyl]-cyclohexanol is treated with a mixture of
formaldehyde and formic acid to produce 1-[1-(4-chlorophenyl)-2-
(dimethylamino)ethyl]cyclohexanol.

35. The process of Claim 30, in which 1-[2-trifluo-
roacetylamino-1-(4-methoxyphenyl)ethyl]cyclohexanol is treated
with methyl iodide and deprotected to produce 1-[1-(4-methoxy-
phenyl)-2-(methylamino)ethyl]cyclohexanol.

36. The process of Claim 30, in which 1-[(4-bromo-
phenyl)(dimethylaminocarbonyl)methyl]cyclohexanol is reduced with
aluminum hydride to produce 1-[1-(4-bromophenyl)-2-(dimethyl-
amino)ethyl]cyclohexanol.

37. The process of Claim 30, in which 1-[(3-bromo-
phenyl)(dimethylaminocarbonyl)methyl]cyclohexanol is reduced with
aluminum hydride to produce 1-[1-(3-bromophenyl)-2-(dimethyl-
amino)ethyl]cyclohexanol.

38. The process of Claim 30, in which 1-[(3-chloro-
phenyl)(dimethylaminocarbonyl)methyl]cyclohexanol is reduced with
aluminum hydride to produce 1-[1-(3-chlorophenyl)-2-(dimethyl-
amino)ethyl]cyclohexanol.

39. The process of Claim 30, in which 1-[2-chloro-
phenyl)(dimethylaminocarbonyl)methyl]cyclohexanol is reduced with

52

aluminum hydride to produce 1-[1-(2-chlorophenyl)-2-(dimethyl-
amino)ethyl]cyclohexanol.

40. The process of Claim 30, in which 1-[3,4-dichloro-
phenyl)(dimethylaminocarbonyl)methyl]cyclohexanol is reduced with
aluminum hydride or with borane tetrahydrofuran and HCI to pro-
duce 1-[1-(3,4-dichlorophenyl)-2-(dlmethylamino)-ethyl]cyclo-
hexanol.

41. The process of Claim 30, in which 1-[(3.4-
dimethylphenyl)(dimethylaminocarbonyl)methyl]cyclohexanol is
reduced with aluminum hydride to produce 1-[1-(3,4-dimethyl-
phenyl)-2-(dimethylamino)ethyl]cyclohexanol.

42. The process of Claim 30, in which 1-[(4-trifluoro-
methylphenyl)(dimethylaminocarbonyl)methyl]cyclohexanol is
reduced with aluminum hydride to produce 1-[1-(4-trifluoromethyl-
phenyl)-2-(dimethylamino)ethyl]cyclohexanol.

43. The process of Claim 30, in which 1-[(3-trifluoro-
methylphenyl)(dimethylaminocarbonyl)methyl]cyclohexanol is
reduced with aluminum hydride to produce 1-[1-(3-trifluoromethyl-
phenyl)-2-(dimethylamino)ethyl]cyclohexanol.

44. The process of Claim 30, in which 1-[(4-methyl-
phenyl)(dimethylaminocarbonyl)methyl]cyclohexanol is reduced with
aluminum hydride to produce 1-[1-(4-methylphenyl)-2-(dimethyl-
amino)ethyl]cyclohexanol.

45. The process of Claim 30, in which 1-[(4-methoxy-
phenyl)(dimethylaminocarbonyl)methyl]cyclohex-2-en-1-ol is
reduced with aluminum hydride to produce 1-[2-(dimethylamino)-1-
(4-methoxyphenyl)ethyl]cyclohex-2-en-1-ol.

46. The process of Claim 30, In which 1-[(3-bromo-4-
methoxyphenyl)(dimethylaminocarbonyl)methyl]cyclohexanol is

53

reduced with aluminum hydride to produce 1-[2-(dimethylamino)-1-
(3-bromo-4-methoxyphenyl)ethyl]cyclohexanol.

47. The process of Claim 30, In which 1-[(3-methoxy-
phenyl)(dimethylaminocarbonyl)methyl]cyclohexanol is reduced with
aluminum hydride to produce 1-[2-(dimethylamino)-1-(3-methoxy-
phenyl)ethyl]cyclohexanol.

48. The process of Claim 30, in which 1-[(4-benzyloxy-
phenyl)(dimethylaminocarbonyl)methyl]cyclohexanol is reduced with
aluminum hydride and the product deprotected by hydrogenolysis to
produce 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclo-
hexanol.

49. The process of Claim 30, in which 1[(3-benzyloxy-
phenyl)(dimethylaminocarbonyl)methyl]cyclohexano is reduced with
aluminum hydride and the product deprotected by hydrogenolysis to
produce 1-[2-(dimethylamino)-1-(3-hydroxyphenyl)ethyl]cyclo-
hexanol.

50. The process of Claim 30, in which 1-[4-bromo-
phenyl)(dimethylaminocarbonyl)methyl]cyclobutanol is reduced with
aluminum hydride to produce 1-[1-(4-bromophenyl)-2-(dimethyl-
amino)ethyl]cyclobutanol.

51. The process of Claim 30, in which 1-[(4-methoxy-
phenyl)(dimethylaminocarbonyl)methyl]cyclopentanol is reduced
with aluminum hydride to produce 1-[1-(4-methoxyphenyl)-2-
(dimethylamino)ethyl]cyclopentanol.

52. The process of Claim 30, in which 1-[(4-methoxy-
phenyl)(dimethylaminocarbonyl)methyl]cycloheptanol is reduced
with aluminum hydride to produce 1-[1-(4-methoxyphenyl)-2-
(dimethylamino)ethyl]cycloheptanol.

54

53. The process of Claim 30, in which 1-[(4-methoxy-
phenyl)(dimethylaminocarbonyl)methyl]cyclooctanol is reduced with
aluminum hydride to produce 1-[1-(4-methoxyphenyl)-2-(dimethyl-
amino)ethyl]cyclooctanol.

54. The process of Claim 30, in which 1-[(4-amino-
phenyl)(dimethylaminocarbonyl)methyl]cyclohexanol is reduced with
aluminum hydride to produce 1-[1-(4-aminophenyl)-2-(dimethyl-
amino)ethyl]cyclohexanol.

55. The process of Claim 30, in which 1-[1-(4-amino-
phenyl)-2-dimethylamino)ethyl]cyclohexanol.

56. The process of Claim 30, in which 1-[1-(amino)-2-
(4-methoxyphenyl-prop-2-yl]cyclohexanol is treated with formalde-
hyde and hydrogenated to produce 1-[1-dimethylamino)-2-(4-
methoxyphenyl)prop-2-yl]cyclohexanol.

57. The process of Claim 30, in which R1 is hydrogen
or alkyl of 1 to 3 carbon atoms; R2 is alkyl of 1 to 3 carbon
atoms; R5 is hydrogen, hydroxy, alkoxy of 1 to 3 carbon atoms,
chloro, bromo, trifluoromethyl or alkyl of 1 to 3 carbon atoms;
R6 is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon
atoms, chloro, bromo, trifluoromethyl of alkanoyloxy of 2 to 3
carbon atoms, R7 is hydrogen or alkyl of 1 to 3 carbon atoms.

58. The process of Claim 57, in which R5 and R6 are in
the meta position and n is 2.



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Title Date
(22) Filed 1983-11-16
(45) Issued 1989-01-10
Expired 2006-01-10

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Description 1993-08-28 44 1,506