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 :
  • HUSBANDS, GEORGE E.M. (United States of America)
  • YARDLEY, JOHN P. (United States of America)
  • MUTH, ERIC A. (United States of America)
(73) Owners :
  • WYETH (United States of America)
(71) Applicants :
(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/Territory 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.


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


PHENETHY:LAMINE DERIVATIVES



Description of the Invention
In accordance with this invention there is provided a group of substituted
phenethylamine derivatives which are central nervous system antidepressants. The
compounds of this invention present the following struc~ural formula:




\


1:~

in which A is a moiety of the formula
fR4 where the dotted
,~J line represents
~CH2)n optional unsaturation,



Rl 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, cyano, 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 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.
The preferred compounds are those of the formula:

~R
~ ~ R

RF~A


in which A is defined supra;
Rl 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, trifluoro-
methyl or alkanoyloxy of 2 to 3 carbon atoms.
R7 is hydrogen or alkyl of 1 to 3 carbon atoms;
or a pharmaceutically acceptable salt thereof.


- 2

lZ'~S ~

The most preferred compounds are those in which R5
and R6 are in meta or para positions and n is 2.
The compounds in which R4 is formyl or alkanoyl of
2 to 7 carbon atoms are not nearly as potent as the corres-
ponding free hydroxy bearing derivatives in the test proce-
dures employed and disclosed herein. However, in long term
therapy the acyloxy derivatives will act as pro drugs as the
acyl group is removed in vivo either via acid hydrolysis in
the stomach or enzymatically.
The pharmaceutically acceptable acid addition salts
of the basic compounds of this invention are formed conven-
tionally by reaction of the free base with an e4uivalent
amount of any acid which forms a non-toxic salt. Illustra-
tive acids are either inorganic or organic, including hydro-
chloric, hydrobromic, fumaric, maleic, succinic, sulfuric,
phosphoric, tartaric, acetic, citric, oxalic and similar
acids. For parenteral administration, the use of water sol-
uble salts is preferred, although either the free base of
the pharmaceutically acceptable salts are applicable for
oral or parenteral administration of the antidepressant
agents of this invention. The halo substituent representing
R5 or R6 is intended to include the chloro, bromo, iodo or
fluoro substituents.
The compounds of this invention are produced by
reaction of a cycloalkanone or a cycloalkenone with an ap-
propriately substituted (ortho or para) phenylacetonitrile
anion following the procedure of Sauvetre et al., Tetrahe-
dron, 34, 2135 (1978) followed by reduction (catalytic hy-
drogenation, borane reducing agents, LiAlH4, etc.) of the
nitrile to a primary amine and alkylation of the amine. In
the presence of cyclo aliphatic unsaturation, lithium alumi-


s Lil ~


num hydride is the preferred reducing agent. Subsequentacylation of the ~-cycloaliphatic hydroxyl group and any
phenolic hydroxyl group present may be effected conventional-
ly with a formylating agent such as formyl fluoride or an
alkanoic acid halide or anhydride. Symmetrical N-methyla-
tion may be accomplished via a modified Eschweiler-Clarke
procedure employing a large excess of water as illustrated
by Tilford et al., J.A.C.S. 76, 2431 (1954); alternatively
the procedure of Borch and ~lassid, J. Org. Chem., 37, 1653
(1972) usin~ sodium cyanoborohydride and formaldehyde may be
employed. Non-symmetrical N-alkylation or monoalkylation
may be accomplished by stepwise a]kylation of the N-tri-
fluoroacetate as illustrated by R.A.W. Johnstone et al., J.
Chem. Soc., (C) 2223 (1969). Where R4 is alkyl it is intro-
duced prior to reduction of the nitrile by conventional O-
alkylation.
The intermediate nitriles prepared during the pro-
duction of the antidepressant agents of this invention repre-
sent an additional aspect of the invention. They are de-
picted by the structural formula:


CN

R5
R6




in which the dotted line represents optional unsaturation,and R4 is hydrogen or alkyl of 1 to 6 carbon atoms;
R5 and R6 are ortho or para substituents, independently
selected from the group consistin~ of hydrogen,




hydroxyl, 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, alkyl-
mercapto of 1 to 6 carbon atoms, halo or trifluoro-
methyl;
R7 is hydrogen or alkyl of 1 to 6 carbon atoms; and
n is one of the integers 0, 1, 2, 3 or 4.
The intermediate primary amines produced by reduc-
tion of the nitrile depicted in the preceding paragraph rep-

resent an additional aspect of the invention. They presentthe following structural formula:
INH2




CH2
R ~ t -

in which the dotted line represents optional unsaturation,
R4 is hydrogen, or alkyl of 1 to 6 carbon atoms;
R5 and R6 are ortho or para substituents independently
selected from the group consisting of hydrogen,
hydroxyl, 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, alkyl-
mercapto of 1 to 6 carbon atoms, halo or trifluoro-

methyl;
R7 is hydrogen or alkyl of 1 to 6 carbon atoms; and
n is one of the integers 0, 1, 2, 3 or 4.
Symmetrical N,N-dimethylation may be performed
readily by reaction of the primary amino derivative with
formaldehyde, formic acid in a large excess of water. An

~2~~


intermediate, 3-aza-1-oxaspiro[5.5]undecane, which repre-
sents an additional intermediate of this invention is formed
during the reaction and is isolatable. It presents the fol-
lowing structural formula:

~ N ~




in which the dotted line represents optional unsaturation,
Rl is methyl;
R5 and R6 are orthor or para substituents independently
selected from the group consisting of hydrogen,
hydroxyl, 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, alkyl-
mercapto of 1 to 6 carbon atoms, halo or trifluoro-
methyl;
R7 is hydrogen or alkyl of 1 to 6 carbon atoms; and
n is one of the integers 0, 1, 2, 3 or 4.
These oxaspiro[5.5]undecane intermediates possess similar
activity to the corresponding open-ring tertiary amino end
cornpounds of the invention. For example, the oxazine pro-
duced in Example 3 is hereinafter compared, in its proper-
ties, with the corresponding dimethylamino end compound ofExample 3. The end compound is produced from the corres-
ponding oxazine by prolonged reflux in the presence of aque-
ous formic acid.
An alternative, and preferred, mode of preparing
the compounds of this invention involves the reaction of a

~Z~:85~(3


cycloalkanone or cycloalkenone with an appropriately substi-
tuted phenylacetamide anion following the procedure of
Sauvetre et al., ibid., followed by reduction of the amide
with lithium aluminum hydride or a borane reducing agent,
except in the case of cycloaliphatic unsaturation as dis-
cussed, supra, to the corresponding amine. This process is
preferred because it is considerably more facile when
dealing with meta-subtituted or halo-substituted phenyl-
acetamide reactants which pose some problems when proceeding
through the acetonitrile intermediate. This route to the
desired end products also permits one to readily vary the
valued Rl and R2 in the initial reactant.
lhe cyano substituent representing R5 and/or R6 is
introduced after all reduction steps have been completed by
displacement of an R5-R6 halo substitution with cuprous cya-
nide. The amino substituents representing R5 and/or R6 are
protected throughout the reaction sequence with a protecting
group such as 1,1,4,4-tetramethy]-1,4-dichlorosilylethylene
which completely blocks the amino nitrogen atom from unde-
sireable reactions. After completion of the reaction se-
quence, the amino group is deprotected and alkylated or
acylated by conventional means to provide a mono- or di-
alkylamine or an alkanamido group in each case of 1 to 6
carbon atoms. Ihe nitro substituent representing R5 and/or
R6 is introduced as an aromatic substituent by diazotization
of the aromatic amine followed by treatment with alkali
metal nitrite in the presence of copper or by formation of
the diazonium tetrafluoroborate and reaction with an alkali
metal nitrite, thusly:

:12~



~R
~ N~Rl


H2N ~ ~ N ~R~

B~4~23~A

~6 02N ~ ~ 1



The cyano substituent may be introduced via the diazonium
salt with cyprous cyanide in analogous manner.
The intermediate amide represents an additional
aspect of this invention and is depicted by the following
structural formula:

~N ~ 2
I




C=O

R5~

in which the dotted line represents optional unsaturation,
Rl is hydrogen or alkyl of 1 to 6 carbon atoms;
R2 is alkyl of 1 to 6 carbon atoms;
R4 is hydrogen or alkyl of 1 to 6 carbon atoms;
R5 and R6 are, independently, hydrogen, hydroxyl, alkyl
of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon
atoms, aralkoxy of 7 to 9 carbon atoms, alkanoyl-

oxy of 2 to 7 carbon atoms, alkylmercapto of 1 to
6 carbon atoms, N-protected amino, halo, trifluoro-
methyl, or when taken together, methylenedioxy;
R7 is hydrogen or alkyl of 1 to 6 carbon atoms; and
n is one of the integers 0, 1, 2, 3 or 4. When R4 is
alkyl it is introduced prior to reduction. The protecting
group employed to prevent reaction at the amino substituent
representing R5 and/or R6 is any protecting group that will
completely prevent reaction at a primary -N~l2 substituent,
such as 1,2-[bis-dimethylsilylchloride]ethane.
More indirect routes for synthesis of the antide-
pressant compounds of this invention involve the reaction of
a cycloalkanone or a cycloalkenone with an anion of an ap-
propriately substituted phenylacetic acid, salt, ester, al-
dehyde or alcohol

CHB




R5~ ~ ~ rH~ ~ R

where B represents a carboxyl group or its salt or ester or
a -CHO or CH20H functional group.
The carboxylic acid group may be converted to an
acid halide, active ester or anhydride and directly reacted
with the desired amine to yield, after reduction of the re-
sulting amide, the end products of this invention. Also,

the carboxylic acid group may be reduced with diisobutyl
aluminum hydride or lithium aluminum hydride to obtain the
corresponding aldehyde. The ester is readily converted to
the aldehyde with diisobutyl aluminum hydride or to the al-
cohol with lithium aluminum hydride. The aldehyde may be
condensed with hydroxylamine to afford the oxime -CH=NO~
with ammonium or a primary amine to afford an imine -CH=NR
Q~l
or with a primary or secondary amine to afford
--CH-NRlR2
The alcohol -C~12011 may be converted to the corresponding
nitro derivative by producing an organic sulfonate (mesyl
ester) or halide followed by displacement with an inorganic
nitrite. Reduction of these intermediates yields the pri-
mary amine intermediates or the secondary or tertiary amine
end products of this invention. The alcohols may be conver-
ted to mesylates or tosylates, reacted with KCN to afford
the nitrile, converted to the amide and subjected to a Hoff-
man rearrangement with bromine or chlorine and an alkali
metal hydroxide.
Additional routes to the desired products include
the reaction of ammonia or HNRlR2 with

CH2
R5~ where Z is a leaving group


such as a halogen or an organo sulfonyloxy (mesyl, tosyl and
the like) group under conventional conditions. If desired,
the amine reactant may be initially blocked with a relative-
ly labile acyl group such as trifluoroacetyl to provide a
, O
reactant of the formula ll prior to reaction with
HNRlCCF3

- 10 -

~L2485~(3


the alkylating reactant employing KOH and a very polar sol-
vent such as dimethylsulfoxide, to provide a tertiary amide
from which the acyl group may be readily removed to prepare
the compound for non-symmetrical N-alkylation to insert R2.
Rather than N-alkylate, one may acylate or react the secon-
dary amine with an aldehyde and subsequently reduce the
amide or Schiff base. Similarly, reaction of the amine with
an alkylchloroformate affords, upon reduction, an N-methyl-
a,ted amine. LiAlH4 is a good reducing agent for these pro-
ccsses,
Reductive amination of the aldehyde

CHO

R5~


with ammonia, a primary amine or a secondary amine (Leuckartreaction) also yields the desired end products.
During the course of the synthesis of the end com-
pounds of the invention by means of processes identified
above, any hydroxy group represented by -OR4, R5 or R6 may
be in the free form or in the -form of hydroxy protected by a
removable protecting group, except of course, that the hy-
droxy group is not protected in any case where it is in-
tended to participate in a reaction. The protected form isrecommended where the hydroxy group may otherwise undergo an
undesired reaction. Examples of protecting groups for hy-
droxy are given in Protec~ive Groups in Organic Chemistry
edited by J.F.W. McOmie, Chapters 3 and 4 (pages 95-182),
published by Plenum Press (1973), and Protective Groups in


Organic Chemistry by T.W. Greene, Chapters 2 and 3 ~pages 10
to 113) published by John Wiley and Sons (1981). The pro-
tecting group may be removed at a suitable later stage in
the synthesis. Similarly any amino or alkylamino group may
be in a protected form where appropriate during the course
of the synthesis of the end compounds. Protecting groups
for amino are described in Chapter 2 ~pages 43 to 94) of the
McOmie book and Chapter 7 (pages 218 to 286) of the Greene
book.
The end products contain either one or two asym-
metric centers depending upon the saturated and unsaturated
state of the cycloaliphatic ring, respectively. Individual
stereoisomeric forms may be obtained or separated by stan-
dard procedures. For instance separation of the mixture in
the case of an amine or carboxylic acid may be carried out
by neutralisation with a suitable optically active compound
to form salts which can be separated. Example 33 illus-
trates the typical resolution of the product of Example 3,
Compound A.
The antidepressant activity of the end compounds
of this invention was established by demonstrating that they
(1) inhibit 3H-imipramine binding in brain tissue when tested
by a method analogous to that of Raisman et. al., Eur. J.
Pharmacol. 61, 373- 3g0 (1980); (2) inhibit synaptosomal
uptake of norepinephrine (3H-NE) and serotonin (14C-5-HT)
following the test procedure of Wood et. al., J. Neurochem.
37, 795-797 (1981); and antagonize reserpine induced hypo-
thermia when tested in accordance with the procedure of
`Askew, Life Sci. 1, 725-730 ~1963).
~30 The results of these procedures affirmed the anti-
depressant activity of the end compounds of this invention
. . .

lZ4~ ?


in agreement with the most widely accepted theory of antide-
pressant activity and in correlation of activity with known
tricyclic antidepressants. In at least two instances, name-
ly, with the dimethylamino product of Example 3, and 4-chloro
product in Example ll, the undesirable attribute of classical
antidepressants observed as an anticholinergic property which
is reflected by the inhibition of binding of the muscarinic
receptor ligand, 3H-quinuclidinyl benzilate (QNB), and in
the inhibition of carbachol-stimulated contraction of the
guinea-pig ileum, is missing. Also missing is the attribute
of classical antidepressants observed as an antihistaminic
property which is reflected by the inhibition of the Hl his-
tamine receptor ligand, 3H-pyrilamine, and in the inhibition
of histamine-stimulated contraction of the guinea-pig ileum.
As representative examples of the activity profile
of the end compounds of this invention, the following data
for testing of the dimethylamino product of Example 3, here-
inafter Compound A, its oxazine variant, hereinafter Com-
pound B, the 4-chloro product of Example ll, hereinafter re-
ferred to as Compound C, the 4-bromo product of Example 15,
hereinafter referred to as Compound D, the 3-chloro product
of Example 17, hereinafter referred to as Compound E, the
3-bromo product of Example 16, hereinafter referred to as
Compound F, and the 3,4-dichloro product of Example 19, here-
inafter referred to as Compound G, are presented as follows:
Inhibition of 3H-imipramine binding: Compound A
~HCl Salt) exhibited an inhibition constant (Ki) vs. 3H-imi-
pramine of 90nM, making it a fairly potent ligand at this
receptor site. Compound B was somewhat less potent, with a
Ki of 350nM. Compound C was virtually equipotent with Com-
pound A, exhibiting a Ki vs. 3H-imipramine of lOOn~. While

- 13 -

~Z~8541~


not as potent as imipramine (Ki=1.7nM), these values fall in
the range of desmethylimipramine ~DMI) (Ki=130nM) and other
tricyclic antidepressants. Atypical antidepressants (non-
tricyclic) which have been tested, exhibit Ki's greater than
5000nM in this assay. Compounds D, E, F and G exhibited
inhibition constants of 62, 130, 52 and 37, respectively.
Compounds A through G, representative o-f the other compounds
of this invention, are thus comparable to known tricyclic
antidepressants in this test.
Inhibition of synaptosomal NE and 5-HT uptake:
Results of the inhibition of NE: and 5-~lT synaptosomal up-
take, expressed as the inhibitory concentration at which the
rate of uptake was reduced to 50 percent (IC50), are presen-
ted in the table below, where they are compared with the
values for imipramine, DMI and amitriptyline:
IC50 (~M)
Compound NE 5-~lT
Imipramine 0.26 0.12
DMI 0.15 3.0
Amitriptyline 0.50 0.60
Compound A 0.64 0.21
Compound B 4.7 2.9
Compound C 0.33 0.25
Compound D 0.21 0.11
Compound E 0.16 0.32
Compound F 0.11 0.23
Compound G 0.07 0.08

These results show that Compounds A and C to G are
approximately equipo~ent to imipramine in NE and 5-HT uptake
inhibition. Again, Compound B is somewhat less potent.

- 14 -

~2~8S~


Inhibition of 3~1-QNB binding: In the QNB receptor
binding assay, the Compounds A and C-G exhibited an IC50
greater than lO 5 molar and were therefore essentially inac-
tive. Imipramine and DMI exhibit Ki's of 37 nM and 50 nM,
respectively. These results suggest that, unlike the tri-
cyclic antidepressants, Compounds A and C-G would have no
muscarinic anticholinergic actioTIs.
Inhibition of Carbachol-stimulated contraction of
guinea-pig_ileum: While imipramine at l ~M exhibits a KB of
approximately lO0 nM against carbachol-stimulated contrac-
tion of the guinea-pig ileum, Compound A was inactive at l
~M. This result supports the suggestion of a lack of musca-
rinic anticholinergic action of Compound A.
Inhibition of 3H-pyrilamine binding: While DMI
exhibits a Ki versus 3H-pyrilamine binding of 124 nM, Com-
pound A was inactive. Compounds D-G exhibited an IC50
~reater than lO molar. These results suggest that, unlike
tricyclic antidepressants, Compounds A and D-G have no anti-
histaminic property.
Inhibition of histamine-stimulated contraction of
the ~uinea-pig ileum: Imipramine at l ~M inhibits the his-
tamine- stimulated contraction of the guinea-pig ileum with
an approximate KB of 8 nM. Compound A, in contrast, had no
effect in this test at a concentration of l ~M. This result
supports the notion that Compound A has no antihistaminic
action.
Antagonism of reserpine-induced hypothermia: The
minimum effective dose (M.E.D.) of compounds A through G
established in antagonism of reserpine-induced hypothermia
in mice (n = 8 per group) in relation to desmethylimipramine
(DMI) were:

- 15 -

~ ~ ~8 S ~3


Compound Dose, m~/kg, i.p.
DMI 0 ~
A 10.0 ~and p.o.)
B 30.0
C 10.0
D 3.0
E 1.0
F 1.0
G 3.0
All mice received 5mg/kg reserpine s.c. 18 h prior to test
compound.

DMI, and Compounds A to G, are of approximately equal effi-
cacy in the reversal of reserpine-induced hypothermla. Com-
pound B was less potent than Compound A, Compound C was ap-
proximately equipotent with Compound A, Compounds D and G
were approximately three times as potent as Compound A, and
Compounds E and F were approximately ten times as potent as
Compound A in the study.
Hence, the end compounds of this invention are
useful in the treatment of depression, for which purpose
they may be administered orally or parenterally in an amount
sufficient to alleviate the symptoms of depression. The
actual amount of antidepressant agent to be used will vary
with the severity and nature of the depressed state, the
animal being treated and the level of relief sought. In the
human, an oral dose of from about 2 ~o about 50 milligrams,
administered as needed represents appropriate posology.
Intramuscular administration of from about 1 to about 25
milligrams provides a dosage comparable to that specified
for oral administration. As with other antidepressants,
therapy should be initiated with lower dosages and increased
until the desired symptomatic relief is obtained.
Pharmaceutical compositions containing the antide-
pressant compounds of this invention represent an additional


- 16 -

12~8S~3


aspect of this invention. The active ingredient can be com-
pounded into any of the usual oral dosage forms including
tablets, capsules and liquid preparations such as elixirs
and suspensions containing various colouring, flavouring,
stabilizing and flavour masking substances. For compounding
oral dosage forms, the active ingredient can be mixed with
various conventional tabletting materials such as starch,
calcium carbonate, lactose, sucrose and dicalcium phosphate
to aid the tabletting or capsulating process. Magnesium
stearate, as an additive, provides a useful lubricant func-
tion when desired.
The active ingredients can be dissolved or sus-

pended in a pharmaceutically acceptable sterile liquid car-
rier, such as sterile water, sterile organic solvent or a
mixture of both. Preferably a liquid carrier is one suit-
able for parenteral injection. Where the active ingredient
is sufficiently soluble it can be dissolved in normal saline
as a carrier; if it is too insoluble for this it can often
be dissolved in a suitable organic solvent, for instance
aqueous propylene glycol or polyethylene glycol solutions.
Aqueous propylene glycol containing from 10 to 75% of the
glycol by weight is generally suitable. In other instances
other compositions can be made by dispersing the finely-
divided active ingredient in aqueous starch or sodium car-
boxymethyl cellulose solu~ion, or in a suitable oil, for
instance arachis oil. Liquid pharmaceutical compositions
which are sterile solutions or suspensions can be utilised
by intramuscular, intraperitoneal or subcutaneous injection.
Preferably the pharmaceutical composition is in
unit dosage form, e.g. as tablets or capsules. In such form,
the composition is sub-divided in unit doses containing ap-




- 17 -

~z~


propriate quantities of the active ingredient; the unit
dosage forms can be packaged compositions, for example,
packeted powders or vials or ampoules. The unit dosage form
can be a capsule, cachet or tablet itself, or it can be the
appropriate number of any of these in package form. The
quantity of the active ingredient in a unit dose of composi-
tion may be varied or adjusted from 2mg. or less to 50mg. or
more, according to the particular need and the activity of
the active ingredient.
The following examples illustrate the preparative
technique employed in production of the compounds of the
invention.




- 18 -

~Z~85~


Example 1
l-[Cyano(p-methoxyphenyl)methyl]cyclohexanol
~-Methoxyphenylacetonitrile (50 gm, 0.3 mole) was
added to dry tetrahydrofuran (250 ml) and the solution cooled
to -70C. under nitrogen. n-Butyl lithium in hexane (210
ml, 0.3 mole) was added dropwise, with stirring. The tem-
perature was maintained below -50C. and a yellow precipi-
tate appeared. After the addition was complete, the reac-
tion mixture was maintained below -50C. for 30 minutes and
109 cyclohexanone (35 ml, 0.3 mole) was added. After a further
45 minutes below -50C. the temperature was allowed to rise
to 0C. and a saturated ammonium chloride solution was added.
The layers were separated and the aqueous layer extracted
with diethyl ether. The combined organic solution was washed
with brine, dried over magnesium sulphate and evaporated.
The product crystallized (25.2 gm, m.p. 125-127C.).
Mass Spectral Analysis: Molecular weight 245
[(M + 1~ by C.I.M.S.]
N.M.R. Analysis: ~ 7.32, 6.95; (4H quartet, p-
substituted aromatic) 3.8 (3H singlet, O-CH3); 3.76 (lH,
singlet, CH-CN); 1.56 (lOH, multiplet, aliphatic cyclohexyl)-
ppm.

Example 2
1-[2-amino-1-(p-methoxyphenyl)ethyl]cyclohexanol
l-[cyano(p-methoxyphenyl)methyl]cyclohexanol (12
g, 0.05 mole) was dissolved on warming in a mixture of ammo-
nia-ethanol (20% v/v, 250 ml) and hydrogenated in a Parr
apparatus over 5% rhodium on alumina (2.8 gm). The catalyst
was filtered, washed well with ethanol and the combined fil-



- 19 -

~B5~


trate evaporated and dried under vacuum yielding an oil (12
gm).
Mass Spectral Analysis: Molecular weight 249
(Mfl) by C.I.M.S.
Thin Layer Chromatography: single spot, ninhydrin
positive [chloroform-methanol-acetic acid (80:10:10 v/v)].

Example 3
5-(4-methoxyphenyl)-3-methyl-3-aza-1-oxaspiro(5.5)-
undecane and 1-[2-dimethyl-amino)-1-(4-methoxyphenyl)-
ethyl]cyclohexanol
1-[2-amino-1-(p-methoxyphenyl)ethyl]cyclohexanol
(12 gm; 0.048 mole) was treated with a mixture of formalde-
hyde (11 ml), formic acid (14.5 ml, 88%) and water (125 ml)
and heated at 100C. for five hours. The reaction mixture
was cooled and extracted with ethyl acetate. This extract
was discarded. The aqueous residue was cooled in ice, ren-
dered basic by the addition of solid potassium hydroxide,
saturated with sodium chloride and thrice extracted with
ethyl acetate. The extract was washed with brine, dried
over anhydrous potassium carbonate and evaporated to an oily
residue (8 gm). This mixture of products was chromato-
A graphed on 1 kg of Mallinckrodt Silicar CC7 silica gel and
the progress of the chromatography was monitored by thin
layer chromatography using a system comprising ethanol:2N
ammonia:ethyl acetate:cyclohexane 45:8:100:100 (v/v). Frac-
tions containing the desired products were combined and the
hydrochloride salts prepared using 4-N-isopropanolic HCl.
The yields of the free bases were 1.4 gm (spiro compound)
and 4.6 gm (dimethyl- amine) respectively.


- 20 -

s~


Compound B5-(4-methoxyphenyl)-3-methyl-3-aza-1-oxaspiro(5.5)
undecane
Melting Point: 242-244C.
Mass Spectral Analysis: Molecular weight 275
(M+l) by C.I.M.S.
N.M.R. Analysis: ~ 7.22, 6.96 (4H quartet, p-sub-
stituted aromatic) 4.78 (2H quartet, O-CH2-NCH3) 3.8 (4H,
O-CH3, CH-CH2-NCH3) 3.3 (2H, multiplet CH-CH2-NCH3) 2.8 (3_,
NCH3) 0.9-1.8 (lOH, broad multiplet, aliphatic cyclohexyl)-
ppm.

Compound A
1-[~2-dimethylamino)-1-t4-methoxyphenyl)ethyl]-
cyclohexanol.
The hydrochloride: m.p. 215-217C.
Mass Spectral Analysis: Molecular weight 279
(M+l) by C.I.M.S. (free base)
N.M.R. Analysis: ~ 7.32, 6.98 (4H quartet, p-sub-
stituted aromatic) 3.78 (3H, O-CH3) 3.64 (2H, multiplet CH2N-
(CH3)2) 3.06 (lH, multiplet CH-CH2(NCH3)2) 2.74 (6H, N(CH3)2)
1.38 (lOH, broad multiplet, alphatic cyclohexyl)ppm.

Example 4
1-[1-(4-methoxyphenyl)-2-dimethylaminoethyl]cyclohexene
8.0 grams (0.029 moles) of 1-[1-(4-methoxyphenyl)-
2-dimethylaminoethyl]cyclohexanol was dissolved in 300 ml of
2.0 N aqueous hydrochloric acid and heated at reflux for 18
hours. It was allowed to cool, neutralized with 15% aqueous
sodium hydroxide and extracted with chloroform. The chloro-
form extract was dried over sodium sulfate, filtered, and

- 21 -

` 12~85~


concentrated in vacuo to yield 7.0 grams of solid. This
-
material was converted to the hydrochloride salt by treat-
ment with 5N isopropanolic HCl and recrystallized a second
time from isopropanol to yield 2.0 grams of the title com-
pound as a white solid hydrochloride salt, m.p. 187-189C.
Analysis for: C17H260NCl
Calculated: C, 69.23; H, 8.91; N, 4.75
Found:C, 69.39; H, 8.95; N, 4.95.

Example 5
l-[(-Aminomethyl)benzyl]-cyclohexanol
Phenylacetonitrile (lOg, 0.08 mole) was added to
dry THF (100 ml) and the solution cooled to -70C. under
nitrogen. n-Butyllithium in hexane (64 ml, 0.1 mole) was
added dropwise, the temperature being maintained below -40C
and a yellow precipitate appeared. After addition the reac-
tion mixture was maintained near -70C. for 30 minutes and
cyclohexanone (10 g, 0.1 mole) was added. After a further
45 minutes at -70C. the temperature was allowed to rise to
0C. and saturated ammonium chloride solution was added.
The layers were separated and the aqueous layer extracted
with diethyl ether. The combined organic solution was
washed with brine, dried over magnesium sulphate and evapo-
rated. The product, l-[-cyanobenzyl]-cyclohexanol, crys-
tallized (4.93 g, m.p. 100-102C).
Mass Spectral Analysis: Molecular weight 215 (M )
N.M.R. Analysis: ~ 7.4 (5H singlet, aromatic 3.8
(lH, singlet, CH- CN) 1.6 (lOH, multiplet aliphatic cyclo-
hexyl) ppm.
A solution of l-(~-cyanobenzyl)cyclohexanol (3.43
g, 0.02 mole) in a mixture of methanol and ammonia (9:1 v/v,

S ~48~0


60 ml) was hydrogenated in a Parr apparatus over 5% rhodium
on alumina (2 g). The catalyst was filtered and the fil-
trate evaporated. The residue was dissolved in ethyl ace-
tate, washed with brine, dried over magnesium sulfate and
evaporated. The hydrochloride m.p. 220-222 (1.2 g) crys-
tallized from diethyl ether-acetone.
Analysis for: C14H21NO HCl
Calculated: C, 64.29; H, 8.67; N, 5.47%
Found: C, 65.74; H, 8.51; N, 5.56%.
N.M.R. Analysis (DMSO) ~ 7.73 (5H singlet, aro-
matic) 3.46 (2H multiplet CH2-NH2), 3.0 (lH multiplet C_-
CH2NH2) 0.9-1.7 (10H multiplet-aliphatic cyclohexyl) ppm.
Mass Spectral Analysis by Chemical Ionization:
220 (M+H) (Mol. Wt. 219) (free base).

Example 6
l-(a-[(Dimethylamino)methyl]benzyl)-cyçlohexanol
l-[~-(aminomethyl)benzyl]cyclohexanol (1.38 g,
0.006 mole) was dissolved in ~ mixture of formaldehyde (2
ml) formic acid (2.6 ml) and water (25 ml), and refluxed at
95C. for 18 hours. The reaction mixture was cooled, basi-
fied with solid KOH and extracted with methylene chloride.
The extract was washed with brine, dried over magnesium sul-
phate and evaporated. The hydrochloride (m.p. 225-227C)
was prepared using 3N-isopropanolic HCl. Yield 589 mg.
Analysis for: C16H25NO'HCl
Calculated: C, 67.36; H, 9.12; N, 4.88%
Found: C, 67.7; H, 9.23; N, 4.93%
Mass Spectral Analysis: Molecular weight 247 (M ,
free base).


- 23 -

~z4ss~0


N.M.R. analysis: (D~ISO) ~ 7.4 (5H singlet, aro-
matic), 3.68 (2H, multiplet CH2-N (CH3)2, 3-18 (lH, multi-
plet CH-CH2N(C~I3)2 2-68 (6H, N(CH3)2; 0-9-1-7 (lOH multiplet
aliphatic cyclohexyl) ppm.

Example 7
[(Methylamino)methyl]benzyl)cyclohexanol
l-[~-(aminomethyl)benzyl]cyclohexanol (1.59 g.,
0.007 mole~ was dissolved in diethyl ether (10 ml.) and
cooled to 5C. Trifluoroacetic anhydride (2g) was added and
the mixture stirred at 0C for 30 minutes. The mixture was
neutralized using saturated sodium bicarbonate solution and
the layers separated. The organic layer was washed with
brine, dried over magnesium sulphate and evaporated. A crys-
talline trifluoroacetamide m.p. 78-80C. was obtained (975
mg.).
The triflworoacetamide (975 mg.) was dissolved in
dry acetone (20 ml.) and treat~d with methyl iodide (2 g.).
The solution was warmed to reflux temperature and dry pow-
dered potassium hydroxide (1 g.) added, followed by excess
methyl iodide. The mixture was refluxed for five minutes,
then cooled and the acetone evaporated. Water (20 ml.) was
added and the mixture refluxed for 15 minutes. It was cooled
and extracted with ethyl acetate. The extract was washed
with water and brine, dried over magnesium sulfate and evapo-
rated to a crystalline product m.p. 92-94C. This was con-
verted to the hydrochloride using 3N-isopropanolic HCl.
Yield 235 mg., m.p. 208-210C.
N.M.R. Analysis (CHC13), ~ 7.3 (7H, aromatic, _Cl
and NH-CH3); 3.9 (lH multiplet CH-CH2NH2); 3.25 (2H multi-



- 24 -

~2~8S~(3


plet CH2-NH2); 2.6 (3H sin~let NH-CH3); 0.8-1.9 (lOH multi-
plet, aliphatic cyclohexyl) ppm.
Mass Spectral Analysis: Molecular weight by chemi-
cal ionization/M.S. 233 (M + 1 at 234, free base).

Example 8
-[(Dimethylamino)methyl]benzyl)cyclohexanol acetate
1- (a - [ (Dimethylamino)methyl]benzyl)cyclohexanol,
(O. 5 g., O. 0025 mole) was treated with acetic anhydride (1
ml.) and pyridine (3 ml.) and the mixture stood at room tem-
perature overnight. The reaction mixture was poured into
water, basified with solid KOH and extracted with ethyl ace-
tate. The extract was washed with water and brine, dried
over magnesium sulphate and evaporated to an oil. After
azetropic distillation with toluene to remove traces of pyri-
dine, the oil was treated with 3N isopropanolic HCl and
crystalline hydrochloride as the title compound was obtained
~70 mg.) m.p. 163-165C.
NMR Analysis: (CHC13) ~ 7.35 (5H singlet, aroma-
tic); 4.2 (lH multiplet C_ CH2N(CH3)2; 3.6 (2H multiplet CH2-
N(CH3)2); 2.65 (6H singlet, N(CH3)2); 2.1 (3H singlet, -O-C-
C_3); O. 9-1. 7 (lOH multiplet, aliphatic cyclohexyl) ppm.
Mass Spectral Analysis: Molecular weight 289 (M ,
free base).

Example 9
l-[cyano(p-chlorophenyl)methyl]cyclohexanol
By replacing the p-methoxyphenyl acetonitrile in
Example 1 by a molar equi~alent amount of p-chlorophenyl
acetonitrile, there was obtained l-cyano(p-chlorophenyl)-
methyl cyclohexanol (13.7 g.) m.p. 115-117.

~4~Sf~ I


Mass Spectral Analysis: Molecular weight 249
(M+l) by C.I.M.S.

Example 10
1-[2-amino-1-(4-chlorophenyl)ethyl]cyclohexanol
Lithium aluminum hydride (3.5 g.) was suspended in
ice cold tetrahydrofuran (125 ml.) and concentrated sulphuric
acid (2.5 ml.) added cautiously, with stirring. After one
hour, 1- [cyano(p-chlorophenyl)methyl]cyclohexanol (15 g.,
0.06 mole) was dissolved in tetrahydrofuran (100 ml.) and
added rapidly dropwise with vigorous stirring and cooling.
After a further two hours, a tetrahydrofuran-water mixture
(1:1; 30 ml.) was added followed by 10% sodium hydroxide
solution (50 ml.). The tetrahydrofuran was decanted and the
residue washed well with diethyl ether and ethylacetate.
The combined organic solution was dried over anhydrous po-
tassium carbonate and evaporated to an oil (12 g.)
Mass Spectral Analysis: Molecular weight 253
(M+l) by C.I.M.S.

Example 11
1-[1-(4-chlorophenyl)-2-(dimethylamino)ethyll-
cyclohexanol
1-[2-amino-1-(4-chlorophenyl)ethyl]cyclohexanol
(12 g., 0.04 mole) was treated with a mixture of formalde-
hyde (13.7 ml.~ formic acid (18.1 ml.) and water (160 ml.)
and refluxed at 100C. for four hours. The reaction mixture
was cooled extracted well with ethyl acetate and the extract
discarded. The aqueous residue was cooled in ice and ren-
dered basic by the addition of solid potassium hydroxide,
saturated with sodium chloride and thrice extracted with




- 26 -

12~85~t~


ethyl acetate. The extract was washed with brine, dried
over anhydrous potassium carbonate and evaporated. A crys-
talline solid (3 g.) was filtered. It was converted to the
hydrochloride salt using 4N-isopropanolic HCl; yielding 4.7
g., m.p. 241-243C.
Mass Spectral Analysis: Molecular Weight 281
(M+l) by C.I.M.S.
NMR Analysis: ~ 7.35 (4H singlet characteristic
of 4-chloro substitution) 3.65 (2~1 multiplet, CH2-CHN(CH3)2),
3.0 (lH multiplet CH2CHN(CH3)2 1.4 (lOH multiiplet, aliphatic
cyclohexyl) ppm.

Example 12
1-[1-(4-methoxyphenyl)-2-(methylamino)ethyl]-
cyclohexanol
By replacing l-[-(aminomethyl)benzyl]cyclohexanol
with a molar equivalent amount of l-[2-amino-1-(p-methoxy-
phenyl)ethyl] cyclohexanol in Example 7, 1-[1-(4-methoxy-
phenyl)-2-methylamino)ethyl]cyclohexanol hydrochloride (m.p.
164-166C.) was obtained.
Mass Spectral Analysis: Molecular Weight 263
(M+l) by C.I.M.S.
NMR Analysis: ~ 7.28, 6.92 (4H quartet, p-substi-
tuted aromatic) 3.76 (3H singlet, OMe) 3.4 (2_ multiplet,
C_2-CHNCH3)2 2.9 (1 multiplet, CH2C_N(CH3)2) 2.54 (3H, NCH3)
1.4 (10_ broad multiplet, aliphatic cyclohexyl) ppm.

Example 13
4-bromo-N,N-dimethylbenzene acetamide
Para-bromophenylacetic acid (50 g., 0.233 mole)
was dissolved in methylene chloride (500 ml) and treated

~.~48~


with oxalyl chloride (23.3 ml., 0.27 mole) and D.M.F. (0.5
ml) at room temperature. The mixture was stirred for four
hours until gas evolution ceased. The solvent was evapora-
ted and the residue dried under vacuum to remove excess
oxalyl chloride. The residue was dissolved in ~ethylene
chloride (300 ml) and treated with an excess of gaseous di-
methylamine. The mixture was stirred overnight and the sol-
vent evaporated. The residue was redissolved in methylene
chloride and the solution washed with saturated sodium bi-

carbonate solution, N-hydrochloric acid, water, brine, dried
over magnesium sulphate and evaporated. The buff-colored
crystals were filtered with hexane and air-dried. Yield
51.2 g., m.p. 73-76C.
Analysis for: ClOH12NOBr
Calculated: C, 49.59; H, 4.96; N, 5.79
Found: C, 48.98; H, 5.14; N, 5.77
NMR Analysis (CHC13): 67.55 (4H quartet, aromatic)
3.65 t2H singlet) 2.95 (6H singlet, N(CH3)2) ppm.

Example 14
1-[(4-bromophenyl)[~dimethylamino)carbonyl]methyl]-
cyclohexanol
4-bromo-N,N-dimethylbenzene acetamide (15 g., .06
mole) was added to dry T.H.F. (250 ml) and the solution
cooled to -78C under nitrogen. Straight chain butyl lithium
in hexane (43.3 ml, 0.06 mole~ was added dropwise, the tem-
perature being maintained below -70C throughout. An orange
coloured precipitate formed. After addition, the reaction
mixture was maintained near -70C for 20 minutes and cyclo-
hexanone (7.5 ml, 0.07 mole) was added. After a further 50
minutes at -78C the reaction mixture was poured into stir-

- 28 -

1248S~

ring saturated ammonium chloride solution. The layers were
separated and the aqueous layer extracted with diethyl ether.
The combined organic solution was washed with brine, dried
over magnesium sulfate and evaporated. The product crys-
tallised and was filtered with isopropanol (9.8 g., m.p.
140-144C).
Analysis for: C16I~22NO2Br
Calculated: C, 56.47; H, 6.47; N, 4.12
-
Found: C, 57.22; H, 6.66; N, 4.21
NMR Analysis (CHC13)~7.35 (4H, aromatic) 3.63 (lH
singlet CH-CON(CH3)2) 2.95 (6H singlet, N-(CH~)2); ~-45 (lO~I
multiplet, aliphatic cyclohexyl) ppm.

Example 15
1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]-
cyclohexanol
Lithium aluminum hydride (0.7 g.) was suspended in
dry THF (25 ml) cooled to 0C and concentrated sulfuric acid
(0.5 ml) cautiously added in an in situ preparation of alu-
minum hydride. The mixture was stirred for one hour at 0C
and the amide, 1-[(4-bromophenyl)[dimethylaminocarbonyl]-
methyl]cyclohexanol (4 g., 0.012 mole) was dissolved in THF
(35 ml) and added rapidly dropwise. The reaction mixture
was stirred at 0C for one hour. A THF-water mixture (1:1
v/v 6 ml) was added slowly followed by 10% sodium hydroxide
(10 ml). Ihe mixture was filtered and the residue washed
well with ethyl acetate. The combined filtrate was dried
over anhydrous potassium carbonate and evaporated to an oil
(3.5 g) which was converted to the hydrochloride salt using
4 N isopropanolic HCl.


- 29 -


Analysis for: C16H24NOBr-~lCl
Calculated: C, 52.97; H, 6,9; N, 3.86
Found: C, 52.71; Il, 6.63; N, 3.71
NMR Analysis: (DMSO):~7.4 (4H, aromatic) 3.55 (2H
doublet CH-CH2N(CH3)2); 3.05 (1}l, triplet, CH-C~I2N(CH3)2~;
2.63 (6H singlet, N-(CH3)2) 1.30 (lOH multiplet, aliphatic
cyclohexyl) ppm.

Example 16
1-[1-~3-bromophenyl)-2-(dimethylamino)ethyl]_
cyclohexanol
By replacing p-bromophenyl acetic acid with a molar
equivalent amount of m-bromophenyl acetic acid in Example
13, and following procedures described in Examples 14 and
15, 1-[1-(3-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol
was obtained as the hydrochloride, m.p. 198-201C.
Analysis for: C16}l24NOBroHCl
Calculated: C, 52.97; H, 6.90; N, 3.86
Found:C, 52.84; H, 6.92; N, 3.99

Example 17
1-[1-(3-chlorophenyl)-2-(dimethylamino)ethyl]-
cyclohexanol
By replacing p-bromophenyl acetic acid with a molar
equivalent amount of m-chlorophenylacetic acid in Example
13, and following procedures described in Examples 14 and
15, 1-[1-(3-chlorophenyl)-2-(dimethylamino)ethyl]cyclohex-
anol was obtained as the hydrochloride, m.p. 214-216C.
Analysis for: C16H24NOCl HCl
Calculated: C, 60.38; H, 7.86; N, 4.4
Found: C, 60.07; H, 7.79; N, 3.93


- 30 -

~24854~3


Example 18
1-[1-(2-chlorophenyl~-2-(dimethylamino)ethyl]-
cyclohexanol
By replacing p-bromophenyl acetic acid with a molar
equivalcnt amount of o-chlorophenylacetic acid in Example
13, and following procedures described in Examples 14 and
15, 1-[1-(2-chlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol
was obtained as the hydrochloride, m.p. 205-206C.
Analysis for C16H24NCl-~ICl
Calculated: C, 60.38; H, 7.86; N, 4.4
Found: C, 60.45; H, 7.71; N, 4.79

Example 19
1-[1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl]-
cyclohexanol
By replacing p-bromophenyl acetic acid with a molar
equivalent amount of 3,4-dichlorophenylacetic acid in Example
13, and following procedures described in Examples 14 and
15, 1-~1-(3,4-dichlorophenyl-2-(dimethylamino)ethyl]cyclo-
hexanol was obtained as the hydrochloride, m.p. 241-244C.
2~ Analysis for: C H NOCl HCl
16 23 2
Calculated: C, 54.47; H, 6.81; N, 3.97
Found: C, 54.8; H, 6.83; N, 3.99

Example 20
1-[1-(3,4-dichlorophenyl-2-(dimethylamino)ethyl]-
cyclohexanol
The product of the preceding example is similarly
produced by the following procedure:

s~i~


Lithium diisopropylamide was prepared by dis-
solving di-isopropylamine (69 ml) in THF (500 ml) followed
by the addition of n-butyllithium (325 ml). After 10 minutes
stirring, the straw colored liquid was cooled to -78C and a
solution of the 3,4-dichloro-N,N-dimethylbenzeneacetamide
(110.9 g, crude) was dissolved in 300 ml THF and added slow-
ly. A dark red slurry was obtained. The mixture was stirred
for a further 20 minutes and cyclohexanone (55.7 ml) was
added. After 60 minutes at -78C the reaction mixture was
poured into a saturated solution of ammonium chloride. The
aqueous layer was extracted with diethyl ether and the com-
bined organic solution was washed with brine, dried over
K2CO3 and evaporated. The product, 1-~(3,4-dichlorophenyl)-
(dimethylaminocarbonyl)methyl]cyclohexanol, crystallized and
was filtered. The crystals were washed with isopropanol and
with petroleum ether and air dried. Yield: 73.6 g., m.p.
118-120C.
To an ice cold solu~ion of Borane THF complex (152
ml, 152 mmole) was added a solution of 1-[(3,4-dichloro-
phenyl)(dimethylaminocarbonyl)methyl]cyclohexanol (30 g,
90 mmole) in THF. The mixture was refluxed for 2 hours and
cooled again in an ice bath. 2N HCl (23 ml) was added and
the mixture refluxed for 1.5 hours. It was cooled over-
night. The reaction mixture was basified to pH 14 with solid
potassium hydroxide and the layers were separated. The or-
ganic layer was washed with brine, dried over magnesium sul-
fate and evaporated to a solid. This was filtered and washed
with diethyl ether and air dried. Yield: 15.4 g.; m.p.
128-130C.
This product was converted to the hydrochloride
which was identical with the product in ~xample 19.

- ~2 -

lZ4~35~


Example 21
1-[2-(dimethylamino)-1-(3-methoxyphenyl)ethyl]cyclohexanol
By replacing p-bromophenyl acetic acid with a molar
equivalent amount of m-methoxyphenyl acetic acid in Example
13, and following procedures described in Examples 14 and
15, 1-[2-(dimethylamino)-1-(3-methoxyphenyl)ethyl]cyclohex-
anol was obtained as the hydrochloride, m.p. 166-168C.
Analysis for: C16H25NO2-~ICl
Calculated: C, 64.11; II, 8.68; N, 4.67
Found: C, 63.12; I-I, 8.54; N, 4.46

Example 22
1-[1-(3,4-dimethoxyphenyl)-2-(dimethylamino)ethyl]-
cyclohexanol
By replacing p-bromophenyl acetic acid with a molar
equivalent amount of 3,4-dimethoxyphenyl acetic acid in
Example 13, and following procedures described in Examples
14 and 15, 1-[1-(3,4-dimethoxyphenyl)-2-(dimethylamino)eth-
yl]cyclohexanol was obtained as the hydrochloride.
Analysis for: C18H29NO3~HCl
Calculated: C, 62.88; H, 8.74; N, 4.08
Found: C, 62.42; H, 8.56; N, 3.98

Example 23
1-[2-(dimethylamino)-1-(4-trifluoromethylphenyl)ethyl]-
cyclohexanol
By replacing p-bromophenyl acetic acid with a molar
equivalent amount of p-trifluoromethylphenyl acetic acid in
Example 13, and following procedures described in Examples
14 and 15, 1-[2-(dimethylamino)-1-(4-trifluoromethylphenyl~-


- 33 -

~L~48S4(~


ethyl]cyclohexanol was obtained as the hydrochloride, m.p.
238-240C.
Analysis for: C17H25NOF3 HCl
Calculated: C, 58.03; H, 7.16; N, 3.98
Found: C, 58.47; H7 7.16; N, 4.07

Example 24
1 [2-(dimethylamino)-1-(3-trifluoromethylphenyl)-
ethyl]cyclohexanol
By replacing p-bromophenyl acetic acid with a molar
equiva]ent amount of m-trifluoromethylphenyl acetic acid in
Example 13, and following procedures described in Examples
14 and lS, 1-[2-(dimethylamino)-1-(3-trifluoromethylphenyl)-
ethyl]cyclohexanol was produced as the hydrochloride, m.p.
194-196C.
Analysis for: C17H25NOF3 HCl
Calculated: C, 58.03; H, 7.16; N, 3.98
Found: C, 58.31; H, 7.09; N, 4.09


1-[2-(dimethylamino)-1-(4-methylphenyl)ethyl]cyclohexanol
By replacing p-bromophenyl acetic acid with a molar
equivalent amount of p-methylphenyl acetic acid in Example
13, and following procedures described in Examples 14 and
15, l-[2-(dimethylamino)-1-(4-methylphenyl)ethyl]cyclohexa-
nol was produced as the hydrochloride.
Analysis for: C H NO-HCl
17 17
Calculated: C, 68.54; H, 9.17; N, 4.70
Found: C, 68.37; H, 9.31; N, 4.83




- 34 -

lZ~54~


Example 26
1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol
By replacing p-bromophenyl acetic acid with a molar
equivalent amount of p-benzyloxyphenyl acetic acid in Example
13, and following the procedures described in Examples 14
and 15, 1-[1-(4-benzyloxyphenyl)-2-(dimethylamino)ethyl]-
cyclohexanol was obtained.
Ilydrogenolysis of this product to remove the benzyl
protecting group from the 4-hydroxyphenyl moiety was accom-

plished by dissolving 1.0 grams of the product in 100 ml.
ethanol. One gram, 10% Pd/C was introduced followed by
cyclohexa-1,4-~eRone (5 ml.). The mixture was stirred for
ninety minutes at ambient temperature. The catalyst was
removed by filtration and the solvent removed by evaporation
to yield 800 mg. of solid. This solid 4-hydroxyphenyl pro-
duct was converted to its fumarate salt via an acetone-
ethanol solution, m.p. 140-142C.
Analysis for: C16l~25N2 C4 4 4
Calculated: C, 63.30; H, 7.70; N, 3.69
Found: C, 62.18; H, 7.90; N, 3.63

Example 27
1-[2-(dimethylamino)-1-(3-hydroxyphenyl)ethyllcyclohexanol
By replacing p-bromophenyl acetic acid with a molar
equivalent amount of m-benzyloxyphenyl acetic acid in Example
13, and following the procedures described in Examples 14
and 15, 1-[1-(3-benzyloxyphenyl)-2-(dimethylamino)ethyl]cy-
clohexanol was obtained.
Hydrogenolysis of this product (2.3 g) was con-
ducted in 200 ml ethanol employing a Paar bomb, 300 mg. 10
Pd/C until uptake of hydrogen ceased. The catalyst was re-

~4~


moved by filtration and the solvent evaporated to afford a
solid product which was converted to its hydrochloride salt
with 5 N isopropanolic hydrochloride, m.p. 162-164C.
Analysis for: C16H25NO2 HCl
Calculated: C, 64.08; H, 8.74; N, 4.67
Found: C, 62.78; H, 8.55; N, 4.55

Example 28
1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclobutanol
By replacing cyclohexanone in Example 14 with a
molar equivalent amount of cyclobutanone and following the
procedure described in Example 15, 1-[1-~4-bromophenyl)-2-
(dimethylamino)ethyl]cyclobutanol was obtained. It was con-
verted to the hydrochloride salt, m.p. 220-222C.
Analysis for: C14H20NOBr HCl
Calculated: C, 50.22; H, 6.28; N, 4.19
Found: C, 50.26; H, 6.11; N, 4.13

Example 29
1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclopentanol
By replacing p-bromophenylacetic acid with a molar
equivalent amount of p-methoxyphenyl acetic acid in Example
13, 4-methoxy-N,N-dimethylbenzene acetamide was obtained.
Subsequently, following the procedure outlined in Example
14, replacing cyclohexanone with a molar equivalent amount
of cyclopentanone, there was obtained the corresponding
cyclopentanol derivative. This intermediate was converted,
following the procedure described in Example 15, to the title
compound as the hydrochloride, m.p. 194C.
Analysis for: C16H25NO2 HCl
Calculated: C, 64.07; H, 8.76; N, 4.67
Found: C, 64.19; H, 8.72; N, 4.33

- 36 -

~Z~8S~


Example 30
1-[2-(dimethylamino)-1-(4-methoxyphenyl)e~hyl]cycloheptanol
By replacing cyclopentanone with a molar equiva-
lent of cycloheptanone in Example 27, the ~itle compound was
obtained as the hydrochloride, m.p. 175-177C.
Analysis for: C H NO HCl-1/4E~2O
- 18 29 2
Calculated: C, 65.03; H, 9.26; N, 4.21
Found: C, 65.25; II, 9.16; N, 4.29

Fxample 31
1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-
cyclooctanol
By replacing cyclopentanone with a molar equiva-
lent amount of cyclooctanone in Example 29, the title com-
pound was obtained as the hydrochloride, m.p. 178-180C.
Analysis for: C H NO I-ICl-l/4H O
19 31 2 2
Calculated: C, 65.87; H, 9.48; N, 4.04
Found: C, 65.79; H, 9.08; N, 3.95

Example 32
1-[2-(dimethylamino)-1-(4-methoxy_henyl)ethyl~-
cyclohex-2-en-l-ol
By replacing 4-bromo-N,N-dimethylbenzeneacetamide
with a molar equivalent of 4-methoxy-N,N-dimethylbenzeneace-
tamide in Example 14, and cyclohexanone with 2-cyclohexen-1-
one, was obtained the corresponding cyclohexenone deriva-
tive. This intermediate was converted following the proce-
dure described in Example 15 to the title compound as the
fumarate, m.p. 128-130C.



- 37 -

~Z~85~1~


Analysis for: C Tl NO ~C H O
17 25 2 4 4 4
Calculated: C, 64.4; H, 7.31; N, 3.58
Found: C, 63.8; H, 7.46; N, 3.88.

Example 33
Resolution of Racemic 1-[2-(dimethylamino)-1-(4-
methoxyphenyl)ethyl]cyclohexanol
1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cy-
clohexanol (48.0 g., 0.173 m) dissolved in ethyl acetate
(350 ml) was treated with di-p-toluoyl-d-taritaric acid (33.5
g., 0.082 m) dissolved in ethyl acetate (250 ml). After
standing overnight, the solid was filtered. The solid was
recrystallized three times by dissolving in boiling ethyl
acetate (300 ml) and methanol (50 ml), concentrating by
boiling to incipient crystallization and chilling. Yield
31.7 g., m.p. 126-128C. []25 = -50.51; c = 1.03 ethanol.
The salt was converted to its free base by shaking
in 2N sodium hydroxide and diethyl ether. The ether layer
was washed with brine, dried over anhydrous sodium carbo-
nate, evaporated and dried in vacuo. Yield 16.4 g., 68.5%.
m.p. 104-5C. [a]25 = +27.95; c = 1.15, 95% ethanol.
The base was dissolved in ether (500 ml) and
treated with 4.5N hydrogen chloride in isopropanol (20 ml).
The resulting hydrochloride salt was recrystallized from
warm methanol (75 ml) by dilution with ether (400 ml) and
chilling. Yield 16.6 g. m.p. 239-241C. [a]25 = -4.38;
c = 1.01, 95% ethanol.
The filtrate and washings from the original di-p-
toluoyl-d-tartrate salt were evaporated to dryness. The
free base was obtained by shaking the solid with 2N sodium
hydroxide (400 ml), extracting with diethyl ether (3 x 250

- 38 -

1~248S~


ml), washing the extracts with brine and drying. Yield 24.2
g. The base was dissolved in ethyl acetate (150 ml) and
treated with di-p-toluoyl-l~tartaric acid (16.75 g, 0.0435 m)
dissolved in ethyl acetate (150 ml). After standing over-
night the salt was filtered and was recrystallized twice
from ethyl acetate (300 ml) and methanol (50 ml) as des-
cribed. Yield 29.4 g. m.p. 124-127C. [a]25 = ~50.77,
c = 0.845 ethanol.
The base was obtained in the manner described.
Yield 14.7 g. m.p. 104-105C. [~]25 = -26.56, c = 1.22%,
95% ethanol.
Ihe free base was converted to the hydrochloride
salt.
Yield 14.5 g. m.p. 239-241C. [a]25 = +4.98, c = 1.01, 95%
ethanol.

Pxample 34
1-[1-(4-aminophenyl)-2-dimethylaminoethyl]cyclohexanol
17.0 g (0.095 moles) of p-aminophenylacetic acid,
dimethylamide was dissolved in 500 ml of tetrahydrofuran,
placed under a nitrogen atmosphere, and cooled to -20C.
23.6 g (1.15 equivalents) of 1,1,4,4-tetramethyl-1,4-di-
chlorosilylethylene was added, followed dropwise by a solu-
tion of 42 g (2.4 equivalents) of sodium bis(trimethylsilyl)-
amide in 250 ml of THF. The mixture was allowed to warm to
room temperature and was stirred for 18 hours.
The mixture was next cooled to -78C and 71.6 ml
(1.2 equivalents) of 1.6 N n-butyl lithium in hexane added.
The reaction was stirred for 45 minutes and then 20 ml (2.0
equivalents) of cyclohexanone added. The mixture was stirred
for an additional 1 hour at -78C and then poured into a

- 39 -

lZ~85'~


saturated aqueous solution of ammonium chloride. The or-
ganic phase was removed and the aqueous phase was extracted
with diethyl ether. The combined organic phases were dried
over sodium sulfate, filtered and concentrated in vacuo to
yield 20 g of crude 1-[(4-aminophenyl)(dimethylaminocar-
bonyl)methyl]cyclohexanol. Column chromatography on silica
gel with 1% methanol in methylene chloride gave 16 g of es-
sentially pure white solid. A sample twice recrystallized
from ethanol had m.p. 169-170C and the following elemental
analysis
AnalySis for: C16~l242N2
Calculated: C, 69.51; 13, 8.77; N, 10.14
Found: C, 69.69; H, 8.96; N, 10.26.

5.0 g (0.018 mole) of the above amide was dis-
solved in 300 ml of dry tetrahydrofuran and added dropwise
to a mixture of 1.1 g of lithium aluminum hydride and 8.0 ml
of concentrated sulfuric acid in 200 ml of tetrahydrofuran
at 0C. The mixture was stirred at 0C for five hours, then
the excess reagent was destroyed by the dropwise addition of
4 ml of 50:50 THF-water, then 4 ml of 15% aqueous sodium
hydroxide and finally 4 ml of water. The mixture was fil-
tered and the precipitate washed several times with THF.
The combined filtrates were evaporated and the residue re-
crystallized from isopropanol to give 3.8 g of the title
compound as the free base. Treatment with excess oxalic
acid in ethyl acetate gave the dioxalate, m.p. 105C(d).
Analysis for: C20H30N2Og
Calculated: C, 54.28; H, 6.84; N, 6.33
Found: C, 53.96; H, 6.83; N, 6.24.


- 40 -


Example 35
1-[1-(4-nitrophenyl~-2-dimethylaminoethyl]cyclohexanol
2.0 g (7.6 mmoles) of 1-[1-~4-aminophenyl)-2-di-
methylaminoethyl]cyclohexanol was dissolved in 50 ml of
methylene chloride and added dropwise to a stirring solution
of 2.2 g (2.5 equivalents) of nitrosonium tetrafluoroborate.
The reaction was stirred at room temperature for four hours.
The methylene chloride was then removed in vacuo and re-
placed with 100 ml of water. This solution was added slowly
to a mixture of 2.0 g of copper in 200 ml of 1 N sodium ni-
trite and the combination stirred for 2 hours at room tem-
perature. Extraction with methylene chloride, drying, and
evaporation in vacuo yielded 2.0 g of the free base of the
title compound. Recrystallization from isopropanolic HCl
gave the hydrochloride, m.p. 211-212C.
Analysis for: C H O N
16 24 3 2
Calculated: C, 58.42; H, 7.37; N, 8.52
Found: C, 58.03; H, 7.53; N, 8.69.
-

ExamPle 36
1-[2-dimethylamino)-1-(3-bromo-4-methoxyphenyl)ethyl]-
cyclohexanol
By replacing 1-[2-amino-1-~p-methoxyphenyl)ethyl]-
cyclohexanol in Example 3 with a molar equivalent amount of
1-[2-amino-1-~3-bromo-4-methoxyphenyl)ethyl]cyclohexanol and
refluxing overnight, the title compound was obtained, m.p.
218-220C.
Analysls for C17H26N2Br'HCl
Calculated: C, 57.g8; H, 6.92; N, 3.56
Found: C, 51.57; H, 6.79; N, 3.46.


- 41 -

S~


Example 37 ~ ~l
(dimethylamino)-2-(4-methoxyphenyl~ ]cyclohexanol
14.7 g (0.10 mole) of p-methoxyphenylacetonitrile
was dissolved in 250 ml o-f dry tetrahydrofuran and placed in
a dry ice/isopropanol bath under N2. 69.0 ml of 1.6 M n-
butyl lithium (0.11 mole) was added dropwise over 30 minutes
and the mixture stirred at -78C for one hour. The lithium
salt of the nitrile precipitated as a yellow solid during
this time. 71.0 g (0.50 mole) of methyl iodide was then
added and stirring at -78C continued for an additional hour
The mixture was then poured into saturated ammonium chloride
and the product extracted into diethyl ether, washed with
saturated sodium chloride and dried over sodium sulfide. It
was filtered and evaporated, redissolved in methylene chlor-
Flc~
ide and passed through FloriEol~. Evaporation gave 15.0 gof ~-(p-methoxyphenyl)propionitrile as an orange oil.
The ~-(p-methoxyphenyl)propionitrile prepared
above was redissolved in 250 ml of tetrahydrofuran and
cooled to -78C in dry ice/isopropanol. 69.0 ml of 1.6 M
n-butyllithium was added over 30 minutes and the mixture
stirred for 1 hour under nitrogen. 20 ml of cyclohexanone
was then added and stirring at 078C was continued for an
additional hour. The mixture was poured into saturated
ammonium chloride solution and the product extracted with
diethyl ether. It was washed with water, saturated sodium
chloride and dried over sodium sulfate. Filtration and eva-
poration gave 21.5 g of white solid. A sample twice re-
crystallized from benzene had m.p. 129C and the following
analysis:
Analysis for: C16H21NO2
Calculated: C, 74.10; H, 8.16; N, 5.40
Found: C, 73.95; H, 8.04; N, 5.29.

- 42 -

~8S~V


4.0 g (15 mmoles) of the ~-hydroxynitrile prepared
above was dissolved in 200 ml of tetrahydrofuran and S0 ml
o-f 1 M borane tetrahydrofuran complex was added. The mix-
ture was refluxed for 2 hours and allowed to cool. 200 ml
of 2 N ~ICl was added and the THF removed in vacuo. The
aqueous solution was made basic by the addition of solid
pottasium carbonate and the product extracted with 500 ml of
ethyl acetate, washed with saturated sodium chloride and
dried over sodium sulfate. This was filtered and evaporated
and treated with isopropanolic HCl and diethyl ether to
yield 3.3 g of the primary amine, m.p. 209C.
Analysis for: C16H26NO2Cl
Calculated: C, 64.09; H, 8.74; N, 4.67
Found: C, 63.70; H, 8.60; N, 4.59.
3.0 g (10 mmole) of the primary amine hydrochlor-
ide was dissolved in 200 ml of absolute ethanol. 5.0 ml of
37% aqueous formaldehyde and 1.0 g of 10% palladium on car-
bon were added and the mixture was treated with 50 psi of
hydrogen on a Parr shaker for 3 days. The mixture was then
filtered and evaporated and the solvent replaced with 300 ml
of water and washed with 300 ml of ethyl acetate. The
aqueous solution was then made pasic with solid sodium car-
bonate and again extracted with ethyl acetate. The organic
extract was washed with saturated brine and dried over
sodium sulfate. It was filtered and evaporated and the
title compound precipitated as the hydrochloride from iso-
propanol/ether by the addition of isopropanolic HCl. A
second crystallization from isopropanol gave 2.0 g of white
solid, m.p. 271C.
0 Analysis for: C H NO Cl
18 30 2
Calculated: C, 65.93; H, 9.22; N, 4.27
Found: C, 65.73; H, 8.93; N, 4.20.

- 43 -

~ 2~8


Example 38
By following a procedure similar to Examples 13 to
15, using (a) 3,4-dibromophenylacetic acid, ~b) 3-methyl-
phenylacetic acid, (c) 4-bromophenylacetic acid and (d) 3-
methoxyphenylacetic acid instead of p-bromophenylacetic acid
and, as the cycloalkanone, (a) cyclohexanone, (b) cyclohexan-
one, (c) cyclobutanone and (d) cyclopentanone, there are
prepared (a) l-[1-(3,4-dibromophenyl)-2-(dimethylamino)-
ethyl]cyclohexanol, (b) 1-[2-(dimethylamino)-1-(3-methyl-
phenyl)ethyl]cyclohexanol, (c) 1-[1-(4-bromophenyl)-2-(di-
methylamino)ethyl]cyclobutanol and (d) l-[2-(dimethylamino)-
1-(3-methoxyphenyl)ethyl]cyclopentanol.

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

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Filing $0.00 1983-11-16
Registration of Documents $50.00 2002-12-09
Current owners on record shown in alphabetical order.
Current Owners on Record
WYETH
Past owners on record shown in alphabetical order.
Past Owners on Record
AMERICAN HOME PRODUCTS CORPORATION
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.

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