AGENTS THERAPEUTIQUES

THERAPEUTIC AGENTS

Abrégé anglais

Abstract
Compounds of formula I
<IMG>
in which n=0 or 1; R1 is C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C3-7 cycloalkyl, C3-6 cycloalkylalkyl or
optionally substituted phenyl when n = 0 or R1 is H or
C1-3 alkyl when n = 1, R2 is H or C1-3 alkyl, R3 and/or
R4 are H, formyl, C1-3 alkyl, C3-6 alkenyl, C3-6 alkynyl,
C3-7 cycloalkyl or R3 and R4 together with the nitrogen
atom form a heterocyclic ring system; R5 and/or R6 are
H, halo, CF3, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio or
R5 and R6 together with the carbon atoms to which they
are attached form a second benzene ring and R7 and/or
R8 are H or C1-3 alkyl show therapeutic activity in the
treatment of depression. Pharmaceutical compositions and
processes for preparing compounds of formula I are dis-
closed.

Revendications

WE CLAIM:
1. A process for preparing compounds of formula I:
<IMG> I
in which, R1 is a straight or branched chain alkyl group
containing 1 to 6 carbon atoms, a cycloalkyl group containing 3
to 7 carbon atoms, a cycloalkylalkyl group in which the
cycloalkyl group contains 3 to 6 carbons and the alkyl group
contains 1 to 3 carbon atoms, an alkenyl group or an alkynyl
group containing 2 to 6 carbon atoms or a group of formula II:
<IMG>
II
in which R9 and R10, which are the same or different, are H, halo
or an alkoxy group containing 1 to 3 carbon atoms;
in which R2 is H or an alkyl group containing 1 to 3 carbon
atoms;
54

in which R3 and R4, which are the same or different, are H, a
straight or branched chain alkyl group containing 1 to 4 carbon
atoms, an alkenyl group having 3 to 6 carbon atoms, an alkynyl
group having 3 to 6 carbon atoms, a cycloalkyl group in which the
ring contains 3 to 7 carbon atoms, a group of formula R11CO where
R11 is H or R3 and R4 together with the nitrogen atoms to which
they are attached form a heterocyclic ring which (a) contains 4
or 5 carbon atoms in addition to the nitrogen atom and is
unsubstituted or substituted, by one or more lower alkyl groups
or (b) contains a second nitrogen atom which is unsubstituted or
substituted by a lower alkyl group; and in which R5 and R6 which
are the same or different are H;
halo, trifluoromethyl, an alkyl group containing 1 to 3 carbon
atoms, an alkoxy or alkylthio group containing 1 to 3 carbon
atoms, phenyl or R5 and R6, together with the carbon atoms to
which they are attached, form a second benzene ring optionally
substituted by one or more halo groups, an alkyl or alkoxy group
containing 1 to 4 carbon atoms or the substituents of the second
benzene ring together with the two carbon atoms to which they are
attached form a further benzene ring;
and their pharmaceutically acceptable salts; said process being
selected from:
(i) the reductive amidation of ketones of formula V:
<IMG> V
to give compounds in which R2= H, R4= CHO and R1, R5 and R6 are
as defined above;
(ii) reductive amination of ketones of formula V:

<IMG> V
to give compounds in which R2 = H and R1, R5 and R6 are as
defined above;
(iii) the reduction of compounds of formula VII:
<IMG> VII
in which:
a) Z is a group of formula -CR=NOH or an ester or ether thereof
to give compounds of formula I in which R2, R3 and R4 are H;
b) Z is a group of formula -CR1=NR3 to give compounds of
formula I in which R2 and R4 are H;
c) Z is a group of formula -CR1= NY in which Y represents a
metal-containing moiety derived from an organometallic reagent to
give compounds of formula I in which R2, R3 and R4 are H;
(iv) the reaction of an organometallic reagent with an imine of
formula VIII:
VIII
<IMG>
56

followed by the hydrolysis of the resulting product to give
compounds of formula I;
(V) the decarboxylative rearrangement of (a) an amide of formula
<IMG> X
57

or (b) an acyl azide formed by reaction of sodium azide with an
acid chloride of formula XII:
<IMG> XII
to give amines
(vi) the reaction of hydrazoic acid with a carboxylic acid
of formula XIV
<IMG> XIV
to give amines;
58

(vii) in the case where R4 is H, the hydrolysis of compounds
of formula I in which R4 is CHO;
(viii) in the case where R4 is methyl, the reduction of
compounds of formula I in which R4 is CHO; and,
(ix) in the case where one or both of R3 and R4 is other
than H, the conversion of a compound of formula I in which one
or both of R3 and R4 are hydrogen to the required compound.
2. Compounds of formula I as given in claim 1 and
pharmaceutically acceptable salts thereof, whenever prepared by
a process according to claim 1 or an obvious chemical equivalent
thereof.
3. A process for the preparation of compounds of formula I as
given in claim 1 comprising the reductive amination of ketones
of formula V
<IMG> V
to give compounds of said formula I in which R2 = H, R4 -CHO
and R1, R3, R5 and R6 are as defined in claim 1.
59

4. Compounds of formula I as given in claim 1 wherein R4 =
CHO, R2 = H and R1, R3, R5 and R6 are as defined in
claim 1, and pharmaceutically acceptable salts thereof, whenever
prepared by a process according to claim 3 or an obvious
chemical equivalent thereof.
5. A proces for the preparation of compounds of formula I as
defined in claim 1 comprising reductive amination of ketones of
formula V:
<IMG> V
to give compounds of said formula I in which R2 = H and R1,
R3, R4, R5 and R6 are as defined in claim 1.
6. Compounds of formula I as given in claim 1, wherein R2 = H
and R1, R3, R4, R5, R6 are as defined in claim 1, and
pharmaceutically acceptable salts thereof, whenever prepared by
a process according to claim 5 or an obvious chemical equivalent
thereof.
7. A process for preparing 1-[1-(4-chlorophenyl) cyclobutyl]
butylamine of formula:

<IMG>
and pharmaceutically acceptable salts thereof comprising the
reductive amination of a compound of formula:
<IMG>
8. 1-[1-(4-chlorophenyl) cyclobutyl]butylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 7 or an obvious chemical equivalent
thereof
9. A process for preparing
1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reductive amination of a compound of formula:
<IMG>
61

10. 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 9 or an obvious chemical equivalent
thereof
11. A process for preparing
.alpha.-[1-(4-chlorophenyl)cyclobutyl]benzylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reductive amination of a compound of formula:
<IMG>
12. .alpha.-[1-(4-chlorophenyl)cyclobutyl]benzylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 11 or an obvious chemical equivalent
thereof
13. A process for preparing
N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of
formula:
<IMG>
62

and pharmaceutically acceptable salts thereof comprising the
reductive amination of a compound of formula:
<IMG>
14. N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine
and pharmaceutically acceptable salts thereof whenever prepared
by a process according to claim 13 or an obvious chemical
equivalent thereof.
15. A process for preparing
N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of
formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reductive amination of a compound of formula:
<IMG>
16. N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-
methylbutylamine and pharmaceutically acceptable salts thereof
63

whenever prepared by a process according to claim 15 or an
obvious chemical equivalent thereof.
17. A process for preparing
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine of
formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reductive amination of a compound of formula:
<IMG>
18. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine
and pharmaceutically acceptable salts thereof whenever prepared
by a process according to claim 17 or an obvious chemical
equivalent thereof
19. A process for preparing
N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of
formula:
<IMG>
64

and pharmaceutically acceptable salts thereof comprising the
reductive amination of a compound of formula:
<IMG>
20. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
butylamine and a pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 19 or an
obvious chemical equivalent thereof.
21. A process for preparing
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine
of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reductive amination of a compound of formula:
<IMG>

22. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-
methylhutylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 21 or an
obvious chemical equivalent thereof.
23. A process for preparing
N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-
methylbutylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reductive amination of a compound of formula:
<IMG>
24. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-
methylbutylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 23 or an
obvious chemical equivalent thereof.
25. A process for preparing
N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of
formula:
<IMG>
66

and pharmaceutically acceptable salts thereof comprising the
reductive amination of a compound of formula:
<IMG>
26. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
ethylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 25 or an
obvious chemical equivalent thereof.
27. A process for preparing
1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reductive amination of a compound of formula:
<IMG>
28. 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 27 or an obvious chemical equivalent
thereof.
67

29. A process for the preparation of compounds of formula I
comprising the reduction of compounds of formula VII:
<IMG>
VII
in which
a) Z is a group of formula CR1=NOH or an ester or ether
thereof to give compounds of said formula I in which R2,
R3 and R4 are H;
b) Z is a group of formula -CR1=NR3 to give compounds of
said formula I in which R2 and R4 ace H; or
c) Z is a group of formula -CR1=NY in which Y represents a
metal-containing moiety derived from an organometallic reagent
to give compounds of said formula I in which R2, R3 and
R are H:
30. A process as claimed in claim 29 in which Y is MgBr or
Li.
31. Compounds of formula I
as given in claim 1 and pharmaceutically acceptable
salts thereof, whenever prepared by a process according to claim
29 or claim 30 or an obvious chemical equivalent thereof.
68

32. A process for preparing
1-[1-(4-chlorophenyl)cyclobutyl]butylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reduction of a compound of formula:
<IMG>
or an ester or ether thereof
33. 1-[1-(4-chlorophenyl)cyclobutyl]butylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 32 or an obvious chemical equivalent
thereof.
34. A process for preparing
1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reduction of a compound of formula:
<IMG>
69

or an ester or ether thereof
35. 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 34 or an obvious chemical equivalent
thereof.
36. A process for preparing
.alpha.-[1-(4-dichlorophenyl)cyclobutyl]benzylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reduction of a compound of formula:
<IMG>
or an ester or ether thereof.
37. .alpha.-[1-(4-dichlorophenyl)cyclobutyl]benzylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 36 or an obvious chemical equivalent
thereof.
38. A process for preparing
1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the 70

reduction of a compound of formula:
<IMG>
or an ester or ether thereof.
39. 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 38 or an obvious chemical equivalent
thereof.
40. A process according to claim 29 wherein a compound of
formula
<IMG>
in which Y represents a metal containing moiety derived from an
organo-metallic agent, is reduced to give a compound of formula
I as defined in claim 1 and in which R2, R3 and R4
are H; and R1, R5 and R6 are as defined in claim 1.
41. The process of claim 40 wherein Y is MgBr or Li.
42. Compounds of formula 1 as given in claim 1, in
which R2, R3 and R4 are H; whenever prepared by a
process according to claim 40 or claim 41 or an obvious chemical
equivalent thereof.
71

43. A process for preparing
1-[1-(4-chlorophenyl)cyclobutyl]butylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reduction of a compound of formula:
<IMG>
wherein Y represents a metal-containing moiety derived from an
organometallic agent.
44. The process of claim 43 wherein Y is MgBr or Li.
45. 1-[1-(4-chlorophenyl)cyclobutyl]butylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 43 or claim 44 or an obvious chemical
equivalent thereof.
46. A process for preparing
1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula:
<IMG>
72

and pharmaceutically acceptable salts thereof comprising the
reduction of a compound of formula:
<IMG>
wherein Y represents a metal-containing moiety derived from an
organometallic agent.
47. The process of claim 46 wherein Y is MgBr or Li.
48. 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 46 or claim 47 or an obvious chemical
equivalent thereof.
49. A process for preparing
1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reduction of a compound of formula:
<IMG>
wherein Y represents a metal-containing moiety derived from an
organometallic agent.
50. The process of claim 49 wherein Y is MgBr of Li.
51. 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 49 or claim 50 or an obvious chemical
equivalent thereof.
73

52. A process for preparing
.alpha.-(1-(4-chlorophenyl)cyclobutyl]benzylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof, comprising the
reduction of a compound of the general formula:
<IMG>
wherein Y is a metal-containing moiety derived from an
organometallic agent.
53. The process of claim 52 wherein Y is MgBr or Li.
54. .alpha.-[1-(4-chlorophenyl)cyclobutyl]benzylamine and its
pharmaceutically acceptable salts whenever prepared by a process
according to claim 52 or claim 53 or an obvious chemical equivalent
thereof.
55. A process for the preparation of compounds of formula I
as given in claim 1 comprising the reduction of compounds of
formula VII b:
<IMG> VIIb
to give compounds of said formula I in which R2 and R4 are
hydrogen, and R1, R3, R5 and R6 are as defined in claim 1.
74

56. Compounds of formula I as given in claim 1 in which R2 and R4
ace hydrogen, and R1, R3, R5 and R6 ace as defined in
claim 1, whenever prepared by a process according to claim 55,
or an obvious chemical equivalent thereof.
57. A process for preparing
N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of
formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reduction of a compound of formula:
<IMG>
58. N-methyL-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine
and pharmaceutically acceptable salts thereof whenever prepared
by a process according to claim 57 or an obvious chemical
equivalent thereof.

59. A process for preparing
N-methyl-1-[1-(4-chlorophenyl)cyclobutyl)-3-
methylbutylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reduction of a compound of formula:
<IMG>
60. N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-
methylbutylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 59 or an
obvious chemical equivalent thereof.
76

61. A process for the preparation of compounds of formula I
as given in claim 1 comprising (a) the reaction of an organometallic
reagent with an imine of formula VIII:
<IMG> VIII
and (b) the hydrolysis of the resulting product to give
compounds of said formula I,
62. A process as claimed in claim 61 in which the
organometallic reagent is a Grignard reagent of formula R1MgBr
or an organolithium compound of formula R1Li.
63. Compounds of formula I as given in claim 1 and
pharmaceutically acceptable salts thereof, whenever prepared by
a process according to claim 61 or claim 62 or an obvious
chemical equivalent thereof.
64. A process for preparing
N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of
formula:
<IMG>
77

and pharmaceutically acceptable salts thereof comprising a first
step in which an organometallic reagent of formula
CH3CH2CH2 W wherein W represents a metal-containing group,
is reacted with an imine of formula
<IMG>
followed by a second step wherein the resultant product is
hydrolysed.
65. The process according to claim 64 wherein said
organometallic reagent is a Grignard reagent of formula
CH3CH2CH2MgBr or an organolithium compound of formula
CH3CH2CH2Li.
66. N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine
and pharmaceutically acceptable salts thereof whenever prepared
by a process according to claim 64 or claim 65 or an obvious
chemical equivalent thereof.
67. A process for preparing
N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of
formula:
<IMG>
78

and pharmaceutically acceptable salts thereof comprising a first
step in which an organometallic reagent of formula
(CH3)2CHCH2W in which W represents a metal-containing
group, is reacted with an imine of formula:
<IMG>
followed by a second step wherein the resultant product is
hydrolysed.
68. The process according to claim 67 wherein said
organometallic reagent is a Grignard reagent of formula
(CH3)2CHCH2MgBr or an organolithium compound of formula
(CH3)2CHCH2Li.
69. N-methyl-1-[1-(4-chlorophenyl)chclobutyl]-3-
methylbutylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 67 or claim 68
or an obvious chemical equivalent thereof.
79

70. A process for the preparation of compounds of formula I
wherein R3 and R4 are H comprising the decarboxylative
rearrangement of
(a) an amide of formula X
<IMG> X
to give amines of said formula I, or
(b) an acyl azide formed by reaction of sodium azide with an
acid chloride of formula XII
<IMG> XII
to give amines of said formula I.
71. Compounds of formula I as given in claim 1 and
pharmaceutically acceptable salts thereof, whenever prepared by a
process according to claim 70 or an obvious chemical equivalent
thereof.
72. A process for preparing 1-[1-(4-
chlorophenyl)cyclobutyl]butylamine of formula:

<IMG>
and pharmaceutically acceptable salts thereof comprising
decarboxylative rearrangement of an amide of formula:
<IMG>
73. 1-[1-(4-chlorophenyl)cyclobutyl]butylamine and
pharmaceutical acceptable salts thereof whenever prepared by a
process according to claim 72 or an obvious chemical equivalent
thereof.
74. A process for preparing 1-[1-(4-
chlorophenyl)cyclobutyl]butylamine of formula:
<IMG>
81

and pharmaceutically acceptable salts thereof comprising
decarboxylative rearrangement of an acyl azide first formed by
reaction of sodium azide with an acyl chloride of formula:
<IMG>
75. 1-(1-(4-chlorophenyl)cyclobutyl]butylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 74 or an obvious chemical
equivalent thereof.
76. A process for preparing
1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising
decarboxylative rearrangement of an amide of formula:
<IMG>
77. 1-[1-(3,4-dichlocophenyl)cyclobutyl]ethylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 76 or an obvious chemical equivalent
thereof.
82

78. A process for preparing
-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising
decarboxylative rearrangement of an acyl azide first formed by
reaction of sodium azide with an acyl chloride of formula:
<IMG>
79. ?1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 78 or an obvious chemical equivalent
thereof.
80. A process for preparing
?-[1-(4-chlorophenyl)cyclobutyl]benzylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising
decarboxylative rearrangement of an amide of formula: :
<IMG>
83

81. .alpha.-[1-(4-chlorophenyl)cyclobutyl]benzylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 80.
82. A process for preparing
.alpha.-[1-(1-(4-chlorophenyl)cyclobutyl]benzylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising
decarboxylative rearrangement of an acyl azide first formed by
reaction of sodium azide within an acyl chloride of formula:
<IMG>
83. .alpha.-[1-(4-chlorophenyl)cyclobutyl]benzylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 82 or an obvious chemical equivalent
thereof.
84. A process for preparing
1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula:
<IMG>
84

and pharmaceutically acceptable salts thereof comprising the
decarboxylative rearrangement of an amide of formula:
<IMG>
85. 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 84 or an obvious chemical equivalent
thereof.
86. A process for preparing
1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula
<IMG>
and pharmaceutically acceptable salts thereof comprising
decarboxylative rearrangement of an acyl azide first formed by
reaction of sodium azide with an acyl chloride of formula
<IMG>
87. 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 86 or an obvious chemical equivalent
thereof.

88. A process for preparing compounds of formula I as defined
in claim 1 in which
R3 and R4 are H comprising the reaction of hydrazoic acid with
(a) a carboxylic acid of formula XIV
<IMG> XIV
to give amines of said formula I.
89. Compounds of formula I as given in claim 1
and pharmaceutically acceptable
salts thereof, whenever prepared by a process according to claim
88 or an obvious chemical equivalent thereof.
90. A process for preparing
1-[1-(4-chlorophenyl)cyclobutyl]butylamine of formula:
<IMG>
86

and pharmaceutically acceptable salts thereof comprising
reacting hydrazoic acid with a carboxylic acid of formula:
<IMG>
91. 1-[1-(4-chlorophenyl)cyclobutyl]butylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 90 or an obvious chemical equivalent
thereof.
92. A process for preparing
1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising
reacting hydrazoic acid with a carboxylic acid of formula:
<IMG>
93. 1-[1-(3-4-dichlorophenyl)cyclobutyl]ethylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 92 or an obvious chemical equivalent
thereof.
87

94. A process for preparing
?-[1-(4-chlorophenyl)cyclobutyl]benzylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising
reacting hydrazoic acid with a carboxylic acid of formula:
<IMG>
95. ?-[1-(4-chlorophenyl)cyclobutyl]benzylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 94 of an obvious chemical equivalent
thereof.
96. A process for preparing
1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula
<IMG>
88

and pharmaceutically acceptable salts thereof comprising
reacting hydrazoic acid with a carboxylic acid of formula
<IMG>
97. 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 96 or an obvious chemical equivalent
thereof.
98. A process for the preparation of compounds of formula I
as given in claim 1
in which R4 is H comprising the hydrolysis of compounds of
formula I in which R4 is CHO.
99. Compounds of formula I as given in claim 1 in which R4 is H and
pharmaceutically acceptable salts thereof, whenever prepared by
a process according to claim 98 or an obvious chemical
equivalent thereof.
100. A process of preparing
1-[1-(4-chlorophenyl)cyclobutyl]butylamine of formula
<IMG>
and pharmaceutically acceptable salts thereof, which comprises
the hydrolysis of an N-formyl compound of formula:
<IMG>
89

101. 1-[1-(4-chlorophenyl)cyclobutyl]butylamine and its
pharmaceutically acceptable salts whenever prepared by a process
according to claim 100 or an obvious chemical equivalent thereof.
102. A process for preparing
1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula
<IMG>
and pharmaceutically acceptable salts thereof, comprising the
hydrolysis of an N-formyl compound, of formula:
<IMG>
103. 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine and its
pharmaceutically acceptable salts whenever prepared by a process
according to claim 102 or an obvious chemical equivalent thereof.
104. A process for preparing
1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula
<IMG>

105. 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and
pharmaceutically acceptable salts thereof whenever prepared by a
process according to claim 104 or an obvious chemical equivalent
thereof.
106. A process for preparing
N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of
formula
<IMG>
and pharmaceutically acceptable salts thereof which comprises
reducing the corresponding N-formyl compound, of formula:
<IMG>
107. N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine
and pharmaceutically acceptable salts thereof whenever prepared
by a process according to claim 106 or an obvious chemical
equivalent thereof.
91

108. A process for preparing
N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of
formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reduction of a compound of formula:
<IMG>
109. N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-
methylbutylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 108 or an
obvious chemical equivalent thereof.
110. A process for preparing
N, N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine of
formula:
<IMG>
92

and pharmaceutically acceptable salts thereof comprising the
reduction of a compound of formula:
<IMG>
111. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-
butylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 110 or an
obvious chemical equivalent thereof.
112. A process for preparing
N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of
formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reduction of a compound of formula:
<IMG>
113. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-
butylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 112 or an
obvious chemical equivalent thereof.
93

114. A process for preparing
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine
of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reduction of a compound of formula:
<IMG>
115. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methyl-
butylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 114 or an
obvious chemical equivalent thereof.
116. A process for preparing
N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methyl-
butylamine of formula
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reduction of a compound of formula
<IMG>
94

117. N,N-dimethyl-1-[1-(3,4-dichlocophenyl)cyclobutyl]-3-
methylbutylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 116 or an
obvious chemical equivalent thereof.
118. A process for preparing
N,N-dimethyl-1-[3,4-dichlorophenyl)cyclobutyl]ethylamine of
formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reduction of a compound of formula:
<IMG>
119. N,N-dimethyl-1-[1-(3,4-dichlocophenyl)cyclobutyl]-
ethylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 118 or an
obvious chemical equivalent thereof.
120. A process as claimed in claim 1 part (IX)thereof for
the preparation of compounds of formula I as given in claim 1 in
which one or both of R3 and R4 is other tnan H comprising
the conversion of a compound of said formula I in which one or
both of R3 and 24 is or are hydrogen to the required compound.
121. Compounds of formula I as given in claim 1 in which one
or both of R3 and R4 is other than H and pharmaceutically
acceptable salts thereof, whenever prepared by a process
according to claim 120.

122. A process for preparing
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine of
formula
<IMG>
and pharmaceutically acceptable salts thereof, comprising the
methylation of the corresponding primary amine compound, of
formula:
<IMG>
96

123. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine
and pharmaceutically acceptable salts thereof whenever prepared
by a process according to claim 122 or an obvious chemical
equivalent thereof.
124. A process for preparing
N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of
formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
methylation of a compound of formula:
<IMG>
125. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
butylamine and its pharmaceutically acceptable salts whenever
prepared by a process according to claim 124 or an obvious
chemical equivalent thereof.
126. A process for preparing
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine
of formula
<IMG>
97

and phacmaceutically acceptable salts theceof compcising the
methylation of a compound of formula:
<IMG>
127. N,N-dimethyl-1-(4-chlorophenyl)cyclobutyl]-3 methyl
butylamine and pharmaceutically acceptable salts whenever
prepared by a process according to claim 126 or an obvious
chemical equivalent thereof.
128. A process for preparing
N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methyl
butylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
methylation of an amine of formula:
<IMG>
98

129. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
-3-methylbutylamine and pharmaceutically acceptable salts
thereof whenever prepared by a process according to claim or
an obvious chemical equivalent thereof.
130. A process for preparing
N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine
formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
methylation of an amine of formula:
<IMG>
131. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
ethylamine and its pharmaceutically acceptable salts whenever
prepared by a process according to claim 130 or an obvious
chemical equivalent thereof.
99

132. A process for preparing
N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of
formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising the
reaction of the corresponding primary amine of formula:
<IMG>
(a) with a methyl halide after suitably protecting the primary
amine with an appropriate protecting group whereafter the
protecting group is removed by a known method; or
(b) with methyl formate followed by reduction of the resultant
formamide.
133. N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine
and pharmaceutically acceptable salts thereof whenever prepared
by a process according to claim 132 or an obvious chemical
equivalent thereof.
134. A process for preparing
N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of
formula:
<IMG>
100

and pharmaceutically acceptable salts thereof comprising the
reaction of the corresponding primary amine of formula:
<IMG>
(a) with a methyl halide after suitably protecting the primary
amine with an appropriate protecting group whereafter the
protecting group is removed by a known method; or
(b) with methyl formate followed by reduction of the resultant
formamide.
135. N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methyl-
butylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 134 or an
obvious chemical equivalent thereof.
136. A process for preparing
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine of
formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising either
I) the reaction of the corresponding primary amine of
formula:
<IMG>
101

(a) with methyl halide; or
(b) with formaldehyde and formic acid;
or II) the reaction of the corresponding secondary amine of
formula:
<IMG>
(a) with methyl halide; or
(b) with formaldehyde and formic acid; or
(c) with methyl formate followed by reduction or the resultant
formamide.
137. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine
and pharmaceutically acceptable salts thereof whenever prepared
by a process according to claim 136 or an obvious chemical
equivalent thereof.
138. A process for preparing
N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of
formula
<IMG>
and pharmaceutically acceptable salts thereof comprising either
I) the reaction of the corresponding primary amine of
formula:
<IMG>
102

a) with methyl halide or
b) with formaldehyde and formic acid
or II) the reaction of the corresponding secondary amine of
formula:
<IMG>
a) with methyl halide, or
b) with formaldehyde and formic acid, or
e) with methyl formate followed by reduction of the resultant
formamide.
139. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
butylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 138 or an
obvious chemical equivalent thereof.
140. A process for preparing
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-
methylbutylamine of formula
<IMG>
and pharmaceutically acceptable salts thereof comprising either
I) the reaction of the corresponding primary amine of formula:
<IMG>
103

a) with methyl halide, or
b) with formaldehyde and formic acid
or II) the reaction of the corresponding secondary amine of
formula:
<IMG>
a) with methyl halide, or
b) with formaldehyde and formic acid, or
c) with methyl formate followed by reduction of the resultant
formamide
141. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-
methylbutylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 140 or an
obvious chemical equivalent thereof.
142. A process for preparing
N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-
methylbutylamine of formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising either
I) the reaction of the corresponding primary amine of formula:
<IMG>
104

a) with methyl halide, or
b) with formaldehyde and formic acid
or II) the reaction of the corresponding secondary amine of
formula:
<IMG>
a) with methyl halide, or
b) with formaldehyde and formic acid, or
c) with methyl formate followed by reduction of the resultant
formamide
143. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-
methylbutylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 142 or an
obvious chemical equivalent thereof.
144. A process for preparing
N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of
formula:
<IMG>
and pharmaceutically acceptable salts thereof comprising either
I) the reaction of the corresponding primary amine of formula:
<IMG>
105

a) with methyl halide, or
b) with formaldehyde and formic acid
or II) the reaction of the corresponding secondary amine of
formula:
<IMG>
a) with methyl halide, or
b) with formaldehyde and formic acid, or
c) with methyl formate followed by reduction of the resultant
formamide
145. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
ethylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 144 or an
obvious chemical equivalent thereof.
106

146. A process for preparing
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine
of formula:
<IMG>
107

and pharmaceutically acceptable salts thereof comprising
hydrolysis of the N-formyl compound of formula:
<IMG>
followed by methylation of the resultant primary amine of
formula:
<IMG>
147. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-
methylbutylamine and pharmaceutically acceptable salts thereof
whenever prepared by a process according to claim 146 or an
obvious chemical equivalent thereof.
108

148. Compounds of formula I:
<IMG>
(I)
in which R1 is a straight or branched chain alkyl group
containing 1 to 6 carbon atoms, a cycloalkyl group containing 3
to 7 carbon atoms, a cycloalkylalkyl group in which the
cycloalkyl group contains 3 to 6 carbons and the alkyl group
contains 1 to 3 carbon atoms, an alkenyl group or an alkynyl
group containing 2 to 6 carbon atoms or a group of formula II
<IMG>
(II)
in which R9 and R10, which are the same or different, are H, halo
or an alkoxy group containing 1 to 3 carbon atoms;
in which R2 is H or an alkyl group containing 1 to 3 carbon
atoms;
in which R3 and R4, which are the same or different, are H, a
straight or branched chain alkyl group containing 1 to 4 carbon
atoms, an alkenyl group having 3 to 6 carbon atoms, an alkynyl
group having 3 to 6 carbon atoms, a cycloalkyl group in which the
ring contains 3 to 7 carbon atoms, a group of formula R11CO where
109

R11 is H or R3 and R4 together with the nitrogen atoms to which
they are attached form a heterocyclic ring which
a) contains 4 or 5 carbon atoms in addition to the nitrogen
atom and is unsubstituted or substituted by one or more alkyl
groups or
b) contains a second nitrogen atom which is unsubstituted or
substituted by an alkyl group;
in which R5 and R6 which are the same or different, are H, halo,
trifluoromethyl, an alkyl group containing 1 to 3 carbon atoms,
an alkoxy or alkylthio group containing 1 to 3 carbon atoms,
phenyl or R5 and R6, together with the carbon atoms to which they
are attached, form a second benzene ring which is unsubstituted
or substituted by one or more halo groups, an alkyl or alkoxy
group containing 1 to 4 carbon atoms or the substituents of the
second benzene ring together with the two carbon atoms to which
they are attached form a further benzene ring; and their
pharmaceutically acceptable salts.
149. Compounds of formula I as claimed in claim 148 in which
R1 is a straight or branched chain alkyl group containing 1 to 4
carbon atoms, a cycloalkyl group containing 3 to 7 carbon atoms,
a cycloalkylmethyl group in which the cycloalkyl ring contains 3
to 6 carbon atoms or a group of formula II in which R9 and R10
are H, fluoro or methoxy and in which R2 is H or methyl.
150. Compounds of formula I as claimed in claim 149 in which
R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
secondary butyl, cyclopropyl, cyclobutyl, cyclopentyl,
110

cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl or phenyl.
151. Compounds of formula I as claimed in claim 148, 149 or
150 in which R3 and R4 are H, methyl, ethyl or formyl.
152. Compounds of formula I as claimed in claim 148, 149 or
150 in which R5 and R6 are H, fluoro, chloro, bromo, iodo,
trifluoromethyl, methyl, methoxy, phenyl, or R5 and R6 together
with the carbon atoms to which they are attached form a second
benzene ring optionally substituted by halo.
153. Compounds as claimed in claim 148 of formula III
<IMG> (III)
in which R1, R2, R3, R4, R5 and R6 are as defined in claim 148.
154. Compounds as claimed in claim 153 in which R5 and R6,
which are the same or different, are H, fluoro, chloro, bromo,
iodo, trifluoromethyl, methyl, methoxy, phenyl or R5 and R6
together with the carbon atoms to which they are attached form a
second benzene ring optionally substituted by a chloro group.
155. Compounds as claimed in claim 148 of formula IV
111

<IMG>
(IV)
in which R1, R2, R3, R4 and R5 are as defined in claim 148 and R6
is fluoro or methyl.
156. Compounds of formula IV as claimed in claim 155 in
which R5 is H, fluoro, chloro, bromo, iodo, trifluoromethyl,
methyl, methoxy or phenyl and in which R6 is fluoro or methyl.
157. Compounds of formula I named in Table I herein.
158. 1-[1-(4-chlorophenyl)cyclobutyl]butylamine and its
pharmaceutically acceptable salts.
159. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-
butylamine and its pharmaceutically acceptable salts.
160. N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-
butylamine and its pharmaceutically acceptable salts.
161. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-
butylamine and its pharmaceutically acceptable salts.
162. N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-
methylbutylamine and its pharmaceutically acceptable salts.
112

163. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-
methylbutylamine and its pharmaceutically acceptable salts.
164. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-
methylbutylamine and its pharmaceutically acceptable salts.
165. 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine and its
pharmaceutically acceptable salts.
166. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-
ethylamine and its pharmaceutically acceptable salts.
167. .alpha.-[1-(4-chlorophenyl)cyclobutyl]benzylamine and its
pharmaceutically acceptable salts.
168. 1-{[1-(3,4-dichlorophenyl)cyclobutyl]methyl}-
propylamine and its pharmaceutically acceptable salts.
169. N,N-dimethyl-1-{[1-(3,4-dichlorophenyl)cyclobutyl]-
methyl}propylamine and its pharmaceutically acceptable salts.
170. N,N-dimethyl-2-[1-(4-iodophenyl)cyclobutyl]ethylamine
and its pharmaceutically acceptable salts.
171. A pharmaceutical composition comprising a
therapeutically effective amount of a compound of claim 148 or a
pharmaceutically acceptable salt thereof in admixture with a
pharmaceutically acceptable excipient.
113

172. A pharmaceutical composition as claimed in claim 171 in
unit dosage form.
114

Description

12~895S
-- 1 --
This invention relates to compounds having useful
therapeutic activity particularly but not exclusively as
antidepressants, to pharmaceutical compositions containing such
compounds and to proces~es for the preparation of such compounds.
The present invention pro~ldes compounds of formula I
R4 ~ ~ ~ R4
in which R1 is a straight or branched chain alkyl group
containing 1 to 6 carbon atoms, a cycloalkyl group containing 3
to 7 carbon atoms, a cycloalkyalkyl ~roup in which the cycloalkyl
~ group contains 3 to 6 carbon atoms and the alkyl group contains 1
- to 3 carbon atoms, an alkenyl group or an alXynyl group
containing 2 to 6 carbon atoms or a group of formula II
" ~ II
: Rg
in which Rg and Rlo, whlch may be the same or different, are H,
halo or an alkoxy group contalning 1 to 3 carbon atoms;
in which R2 is H or an alkyl group containing 1 to 3 carbon
atoms;
' ` ~:
,. ~ ..
:: :
'' ~ . .

~LZL~955
-- 2 --
in which R3 and R4, which may be the same or different, are H, a
straight or branched chain alkyl group containing 1 to 4 carbon
atoms, an alkenyl group having 3 to 6 carbon atoms, an alkynyl
group having 3 to 6 carbon atoms, a cycloalkyl group in which the
ring contains 3 to 7 carbon atoms, a group of formula R1lCO where
~11 is H or R3 and R4 together with the nitrogen atom to which
they are attached form an optionally substituted heterocyclic
ring having 5 or 6 atoms in the ring which may contain further
hetero atoms ln addltion to the nitrogen atom:
in which R~ and R6, which may be the same or dif~erent, are H,
halo, trifluoromethyl, an alkyl group containing 1 to 3 carbon
atoms, an alkoxy or alkylthio group containing 1 to 3 carbon
atoms, phenyl, or R5 and R~, together with the carbon atoms to
which they are attached, form a second benzene ring which may be
substituted by one or more halo groups, an alkyl or alkoxy group
containing 1 to 4 carbon atoms or the substituents of the second
- benzene ring together with the two carbon atoms to which they are
attached may form a further benzene ring;
and their pharmaceutically acceptable salts.
In the formulae included in this specification the
symbol
represent~ a 1,1-dl ub~tltuted ~yclobut~ yroup of ~ormula
--C CH2

1~4~5
-- 3 --
In the preferred compounds of formula I, Rl is a
straight or branched chain alkyl group containing 1 to 4 carbon
atoms, a cycloalkyl group containing 3 to 7 carbon atoms, a
cycloalkylmethyl group in which the cycloalkyl ring contalns 3 to
6 carbon atoms or a group of formula II in which Rg and/or Rlo
ars H, fluoro or methoxy and in which R2 is H or methyl.
Examples of particularly preferred compounds of formula I are
those in which R2 is H, Rl is methyl, ethyl, propyl, isopropyl,
butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl and phenyl.
In preferred compounds of I, R3 and/or R4 are hydrogen,
methyl, ethyl or formyl or, when R3 and R4 together with the
nitrogen atom to which they are attachsd form a heterocyclic
ring, the preferred compounds of formula I contaln a heterocyclic
group containing one nitrogen atom and 4 or 5 carbon atoms (e.g.
pyrrolidinyl, piperidino) which is optlonally substituted by one
or more alkyl (e.g. methyl) groups (e.g. pyrrolidinyl substituted
by two methyl groups), a heterocyclic group contalning a second
nitrogen atom which is optionally alkylated (e.g. 4-
methylpiperazinyl) or a heterocyclic group including one or more
double bonds (e.~. 1,2,3,6-tetrahydropyridyl). In particularly
preferred compound~ of formula I R3 and/or R4 are H, methyl,
ethyl and ~ormyl.
In preferred compound~ of formula I R5 and/or R6 are ~,
fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy,
phenyl or Rs and R6 together with the carbon atom to which they
are attached form a second benzene ring whlch may optionally be
substituted by halo.
A first group of preferred aompounds is repreaented by
for~uls III
R5 ~ Trr
R6
y,f;~
C''~
''
':

413~5~
in which R5 and R6 are as defined above. In preferred compounds
of formula III Rs and R6 which may be the same or different, are
H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy,
phenyl or R5 and ~6 together with the carbon atoms to which they
are attached form a second benzene ring whlch may optlonally be
substituted by a chloro group. In particularly prefsrred
compounds o~ formula III R5 and/or R6 are H, fluoro, chloro,
iodo, trifluoromethyl, methyl, phenyl or R5 and ~6 together with
the carbon atoms to which they are attached form a second benzene
ring which may optionally be substituted by a chloro group.
A second group of preferred compounds is represented by
formula IV
R6
in which R5 may be H, fluoro, chloro, bromo, iodo,
trifluoromethyl, methyl, methoxy or phanyl and in which R6 ls
fluoro or methyl. In particular preferred compound~ of formula
IV R5 i~ H or chloro.
Compound~ of ~ormula I may exi3t a-~ salts wlth
pharmaceutiaally acceptable acids. Examples o~ ~uch salt~
include hydrochloride~, maleates, acetates, citrate~, fumarates,
tartrate~, succinates and salts with acidlc amino acids such as
aspartlo and glutamic aclds.
Compounds o~ ~ormula I which contain one or more
asymmetric carbon atoms can exist ln different optically active
forms. When Rl and R2 are different, the compounds of formula I
contain a chiral centre. Such compound~ exi~t in two
.~ .
,~,
-
~,, '
~' '

12~89,.:)5
-- 5 --
enantiomeric forms and the present invention includes both
enantiomeric forms and mixtures thereof.
The present invention also includes pharmaceutical
compositions containing a therpeutically effective amount of a
compound of formula I together with a pharmaceutically acceptable
diluent or carrier.
In therapeutic use, the ac:tive compound may be
administered orally, rectally, parenterally or topically,
preferably orally. Thus th0 therapeutic compositions of the
present invention may take the form of any of the known
pharmaceutical compositions for oral, rectal, parenteral or
topical administration. Pharmaceutically acceptable carriers
suitable for use in such compositions are well known in the art
of pharmacy. The compositions of the invention may contain O.1-
9O~ by weight of active compound. The compositions of the
invention are generally prepared in unit dosage form.
Compositions for oral administration are the preferred
compositions of the inv~ntion and these are the known
pharmaceutical forms for such administration, for example
tablets, capsules, syrups and aqueous or oily suspensions. The
excipients used in the preparation of these compositions are the
excipients known in the pharmacists' art. Tablet~ may be
prepared by mixing the active compound with an inert diluent such
as calcium phosphate in the presence of disintegrating agents,
for example maize starch, and lubricating agents, for example
magnesium stearate, and tableting the

~ i
9t~5
mixture by know~ me-tk.ods. The tablets may be formulated in
a manner known to those skilled in the art so as to give a
sustained release o~ the compo~ds of the present invention.
Such tab]ets may, il desired, be provided with enteric
coatings by known methods, for example by the use of celluLose
acetate phthalate. Similarly, capsules, for example hard or
soft gelatin capsules, containing the active compaund w~ih or
without added excipients, may be prepared by conven-tional
means and, if desired, provided with enteric coatings in a
know~ mar~ner. The tablets and capsulas may conveniantly each
contain 1 to 500 mg of the active co~pound. Other compositions
for oral administration include, for example, aqueous suspen- j
sions containing the active compound in an aqueous medium
in the presence of a non-toxic suspending agent such as
sodium carbox~nethylcellulose, and oily suspensions con-
taining a com~ound of the present imrention in a suitab~le
vegetable oil, ~or example aracr.is oil.
Compositions of the ir.vention suitable ~or rectal
administration are the known pharmaceutical forms for
such administration, for example suppositories with cocoa
butter or polyethylene glycol b~ses.
Compositions of the invention suitable for parentaral
administration are the kncwn pharmaceutical forms for such
administration, ~or example sterile suspensions in a~ueGus
and oily med~a or sterile solutions in a suitable solvant.
Compositions for topical administration ~ay comprise
a matrix in which the pharmacologically active compounds
of the present invention are dispersed so that the compounds
are held in contact with the skin in order to administer the
compounds transdermally. Alternatively the active compounds
may be dispersc-d in a pharmaceutically acceptable cream or
ointment base.
In some formulations it may be bene~icial to use the
compounds o~ the present invention in the ~orm of par-ticles
o~ very small size, ~or example as obtained by ~luid energy
milling~
:

12~9~S
-- 7 --
In the compositions of the present invention the active
compound may, if desired, be associated with other compatible
pharmacologically active ingradients.
The pharmaceutical compositions containing a
therapeutically effective amount of a compound of formula I may
be use~ to treat dspresslon in mammials includlng human beings.
In such treatment the amount of the compound of formula I
administered per day is in the ranye 1 to 1000 mg preferably 5 to
500 mg.
Compounds of formula I in which R4 iS CHO may be
prepared by the redutive amidation of ketones of formula V
R~- ~
for example with formamide and formic acld or ammonlum formate
and ~ormic acid to give compounds of ~ormula I in which R4 is CHO
and R3 ls H or with formamldes of ~ormula HCON~R3 in whlch R3 is
an alkyl or cycloalkyl group and orm1c acid or amlne~ of formula
R3NH2 in which R3 i8 an alkyl or cycloalkyl group and formic
acld.
:
Compounds o~ formula I ln whloh R4 is CHO may be
prepared by the formylation of compound~ of Formula I ln whlch R4
lq H for example by reaction with methyl formate.
Compounds of formula I ln which R3 is other than H and
R4 is CHO may be prepared ~y reactlng compounds of formula I in
which R3 is H and R4 is C~O with a compound of formula R3X where
X is a leaving group suah as a halo group in the presence of a
base.
'~
, :

8 lZ ~8~5
Compounds of formula I may be prepared by the reductive
amination of ketones of formula V.
Examplas of suitable reductive amination processes are
given below:
a) for compounds of formula I in which R3 and R4 are H, by
reaction of the ketone wlth an ammonium salt for example ammonium
acetate and a reducing agent such a sodium cyanoborohydride;
b) for compounds of formula I in which R3 is an alkyl or
cycloalkyl and R4 is H by reaction of the ketone with an amine of
formula R3NHz and a reducing agent such as ~odium
cyanoborohydride;
c) for compounds of formula I in.which neither R3 nor R4 i9
hydrogen or in which R3 and R4 togethar with the nitrogen atom
form a heterocyclic ring, by reaction of the ketone with an amine
of formula HNR3R4 and either formic acid or a reducing agent such
as sodium cyanoborohydride,
d) for compounds of formula I in which ona or both of R3 and R4
are H or an alkyl or a cycloalkyl group or in which R3 and R4
together with the nitrogen atom form a heterocyclic ring, by
catalytlc hydrogenation at elevated temperatur~ and pres urs o~ a
mixture of the ketone and an amine of ormula HNR3R~.
Compounds of formula I in whlch R3 and R4 are both
alkyl groups may be pr0pared by reacting a ketone of formula Y
with a dialkyl formamide o~ formula HCONR3R4 for example in the
prssence of formic acid.
Compounds of formula I may be prepared by the rsduction
of compound~ of formula V~I
R6
, ~ ~
. .

lZ~9~5
g
in which:
a) Z is a group of formula - CR1=NOH or an ester or ether
thereof to give compounds of formula I in which R2, R3 and R4 are
H;
b) Z is a group of formula - CR1=:NR3 (where R3 is other than H
or C~0) to give compoundY of formula I ln which R2 and R4 are H;
c) Z is a group of formula - CRl=NY in which Y represents a
metal-containing molety derived frolm an organometallic reagent to
give compounds of formula I in which R2, R3 and R4 are H.
Sultable reducing agents for the above reactions
include sodium borohydride, sodlum.cyanoborohydride, lithium
aluminium hydride.or borane-dimethylsulphide complexO
In (c) above Y is preferably MgBr derived from a
Grignard reagent or Li derived from an organolithium compound.
Compounds of formula I ln which n = 0 may be prepared
by the raaction of an or~anometallic reagent for example a
Grignard reagent of formula R~ MgX where X 18 Cl, Br or I or an
organollthium oompo~nd o~ ~ormula R~Li with an imlne of formula
VIII
~ VIII
followed by hydroly~is ~o giv~ a seoondary ~mlno o~ formula I.
:
Compounds of formula I in which R3 and R~ are ~ may be
prepared by the decarboxylative rearrangement, for example using
iodosobenzene-bist:rifluoroacetate or by a Hofmann reaction using
bromine in alkaline solution, of amides of fo~mula X
~ ~,
:
~ . ',

- lo - lZ~5S
~ 2 X
to give amines of formula I.
Compounds of formula I in which R3 and R4 are H may be
prepared by the decarboxylative rearrangement of acyl azides in
the Curtiu~ reaction. The acyl azide may be formed for example
by reaction of acid chlorid~ of formula XII ~ith sodium azide
~ ,
Compou~ds o~ ~on~ula I in wh b ~ an~ ~ are H ~ay be
prepared by a Sohmidt reaction in which a carboxylic acid of
formula XIV reacts with hydra~olc ac~d
:
::
.;~,~7- : : :
,
,.
:: : : - ~
.

- 11 - 129~
Compounds of formula I in which R4 is H may be prepared
by hydrolysis of compounds of formula I in which R4 is CHO, for
example by acld hydrolysis.
Compounds of formula I in which R4 is methyl may be
prepared by reduction of compounds of formula I in which R4 is
CHO, for example by lithium aluminium hydride or by sodium bis(2-
methoxyethoxy)aluminium hydride.
r
.
....
:` ` :
~, .
,
:

12~
Compounds sf formula I in which one or both of R3 and
RL~ i5 OtheI' than ~ may be prepared from compounds o~ formula
I in which one or ~voth of R3 and R4 are hydrogen by methods
which are well kno~m in the art for the conversion of prim-
ary to seccndary or tertiary amines or for the conversion of
secondary to tertiary amines. The following are given as
examples of suitahle processes:-
a) by alkylating primary amines of formula I to giveseconJary aminQs ~f fcrmula I for example by a process wh~ch
includes -the s-teps of protecting the primary amine with a
protecting group such as tri*].uoroacetyl, alkylating with an
~lky' haliA.e and removing the protecting group for example
by hydrolysis;
b) by alkylating primary amines of for3lula I, for example,
with an alkyl haiide to give tertiary amines of formula I in
which R3 and R4 are the same;
c) by alkylating secon~ary dmines of formula I, for example,
with an alk~fl halide to giVQ tertiary amineS of formula I
in ~ich P3 anà R4 may be di~ferent;
d) by reacting primary amines of formula I with s~dium
borohydride and acetic ac.id to give ~secondary amines of~
formula I in which R~ lS ethyl and P~4 is H;
e) by reacting primary amines of formula I wiih formalde-
hyde and formic acid to give tertiary amines o~ formula I
in which both R3 and R4 are methyl
f) by reacting secondary amines of Lormula I in which R4
is H with formaldehyde and formic acid to give tertiary
amines of formula I in which R4 is methyl
g) by formylating primary amines of formula I, for ~_
examp~e by reaction with methyl formate, and reducing the
resulting formamides, for example with li~hium~aluminium
hydride to give secondary amines o~ formula I in which R3
is methyl vnd R4 i~ H;
: ~ ' ~ : ;
.

1~ 9~
- 13 -
h~ by formylating ~econdary amines of formula I, for example by
reaction with methyl formate, and reduclng the resulting
formamides, for example with lithlum aluminium hydrlde to give
tertiary amines of formula I in which R4 is methyl;
i) by acylating primary amlnes of formula I, for example by
reaction with an acyl chloride of formula R12COC1 or an anhydride
of formula (Rl2CO~20 in which R12 is an alkyl, alkenyl or alkynyl
group and reducing the resulting ami.des for example with lithium
aluminium hydride to give secondary amines of formula I in whlch
R3 is -CH2R12 and R4 is H;
j) by acylating secondary amines of formula I in which R4 is H
for example by reaction with an acyl chloride o formula R12COCl
or an anhydride of formula (R1 2 C )2 in which R~ 2 iS an alkyl,
alkenyl or alkynyl group and reducing the resulting amides for
example with lithium aluminium hydride to give tertiary amines in
which R4 is C~2 R1 2;
k) by reacting primary amines of formula I wlth an aldehyds of
formula R13CHO in which R13 may be an alkyl group, an alkenyl or
alkynyl group or a ketone of formula R1 4 CORl 5 in which R14 and
Rl 5 which may be the same or different are an alkyl group,
alkenyl group, alkynyl group or R14 and R1 5 together with carbon
atom to which they are attached may form an alicycllc ring and
reducing the resulting imine~ or anamines for example wlth sodium
cyanoborohydride or, when R13, R1 4 or R1 5 are not alkenyl or
alkynyl, by catalytic hydrogenation to give econdary amines of
formula I in which
Rl5
R3 is R13~H2- and R1 4 - CH- respectively;
l) by reacting primary amines of formula I with a non-geminally
disubstltuted alkane containing 2 or 3 carbon atoms between the
carbon atoms carrylng the -~ubstituents whlch may be for example
halo preferably bromo, or p-toluenesulphonyloxy to give compounds
of formula I ln which R3 and R4 together with the nitrogen to
which they are attached form a heterocyclic ring containing no
heteroatoms other than the nitrogen atom.

~Z4~3~SS
- 14 -
The ketones o~ formula V may be prepared by the
hydrolysis of imlne~ o formula XVI
in which Y represent.q a metal-containing ~oloty dorlYed from an
organometallic rsagent. The lmine~ of formula XVI may be
prepared by the reaction of said organomatallic reagent with a
cyano compound of formuls XVII
Suitable organometallic reagent~ Include ~rignara rsag~nts o~
formula RlMgX where X i9 Cl, Br or I (~ = MgX) and organolithium
aompound~ of formula RlLi (Y - Li).
~: :
:
,: ~
~: i ` ,
,

12~ S
Ketones of formula V may be prepared by the reaction of
carboxylic acid derivatives such a~ an amide or acid halide with
an organometallic reagent for example by the reaction of an acid
chloride of formula XX
~'~g
with a Grignard reagent of formula R1MgX where X i9 Cl,-Br or I
at low temperatures or by the reaction of a oarboxylic acld of
formula XXI
:: :
: ~
. ~ :
.... . .
- . -
:
.

- 16 - ~Z~955
with an organometallic reagent, for example an organollthium
compound of formula R1Li.
Ketones of formula V in which R1 is alkyl (e.g. methyl)
may be prepared by the reaction of a dlazoalkane (e.g.
diazomethane) with aldehydes of formula XXII
~,~b
Compounds of formula VII ~n which Z i~ a group of
formula -CR1=NOH or ethers or esters thoreo~ may be prepared by
the reaction of hydroxylamine or an ether or e~ter thereo wlth
katones of formula V. :
:
: -.

- 17 _ 1 2 489 ~ ~
Compounds of formula VII iLn which Z i5 a ~roup of
formula -CR1=NR3 may be prepared by the reaction of amines of
formula NHiR3 with ketones of formula V.
,
The preparation of compounds of formula VII in whlch Z
iLs a group o~ formula -CRl=NY has been described above in respect
of compounds of formula XVI
'
: ~.r
: :

~ ~12'18~5
- 18 -
Imines of formula VIII may be prepared by reactlon of
amines of formula R3 NH2 with aldehydes of formula XXII
respectively.
Amides of formula X may be prepared by the reaction of
ammonia with carboxylic acid derivatives for example acid
chlorides of formula XII or they may be prepared from cyano
compounds of formula XIX for example by hydration with aqueous
acids or by reaction wlth hydrogen peroxide in the presence of a
base.
Amlde~ of formula X in which Rl and R2 are H may be
prepared from acld chlorldes of formula XX re~pectlvely by
reactlon with dlazomethane to form a dlazoketone which rearranges
ln the presence of ammonia and a catalyst for example silver ~to
glve the required amide.
~,
..
~ ` ~

~124l~39S~
-- 19 --
Carboxylic acids of formula XIV, and XXI may be
prepared by the hydrolysis, for example basic hydrolyQis, of
cyano compounds of formula XIX, and XVII respectively.
Carboxylic acids of formula XIV may be prepared by the reaction
of amides of formula X w~th nitrous acid. Carboxylic acids of
formula XXI may be prepared by the reaction of nitrou3 acid with
the amides formed by the reaction oi ammonia with carboxylic acid
derivatives for example acid chloricles of formula XX or by the
reaction of cyano compounds of formula XVII wlth hydrogen
peroxide in the presence of a base.
Carboxylic acids of formula XIV in whlch Rl and R2 are
H may be prepared from acid chlorldes ffl formula XX respectlvely
by reactlon with diazomathane to form dlazoketone~ which
rearranges in the presence of water and a cataly~t for example
silver to give the required acid.
Cyano compounds of formula XVII may be prepared by the
reaction of cyano compound~ of formula XXIV
R6 : X~I

~12~55
- 20
with a 1,3-disubstituted propane for example 1,3-dibromopropane
and a base such as sodium hydride.
Acid chlorides of formula XX, XII may be prepared by
the reaction of carboxylic aclds of formula XXI, XIV respectively
with for example thionyl chloride.
Aldehydes of formula XXII may be prepared by methods
well known to those skilled in the art. The following ars given
as examples of suitable methods:
a) by the reduction of cyano compounds of formula XVII with for
example di-tert-butylaluminium hydrids or di-isobutylaluminium
hydride.
b) by the reduction of carboxylic acid derivative-~, for exampls
i) by the reduction of tertlary amide~ fo~med by the
reaction of secondary amlnes with acid chlorides
of formula XX for exampls when the secondary amine
is a dialkylamine using lithium d1ethoxyaluminohydr1de
a~ reducing agent or when the secondary amine is
ethyleneimlne using lithlum aluminium hydride a~
the reducing agent;
ii) by the reduction of acid chloride~ of formula XX
for example with lithium tri-tert~butoxyaluminohydride;
~,
..
" ~ , ~ . ., '
, , . , - . : . :
' ~ : ' ' '` '

- 21 - 'IX~89S~
c) by the oxldation of alcohols (prepared by the reduction of
carboxylic acids of formula XXI) wi1;h, for example, chromium
trioxide-pyridine complex in dichloromethane under anhydrous
conditions.
~,... ~ . . ~, .
`

~3 ~z~s~
- 22 -
The therapeutic activity of the com~Qunds of formula
I has been indicated by assessing the ability of the
compounds to reverse the hypothermic effects of reser2ine
in the following manner. Male mice cf the Charles Rive~ CDl
strain weighin~ ~etween 18 and 30 grammes were separated
into groups of five and were supplied with food and wa',er
ad lib tum. 4fter five hours the body temperature OI each
mouse was taken orally and the mice were in~'ected intra-
peritotleally with reserpine (5 mg/kg) in solution in deionised
water containing ascorbic acid t50 mg/ml). The ~mo~nl ^f
liquid injected was 10 ml/Xg of body weight. Nine hours
after the start of the'test food ~'2S with~2wn but wzter
was still available ad libitum. Twenty-four hours alter the
start of the iest the temperatures of the mice were ta~en
and the mice were gi-~en the test compcund suspended in a il
0.25% solution of hydroxy ethyl cellulose (sold ~nder the
trade name Cellosize QP 15000 by Union Carbide) in deionised
water at a dose voll~e of lOml/kg OL bod~ weight. ~hr~e
hours later ihe temperatures of,all ihe mice were again t~ken.
The percentage reversal of the reserpine-induced 1GSS OI body
t.emperature is t~en calculated by the formula:
(Temperature alter 27 hrs - Temperature after 24 hours) X lOG
(Temperature after 5 hrs - Temperature after 24 hours)
The mean value for each gro~lp of five mice was taken at
several dose rates to enable a value o the mean dose
which causes a 50% reversal (ED50) to be obtained. All
the compounds which are the final products of the
Examples hereinafter gave values of ED50 of 30 mg/kg or
less. It is widely understood by those skilled in the
art that this tes-t is indicative of com~ounds having anti~ -
depressant activity in humans.
Table I lists compounds of formula I which gave a
value of ED50 in the above test of 10 mg/~g or less.
. . . .
' ''-'
~'
.

89 SS
Table I
1-[1-(3,4-dichlorophenyl)cyclobutyl~ethylamine hydrochloride
N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl~ethylamine
hydrochloride
N,N-dimethyl-l- Ll- (3,4-dichlorophenyl)cyclobutyl]ethyla~ine
hydrochloride
1-[1-(4-iodophenyl)cyclobutyl]ethylamine hydrochloride
N-methyl-1-[1-(4-iodophenyl)cyclobutyl]ethylamine hydro-
chloride - `
N,N-dimethyl-1-[1-(4-iodophenyl)cyclobutyl]ethylamine
hydrochloride
N-methyl 1-[1-(2-naphthyl)cyclobutyl]ethylamine hydrochloride
N,N-dimethyl-1-[1-(4-chloro-3-tri~luoromethylphenyl)cyclo-
butyl~ethylamine hydrochloride
1-~1-(4-chlorophenyl)cyclobutyl~butylamine hydrochloride
N-methyl-1-[1-(4-chlorophenyl)cyclobutyl~butylamine hydro-
: chloride :
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine:
hydrochloride
1-(3,4-dichlcrophenyl)cyclobutyl]butylamine hydrcchloride :: ~ :
-methyl-1-~1-(3,4-dichlorophenyl)cyclcbutyl3butylamine~
25 hydrochloride :
N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine
hydrochloride
[1-(4-biphenylyl)cyclobutyl]butylamine hydrochlorLde
~ 30 N,N-dimèthyl-1-{1-~4-biphenylyl)cyclobu~yl]butyIamine~
hydrochloride
~: : 1-[1-(4-chloro-3-fluorophenyl)cyclobutyl]butylamine hydro~
: ~ chloride
~ N-formyl-1-C1-(4-chloro-3-Pluorophenyl)cyclobutylJbutyl~
:~ 35 amine
:: ~
.
` ~ : : :
.~.. :........................................... ' :
.

~Z~8'~55
- 24 -
1- Cl- (3-chloro-4-methylphenyl)cyclobutyl]butylamine hydro-
chloride
N-formyl-l-Cl-phenylcyclobutyl~butylamine
1-[1-(3-trifluoromethylphenyl)cyclobutylJbutylamine hydro-
chloride
l-[l-(naphth-2-yl)cyclobutyl]butylamine hydrochloride
1-[1-(6-chloronaphth-2-yl)cyclobutyl]butylamine
N-methyl-1-[1-(4-chlorophenyl)c,yclobutyl]-2-met~ylpropylamine
hydrochloride
1-[1-(4-chlorophenyl)cyclobutyl]pentylamine hydrochloride
N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]pentylamine hydro-
chloride
E,N-dimethyl-l-[l-phenylcyclobutyl]-3-methylbutylamine
hydrochloride
1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl~mine hydro-
chloride
N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine
hydrochloride
N,E-dimethyl-1-~1-(4-chlorophenyl)cyclobutyl]-3-methyl- ;
butylamine hydrochloride
N-formyl-1-[1-(4-chlorophenyl)cyclGbutyl~-3-methylbutylamine
N,E-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-~-methyl-
butylamine hydrochloride
N-methyl-l-[l-(naphth-2-yl~cyclobutyl]-3-methylbu-tylamine
hydrochloride
: N-methyl-1-[1-(3,4-dimethylphenyl)cyclobutyl]-~-methyl-
butylamine hydrochloride
[1-(4-chlorophenyl)cyclobutyl](cyclopropyl)methylamine
: hydrochloride ~ :
N-methyl-[1-(4-chlorophenyl)cyclobutyl~(cyclopentyl)methyl-
amine hydrochlorlde : ~ :
~1-(4-chlorophenyl)cyclobuty ~ cyclohexyl)methylam~ne hydro-
chloride
:
:
~_ . . . . _ .

S5
. .
- 25 -
N-methyl-[l-(4-chlorophenyl)clJclobutyl~c~cloheyyl)meth
amine hydrochloride
[1-(3,4-dichlorophenyl)cyclobutylXc~clohe-~l)methylamine
5 hydrochloride
N-methyl-[1-(3,4-dichlorophenyl)cyclobuty~(c~clohexyl)methyl-
~mine hydrochloride
[1-(4-chlorophenyl)cyclobutyl~(cyclohe~ll)methyl~mine hydro-
chlo-ide
1-[1-(4-chlorophenyl)cyc'^butyl~-2-cyclo~ro~ylethylamine
10 hydrochloride ~ ,
N.N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl~-2-cyclohexyl-
ethylamine hydrochloride
-[1-(4-chlorophenyl)cyclobutyl]benzyl~mine hydrochloride
N-methyl-~-[1-(4-chlorophenyl)cyclobutyl]benzylamine hydro-
chloride
1-[1-(4-chloro-2-fluorophenyl)cyclobutyl]butylamine
N,N-dimethyl-1-[1-(4-chloro-2-fluoropherlyl)cyclobutyl]
butylamine hydrochloride
1-~[1-(3,4-dichlorophenyl)cyclobutyI]methyl~propylamine
. hydrochloride
N,N-dimethyl-1-~[1-(3,4-dichlorophenyl)cyclobutyl]methyl~
propylamine hydrochloride
N-ethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine
hydrochloride
N,N-diethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]eth-;l~mine
hydrochloride
,
, ~ :
:
`~ ':
.
-.

` ~ 2
- 26 -
The invention will now be illustrated by the ~ollow-
ing Examples which are given by way of example only. All
compounds were characterised by conventional analytical
techniques and gave satisfactory elemental analyses. All
melting and boiling points are expressed in degrees Celsius.
Example 1
A solution of 3,4-dichlorobenzyl cyanide (25 g) and
1,3-dibromopropane (15 ml) in dry dimethyl sulphoxide (150
ml) was added ~ropwise under nitrogen to a stirred mixture
of sodium hydride (7.5 g) dispersed in mineral oil (7.5 g)
and dimethylsulphoxide (200 ml) at a temperature in the
range 30 to 35C. The mixture was stirred at room tempera-
ture for two hours and propan-2-ol (8 ml) and then water
~110 ml) were added dropwise. The mixture was filtered
through a diatomaceous earth sold under the Registered
Trade Mark CELITE and the solid residue washed with ether.
The ether layer was separated, washed with water, dried
and evaporated. 1-(3,4-Dichlorophenyl)-l-cyclobutanecarbo-
nitrile (b.po 108-1?0 C at 0.15 Hg) was isolated by distil-
lation. This method is a modification o~ that described byButler and Pollatz (J.Org.Chem., Vol. 36, Nu. 9, 1971, p.l308).
The 1-(3,4-dichlorophenyl)-1-cyclobutanecarbonitrile
prepared as above (2107 g) was dissolved in dry etner ~50 ml)
and the solution was added under nitrogen to the product of
the reaction of gaseous methy] bromide with magnesium tur-
nings (3.9 g) in dry ether (150 ml). The mixture was stirred
at room temperature for two hours and then under reflux for
*wo hours. Crushed ice and then concentrated hydrochloric
acid (100 ml) were added and the mixture heated under re~lux
30 for two hours. The ether layer was separated, washed with ~~
water and aqueous sodium bicarbonate~ dried and evaporated.
l-Acetyl-1-(3,4-dichlorophenyl)cyclobutane (b.p. 108-110
- at 0.2 mm Hg? was isolated by distillation.
l-Acetyl-1-(3,4-dichlorophenyl)cyclobutane (9.1 g) pre-
pared as above, formamide (6.5 ml) and 98% formic acid t3 mlj
were heated at 180C ~or sixteen hours to give N-formyl~
I
.
:: ~

- 27- lZ~95S
[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine. Concentrated
hydrochloric acid (20 ml) was added and the mixture heated
under reflux for three hours. The solution was then cooled,
washed with ether and sodium hydroxide solution added. The
product was extracted with ether, and the ether extract
washed with water, dried and evaporated. 1-[1-(3,4-Dichloro-
phe~yl)cycloDutyl~ethylamine (b.p. 112-118 at 0.2 mm Hg)
was isolated by distillation. The amine was dissolved in
propan-2-ol and concentrated hydrochloric acid and the
solution evaporated t~ dryness to give l-[l-(3,4-dichloro-
phenyl)cyclobutyl]ethylamine hydrochlo~ide (m.p. 185-195GC).
(Formula I -Rl=Me; R2,R3 c~nd R4=H; R5=4-Cl; R6=3-Cl).
Ex2mple la
The preparation of N-formyl-1-['-(3,4-dichlorophenyl)cyclo-
butyl]ethylamine (m.p. 124-125C) (Example l(a) Formula I
Rl=Me; R2=H; R3=H; R4=CH0; R5=4-Cl and R6=3-Cl)
described above was repeated and the product isolated
by cooling the reaction mixtu.e ar.d collecting the solid
produced by filtration. The formamide was then hydrolysed
by concentrated hydrochloric acid in industrial methylated
spirit to give the hydrochloride salt of 1-[1-(3,4-dichioro-
phenyl)cyclobutyl]ethylamine.
In a similar manner to that described above in ExampleIa the following compounds were prepared. The conditions for
the hydrolysis of the form~mides which were isolated by
appropriate methods are shown in ~he footnotes.
R5 ~ MH2.HCl
.
Example Rl R5 R6 b.p. ~free base) m p. of Note
l(b) methyl Cl H 107/1.2 mm Hg A
l(c) n-butyl C1 H 138-139 B
l(d) methyl I H 205-207 C
l(e) methyl Cl CF3 216-217 D
~ . :

~Z~8~S~
-- 28 --
A. aqueous HCljindustrial methylated spirit
B. The l-valeryl-1-(4-chlorophenyl)cyclobutane was prepared
in tetrahydrofuran. Hydrolysis was perfor~ed using
concentrated HCl/industrial methylated spirit.
C. concentrated HCl/diethyleneglycoldimethyl ether (in a
similar manner to that described later in Example 12).
D. concentrated HCl/industrial methylated spirit. --
Example 2
The product of Example 1 (4.04 g), water (0.5 ml) and
98% formic acid (3.6 ml~ were mixed with coo~ing. 37-40/0
Aqueous formaldehyde (3.8 ml) was added and the solution was
heated at 85-95C for five hours. The solution was evapo-
rated to dryness and the residue acidified with concentrated
nydrochloric acid ~nd the water removed by repeated addition
of propan-2-ol followed by evaporation in vacuo. Crystals
of N,N-dimethyl-1-[1-(~,4-dichloropheryl)cyclobutyl]ethyl-
amine hydrochloride (m.~. 211-21~C) (~ormula I Rl=
Me; R2=H; R3,R4 = Me; R5=4-Cl; R6=3-Cl) were isolated.
In a similar way to thai described above the compounds
of Example l(b) and l(d) were converted into the compounds
listed below.
R5 ~ ~HRlh~e2.HCl
Example Starting ~ R R R6 ~ P of b.p. of free
Material 1 5 HCl salt base
2(a) l(b) methyl Cl H 98-100/0.5 mm
2(b) l(d) ~ methyl I H 260-261
,:
Example
In a similar manner to that described above in Examples
1 and 2 N,N-dimethyl-1-[1-(4-biphenylyl)cyclobutyI]ethylamine
hydrochloride (m.p. 196-197C) was prepared. (Formula I
1 e; R2 H; R3~R4=Me; Rs=4-phenyl and R6=H).
~ : :
:: : : : :
,
- . . ,
- . .
-. . . .
: : . : ~
- ., ~.
~ -

~iL24~5
- 29
. .
Example 4
l~Acetyl-1-(3,4-dichlorophenyl)cyclobutane (15 g) pre-
pared as described in Example 1, N-methylformamide (47.5 ml)
98% formic acid (10.3 ml) and a 25% aqueous solution of
methylamine (1.5 ml) were mixed and heated with stirring at
170-180 for eight hours. The mixture was cooled and
extracted with ether. The ether extract was washed, dried
and evaporated to yield a light yellow oil which was heated
under reflux with concentrated hydrochloric acid (50 ml)
for two hours. Industrial methylated spirit (IMS) (50 ml)
was added and the mixture heated under reflux for sixteen
hours. The mixture was then cooled to 0C and the white
precipitate collected by filtration, washed with acetone
and dried. The product, N-methyl-l-rl-(3,4-dichloro-
phenyl)cyclobutyl]ethylamine hydrochloride, had a melting
point of 254 to 256C (Formula I Rl = Me; R2 = H;
3 ; R4 H; R5 = 4-Cl and R6 = 3-Cl)
In a similar manner to that described above the follow-
ing compounds of formula I were prepared
~ ICHRlNHMn.HC
~ ' ~ ,,
Exa~ple Rl R5 R6 b.p. of amine m.p. of Note
. , HCl salt
4(a) Me Cl H 98-100/0.15 mm 240-241
4(b) Me - H Cl ~69-27~
4(c) Me Br H 96-98/0.1 mm
304(d) Me H Br 251-255
4(e) Me CF3 H 219-221
4(f) Me H CF3 225-228
4(g) Me --fCH = CH)2_ ~54-257
4(h) Me Cl CF3 198-200
4(i) Et Cl H 238-240
35 4(j) Pr Cl H 228-229 A :
4(k) Bu Cl H 152-153 A
4(1) Me I H 242-243
..
,. . i ::
.

1~895
-- 30 --
Note A The starting ketone was prepared in tetrahydro-
furan as reaction solvent in place of ether.
Example 5
A mixture of 70% aqueous ethylamine (50 ml) and water
(100 ml) was gradually mixed w:ith a mixture of 98% formic
acid (50 ml) and water (100 ml) to give a neutral solution
which was evaporated at 100C/100 mm Hg until 180 ml of
water had been collected. The residue was heated to 140C
and l-acetyl-1-(4-chlorophenyl)cyclobutane (10.4 g) prepared
in a similar manner to that described in Example 1 ~or
l-acetyl-1-(3,4-dichlorophenyl)cyclobutane and 98%
formic acid (10 ml)were added. The mixture was heated on
an oil bath at 2 temperature of 180-200C for sixteen hours.
me mixture was distilled until an internal temperature of
170C was ob~ained and this temperature was maintained for
two hours. Any volatile material was removed by distillation
at 160C/20 mm and the residue heated ur.der reflux with concen-
trated hydrochloric acid (15 ml) and industrial methylated
spirit (IMS) (15 ml) for three,hoursO The IMS was evaporated
on a rotary evaporator and the residue washed with ether.
The aqueous phase was brought to pH 12 with sodil~lm kydroxide
~ and extracted with ether. The ether extract was dried and on
evaporation yielded a residue which was treated with aqueous
hydrochloric acid to give N-ethyl~ 1-(4-chlorophenyl)-
c~clobutyl]eth~lamine hydrochloride (m~p. 203-2C5CC~
(Formula I 1 ; 2 ; 3 ; 4 ; 5
4-Cl; R6 = H).
Example 6
1-(4-Chlorophenyl)-l-cyclobutanecarbonitrile (15 g)
prepared in a similar manner to the 1-(3,4-dichlorophenyl)-
cyclobutanecarbonitrile of Example 1 in dry ether (50 ml)
was added to the product of the reaction between magnesium
turnings (3~18 g) and propyl bromide (15.99 g) in dry ether
(50 ml). The ether was replaced by tetrahydrofuran and the
mixture heated with stirring under reflux for eighteen hours.
'Themixturewas cooledandl'ce andthenconcentrated hydro~hloric
:,
:~
- ~ ", `,~.;. '` .. .
,

3lZ489~S
-- 31 -
acid (52 ml) added. The resulting mixture was stirred under
reflux for ten hours and extracted with ether. The ether
extract yielded a residue from which l-butyryl-1~(4-chloro-
phenyl)cyclobutane (b.p. 106-108/0.3 mm Hg) was distilled.
A mixture of the ketone produced as described above
(21 g) and 98% formic acid (6 ml) was added over a period
of one and a half hours to formamide (15 ml) at 160C.
After completion of the addition the temperature was raised
to 180 to 185C and maintained in this range for five hours.
The mixture was cooled and extracted with chloroform to
yield a thick gum which on heating with petroleum ether
(b.p. 60-80) gave a colourless sol,d which was recrys-tal-
lised from petroleum ether (b.p. 60-~0) to yield N-
formyl-l-[l-(4-chlorophenyl)c~rclobuty']butylamine (m.p.
97.5 to 98.5C) (Formula I Rl = propyl; R2 = H;
R~ = H; R4 = CHOi R5 = 4-C1; R6 = H)-
Example 7
A solution of 1-(3,4-dichiorophenyl)-1-cyclobutane-
carbonitrile prepared as described in Example 1 (35.2 g)
in ether (100 ml) was added to a solution of propyl magne-
sium bromide prepared by the reaction of propyl bromide
(32 g) with magnesium turnings (6.36 g) in ether (100 ml).
The ether was replaced by dry toluene and the mixture
heated under reflux for one hour. Water (200 ml) and then
concentrated hydrochloric acid (120 ml) were added and
the mixture heated under reflux for one hour. The reac-
tion mixture was extracted with ether and after washing
and drying the extract yielded a residue from which 1-
butyryl-1-(3,4-dichlorophenyl)cyclobutane (b.p. 120-128C
at 0.25 mm) was distilled.
The ketone produced as described above (37.0 g) and
98% formic acid (9 ml) were added to formamide (23.5 ml) a~
170C and the temperature kept at 175-180C for five hours.
A further portion of formic acid (4.5 mI) was added and
35 the mixture was maintained at 175-180C for a further
fifteen hours. The mixture was extracted with ether which
., ~
~" dL , A
: ~
. ' '~'` '' '
. ~ " ' ` ` " ~ ' ' ' ' ~' ' j
:
,

~ ~ 8~S S
- 32 -
on evaporation gave a thick oil which was crystallised
from petroleum ether (b.p. 60-80) to give N-formyl-l-
[1-(3,4-dichlorophenyl)cyclobutyl]butylamine having a
melting point of 103-105C (Formula I Rl = propyl;
R2 = H; R3 = H; R4 = CH0; R5 = 4-Cl and R6 = 3-C1).
In a similar manner to that described above the
following compounds were made
~=~ CHRlNHCHO
5 ~
R6
Example Rl R5 R6 m.p. (C)
7(a) isobutyl Cl H 110-112
57(b) propyl Cl F 115-116
7(c) phenyl Cl H 94-96
?(d) propyl H H 98-102
Example 8
The produci of Example 7 (4.0 g~ in dry tetrahydro-
furan (25 ml) was added rapidly to a stirred mixture o~
lithium aluminium hydride (1.4 g) in dry tetræhydrofuran
(25 ml) under nitrogen. The mixture was heated under
reflux for five hours and then cooled. Water ~15 ml) and
25 then 10% sodium hydroxide solution (3 ml) were added and
the mixture filtered through diatomaceous earth sold under
the Registered Trade Mark CELITE. The product was extrac-
ted in-to ether, back extracted in~o 5N hydrochloric acid
and the aqueous layer was basified and extracted with
30 ether. The ether extract yielded an oil which was dissol-
ved in propan-2-oi (5 ml~ and concentrated hydrochloric
acid was added to pH 2 Evaporation of the resulting
solution gave a white solid which was collected, washed
with acetone and dried. The product was N-methyl-l-[l-
35 (3,4-dichlorophenyl)cyclobutyl]butylamine hydrochloride and
" ' ':
.
. . . :~ -
..
~ .
.

had a melting point of 234-2~5C (Formula I R1 =
propy~; R2 = H; R3 = H; R4 = Me; R5 = 4-C1 and R6 = 3-Cl)
In a similar manner to that described above the
following compounds were prepared
0 5~E~Me.HCl
ExampleRl R5 R6 m.p. (C)
8(a)phenyl Cl H 275-278
8(b)propyl Cl H 223-228
Example 9
The product of Example 7 (10 g) in solution in ether
(50 ml) was added to a 70% toluene solution of sodium bis-
(2-methoxyethoxy)aluminium hydride sold under the trade
markRed-al (40 ml) at a temperature in the range 25 to 30C~
m e mixture was stirred at this temperature for four hours.
Water (25 ml) was added dropwise with cooiing and t~le mix-
ture filtered through diatomaceous earth (CELIlE). Aqueous
NaOH was added and an ether extraction~eriormed. The ether
extract was~washed with wa~er and back extracted with 5N
25 hydrochloric acid. A white solid (m.p. 2~2-235C) appeared
at the interface which was collected. Base was added to
the aqueous phase and~a further ether extraction performedO
Evaporation of the ether extract yielded an oil which ~as
dissolved in propan-2-ol (5 ml3 and concentrated hydrochloric
30 acid added to pH 2. Evaporation to dryness gave a white
solid (m.p. 233-236C). The white solids were combined and
recrystallised from propan-2-ol to yield N-methyl-l-[l-
(3,4-dichlorophenyl ~yclobutyl~butylam~ne hydrochloride
(m.p. 236-237C) (Formula I Ri = propyl; Rz = H;
R3 = H; R4 = Me; R5 = 4-Cl and~R6 = ~-Cl).
.. ii :
:
. . .
, ' - . '
.
.: : . . ~. . .
: ' :" :'';. ' ~

:~Z4~ ;S
-- 34 --
In a similar manner to that described above the following
compounds were prepared. Where the formyl starting material
was insoluble in ether, a solution of the reducing agent was
added to a stirred suspension of the formyl compound. As the
size of the gr~p Rl is increased the hydrochloride salts of
the desired compounds become less soluble in the aqueous
phase and more soluble in the organic phase so -that appropriate
modifications in the isolation procedure are required as will
be apparent to those skilled in the art.
~ CHRlNHMe.HCl
5 ~
Example Rl R5 R6 m.p.
9(a) isopropyl Cl H 257-259
15 9(b) sec-butyl Cl H 209-212
9(c) isobutyl Cl H 225-233
9(d) cyclopentyl Cl H 252-256
9(e) n-hexyl Cl H 117-118
9(f) 4-methoxyphenyl Cl H 264-266
20 9(g) 3-methoxyphenyl Cl H 254-255
9(h) 2-methoxyphenyl Cl H 149-15~
9(i) cyclohexyl Cl H 170-172
9(j) isobutyl -(CH = CH)2-256-259
9(k) cyclohexyl Cl Cl 223-224
9(1) isobutyl Me Me (1)
259(m) propyl OMe H 173-175
9(n) methyl phenyl H 116-118
(1) Boiling point of free base >150 ~tl.O mm Hg.
Example 10
The product of Example 7 (4 g), diethyleneglycol-
dimethyl ether (25,ml), water ~10 ml) and concentrated
hydrochloric acid ~10 ml) were mixed and heated under
: `~
, ~ ', ' , .
:

-- :12'~8~.5
- 35 -
reflux for nine hours. The solutio~ was washed with
ether and aqueous NaOH added before an ether extraction was
performed. The ether extract was washed with brine and
water and yielded an oil on evaporation. The oil (3.19 g~
was dissolved in amixture of propan-2-ol (4 ml) and ether
(20 ml) and concentr2ted hydrochloric acid (1.5 ml) added.
The solvent was evaporated n vacuo. Repeated dissolution
in industrial methylated spirit and evaporation in vacuo
gave a gum which solidified on warming in vacuo. The pro-
duct was recrystallised from petroleum ether (b.p. 100-
120C) and had a melting point of 201-203C. The product
was 1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine hydro-
chloride (Forlrula I Rl = propyl; R2 = H; R3, R4 = H;
R5 = 4-Cl and R6 = 3-Cl).
In a similar manner to that described above the
following compounds were prepared. As the size of the
group Rl is increased the hydrochloride salts of the
desired compounds become less soluble in the aqueous phase
and more soluble in the organic phase so that appropriate
modifications in the isolation procedure are reGuired as
will be apparent to those skilled in the art.
~ CHRlNH2.HCl
5 ~
R6
Example Rl R5 R6 m.p.
lO(a) isopropyl Cl H 200-202
lO(b) sec-butyl Cl H 170-179
lO(c) i~obu;:-yl Cl H 163-165
lO(d) cyclopentyl Cl H 185-210(dec)
lO(e) phenyl Cl H 271-276
10~f) 4-methoxyphenyl Cl H 214-219
lO(g) cyclohexyl Cl H 206-210
lO(h) isobutyl H H 210-212
35lO(i) cyc~opropyl Cl H 204-206
i~ :
~:
:

36 ` lZ48955
Example Rl R5 R6 m.p.
lO(j) propyl Ph H 235-236
lO(k) propyl Me Cl 214-217
10(1) propyl -(CH=CH)2- 157-159
lO(m) cycloheptyl Cl H 156-162
lO(n) cyclohexyl Cl Cl 215
lO(p) methyl Cl F 215-217
lO(q) propyl OMe H 178-179
lO(r) propyl C1 F 186-188
lO(s) propyl Cl H 174-175
lO(t~ cyclohexylmethyl Cl H 148-150
lO(u) cyclopropylmethyl Cl H 184-185
lO(v) propyl -CH=CH-CCl=CH- (a)
lO(w) propyl ~I CF3 126-128b
lO(x) 4-fluorophenyl Cl H 279
lO(y) (b) methyl /C = C\CH=CH- 248-262
C~ CH
. ~CH- CH
5a~ boiling point of free base 168 C/0.05 mm Hg.
~bJ diethyleneglycoldimethyl ether replaced b~J ethylene-
glycoldimethyl ether.
In a similar manner to that described above, l-tl-(4-
chloro-2-fluorophenyl)cyclobutyl]butylamine (b.p. 99C/0.05 mm).
(Formula I ; Rl = propyl; R2, R3 and R4 = H; R5 = 4-Cl;
R6 = 2-F), l-ll-(2-fluorophenyl)cyclo~utyl]butylamine
hydrochloride (m.p. 175-177C). (Formula I ,Rl = propyI;
R2, R3, R4, R5 = H and R6 = 2-F) and ~1-[1-(4-chloro-2-methyl)
cyclobutyl]butylamine hydrochloride (m.p. 188-190C) (Formula
: 25 I ~Rl = propyl; R2, R~ and R4 = H; R5 = 4-Cl and R6 =
2-Me) were prepared as EXamples lO(z),lO(aa) and lO(bb~
Example 11 respectively.
The prod-~ct of Example lO(c) (3.3 g) in the form of the
free base, formic acid (2.99 g) and water (1 ml) were mixed
with cooling. 37-4~ Aqueous formaldehyde (3.93 ml) ~as
added and the mixture heated for eighteen hours at a tempera-
ture of 85-95~C. Excess dilute hydrochloric acid was added
and the solution evaporated to dryness. The residue was
basified with 5N sodium hydroxide solution and the product
was extracted into ether. Evaporation of the ether yielded
a pale yellow oil which was dissolved in a mixture of
propan-2-ol (4 ml) and ether (20 ml~ and concentrated
: ~ .
,.
,

~ 5
- 37 -
hydrochloric acid (2 ml) was added dropwise. The solution
was evaporated and the residue dissolved repeatedly in
ethanol and evaporated in vacuo to give a gum which was
triturated with petroleum ether (b.p. 60-80) to yield
a yellow solid which was recrystallised from acetone. The
product was N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-
3-methylbutylamine hydrochloriàe (m.p. 195-197C~. (Formula
I ; Rl = isobutyl; R2 = H; R3, R4 = Me; R5 = 4-Cl;
R6 = H).
In a similar manner to that described above the
following compounds of Formula I were prepared
CHRlNMe2. HCl
R
R6
5 ExampleStarting Rl R5 R6 m.p.
ll(a)lO(h) isobutyl H H 195-198
ll(b)lO(j) propyl Ph H 194-196
l](c)lO(n) cyclohe~yl Cl Cl 227-228
ll(d)lO(q3 propyl OMe H 187-188
ll(e)lO(s~ pro~yl Cl H 194-196
ll(f)lO(t~ methyl Cl H 194-196
ll(g)lO(u) methyl Cl H 165-167
ll(h) . lO~v) propyl -CH=CH-CCl=CH- (a)
~ ~ isobutyl Cl Cl 225-226
ll(j)lO~x) 4-fluorophenyl Cl H 234
ll(k)- propyl isoproprl H 211-213
(a) bo~ling point of free base <25~C/0.05 mm Hg.
Example 11(1)
In a ~imilar manner to that described above N,N-
dimethyl-l-[l--(4-chloro-2-fluorophenyl)cyclobutyl]
butylamine hyclrochloride (m.p. 183) was prepared.
(Formula I ~ i Rl = propyl; R2 = H; R3, R~ = Me;
Rs = 4-Cl; R6 = 2-F)
.
~.~
.

~l~4~395S
- 38 -
Example 12
The product of Example 7 (8.3 g), diethyleneglycol-
dimethyl ether (50 ml), water (20 ml) and concentrated
hydrochloric acid (20 ml) were mixed and heated under
reflux for sixteen hours. The mixture was poured into
water, aqueous NaOH was added and the product extracted
into ether. Evaporation gave a dark oil. A sample of this
oil (7.9 g), water (0.7 ml) and formic acid (6.5 ml) were
mixed and formaldehyde (6.5 ml) added. The mixture was
heated under reflux for three hours and then concentra~ed
hydrochloric acid (10 ml) and propan-2-ol (10 ml) were
added. Evaporation to dryness gave W,N-dimethyl-1-[1-(3,4-
dichlorophenyl)cyclobutyl]butylamine hydrochlor de (m.p.
195-196) as a white solid (Formula I Rl = propyl;
R2 = H; R3, R4 = Me; R5 = 4-Cl and R6 = 3-Cl).
Example 1~
1-(4-Chlorophenyl)-l-cyclobutanecarbonitrile (37.6 g)
prepared in a similar manner to the 1-(3,4-dichlorophenyl)-
l-cycIobutanecarbonitrile described in Example 1 was added
to a solution of potassium hydroxide (32.4 g) in diethyle-
neglycol (370 ml) and the mixture hea-ced under refl~x fQr
three and a half hours. The reaction mixture was poured
into an ice~water mixture ~ld the resuiting solution was ~ ;
washed with ether. The aqueous layer was added to a mix-
ture of concentrated hydrochloric acid (100 ml) and ice
and the resulting precipitate of 1-(4-chlorophenylj~
cyclobutanecarbox~lic acid (m.p. 86-88) collected, washed
with water and dried.
A solution of the acid (10.5 g) prepared as above in
tetrahydrofuran (150 ml) was added dropwise under nitrogen
to a stirred suspension of lithium aluminium hydride (2 g)
in tetrahydrofuran (150 ml). The mixture was stirred under
reflux for two hours and water added. The mixture was
filtered through dlatomaceous earth (CELITE - RTM) and the
product extracted into ether. After washing with water
and drying, the ether was evaporated to give a residue
-
__.. .~. . .
., . : ~

~Z9L89~S
-- 39 --
.
which was recrystallised from petroleum ether (b.p. 60-
80). The product was 1-[1-(4-chlorophenyl)cyclobutyl~-
methyl alcohol (m.p. 60-62C).
A solution of the alcohol prepared as described above
(60 g) in pyridine (52 ml) was added dropwise to a solution
of p-toluenesulphonylchloride (60 g~ in pyridine (100 ml)
cooled in ice. The temperature was allowed to rise to room
temperature and remain there for eighteen hours. 1-[1-(4-
Chlorophenyl)cyclobutyl]methyl p-toluene sulphonate
(m.p. 99-100C) was precipitated by pouring the reaction
mixture into a mixture of ice and concentrated hydrochloris
acid (200 ml).
A solution of the sulphonate compound (97 g) prepared
as described above and sodium cyanide (16.6 g) in dimethyl
sulphoxide (370 ml) was heated on a steam bath for eighteen
hours. The mixture was poured into water and extracted
with ether. After washing and drying ihe ether was evapo-
rated to leave a solid residue of 2-[1-(4-chlorophenyl)-
cyclobutyl~acetonitrile (m.p. 63-65C).
A solution of di-isopropylamine (16.5 g) in dry tetra-
hydrofuran (50 ml) was stirred under nitrogen at a tempera-
ture of 0C and a 1.6 M solution of n butyllithium in
hexane (100 ml) added dropwise. The raaction mixture was ~-
stirred for 30 minutes and then cooled to -78C. A solu-
tion of 2-Ll~4-chlorophenyl)cyclobutyl]acetonitri-Le (9.5 g)
prepared as described above in dry tetrahydrofuran (25 ml)
was added dropwise. The t,emperature of the mixture was
allowed to rise to 0C and the mixture was stirred for ten
minutes be~ore a solution of methyl iodide (10 ml) in
tetrahy~rofuran (10 ml) was added. Tetrahydrofuran (75 ml)
was added to give a homogeneous solution and a further
solution of methyl iodide (4 ml) in tetrahydrofuran (10 ml)
added. The mixture was stirred at ambient temperature for
two hours and then water (50 ml) added. The aqueous phase
was washed with ether and the ether combined with the
organic phase of the reaction mixture. The combined organic
.
.. .. , ....... .~ :
'
'

S~
-- 40 -- `
phases were washed three times with 5N hydrochloric acid,
three times with water, dried and evaporated to yield an
oil which solidified and was recrystal-
lised from industrial methylated spirit to give 2-[1-(4-
chlorophenyl)cyclobutyl]-2-methylpropionitrile (m.p. 73-75C).
The nitrile p-epared above (4 g) was heated under
reflux with potassium hydroxide (8 g) in diethyleneglycol
(40 ml) for 24 hours. The reaction mixture was cooled,
added to water (50 ml) and the aqueous phase washed twice
with ether. The aqueous phase was acidified with 5N hydro-
chloric acid and extracted with thrae portions of ether.The combined ether extracts were washed with water, dried
and evaporated to give a white solid which was recrystal-
lised from petroleum ether (b.p. 60~0) to give 2-[1-
(4-chlorophenyl)cyclobutyl]-2-methylpropionic acid (m.p. 95-
110C).
Oxalyl chloride (10 ml) was added to the acid (2 g)prepared as above and after the initial effervesence had
subsided the mixture was heated under reflux for one hour.
Excess oxalyl chloride was removed by distillation and the
residual oil added to concentrated aqueous ammonia (75 ml).
An oily solid formed which was extracted into ethyl ace-
tate. The extract was washed with water, dried and e~apo-
rated to give 2-[1-(4-chlorophenyl)cyclobutyl]-2-methyl
propionamide.
The amide prepared as above (1.34 gj was dissolved in
a mixtùre of acetonitrile (8 ml) and water (8 ml) and iodo-
sobenzene bistrifluoroacetate (3.4 g) added and the mixture
stirred at ambient temperature for ~ive and à half hours.
Water (75 ml) and concentrated hydrochloric acid (8 ml)
were added and the mixture extracted with ether. The ether
extract was washed with 5N hydrochloric acid and the
aqueous phase basified and extracted with further portions
of ether ~hich were dried and evaporated to give an oil.
The oil was dissolved in petroleum ether (b.p. 80-100) ~ -
and dry hydrogen chloride gas passed through the solution.
:
~. .

~2~8~ s
- 41 -
1-[1-(4-Chlorophenyl)cyclobutyl]-l-methylethylamine hydro-
chloride (m.p. 257-259C) was collected by filtration
(Formula I Rl~ R2 = Me; R3, R4 = H; R5 = 4-Cl;
R6 = H).
Tpe product of Example 4(h) (3.4 g) was mixed with
anhydrous sodium formate (0.72 g), 98% formic acid (10 ml)
~nd 37-40% aqueous formaldehyde solution (5 ml) and the
mixture heated at a temperature of 85-95C for sixteen hours.
The mixture was diluted with water (50 ml) and basi~ied to
pH 10 with aqueous sodium hydroxide solution. The basic
aqueous solution was extracted with ether, washed with
water and dried with magnesium sulphate. Dry hydrogen chloride
gas was bubbled through the ether extract to give a white
precipitate of N,N-dimethyl-1-[1-(4-chloro-3-tri~luoromethyl-
phenyl)cyclobutyl]ethylamine hydrochloride (m.p. 246-247C)
(Formula I Rl Me; R2 = H~ R3, R4 = Me; R5 = 4-Cl
and R6 =3-CF3).
Example 15
The production of salts of the compour.ds of the
invention is illustrated by the following Examples in which
equimolar amounts of the base and the acid were taken up in
a solvent. The salt was then obtained from the solution by
conventlonal techniques.
Example Base Acid Solvent m.p. of salt
15(a) 10(9)citric a~ueous acetone 158-160
15(b) lO(s)maleic ether 155-157
15(c) lO(s)succinic ether 152-I55~
15(d) 2L(*)tart~riG I.M.S. 150-153
15(e) Note (a) citric ether/methanol 163-164(dec)
(a) The base was l-C1-(3,4-dimethylphenyl~cyclobutyl]-3-
methylbutylamine prepared in a similar manner to that
l ~ described in EXample 10.
,.,: ,~
- ,~ ,., ~ .
` .
.
: .

lZ~ 5
42 -
Example 16
A solution of bromobenzene (15.7 g) in ether (50 ml)
was added dropwise with cooling to magnesium turning (2.4 g)
under an atmosphere of nitrogen. A solution of 1-(4-chloro-
phenyl)-cyclobutanecarbonitrile (19.1 g) prepared in a similar
manner to that described in Example 1 for the 1-(3,4-dichloro-
phenyl)cyclobutane carbonitrile in ether (50 ml) was added
and the ether replaced by dry toluene (130 ml). The reaction
mixture was heated on a steam bath for one hour. A sample
(20 ml) of the resulting solution was added to a solution of
sodium borohydride (1 g) in diethyleneglycoldimethyl ether
(60 ml) and -the mixture was stirred for one and a half hours.
Water (60 ml) was added slowly and the aqueous layer extracted
with toluene. The toluene extracts were washed with water,
dried and evaporated to give a residue which was dissolved
in methanol (50 ml). 6N Hydrochloric acid (5 ml) was added
and the solution filtered and evaporated. Trituration with
clry acetone gave -[1-(4-chlorophenyl)cyclobutyl]benzylamine
hydrochloride (m.p. 277-279C) (Formula I Rl=Ph; R2=
H; R3,R4=H; R5=4-Cl; R6
Example 17
Methyl formate (62 ml) was added dropwise to isopropyl-
amine (85.5 ml) with stirring at a rate which maintained
gentle reflux conditions. Stirring was continued for two
hours after the addition. Methanol was distilled off
at I00C and N-isopropylformamlde (b.p. 108-109C/25 ~ Hg)
obtained by distillation.
l-~cety~-1-(4-chlorophenyl)cyclobutane (10.4 g~ prepared
,n a similar manner to that described in Example 1 for 1-
acetyl-1-(3,4-dichlorophenyl)cyclobutane and 98% formic acid
(5 ml)were added to N-isopropylformamide (43.5 g) and the
3G mixture heated at i80C for four hours. Excess starting
material was clistilled off ~nder reduced pressure (20 mm
Hg) to leave a viscous residue which was heated under
reflux with concentrated hydrochloric acid (30 ml) for
slx hours. The reaction mixture was washed with ether
until a colourless solution was obtained. The aqueous
phase was basi~ied,- extracted with ether, dried and evapo-
` '''

lZ~ 5
.
- 43 -
rated to give an oil which was dissolved in 5N hydro-
chloric acid. On evaporation a yellow oil was obtained
which was triturated with petroleum ether (b.p. 62-68C)
to give N-isopropyl-1-[1-(4-chlorophenyl)cyclobutyl]
ethy amine hydrochloride (m.p. 170-174PC) (Formula I
Rl = Me; R2 = H; R3 = isopropyl; R4=H; R5 =4-Cl;
R6 ~1 ) . . ..
Example 18
l-Acetyl-1-(3,4-dichlorophenyl)cyclobutane (7.0 g)
prepared as described in Example 1 was slowly added to a
mixture of pyrrolidine (25 ml) and 98% formic acid (15 ml)
heated to 130-135C for fiva hours. The mixture was stirred
and heated at 160-165C for sixteen hours. After cooling
the mixture was poured into 5N hydrochloric acid (200 ml).
The solution was washed with ether, basified with aqueous
sodium hydroxide solution and extracted with ether. The
ether extract was washed with water, dried and hydrogen
chloride gas was passed into the extract which was then
evaporated to dryness. The residue was triturated with
dry ether to give a solid which was recrystallised from
propan-2-ol to give N-1-[1-(3,4 dichlorophenyl)cyclobutyl]
ethyl pyrrolidine hydrochloride (m.p. 233-235C) (Formula I
Rl = Me; R2 = H; R3 and R4 together with the nitrogen
to which they are attached form a pyrrolidine ring; R5 = 4-Cl
and R6 = 3-Cl).
Example`l9
1-(4-Chlorophenyl)-l-cyclobutane carboxylic acid (10.5 g)
prepared as described in Example 13 was heated under reflux
with thionyl chloride (20 ml)for 2~ hours. Excess thionyl
chloride was evapora'ed off and the acid clloride of the above
acid distilled tb.p. 82-96/0.2 mm Hg).
A solution of the acid chloride (23.0 g) in dry tetra-
hydrofuran (100 ml)~was added slowly to ~he product of the
reaction of magnesium turnings (3.0 g) and ethyl bromide
(12.0 g) in dry tetrahydrofuran at a temperature of -70 to
,, : : ~

~ 2~ 5
- 44 -
-60C. The temperature was kept at -60C for an hour and
was then allowed to rise to 0C. Water (50 ml) was added
followed by 5N hydrochloric acid (150 ml) with cooling. The
reaction mixture was extracted with ether, was~ed with water,
sodium bicarbonate solution, dried~ The solvent was removed
by evaporation and l-propionyl-1-(4-chlorophenyl)cyclobutane
obtained by distillation (b.p. 96-104C/0.25 mm)
The ketone produced above was converted to N,N-dimethyl-
1-[1-(4-chlorophenyl)cyclobutylpropylamine hydrochloride
(m.p. 213-215C) in a similar manner to that described in
Example 12 (Formula I Rl = Et; R2 = H;
R~, R4 = Me; R5 = 4-Cl; R6 = H).
.
Example 20
1-Acetyl-1-(4-chlorophenyl)cyclobutane (61 g prepared
in a similar manner to that described in Example 1 for 1-
acetyl-l-(3,4-dichlorophenyl)cyclobutane, platinum oxide
(0.75g), 33~0 solution of methylamine in ethanol (60 g) and
ethanol (30 ml) were charged into an autoclave. The auto-
20 clave was filled with hydrogen and maintained at about 60C and
20 bar pressure for ten hours. The reaction mixture was
filtered through charcoal and the solids washed with abso-
lute alcohol. The solvents were removed by evaporation and
a sample of the residue (10 g) was shaken with ZM hydro-
chloric acid (50 ml) and ether (50 ml). The aqueous
layer was basified and extracted with ether. The ether
extract yielded a liquid on evaporation which was distilled
(109C/0.3 mm Hg) to give N-methyl-1-[1-(4-chlorophenyl`
cyclobutyl]ethylamine (Formula I Rl = Me, R2 = H;
R3 = Me; R4 = H; R5 = 4-Cl and R6 = H).
.
,~ .

lZ4~
- 45 -
Example 21
'Sodium borohydride (2.0 g) was added to solution o~
1~[1-(3,4-dichlorophenyl)cyclobutyl~ethylamine (1.5 g prepared
by treating theproductofExample lwith aqueous sodium hydroxi~e)
in glacial acetic acid (30 ml),. The mixture was heated at
95-100C for sixteen hours and then cooled. Aqueous sodium
hydroxide solution was added and the reaction mixture
extracted with ether. The ether extract was shaken with
5N hydrochloric acid and the aqueous layer was washed with
ether, basified and extracted with ether. Hydrogen chloride
gas was passed into the ether extract which was evaporated
to dryness. Trituration with acetone gave N-ethyl-l-
[1-(3,4-dichlorophenyl)cyclobutylle~hylamine hydrochloride
(m.p. 211-212C). (Formula I Rl = Me; R2 = H;
R3 = Et; R4 = H; R5 = 4-Cl and R6 = 3-Cl.)
Example 22
A mixture of N-ethyl-1-[1-(3,4-dichlorophenyl)
cyclobutyl]ethylamine (0.5 g prepared by treating the product
of Example 21with aqueous sodium hydroxide) and acetic anhydride
~1 ml) was heated at 40-45C for thirty minutes. The
reaction mixture was basified and extracted,with ether.
The ether extract was washed, dried and evaporat~d to give -
N-acetyl-N-ethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
ethylam,ine as an oil.
This oil was dissolved in tetrahydrofuran tlO ml) and
borane-dimethylsulphide comple~ (0.5 ml) added dropwise.
The reaction mixture was stirred at room temperature for
two hours and then heated to 35-40C for thirty minutes.
After cooling the reaction mixture was basified and
extracted with ether. Hydrogen chloride gas was passed into
the dried ether extract which was evaporated to dryness.
Trituration with ether gave N,N-diethyl-1-[1-(3,4-
dichlorophenyl)cyclobutyl]ethylamine hydrochloride '
(m.p. 199-201C). (Formula I Rl = Me; R2 = H;
R3, R4 = Et; R5 = 4-Cl and R6 = 3-Cl.)
,.~,, ,
..
;:
....

. ~ 2 ~9 S S
- 46 -
Example 2~
A mixture of l-acetyl-1-(3,4-dichlorophenyl)
cyclobutane (2.2 g) prepared as described in Example 1
ammonium acetate (7 g),sodium cyanoborohydride (0.4 g)
and methanol (28 ml) was stirred at room temperature ~or
~our days. The reaction mixture was poured into a mixture
o~ ice and water and the resulting mixture extracted with
ether. The ether extract was washed with water, dried
and the ether removed to leave 1-[1-(3,4-dichlorophenyl)
cyclobutyl]ethylamine as an oil which ~as identified by
standard analytical techniques as the Gompound of Example 1
in the form of its free base.
Example 24
1~ - .
A mixture o~ l-acetyl-1-(3,4-dichlorophenyl)cyclobutane
(4.86 g) prepared as described in Example 19 hydroxylamine
hydrochloride (1.6 g), sodium acetate trihydrate (3.3 g),
industrial methylated spirit (15 ml) and water (2 ml) was
heated under refl~x for twenty hours. The cooled reaction
mixture was poured into water and the oil which separated
was cooled to give a solid which was recrystallised from ~;
industrial methylated spirit to give 1-acetyl-1-(3,4-
dichlorophenyl)cyclobutane oxime (m.p. 120-121C). ~`
A solution of the oxime prepared above (4.0 g) in ether
(50 ml) was added slowly to a stirred suspension of lithium
aluminium hydride (0.9 g) in ether (50 ml) under nitrogen. ~;
The mixture was heated under reflux ~or one hour and, after
cooling, water and then a 20% aqueous solution of Rochelle's
salt.(potassium ~odium tartrate tetrahydrate) (27 ml) ar
a 10~ a~ueous solution of sodium hydroxide (6 ml) added.
The reaction mixture was stirred for one hour and then
continuously extracted with ether during eighteen hours.
The ether extract was dried and the ether removed to leave
a solid from which 1-[1-(~,4-dichlorophenyl)cyclobutyl]
ethylamine was separated by high pressure li~uid
chromatography. The product was identified by standard
: '
. .
.
'~ ' '"' ' .-

- 47 -
analytical techniques as the compound o~ Example 1 in the
form of its free base.
Example 25
A lM solution of diisobutylaliminohydride in
hexane (200 ml) was added under nitrogen to a solution of
l-phenyl-l-cyclobutane carbonitrile (31.4 g) in ether (100 ml)
at a temperature below -30C. The temperature
was maintained below 0C ~or thirty minutes and 5N
hydrochloric acid (200 ml) at a temperature of -10C added.
m e reaction mixture was washed with petroleum ether
(b.p. 60-80C) and then warmed to 40C. The reaction
mixture was extracted with petroleum ether (b.p. 60-80C)
and the extract dried and evaporated to yield
l-phenyl-l-cyclobutane-carbaldehyde as an oil.
Methylamine was bubbled through a solution of the
aldehyde (9.4 g) prepared as above in toluene (100 ml)
whilst the temperature o~ the reaction mixture was
maintained below 0C. Magnesium sulphate (20 g) which had
been dried over a flame andthencooled under nitrogen was
added to the reaction mixture which was left for sixteen
hours at room temperature be~ore being filtered. The
toluene was then remov2d by evaporation~and the residue
dissolved in ether (50 ml). ~his solution was added to a~
solution ofpropyll~hium prepared by slowly adding excess
propyl bromide (12.8 g) to a suspension of lithium (1.26~g~
in ether (50 ml). The resulting mixture was left for
sixteen hours at room temperature~ A trace of unreacted
lithium was removed by filtration and the filter washed
~; with ether, ~ater and then 5N hydrochloric acid. The
filtrate and washings were heated on a steam bath for one
hour. After cooling the reaction mixture was washed wi~th
ether and the aqueous layer was basified u3ing aqueous
sodium hydroxide solution. The reaction mixture was
extracted wit;h ether and the extract~dried and the ether
` 35 removed to give a residue~from which N-methyl~
phenylcyclobut~l)butylamine (b.p. 80-86/O.l~mm~Hg.)~
:
: ~ :
, , .

~Z485~3~;
- 48 -
was distilled.
The ~mine (2.3 g) prepared as described above was
dissolved in ether (40 ml) and hydrogen chloride gas passed
through the solution to precipi~ate N-methyl-l-(l-
phenylcyclobutyl)butylamine hydrochloride (m.p. 196-197C).
(Formula I Rl = propyl; R2 = H; R3 = Me; ~4, R5
and R6 are H.)
Example 26
A solution of 1-(3-chloro-5-metnylphenyl)-1-cyclobutane
carbonitrile (8.0 g) in ether ~40 ml) was added to a solution
of propyl mag~.esium bromide [prepared by the reaction of
l-bromopropane (6.7 g) and magnesium (1.3 g)] in ether
(80 ml) and the mixture heated under reflux for two and a
half hours. Two thirds of the ether was evaporated off and
then, after cooling t a solution of sodium borohydride (3.5 g)
in ethanol (150 ml) added. The mixture was maintained at 50C
for one hour and water (50 ml) and then 5N hydrochloric
acid (50 ml) added. The ether layer was separated, dried
and evaporated to yield a solid which was recrystallised
~rom propan-2-ol to give 1-[l-(3-chloro-s-methylphenyl)cyclobut
butylamine hydrochloride (m`.p. 145-146C~.
The hydrochloride salt prepared as above was shaken
with ether and 5N sodium hydroxide solution and the ether
layer evaporated to give the primary amine which was
-converted into N,N-dimethy~ (3-chloro-5-met~ly1phenyl~
cyclobutyl]butylamine hydrochloride (m.p. 148~C) (Formula
I Rl = propyl; R2 = ~i R3 and R4 = Me; R5 = 3-Cl
and R6 = 5-Me) in a similar manner to that described in
;~ Example 2.
~0 ~.
:
:: :
. . .
- ; ,
, . . .
: " ,.
. .~
:~ :

1 2
Examplc 27
solution of isobutylmagnesium bromide was
~repared by the addition under nitrogen of isobutyl
bromide ~9 g) in ether (150 ml) to a stirred mixture
S of ma~nesium turnings (18 g) and ether over a period of
one and three auarter hours. The mixture was heated
under reflux for 30 minutes. The ether was replaced by
toluene (300 ~L) and a solution of 1-(4-chlorophenyl)1-
cyclobutanecarbonitrile (97.2 g prepared as described
in Example 1) in ~oluene (60 ml) ~ras added to the
solution of isobutyl nagnesium bromide prepared as
described above over a period of 30 minutes. The
reaction mixture was he2ted at around 90C or 19 hours
and then cooled. A suspension of sodium borohydride
(30 g) in ethanol (750 ml) was added dropwise over a
period of one and three quarter hours. The reaction
~ixture was maintained at iOC for two hours and then
ethanol (580 ml) was removed by evaporation. Water (70
ml) was added and 16 hours later concentrated
hydrochloric acid (200 ml~ was added dropwise. The
toluene phase of the reaction mixture was washed, dried
and the solvent removed to leave a residue which was
stirred with a mixture of e~her and petroleum e~her
(b.p. 40-60C) and 16M aqueous sodium hydroxide
solution. The organic layer was washed, dried and
evaporat~d to leave 1-[1-(4-chlorophenyl)cyclobutyl]-
3-methylbutylamine (b.p. 124-128C/0.2 mm Hg) as a
brown oil (Formula I n = 0; R1 - isobutyl; R2, R3 and
R4 = H; R5 - 4-Cl and R6 = H).
The primary amine (1n2.7 g) and 98% formic acid
(310 ml) were mîxed with ice cooling and 37-40% aqueous
formaldehyde (123 ml) was added. The mixture was
heated at 90-100C fo~ 16 hours and ~Jas then cooled and
poured into a mixture of ice (500 g) and 16~1 aqueous
sodium hydroxide solution (250 ml). Thc produc~ s
~ ~`
- , ,:

1291~9 j5
- 50 -
extracted with ether and the extracts wera washed, drled and
evaporated to leave N,N-dimethyl-1-~1-(4-
chlorophenyl)cyclobutyl]-3-methylbutylamlne (m.p.53-55C)
(Formula I n = O; R1 = isobutyl; R2 = H~ R3 and R4
Me; Rs = 4-C1 and R6 = H ) .
Example 28
Pharmaceutical compositions containing any one of the
compound~ of formula I disclosed in Examples 1 to 27 are prepared
in the following manner.
.
' .
.. -
.

~L~489~5
Example 28(a)
Tablets are prepared from the following ingredients:
Parts by ~ t
5 Active Ingredient 50.0
Lactose 78.5
Polyvinylpyrrolidone 5.0
Maize Starch 15.0
Magnesium Stearate 1.5
The active ingredient, the lactose and some of the
starch are mixed and grar.ulated with a solution of the
~olyvinylpyrro idone in ethanol. The granulate is mixed
with the stearic acid and the rest of the starch and the
mixture is compressed in a tabletting machine to give
ablets containing 50.0 mg. of the active ingredient.
Example 28tb)
Capsules are prepared in the following way. A mixture
o~ the active ingredient (45 parts by weight) and lactose
20 powder (205 parts by weight) is filled into hard gelatin !
ca~sules, eac~ capsule containing 45 mg. of the active
irgredient.
I
Exam~le 28(c) ;~
:~ ,
In the preparation of enteric coated tablets, the
tablets described in Example t28a) ~re gi~en a thin coat
of shellac vPrnish, followed by 20 coats of cellulose
acetate phthalate in a manner well known in the art. In
a similar m~ner the capsules of Examp le t28b) may be
provided with an enteric coating.
Example 28~d)
Vials containing a solution of water_soluble compounds
o~ the present invention suitable for injection are prepa-
red from the fol~owing ingredients~
:: :

12~ 55
Active Ingrcdient 1100 ga
Mannitol 1100 g.
Water, fr~shly distilled to 11 litres
The active ingredient and mannitol are dissolved insome of the water and the volume of the solution is
adjusted to 11 litres. The resulting solution is sterilised
by filtration and filled into sterile vials each con-taining
1.65 ml. of solution.
Example 28~e)
In the preparation of suppositories, 100 parts by weight
of the finely ground active ingredient is incorporated in
1214 parts by weight of triglyceride suppository base and
the mixture is formed into suppositories each containing
100 mg. of the active ingredient.
In the preceding Examples novel ketones of formula ~
have been disclosed in which Rl, R5 and R6 have the meaning
given in Examples 1, l(a) to l~e), 3, 4, 4(a~ to 4(~), 6,
7, 7(a) to 7(d) 9, 9(a) to 9(n), 10, lO(a) ~o lO(z), lO(aa),
lO(bb), ll(i), ll(k) and 11(1). These novel ketones of
formula V are prepared by hydrolysis of novel imines of
iormula XVI in which Y = MgBr and Rl, R5 and R6 have the
meanlng given in the Examoles specifiod above.
: ::
~ :
In the preceding `Examples novel cyano compound~ of
iormula XVII are disclosed in whlch R5 and R6 have the
meaning given in Examples l, l(d), l(e), 4(g), 9(e), 9(m),
lO(k), lO(e)~ lO(p), lO(r), lO(v), lO~y), lO(z), lO(aa)~
lO(bb), ll(k), 11(1) and 26.
. , .. ~ , : ,
:
, ~ . .,

1248~3S5i
53
In the preceding Examples novel formamides of rormula
XXVTII are disclosed in which Rl, R3, R5, R6, R7, R8 and n
have the meaning given in Exa~ples 1, l(a) to l(e), 3, 4,
4(a) to 4(e), 6, 7, 7(a) to 7(d), 9, 9(a) to 9(n), 10,
lO(a) to lO(z), lO(aa), lO(bb), ll(i), ll(k), 11(1).
.:
: