BENZYLAMINES

BENZYLAMINES

English Abstract

ABSTRACT OF THE DISCLOSURE
This invention relates to new benzylamines
having interesting pharmacological properties, in
particular a secretolytic and antitussive effect as
well as a stimulating effect on the production of the
surfactant or antiatelectasis factor of the alveoli.
Details of tests on certain of the new compounds to
determine their biological activities are given.
Processes for the preparation of the new compounds
are described and exemplified and examples of
pharmaceutical compositions containing the same are
given.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of new benzylamines and their pharmaceutically
acceptable addition salts with inorganic and organic acids, wherein the benzyl-
amines conform to the general formula I:
<IMG>
in which Hal represents an atom of chlorine or bromine,
R1 represents an atom of hydrogen, chlorine or bromine,
R2 represents morpholino-carbonylmethyl, a branched alkyl radical
containing 3 to 5 carbon atoms substituted by 1 to 3 hydroxyl groups, the
isopropyl, tert.butyl or tert.pentyl group, or a group of the formula:
<IMG>
in which R3 represents a hydrogen atom, or hydroxy group or an alkyl group
containing 1 to 4 carbon atoms, n represents zero, one or two and the two
substitutents A and B either both represent hydrogen atoms or together represent
the group:
<IMG>
in which R5 represents a hydrogen atom or an alkyl radical containing one or
two carbon atoms and m represents the integer 1 or 2;
R4 represents a straight or branched alkyl group containing from 1 to
4 carbon atoms, an alkenyl group containing from 2 to 4 carbon atoms, a cyclo-
alkyl group containing 3 or 4 carbon atoms, or a hydrogen atom (if R3 is other
than hydrogen or R2 represents a branched alkyl group with 3 to 5 carbon atoms
substituted by 1 to 3 hydroxyl groups, the isopropyl, tert.butyl or tert.-
pentyl group); and y represents the integer 1 or 2; which comprises either:
(a) reacting a compound of the general formula II
<IMG> II
100

in which R1, Hal and y have the meanings given to them above and R6 represents
a hydroxyl group, an atom of chlorine, bromine or iodine or an acyloxy group,
of a carboxylic acid, sulfonyloxy, or lower alkoxy radical, with an amine of
the general formula
III
<IMG> III
in which R2 and R4 are as previously defined; or
(b) reacting in the presence of formic acid an aldehyde of the general
formula
<IMG> IV
in which R1, Hal and y are as previously defined with an amine of the general
formula III as defined above or with a corresponding formamide; or
(c) for preparing those compounds of general formula I in which R4
represents a hydrogen atom, reducing a compound of the general formula
<IMG> V
or a compound of the general formula Va
<IMG> Va
wherein in these two formulae R1, R2, Hal and y are as defined above, Z
represents a cyclohexylidene radical optionally substituted by a hydroxy
group or by an alkyl group containing 1 to 4 carbon atoms or Z is a morpholino-
carbonyl-methylidene radical and R7 represents a hydrogen atom or a radical
of a carboxylic acid, or
101

(d) for preparing a compound of general formula I in which R4 is other
than a hydrogen atom and the substituents R2 and R4 do not represent radicals
substituted by a hydroxy group by alkylating a compound of the general
formula VI
<IMG> VI
in which R1, Hal and y are as previously defined and R2 represents a hydrogen
atom or an alkyl radical containing 1 to 4 carbon atoms or one of the groups
represented by R2 as defined above excepting the radicals isopropyl, tert.-
butyl, tert.pentyl and radicals substituted by one or more hydroxy groups
with a compound of the general formula VII
R4-W VII
in which R4 represents an isopropyl, tert.butyl, tert.pentyl or cyclohexyl
radical or represents one of the values given above for the radical R4
with the exception of a hydrogen atom and W represents a halogen atom or
a sulphonic acid radical; or
(e) reacting a phenol of the general formula
VIII
<IMG>
in which R1, Hal and Y are as defined above and in which one of the substituents
Hal is in the 2-position of the compound of general formula VIII, with
formaldehyde or paraformaldehyde and an amine of the general formula III as
defined above, in which R2 and R4 are as defined above; or
(f) halogenating a compound of the general formula
<IMG> IX
102

in which R1, R2 and R4 are as defined above; or
(g) eliminating one or two protecting radicals from a compound of the
general formula
<IMG> X
in which R1, R2, Hal and y are as defined above, X represents a group which
may be split off by means of hydrolysis or catalytic hydrogenation or repre-
sents one of the values given above for R4, and Y represents a group which
may be split off by means of hydrolysis or catalytic hydrogenation or a hy-
drogen atom at least one of the radicals X and Y representing a protecting
group for the amino or hydroxy group; or
(h) reducing a compound of the general formula
<IMG> XI
in which R1 and R2 are as defined above with the exception of the morpholino
carbonyl methyl radical and Hal and y are as previously defined, R4 represents
a formyl or acetyl radical or represents one of the values given above for
R4 and R7 represents a hydrogen atom or a carboxylic acid residue; or
(i) for preparing the compounds of formula I in which a hydroxy group is
present in the 2-position and R4 represents a hydrogen atom, hydrolysing a
compound of the general formula
<IMG> XII
in which R1, R2, Hal and y are as defined above; or
103

(j) reacting a compound of the general formula
<IMG> XIII
in which R1, Hal and y are as previously defined and R8 represents an organic
acyl radical with an amine of the general formula III as defined above; or
(k) for preparing those compounds of formula I in which the hydroxy group
is present in the 2-position, reacting a compound of the general formula
<IMG> XIV
in which R1, Hal and y are as previously defined and R9 represents an alkyl,
aryl or aralkyl radical with an amine of the general formula III as defined
above and subsequently hydrolysing the reaction product obtained; or
(l) for preparing the compounds of general formula I in which R4 represents
a hydrogen atom and a hydroxyl group is present in the 2-position, hydrolysing
a compound of the general formula
<IMG> XV
in which R1, R2, Hal and y are as previously defined or
(m) for preparing the compounds of general formula I in which R2 repre-
sents a cyclohexyl radical and R4 represents a methyl radical, reacting a
compound of the general formula
<IMG> IIa
in which R1, Hal and y are as previously defined with an amide of the general
formula
104

<IMG> XVI
or with an amide of the general formula
<IMG> XVIa
in which formulae R2 and R4 are as previously defined and R10 represents a
lower alkyl radical; and where one of the steps (a) to (m) as set out above
may be followed by conversion of a base of formula I into a corresponding
pharmaceutically acceptable acid addition salt with an inorganic or organic
acid.
2. A process according to claim 1(e) in which a compound formed in
situ of the general formula
<IMG> IIIa
in which R2 and R4 are as defined in claim 1 and alc represents a lower alkyl
radical is reacted with a compound of the general formula VIII as defined in
claim 1.
3. A benzylamine conforming to the general formula I as defined in
claim 1 or a pharmaceutically acceptable addition salt thereof with an in-
organic or organic acid whenever prepared by the process of claim 1 or 2 or
by an obvious chemical equivalent thereof.
4. A process according to claim 1 in which R2 represents a group of
the formula:
<IMG>
105

in which A, B, R3 and n are as defined in claim 1.
5. A process according to claim 1 in which R2 represents a cyclohexyl,
hydroxycyclohexyl or morpholinocarbonylmethyl group, R4 represents a methyl
or ethyl group or a hydrogen atom, and y represents one or two.
6. A process according to claim 1 in which R2 represents a branched
alkyl group containing 3 to 5 carbon atoms substituted by one to three
hydroxyl radicals, R4 is a hydrogen atom and y represents one or two.
7. A process according to claim 1 in which R2 represents the isopropyl,
tert.-butyl or tert.pentyl radical, R4 represents a hydrogen atom and y
represents one or two.
8. A process according to claim 1 in which R2 represents a branched alkyl
group containing 3 to 5 carbon atoms and substituted by one to three hydroxyl
radicals, or a cyclohexyl or hydroxy-cyclohexyl radical, R4 represents a
straight or branched alkyl radical containing 1 to 4 carbon atoms or R4 may
also represent hydrogen if R2 represents a hydroxycyclohexyl radical or a
branched alkyl radical containing 3 to 5 carbon atoms and substituted by one
to three hydroxy radicals.
9. A process for the preparation of compounds of general formula I as
defined in claim 1 which comprises reacting a compound of formula
<IMG>
wherein R1, Hal and y are as defined in claim 1 and R6 represents a hydroxyl
group, a chlorine, bromine or iodine atom, or an acyloxy group of a carboxylic
acid, sulfonyloxy, or a lower alkoxy group; with a compound of formula
<IMG> (III)
wherein R2 and R4 are as defined in claim 1.
10. A process as claimed in claim 9 wherein the reaction is effected in
the presence of a solvent.
106

11. A process as claimed in claim 9 wherein the reaction is effected at
temperatures from -70 to 200°C.
12. A process as claimed in claim 9 wherein a compound of formula II
wherein R6 represents a halogen atom is used and the reaction is effected at
temperatures from 0 to 150°C.
13. A process as claimed in claim 12 wherein the reaction is effected in
the presence of a hydrogen halide binding agent or in the presence of an ion
exchanger.
14. A process as claimed in any of claims 9 to 11 wherein a compound of
formula II wherein R6 represents a sulfonyloxy group is used and the reaction
is effected at temperatures from -70 to 50°C.
15. A process as claimed in claim 9 wherein a compound of formula II
wherein R6 represents an acyloxy group of a carboxylic acid or a lower alkoxy
group is used and the reaction is effected at temperatures from 0 to 200°C.
16. A process as claimed in claim 15 wherein the reaction is effected in
the presence of an acid catalyst.
17. A process as claimed in claim 16 wherein the acid catalyst comprises
ammonium chloride.
18. A process as claimed in claim 9 wherein a compound of formula II
wherein R6 represents a hydroxyl group is used and the reaction is effected
at temperatures from 120 to 180°C.
19. A process as claimed in claim 18 wherein the reaction is effected in
the presence of an acid or basic catalyst.
A process for the preparation of compounds of general formula I as
defined in claim 4 which comprises reacting a compound of formula
<IMG> (IIa)
107

wherein R1, y and Hal are as defined in claim 4 and Hal' represents a chlorine,
bromine or iodine atom with a compound of formula
<IMG> (IIIa)
wherein R3, R4, A and B are as defined in claim 4.
21. A process for the preparation of compounds of general formula I as
defined in claim 5 which comprises reacting a compound of formula
<IMG> (IIa)
wherein R1, Hal and y are as defined in claim 5 and Hal' represents a chlorine,
bromine or iodine atom with a compound of formula
<IMG> III
wherein R2 and R4 are as defined in claim 5.
22. A process for the preparation of compounds of general formula I as
defined in claim 6 which comprises reacting a compound of formula
<IMG> (II)
wherein R1, Hal and y are as defined in claim 6 and R6 represents a hydroxyl
group, a chlorine, bromine or iodine atom, or an acyloxy group of a carboxylic
acid, sulfonyloxy or a lower alkoxy group with a compound of formula
<IMG>
wherein R2 is as defined in claim 6.

23. A process for the preparation of compounds of general formula I as
defined in claim 1 which comprises reacting a compound of formula
<IMG>
wherein R1, Hal and y are as defined in claim 1 with a compound of formula
<IMG> (III)
wherein R2 and R4 are as defined in claim 1) or with a corresponding formamide
in the presence of formic acid.
24. A process as claimed in claim 23 wherein the reaction is effected in
the presence of a solvent.
25. A process as claimed in claim 23 wherein the reaction is effected at
temperatures from 50 to 250°C.
26. A process as claimed in any of claims 23 to 25 wherein a compound
of formula III wherein R4 represents a hydrogen atom is used and the
reaction mixture is subsequently heated with a dilute acid.
27. A process for the preparation of compounds of general formula I as
defined in claim 4 which comprises reacting a compound of formula
<IMG> (IV)
wherein R1, Hal and y are as defined in claim 4 with a compound of formula
<IMG> (IIIa)
109

wherein R3, R4, A and B are as defined in claim 4 or with a corresponding
formamide in the presence of formic acid.
28. A process for the preparation of compounds of general formula I as
defined in claim 5 which comprises reacting a compound of formula
<IMG> (IV)
wherein R1, Hal and y are as defined in claim 5 with a compound of formula
<IMG> (III)
wherein R2 and R4 are as defined in claim 5 or with a corresponding formamide
in the presence of formic acid.
29. A process for the preparation of compounds of general formula I as
defined in claim 6 which comprises reacting a compound of formula
<IMG> (IV)
wherein R1, Hal and y are as defined in claim 6 with a compound of formula
<IMG> (IIIb)
wherein R2 is as defined in claim 6 or with a corresponding formamide in the
presence of formic acid.
30. A process for the preparation of compounds of general formula I wherein
R1, R2 and y are as defined in claim 1 and R4 represents a hydrogen atom which
comprises reducing a compound of formula
<IMG> (V)
110

or a compound of formula
<IMG> (Va)
wherein R1 3 R2, Hal and y are as defined in claim 1, Z represents a cyclo-
hexylidene group optionally substituted by a hydroxy group or by an alkyl
group containing from 1 to 4 carbon atoms, a branched alkylidene group con-
taining from 3 to 5 carbon atoms or a morpholincarbonylmethylidene group,
and R7 represents a hydrogen atom or an organic acyl group.
31. A process as claimed in claim 30 wherein the reaction is effected in
the presence of a solvent.
32. A process as claimed in claim 30 wherein a compound of formula V or
Va wherein R7 represents a hydrogen atom is used and the reduction is effected
by means of catalytically activated hydrogen, nascent hydrogen or a complex
metal hydride.
33. A process as claimed in claim 30 wherein a compound of formula V or Va
wherein R7 represents an organic acyl group is used and the reduction is ef-
fected by means of nascent hydrogen or a complex metal hydride.
34. A process as claimed in any of claims 30 to 33 wherein the reduction
is effected at temperatures from -50 to 100°C.
35. A process for the preparation of compounds of general formula I as
defined in claim 1 with the proviso that R4 is other than a hydrogen atom and
R2 and R4 do not represent radicals substituted by a hydroxyl group which
comprises alkylating a compound of formula
<IMG> (VI)
wherein R1, Hal and y are as defined in claim 1 and R? represents a hydrogen
atom, an alkyl group containing from 1 to 4 carbon atoms or one of the groups
111

represented by R2 as defined in claim 1 excepting the radicals isopropyl,
tert.-butyl, tert-pentyl and radicals substituted by one or more hydroxy
groups with a compound of formula
R? - W (VII)
wherein R? represents an isopropyl, tert.-butyl, tert.-pentyl or a cyclohexyl
group or represents one of the groups represented by R4 but not a hydrogen
atom, and W represents a halogen atom or a sulfonic acid group.
36. A process as claimed in claim 35 wherein the reaction is effected in
the presence of a solvent.
37. A process as claimed in claim 35 wherein the reaction is effected at
temperatures from -20 to 150°C.
38. A process as claimed in any of claims 35 to 37 wherein the alkylation
is a methylation and is effected by means of formaldehyde in the presence of
formic acid.
39. A process for the preparation of compounds of general formula I as
defined in claim 4 with the proviso that R4 does not represent a hydrogen
atom which comprises alkylating a compound of formula
<IMG> (VIa)
wherein R1, R3, Hal, y, A, B and n are as defined in claim 4 with a compound
of formula
R4 - W (VIIa)
wherein R4 is as defined in claim 4 and W represents a halogen atom or a
sulfonic acid group.
40. A process for the preparation of compounds of general formula I as
defined in claim 5 with the proviso that R4 does not represent a hydrogen
atom which comprises alkylating a compound of formula
112

<IMG> (VI)
wherein R1, Hal and y are as defined in claim 5 and R? represents one of the
groups represented by R2 and R4 as defined in claim 4 with the exception of
the hydrogen atom with a compound of formula
R? - W (VII)
wherein R? represents one of the groups represented by R2 as defined in claim
5 or a methyl or ethyl group, and W represents a halogen atom or a sulfonic
acid group.
41. A process for the preparation of compounds of general formula I as
defined in claim 6 with the proviso that R2 does not represent an isopropyl,
tert.-butyl, tert.-pentyl or a radical substituted by one or more hydroxy
groups which comprises alkylating a compound of formula
<IMG> (VIb)
wherein R1, Hal and y are as defined in claim 6 with a compound of formula
R? - W (VII)
wherein R? represents an isopropyl, tert.-butyl, tert.-pentyl or cyclohexyl
or one of the groups represented by R4 except a hydrogen atom, and W re-
presents a halogen atom or a sulfonic acid group.
42. A process for the preparation of compounds of general formula I as
defined in claim 1 which comprises reacting a phenol of formula
<IMG> (VIII)
wherein R1, Hal and y are as defined in claim 1 with the proviso that (one of
the radical(s) Hal is in the 2-position) with formaldehyde or paraformaldehyde
and a compound of formula
113

<IMG> (III)
wherein R2 and R4 are as defined in claim 1.
43. A process as claimed in claim 42 wherein the reaction is performed
in the presence of a solvent.
44. A process as claimed in claim 42 or claim 43 wherein the reaction is
performed at temperatures from 0 to 100°C.
45. A process for the preparation of compounds of general formula I as
defined in claim 4 which comprises reacting a phenol of formula
<IMG> (VIIIa)
wherein R1 and Hal are as defined in claim 4 with formaldehyde or para-
formaldehyde and an amine of general formula
<IMG> (IIIa)
wherein R3, R4, A, B and n are as defined in claim 4.
46. A process for the preparation of compounds of general formula I as
defined in claim 5 which comprises reacting a phenol of formula
<IMG> (VIII)
wherein R1, Hal and y are as defined in claim 1 with the proviso that (one of)
the radical(s) that is in the 2-position with formaldehyde or paraformaldehyde
and an amine of formula
<IMG> (III)
114

wherein R2 and R4 are as defined in claim 5.
47. A process for the preparation of compounds of general formula I as
defined in claim 6 which comprises reacting a phenol of formula
<IMG> (VIII)
wherein R1, Hal and y are as defined in claim 6 with the proviso that (one of)
the radical(s) Hal is in the 2-position with formaldehyde or paraformaldehyde
and a compound of formula
<IMG> (IIIb)
wherein R2 is as defined in claim 6.
48. A process for the preparation of compounds of general formula I as
defined in claim 1 which comprises reacting a phenol of formula
<IMG> (VIII)
wherein R1, Hal and y are as defined in claim 1 with the proviso that (one of)
the radical(s) is in the 2-position with a compound of formula
<IMG> (IIId)
wherein R2 and R4 are as defined in claim 1 and Alk represents a lower alkyl
group, optionally prepared in situ.
49. A process as claimed in claim 48 wherein the reaction is performed
in the presence of a solvent.
50. A process as claimed in claim 47 or claim 48 wherein the reaction is
performed at temperatures from 0 to 100°C.
115

51. A process for the preparation of compounds of general formula I as
defined in claim 1 which comprises halogenating a compound of formula
<IMG> (IX)
wherein R1, R2 and R4 are as defined in claim 1.
52. A process as claimed in claim 51 wherein the halogenation is performed
in the presence of a solvent.
53. A process as claimed in claim 51 wherein the halogenation is effected
by means of chlorine, bromine, iodosobenzene dichloride or tribromophenol
bromine.
54. A process as claimed in any of claims 51 to 53 wherein the halogena-
tion is performed at temperatures from -20 to 50°C.
55. A process for the preparation of compounds of general formula I as
defined in claim 1 which comprises splitting off one or two protecting groups
from a compound of formula
<IMG> (X)
wherein R1, R2, Hal and y are as defined in claim 1, X represents a group
which may be split off by means of hydrolysis or catalytic hydrogenation or is
as defined in claim 1 for R4, and Y represents a protecting group for a hy-
droxyl group or, in the case where X represents a protecting group for an
amino group, a hydrogen atom.
56. A process as claimed in claim 55 wherein the reaction is performed in
the presence of a solvent.
57. A process as claimed in claim 55 or claim 56 wherein X and/or Y in the
compound formula X represent acyl groups which are split off hydrolytically.
58. A process as claimed in claim 55 or claim 56 wherein X and/or Y in the
116

compound of formula X represent benzyl groups which are split off hydro-
genolitically.
59. A process as claimed in claim 55 or claim 56 wherein Y in the compound
of formula X represents an alkyl, aryl or aralkyl group and is split off by
means of hydrobromic acid, hydroiodic acid, a halide of a carboxylic acid, a
phosphoryl halide, a phosphorus pentahalide, an aluminium halide, sulfuric
acid or an organometallic compound.
60. A process as claimed in claim 55 or claim 56 wherein Y in the compound
of formula X represents an acyl group derived from a carboxylic acid which is
split off by means of a complex metal hydride.
61. A process for the preparation of compounds of general formula I as
defined in claim 1 which comprises reducing a compound of formula
<IMG>
wherein R1, R2, Hal and y are as defined in claim 1 with the proviso that R2
does not represent a morpholinocarbonylmethyl group, R? represents a formyl
or acetyl group or one of the groups represented by R4 as defined in claim 1
and R7 represents a hydrogen atom or an acyl group derived from a carboxylic
acid.
62. A process as claimed in claim 61 wherein the reduction is effected
in the presence of a solvent.
63. A process as claimed in claim 61 wherein the reduction is effected
at temperatures from room temperature up to the boiling temperature of the
solvent used.
64. A process as claimed in any one of claims 61 to 63 wherein a compound
of formula XI wherein R7 represents a hydrogen atom is used and the reduction
is effected by means of catalystically activated hydrogen.
117

65. A process as claimed in any of claims 61 to 63 wherein the reduction
is effected by means of nascent hydrogen or a complex metal hydride.
66. A process for the preparation of compounds of general formula I as
defined in claim 4 which comprises reducing a compound of formula
<IMG> (XIa)
wherein R1, R3, A, B, Hal, y and n are as defined in claim 4, R? represents
a carboxylic acyl group containing from 1 to 4 carbon atoms or one of the
groups represented by R4 as defined in claim 4, and R7 represents a hydrogen
atom or an acyl group derived from a carboxylic acid.
67. A process for the preparation of compounds of general formula I as
defined in claim 5 which comprises reducing a compound of formula
<IMG> (XI)
wherein R1, R2, Hal and y are as defined in claim 5, R? represents a formyl
or acetyl group or one of the groups represented by R4 as defined in claim 5,
and R7 represents a hydrogen atom or an acyl group derived from a carboxylic
acid.
68. A process for the preparation of compounds of general formula I as
defined in claim 6 which comprises reducing a compound of formula
<IMG> (XIb)
wherein R1, R2, Hal and y are as defined in claim 6 and R7 represents a hydro-
gen atom or an acyl group derived from a carboxylic acid.
118

69. A process for the preparation of compounds of general formula I
wherein R1, R2, Hal and y are as defined in claim 1, R4 represents a hydrogen
atom and the hydroxyl group is in the 2-position which comprises hydrolysing
a compound of formula
<IMG> (XII)
wherein R1, R2, Hal and y are as defined in claim 1.
70. A process as claimed in claim 69 wherein the reaction is effected in
the presence of a solvent.
71. A process as claimed in claim 69 wherein the reaction is effected at
temperatures up to the boiling point of the solvent used.
72. A process as claimed in any of claims 69 to 71 wherein the reaction is
effected in the presence of an acid or base.
73. A process for the preparation of compounds of general formula I
wherein R1, R3, Hal, A, B, y and n are as defined in claim 4, R4 represents
a hydrogen atom and the hydroxyl group is in the 2-position which comprises
hydrolysing a compound of formula
<IMG> (XIIa)
wherein R1, R3, A, B, Hal, y and n are as defined in claim 4.
74. A process for the preparation of compounds of general formula I wherein
R1, R2, Hal and y are as defined in claim 5, R4 represents a hydrogen atom and
the hydroxyl group is in the 2-position which comprises hydrolysing a compound
of formula
119

<IMG> (XII)
wherein R1, R2, Hal and y are as defined in claim 5.
75. A process for the preparation of compounds of general formula I as
defined in claim 6 with the proviso that the hydroxyl group is in the 2-position
which comprises hydrolysing a compound of formula
<IMG> (XII)
wherein R1, R2, Hal and y are as defined in claim 6.
76. A process for the preparation of compounds of general formula I as
defined in claim 1 which comprises reacting a compound of formula
<IMG> (XIII)
wherein R1, Hal and y are as defined in claim 1 and R8 represents an organic
acyl group with a compound of formula
<IMG> (III)
wherein R2 and R4 are as defined in claim 1.
77. A process as claimed in claim 76 wherein the reaction is performed in
the presence of a solvent.
78. A process as claimed in claim 76 wherein the reaction is effected at
temperatures from 100 to 220°C.
120

79. A process as claimed in claim 78 wherein the reaction is effected at
temperatures from 120 to 180°C.
80. A process for the preparation of compounds of general formula I where-
in R1, R4, Hal and y are as defined in claim 1 and R2 is as defined in claim 1
with the proviso that it does not represent a branched alkyl group containing
from 3 to 5 carbon atoms optionally substituted by 1 to 3 hydroxyl groups
which comprises reacting a compound of formula
<IMG> (XIII)
wherein R1, Hal and y are as hereinbefore defined and R8 represents an acyl
group derived from a carboxylic acid with a compound of formula
<IMG> (III)
wherein R2 and R4 are as hereinbefore defined.
81. A process for the preparation of compounds of general formula I as
defined in claim 6 which comprises reacting a compound of formula
<IMG> (XIII)
wherein R1, Hal and y are as defined in claim 6 and R8 represents an acyl
group derived from a carboxylic acid with an amine of formula
<IMG> (IIIb)
wherein R2 is as defined in claim 6.
82. A process for the preparation of compounds of general formula I as
defined in claim 1 but wherein the hydroxyl group is in the 2-position which
comprises reacting a compound of formula
121

<IMG> (XIV)
(wherein R1, Hal and y are as defined in claim 1 and R9 represents a lower
alkyl group) with a compound of formula
<IMG> (III)
wherein R2 and R4 are as defined in claim 1, and subsequently hydrolysing the
reaction product obtained.
83. A process as claimed in claim 82 wherein the reaction is effected in
the presence of a polar solvent.
84. A process as claimed in claim 82 wherein the reaction is effected at
temperatures from 100 to 200°C.
85. A process as claimed in claim 84 wherein the reaction is effected at
temperatures from 120 to 180°C.
86. A process as claimed in any of claims 82 to 84 wherein the reaction
is effected in the presence of an acid.
87. A process for the preparation of compounds of general formula I as
defined in claim 80 but wherein the hydroxyl group is in the 2-position which
comprises reacting a compound of formula
<IMG> (XIV)
wherein R1, Hal and y are as defined in claim 80 and R9 represents a lower
alkyl group with a compound of formula
<IMG> (III)
122

wherein R2 and R4 are as defined in claim 80 and subsequently hydrolysing the
reaction product.
88. A process for the preparation of compounds of general formula I as
defined in claim 6 but wherein the hydroxyl group is in the 2-position which
comprises reacting a compound of formula
<IMG> (XIV)
wherein R1, Hal and y are as defined in claim 6 and Rg represents a lower
alkyl group) with a compound of formula
<IMG> (III)
wherein R2 is as defined in claim 6 and subsequently hydrolysing the reaction
product.
89. A process for the preparation of compounds of general formula 1
wherein R1, R2, Hal and y are as defined in claim 1, R4 represents a hydrogen
atom and the hydroxyl group is in the 2-position, which comprises hydrolysing
a compound of formula
<IMG> (XV)
wherein R1, R2, Hal and y are as defined in claim 1.
90. A process as claimed in claim 89 wherein the hydrolysis is effected
in the presence of a solvent.
91. A process as claimed in claim 89 wherein the hydrolysis is effected
in the presence of an acid.
123

92. A process as claimed in any of claims 89 to 91 wherein the hydrolysis
is effected at temperatures from 0°C up to the boiling temperature of the sol-
vent used.
93. A process for the preparation of compounds of general formula I
wherein R1, Hal and y are as defined in claim 1, R2 represents a cyclohexyl
group and R4 represents a methyl group which comprises reacting a compound
of formula
<IMG> (XVI)
wherein R1, Hal and y are as defined in claim 1, with an amide of formula
<IMG> (XVII)
or with an amide of formula
<IMG> (XVIIa)
wherein R2 and R4 are as defined in claim 1 and R10 represents a lower alkyl
group.
94. A process as claimed in claim 93 wherein the reaction is effected in
the presence of a solvent.
95. A process as claimed in claim 93 wherein the reaction is effected at
temperatures from 100 to 250°C.
96. A process as claimed in claim 95 wherein the reaction is effected at
temperatures from 120 to 180°C.
97. A process according to claim 1 in which R1 is a hydrogen atom, R2 is
cyclohexyl, R4 is ethyl, Hal is bromine in the 3- and 5-positions, the hy-
droxy group is attached in the 2-position and y is two.
98. A process for the preparation of N-ethyl-N-cyclohexyl-3,5-dibromo-2-
124

hydroxybenzylamine and its hydrochloride which comprises either:
(a) reacting 3,5-dibromo-2-hydroxybenzylbromide with N-ethylcyclohexylamine;
or
(b) reacting N-ethylcyclohexylamine with paraformaldehyde and 2,4-dibromo-
phenol; or
(c) brominating N-ethyl-N-cyclohexyl-2-hydroxybenzylamine; or
(d) hydrolysing 2-acetoxy-N-ethyl-N-cyclohexyl-3,5-dibromobenzylamine; or
(e) demethylating N-ethyl-N-cyclohexyl-3,5-dibromo-2-methoxybenzylamine; or
(f) reducing N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxybenzamide by
reacting with sodium borohydride, lithium aluminium hydride; or
(g) reacting 2-acetoxy-N-ethyl-N-cyclohexyl-3,5-dibromobenzamide with
lithium aluminium hydride; or
(h) reacting 3,5-dibromo-2-hydroxybenzyl alcohol alone or in the presence
of hydrobromic acid, butyric acid or magnesium oxide or potassium hydroxide or
its acetate, benzoate or p-toluenesulfonate with N-ethylcyclohexylamine; or
(i) reacting 3,5-dibromo-.alpha.-methoxy-o-cresol with N-ethyl-cyclohexylamine; or
(j) reacting 6,8-dibromo-2-methyl-1,3-benzodioxane with N-ethyl-cyclohexyl-
amine; and when the hydrochloride is required reacting the base so obtained
with hydrogen chloride.
99. N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine and its
hydrochloride whenever prepared by the process of claim 98 or by an obvious
chemical equivalent thereof.
100. A process according to claim 1 in which R1 and R4 are hydrogen atoms,
R2 is cis-3-hydroxycyclohexyl, Hal is bromine in the 3- and 5-positions, the
hydroxy group is attached in the 4-position and y is two.
101. A process according to claim 1 in which 3,5-dibromo-4-hydroxy-N-(cis-
3-hydroxycyclohexyl)benzylamine and its hydrochloride are prepared by either:
(a) reducing N-(3,5-dibromo-4-hydroxybenzylidene)-cis-3-aminocyclohexanol; or
(b) reacting 3,5-dibromo-4-hydroxybenzylbromide with cis-3-methylamino-
cyclohexanol; or
(c) brominating 4-hydroxy-N-(cis-3-hydroxycyclohexyl)benzylamine hydrochlor-
ide; or
125

(d) debenzylating N-benzyl-3,5-dibromo-4-hydroxy-N-(cis-3-hydroxycyclohexyl)-
benzylamine hydrochloride; or
(e) demethylating 3,5-dibromo-N-(cis-3-hydroxycyclohexyl)-4-methoxy-
benzylamine hydrochloride; or
(f) reacting 3,5-dibromo-4-hydroxybenzylamine with 3-hydroxycyclohexanone
in the presence of a reducing agent; or
(g) reducing 3,5-dibromo-4-hydroxy-N-(cis-3-hydroxycyclohexyl)benzamide
or 4-acetoxy-3,5-dibromo-N-(cis-3-hydroxycyclohexyl)benzamide; or
(h) reacting cis-3-aminocyclohexanol with 3,5-dibromo-4-hydroxybenzyl acetate
the corresponding alcohol alone or in the presence of butyric acid or
magnesium oxide or 4-acetoxy-3,5-dibromobenzyl alcohol; or
(i) reacting 3,5-dibromo-.alpha.-methoxy-p-cresol with cis-3-aminocyclohexanol;
and where a base obtained may be converted into the corresponding hydrochloride
by reaction with hydrogen chloride.
102. 3,5-Dibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine and its
hydrochloride whenever prepared by the process of claim 101 or by an obvious
chemical equivalent thereof.
103. A process according to claim 1 in which R1 and R4 are hydrogen atoms,
R2 is trans-3-hydroxycyclohexyl, Hal is bromine in the 3- and 5-positions, the
hydroxy group is attached in the 4-position and y is two.
104. A process according to claim 1 in which 3,5-dibromo-4-hydroxy-N-(trans-
3-hydroxycyclohexyl)benzylamine and its hydrochloride are prepared by either:
(a) reacting 3,5-dibromo-4-hydroxybenzylbromide with trans-3-aminocyclo-
hexanol; or
(b) brominating 4-hydroxy-N-(trans-3-hydroxycyclohexyl)benzylamine hydro-
chloride; or
(c) debenzylating N-benzyl-3,5-dibromo-4-hydroxy-N-(trans-3-hydroxycyclo-
hexyl)benzylamine hydrochloride; or
(d) demethylating 3,5-dibromo-N-(trans-3-hydroxycyclohexyl)-4-methoxybenzyl-
amine hydrochloride; or
(e) reacting 3,5-dibromo-4-hydroxybenzylamine with 3-hydroxycyclohexanone
in the presence of a reducing agent; or
126

(f) reducing 3,5-dibromo-4-hydroxy-N-(trans-3-hydroxycyclohexyl)benzamide
or 4-acetoxy-3,5-dibromo-N-(trans-3-hydroxycyclohexyl)benzamide; and
where a base obtained may be converted into its corresponding hydrochloride by
reaction with hydrogen chloride.
105. 3,5-Dibromo-4-hydroxy-N-(trans-3-hydroxy-cyclohexyl)benzylamine and
its hydrochloride whenever prepared by the process of claim 104 or by an obvious
chemical equivalent thereof.
106. A process according to claim 1 in which R1 and R4 are hydrogen atoms,
R2 is dihydroxy-tert.-butyl, Hal is bromine in the 3- and 5-positions, the
hydroxy group is attached in the 2-position and y is two.
107. A process according to claim 1 in which 3,5-dibromo-N-(dihydroxy-tert.-
butyl)-2-hydroxybenzylamine and its hydrochloride are prepared by either:
(a) reacting 3,5-dibromo-2-hydroxybenzyl alcohol or the corresponding bromide or
acetate with dihydroxy-tert.-butylamine; or
(b) reacting 3,5-dibromo-2-hydroxybenzylmethyl ether with dihydroxy-tert.-
butylamine; or
(c) reacting 3,5-dibromosalicylaldehyde with dihydroxy-tert.-butylamine and
formic acid; or
(d) reducing N-(3,5-dibromo-2-hydroxybenzylidene)dihydroxy-tert.-butylamine;
or
(e) reacting dihydroxy-tert.-butylamine, paraformaldehyde and 2,4-dibromo-
phenol; or
(f) brominating N-(dihydroxy-tert.-butyl)-2-hydroxybenzylamine hydrochloride;
or
(g) debenzylating N-benzyl-3,5-dibromo-N-(dihydroxy-tert.-butyl)-2-hydroxy-
benzylamine hydrochloride; or
(h) hydrolysing 6,8-dibromo-3,4-dihydro-3-(dihydroxy-tert.-butyl)-2H-1,3-
benzoxazine-2-one; or
(i) reacting 2-benzoyloxy-3,5-dibromobenzyl alcohol with dihydroxy-tert.-
butylamine; or
(j) reacting 6,8-dibromo-2-methyl-1,3-benzodioxane with dihydroxy-tert.-
butylamine; and where a base obtained may be converted into its corresponding
127

hydrochloride by reaction with hydrogen chloride.
108. 3,5-Dibromo-N-(dihydroxy-tert.butyl)-2 hydroxy-benzylamine and its
hydrochloride whenever prepared by the process of claim 107 or by an obvious
chemical equivalent thereof.
109. A process according to claim 1 in which R1 and R4 are hydrogen atoms,
R2 is trans-4-hydroxycyclohexyl, Hal is bromine in the 3- and 5-positions, the
hydroxy group is attached in the 2-position and y is two.
110. A process according to claim 1 for the preparation of 3,5-dibromo-2-
hydroxy-N-(trans-4-hydroxycyclohexyl)benzylamine and its hydrochloride which
comprises either:
(a) reacting 3,5-dibromo-2-hydroxybenzylbromide with trans-4-aminocyclo-
hexanol; or
(b) debenzylating N-benzyl-3,5-dibromo-2-hydroxy-N-(trans-4-hydroxycyclo-
hexyl)benzylamine; or
(c) hydrolysing 6,8-dibromo-3-(trans-4-hydroxyeyclohexyl)-3,4-dihydro-2H-1,
3-benzoxazin-2-one; or
(d) brominating 2-hydroxy-N-(trans-4-hydroxycyclohexyl)benzylamine hydro-
chloride; or
(e) demethylating 3,5-dibromo-N-(trans-4-hydroxycyclohexyl)-2-methoxy-
benzylamine hydrochloride; or
(f) reacting 3,5-dibromo-2-hydroxybenzylamine with 4-hydroxycyclohexanone
in the presence of a reducing agent; or
(g) reducing 3,5-dibromo-2-hydroxy-N-(trans-4-hydroxycyclohexyl)benzamide
or 2-acetoxy-3,5-dibromo-N-(trans-4-hydroxycyclohexyl)benzamide; or
(h) reacting 6,8-dibromo-2-methyl-1,3-benzodiaxane with trans-4-amino-
cyclohexanol; or
(i) hydrolysing 6,8-dibromo-3,4 dihydro-3-(trans-4-hydroxycyclohexyl)-2H-
1,3-benzoxazine; or
(j) reacting 3,5-dibromo-2-hydroxybenzyl alcohol alone or in the presence of
magnesium oxide or its butyrate or acetate with trans-4-aminocyclohexanol; or
(k) reacting 2-benzoyloxy-3,5-dibromobenzyl alcohol with trans-4-amino-
128

(1) reacting 3,5-dibromo-.alpha.-methoxy-o-cresol with trans-4-amino-cyclohexanol;
and where a base obtained may be converted into its corresponding hydrochloride
by reaction with hydrogen chloride.
111. 3,5-Dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)benzylamine and its
hydrochloride whenever prepared by the process of claim 110 or by an obvious
chemical equivalent thereof.
112. A process according to claim 1 in which R1 and R4 are hydrogen atoms,
R2 is dihydroxy-tert.-butyl, Hal is chlorine in the 3- and 5-positions, the
hydroxy group is attached in the 4-position and y is two.
113. A process according to claim 1 in which 3,5-dichloro-N-(dihydroxy-
tert. butyl)-4-hydroxybenzylamine and its hydrochloride are prepared by
reacting 3,5-dichloro-4-hydroxybenzylbromide with dihydroxy-tert.-butyl-
amine and when the hydrochloride is required reacting the base so obtained
with hydrogen chloride.
114. 3,5-Dichloro N-(dihydroxy-tert.butyl)-4-hydroxybenzylamine and its
hydrochloride whenever prepared by the process of claim 113 or by an obvious
chemical equivalent thereof.
115. A process according to claim 1 in which R1 and R4 are hydrogen atoms,
R2 is tert.-butyl, Hal is bromine in the 3- and 5-positions, the hydroxy
group is attached in the 2-position and y is two.
116. A process according to claim 1 in which N-tert.-butyl-3,5-dibromo-
2-hydroxybenzylamine and its hydrochloride are prepared by reacting together
3,5-dibromosalicylaldehyde, tert.-butylamine and formic acid; and when the
hydrochloride is required reacting the base so obtained with hydrogen chloride.
117. N-tert.-Butyl-3,5-dibromo-2-hydroxybenzylamine and its hydrochloride
whenever prepared by the process of claim 116 or by an obvious chemical
equivalent thereof.
129

Description

This in~ention relates to new benzylam-ines hav:ing interesting
pharamacological properties and to processes for the:ir preparation.
According to one feature of the present invention there are
.
provided compounds of general formula
1 ~ CH -N / 2 (I)
(Hal) OH
~wherein Hal represents a chlorine or bromine atom; Rl represents a hydrogen,
chlorine or bromine atom; R2 represents a morpholinocarbonylmethyl group, a
branched aIkyl group with from 3 to 5 carbon atoms substituted by 1 to 3
hydroxyl groups, the isopropyl, tert.butgl or tert pentyl group or a group
of formula A
(CH2)~,
~<JR
B 3
(wherein R3 represents a hydrogen atom, a hydroxyl group or an alkyl group
containing from 1 to 4 carbon atoms, n represents the integer 0, 1 or 2,
and the radicals A and B either both represent hydrogen atoms or together
represent the group
(R5 - C ~ R5)m
(wherein the groups R5 which may be the same or different represent hydrogen
atoms or alkyl groups containing 1 or 2 carbon atoms and m represents the
integer 1 or 2); R~ represents a straight or branched alkyl group containing
from 1 to 4 carbon atoms, an aIkenyl group containing from 2 to 4 carbon
atoms, a cycloaIkyl group containing 3 or 4 carbon atoms or (if R3 is other
than hydrogen or R2 represents a branched alkyl group with 3 to 5 carbon
atoms substituted by 1 to 3 hydroxyl or R3 is the isopropyl, tert.butyl or
tert pentyl group) a hydrogen atom; and y represents the integer 1 or 2]
. . ,

3Z~3
and acid addition salts thereof.
In general the compounds of general formula I ancl their physio-
logical~y compatible acid addition salts with inorganic or organic acids
possess valuable pharmacological properties, in particular a secretolytic
and antitussive effect as well as a stimulating effect on the production of
the surfactant or antiatelectasis factor of the alveoli.
Preferred compounds of general formula I by virtue of their part-
icularly favourable pharmacological properties are those wherein Hal represents
a chlorine or bromine atom, Rl represents a hydrogen, chlorine or bromine
atom; R2 represents a branched alkyl group containing from 3 to 5 carbon
atoms optionally substituted by from 1 to 3 hydroxyl groups, or a cyclohexyl
or hydroxycyclohexyl group, R4 represents a straight-chain or branched alkyl
group containing 1 to 4 carbon atoms or (if R2 represents a hydroxycyclohexyl
group or a branched alkyl group containing from 3 to 5 carbon atoms optionally
substituted by 1 to 3 hydroxy groups) a hydrogen atom, and y represents the
integer 2; and physiologically compatible acid addition salts thereof.
~specially preferred are the following compounds:
~-ethyl-N-cyclohexyl-3,5-dibromo-2-hydro~y~benzylamine, 3,5-dibromo-~-
hydroxy-N-(trans 3-hydroxy-cyclohexyl)-benzylamine,
3,5-dibromo-N-(dihydroxy-tert.butyl)-2-hydroxy-benzylamine, 3,5~dibromo-
2-hydroxy~N-(trans-4-hydroxy-cyclohexyl)-ben7ylamine,
3,5-dichloro-N-(dihydrox~-tert.butyl)-4-hydroxy-benzylamine, and
physiologically compatible acid addition salts thereof.
According to this invention there is provided a process for the
preparation of new benzylamines and thier pharmaceutically acceptable addition
salts with inorganic and organic acids, wherein the benzylamines conform to
the general formula I: R2
1 ~ CH2-N /
(Hal) OH
-3-

JZ~13
in which Hal represents an atom of chlorine or bromine,
Rl represents an atom of hydrogen, chlorine or bromine,
R2 represents morpholino-carbonylmethyl, a branched alkyl radical
containing 3 to 5 carbon atoms substituted by 1 to 3 hydroxyl groups, the
isopropyl, tert.butyl or tert.pentyl group, or a group of the formula:
A
CH2)n
B R3
in which R3 represents a hydrogen atom, or hydroxy group or an alkyl group
containing 1 to 4 carbon atoms, n represents ~ero, one or two and the two
substitutents A and B either both represent hydrogen atoms or together
represent the group:
(R5 - C R5)m
in which R5 represents a hydrogen atom or an alkyl radical containing one or
two carbon atoms and m represents the integer 1 or 2;
R4 represents a straight or branched aIkyl group containing from 1 to
4 carbon atoms, an alkenyl group containing from 2 to 4 carbon atoms, a cyclo-
alkyl group containing 3 or 4 carbon atoms, or a hydrogen atom (if R3 is
other than hydrogen or R2 represents a branched alkyl group with 3 to 5
carbon atoms substituted by 1 to 3 hydroxyl groups, the isopropyl, tert.butyl
or tert.pentyl group); and y represents the integer 1 or 2; which comprises
either:
~a) reacting a compound of the general formula II
,~ CH2 - R6
1 ~ II
(Hal) OH
in which R , Hal and y have the meanings given to them above and R represents
~ 6
a hydroxyl group, an atom of chlorine, bromine or iodine or an acyloxy,

~g~
sulfonyloxy, alkoxy, aryloxy or aralkoxy radical, with an amine of the general
formula III / R2
H - N \ III
R4
in which R2 and R4 are as previously defined; or
(b) reacting in the presence of formic acid an aldehyde of the general
formula
~ ~ CHO
Rl ~- ~ IV
(Hal)y OH
in which Rl, Hal and y are as previously defined with an amine of the general
formula III as defined above or with a corresponding formamide; or
(c) for preparing those compounds of general formula I in which R4
represents a hydrogen atom, reducing a compound o~ the general formula
Rl ~ l 2 V
(Hal)y OR7
or a compound of th~ general formula Va
~ ~ 2 N Z
R ~ ¦~ Va
(Hal)y ~ 7
wherein in these two formulae Rl, R2, Hal and y are as defined above, Z
represents a cyclohexylidene radical optionally substituted by a hydroxy
group or by an alkyl group containing 1 to 4 carbon atoms or Z is a mor-
pholino-carbonyl-methylidene radical and R7 represents a hydrogen atom or a
radical of a carboxylic acid, or
(d) for preparing a compound of general formula I in which R4 is other
than a hydrogen atom and the substituents R2 and R4 do not represent radicals
substituted by a hydroxy group by alkylating a compound of the general
-4a-

~9Z~3
formula VI H
CH2 ~ N
Rl ~ ~ VI
(Hal) OHin which Rl, Hal and Y are as previously defined and R2 represents a hydrogen
atom or an alkyl radical containing 1 to 4 carbon atoms or one of the groups
represented by R2 as defined above excepting the radicals isopropyl, tert.-
butyl, tert.pentyl and radicals substituted by one or more hydroxy groups
with a compound of the general formula YII
R4 - W VII
in which R4 represents an isopropyl, tert.butyl, tert.pentyl or cyclohexyl
radical or represents one of the values given above for the radical R4
with the exoeption of a hydrogen atom and W represents a halogen atom or
a sulphonic acid radical, or
~e) reacting a phenol of the general formula
,~
~ ~ VIII
(Hal)
in which Rl, Hal and Y are as defined above and in which one of the sub-
stituents Hal is in the 2-position of the compound of general formula VIII,
with formaldehyde or paraformaldehyde and an amine of the general formula
III as defined above, in which R2 and R4 are as defined above; or
(f) halogenating a compound of the general formula
/
CH - N
R1 ~ 2 \ R4 IX
OH
.
in which Rl, R2 and R4 are as defined above; or
~4b-

L3
(g) eliminating one or two protecting radicals :from a compound of the
general formula
/ X
Rl ~ CH2 ~ N X
(Hal) OY
in which Rl, R2, Hal and y are as defined above, X represents a protecting
radical for the amino group or represents one of the values given above for
R~, and Y represents a protecting radical for the hydroxy group or a hydrogen
atom at least one of the radicals X and Y representing a protecting group
for the amino or hydroxy group; or
(h) reducing a compound of the general formula
11 R2
C - N
1 ~ R4 XI
in which Rl and R2 are as defined above with the exception of the morpholino
carbonyl methyl radical and Hal and y are as previously defined, R4 represents
a formyl or acetyl radical or reprèsents one of the values given above for
R4 and R7 represents a hydrogen atom or a carboxylic acid residue, or
(i) for preparing the compounds of formula I in which a hydroxy group is
present in the 2-position and R4 represents a hydrogen atom, hydrolysing a
compound of the general formula
(Hal y ~ 2`N - Y2 XII
in which Rl, R2? Hal and y are as defined above; or
(j) reacting a compound o the general formula
-4c-

` 31q31~Z~3
C~2 0~1
~ ~ ~ XIII
(Hal ~ R8
in which Rl, Hal and y are as previously defined and R8 represents an organic
acyl radical with an amine of the general formula III as defined above; or
(k) for preparing those compounds of formula I in which the hydroxy group
is present in the 2-position, reacting a compound of the general formula
Rl ~ CH - Rg XIV
(Hal)y
in which Rl, Hal and y are as previously defined and Rg represents an alkyl,
aryl or aral~yl radical with an amine of the general formula III as defined
above and subsequently hydrolysing the reaction product obtained; or
(1) for preparing the compounds of general formula I in which R4
represents a hydrogen atom and a hydroxyl group is present in the 2-position,
hydrolysing a compound of the general formula
~ ~ CH2 ~ ~ R~
Rl ~ o 5H2 XV
~Hal)y
in which Rl, R2, Hal and y are as previously defined or
(m) for preparing the compounds of general formula I in which R2
represents a cyclohexyl radical and R4 represents a methyl radical, react ng
a compound of the general formula
~ CH2 ~ OH
1 ~ ~ IIa
(Hal)y OH
in which Rl, Hal and y are as previously defined with an amide of the general
:Eormula
-4d-

312~L3
O = P /N / R2 ~
R4 / XVI
or with an amide of the general formula
O ~ R2
Rlo - C - N XVIa
R~
in which formulae R2 and R4 are as previously defined and Rlo represents
an alkyl, aryl or aralkyl radical, and where one of ~he steps (a) to (m)
as set out above may be followed by conversion of a base of formula I into
a corresponding pharmaceutically acceptable acid addition salt with an in-
organic or organic acid.
Thus the compounds according to the invention may be prepared
according to the following processes, which processes constitute further
features of the invention:
a) Reaction of a compound of formula
.
2 6
~
(HaI) OH (II)
_4e-
..~

31V9,'~1~3
(wherein Rl, Hal and 1 are as hereinbe~ore defined and R6
represents a hydroxyl group, a chlorine, bromine or iodine
atom, or an acyloxy, sulfonyloxy, alkoxy, aryloxy or
aralkoxy group) with a compound of formula
/R2
H - N (III)
\ R4
(wherein R2 and R4 are as he~einbefore defined),
The reaction is conveniently performed in the presence
of a solvent, suitable solvents being acetone, carbon
tetrachloride, chloroform9 ethanol, tetrah~drofuran, benzene,
toluene, dioxane and tetralin, or in the presence of an
excess of the amine of general formula III used. The
reaction may however, if desired also be carried out in the
absence of a solvent.
The reaction i5 preferably carried out at temperatures from
-70 to 200C., depending on the nature of the group R6.
If R6 represents a halogen atom the reaction is preferably
carried out at temperatures from 0 to 150Co ~ e~g. at the
boiling point of the solvent usedO In this case the reaction
is with advantage perfonmed in the presence of a hydrogen
halide binding agent, for example an inorganic base such as
sodium carbonate or sodium h~droxide, or in the presence of
an ion exchanger or a tertiary organic base, e.gO triethylamine
or pyridine. The latter may conveniently at the same time
serve as a solvent.
- 5 -

~ 3
If R6 represents a sulfonyloxy group, for example
the 4-methyl-phenyl-sulfonyloxy group, the reaction is
preferably performed at temperatures from-70 to 50C.
If R6 represents an acyloxy group, for example the
acetoxy or benzoyloxy group, or an alkoxy, aryloxy or
aralkoxy group, the reaction may if desired be carried out
in the presence of an acid catalyst such as ammonium
chloride, preferably at temperatures from 0 to 200C.
If R6 represents a hydroxyl group, the reaction is
advantageously performed in the presence of an acid
catalyst, e.gO hydrobromic acid, ~-toluene-sulfonic acid
or butyric acid, or in the presence of an alkaline catalyst,
e.g. potassium hydroxide or magnesium oxide, preferably
at temperatures from 120 to 180C. The reaction may~ however,
if desired also be performed in the absence of a solventO
b~ Reacion of a compound of formula
; Rl. ~ ~ CHO (IV)
(Hal)~ OH
(wherein Rl, Hal and ~ are as hereinbefore defined) with a
compound of formula R~
H - N ~ (III)
~4

~9 Z ~ ~ 3
(wherein R2 and R4 are as hereinbefore defined) or with
a corresponding formamide in the presence of formic acid.
The reductive amination is preferably carried out at
tem~eratures from 50 to 250C, optionally in the presence of
a solvent and optionally whilst distilling off at the
same time the water which formsO It is of special advantage
however, to use an excess of the amine of formula II and/or
the fonmic acid during the reaction as solventr If R4
in the compound of formula III represents a hydrogen atom,
the reaction mixture obtained is refluxed after the reaction
with a dilute acid, e.g 2N hydrochloric acid.
~e~rc~lly
c) Fo~ preparation of compounds of ~e~e~ formula I
wherein R4 represents a hydrogen atom:
Reduction of a compound of formula
Rl Q \ R
(Hal)~ OR7
~''
or of a compound of formula
.
~ CH ~ N = Z
Rl t~l (Va)
~Hal)~y OR7

(wherein Rl~ R2, Hal and ~ are as herelnbefore deflned,
Z represents a cyclohexylidene group optionally substituted
by a hydroxy group or an alkyl group with 1 to 4 carbon
atoms, a branched alkylidene group with 3 to 5 carbon atoms
or a morpholinocarbonylmethylidene group and
R7 represents a hydrogen atom or an organic acyl group.)
If a compound of formula V or Va wherein R7 represents
a hydrogen atom is used the reduction is conveniently
effected by means of catalytically activated hydrogen
(e.g. hydrogen in the presence of Raney nickel or Raney cobalt),
nascent hydrogen (e.g. activated metallic aluminium and water,
sodium amalgam and ethanol or zinc and hydrochloric acid),
or advantageously a complex metallic hydride (e.g. lithium
aluminium hydride or sodium borohydride) in the presence
of an appropriate solvent, for example methanol, ethanol,
ethanol~water, tetrahydrofuran, dioxane, dioxane/water
pyridine or ether, and at temperatures up to the boiling point
of the solvent used, for example temperatures from -50 to 100C.
If a compound of formula V or Va wherein R7 represents
an organic acyl group is used, the la~ter issplit off during
the reduction with nascent hydrogen or with a complex metallic
hydride.
d) For the preparation of compounds of ~eneraly formula I
as hereinbefore defined with the proviso tha~ R4 is other than

~ ~ Z~ ~ 3
a hydrogen atom and R2 and R4 do not ~epresent radicals
substituted by a hydroxyl group: Alkylation of a cornpound
of formula
1 ~ CH2 ~ N (VI)
(Hal)~; OH
; (wherein Rl, Hal and ~ are as hereinbefore defined and
R2' represents a hydrogen atom, an alkyl group containing
from 1 to 4 carbon atoms or one of the groups represented
by R2 as hereinbefore defined but not a br~nched alkyl
group containing from 3 to 5 carbon atoms or a radical
substituted by a hydroxyl group) with a compound of
formula
4 (VII)
(wherein R4' represents a branched alkyl group containing
~: from 3 to 5 carbon atoms, a cyclohexyl group or one of the
groups represented by R~ but not a hydrogen atom, and W
represents a halogen atom or a sulfonic acid group).
The reaction is advantageously carried out in the
presence of a solvent, for example methanol, dioxane or
dimethylformamide, conveniently at temperatures from ~20
to 150C~ preferably, however, at the boiling point of the
solvent used. A methylation may also be effected using
formaldehyde in the presence of formic acid at elevated
temperatures, for example at th~ boiling point of the
reaction mlxture~
; _ 9 _

~31YI2~ l3
e) Reaction of a phenol of for~ula
1 ~ (VIII)
(Hal)~y OH
(wherein Rl, Hal and ~ are as hereinbefore defined with
the proviso that ~one of) the radical(s) Hal is in
the 2-position) with formaldehyde or paraformaldehyde
and a compound of formula
H - N ~ (III)
R4
(wherein R2 and R4 are as hereinbefore defined).
The reaction is advantageously carried out in thP
presence of a solvent such as water, methanol, ethanol or
dioxane, at temperatures from 0 to 100C, preferably,
however at the boiling point of the solvent used.
Alternatively a compound of formula
Alk - 0 - CH2 - N / 2 (IIIa)
\ R~
(wherein R2 and R4 are as hereinbefore defined and Alk
; represents a lower alkyl group) formed optionaily in situ,
may be used in the place of the fomaldehyde or paraformaldehyde
and amine.
- 10 -

~0 ~ 21 ~ 3
f) Halogenation of a compound of formula
"R2
Rl ~ ~ R4
0~1
(wherein Rl, R2 and R4 are as hereinbefore defined)~
The halogenation is effected by means of a halogenating
agent, e.g~ with chlorine, bromine, iodosobenzene dichloride or
tribromophenolbromine, preferably in the presence of a
solvent, for example in 50-100% acetic acid, in methylene
chloride or in tetrahydrofuran. The reaction is advantageously
effected in the presence of a tertiary organic base, and
conveniently at temperatures from -20 to 50C. 1 or 2
moles of the halogenating agent or a slight excess thereof
are generally used per mole of the compound of formula IX
present as the base or as a salt~ for example as the
hydrochloride, If a hydrohalic acid salt is formed during
the reaction it may be isolated as such or, if desired,
be further purified via the baseD
g) Removal of one or two protecting groups from a compound
of formula
Rl ~ CH N / (~)
~H~ OY

~9Z~L3
~, ~
~wherein Rl, R2~ Hal and ~ are as hereinbefore defined) X
represents a protecting group for an amino group or is as
herei~before defined for R4, and Y represents a pro~ecting
group for a hydroxyl group or, in the case where X represents
a protecting group for an amino group, a hydrogen atom).
If X and/or Y in the compound of formula X represents
an acyl group, for example an acetyl, benzoyl or p-toluene-
sulfonyl group, these groups are preferably split off
hydrolytically in the presence of a solvent, ~gO with
ethanolic hydrochloric acid or with aqueous alcoholic
sodium hydroxide solution, at temperatures up to the
boiling point of the solvent used.
If X and/or Y in the compound of formula X represents
a benzyl group, this group is preferably split off by
hydrogenation, for example using hydrogen ;n the presence
of a catalyst, preferably in the presence of a solvent,
such as ethanol, methanol/hydrochloric acid, water/
hydrochloric acid 9 and at room temperature. During the
reaction any alkenyl group present in the starting material
may be converted into the corresponding alkyl group.
If Y in the compound of fonmula X represents an alkyl,
aryl or aralkyl group, these groups are preferably split
off with hydrobromic acid or hydroiodic acid at elevated
- 12 -

~ 3
temperatures. These protecting groups may also be removed
with acid halides, phosphoryl halides, phosphorus pentahalides,
aluminium halides, with sulfuric acid or with organometallic
compounds.
If Y in the compound of formula X represents an acyl
group, for example an acetyl or benzoyl group, this group
may be split off with a complex metal hydride, e.g. sodium
borohydride in pyridine, or with lithium aluminium hydride
in an inert solvent such as either or tetrahydrofuran,
conveniently at temperatures from 0C to the boiling point
of the solvent used. If X represents a formyl or acetyl
group, this group is simultaneously reduced to a methyl
or ethyl group respectively.
h) Reduction of a compound of formula
O R
Rl ~ ~ N / (XI)
(Hal)~ OR7
_, Y
(wherein Rl, R2, Hal and ~ are as hereinbefore defined with
the proviso that R2 does not represent a morpholinocarbonyl-
methyl group, R4" represents a formyl or acetyl group or
one of the groups represented by R4 as hereinbefore
defined and R7 represents a hydrogen atom or an organic acyl
group),

92113
The reduction is conveniently effected using
catalytically activated hydrogen, or nascent
hydrogen, (for example using an alkali metal
: in an alcohol such as sodium in ethanol) preferably at
temperatures from room temperature up to the boiling point
of the solvent used. It is of special advantage, however,
to perform the reaction with a complex metal hydride, for
example with sodium borohydride in pyridine or with lithium
aluminium hydride in ether or tetrahydrofuran. If R4" in the
compound of formula XI represents a formyl or acetyl
group this group is reduced at the same time to the
corresponding alkyl group. Where R7 in the compound of
formula XI represents an organic acyl group, the reaction
~ ~ is effected with nascent hydrogen or with a complex metal
: 15 hydride, where~y the organic acyl group is simultaneously
removed O
: i) For the preparation of compounds of general formula I
wherein the hydroxyl group is in the 2-position and R4
represents a hydrogen atom:
Hydrolysis of a compound of formula
l ~ ~`N - R2 (XII).
(Hal)~y
- 14 -

~9Z~13
(wherein Rl, R2, Hal and ~ are as hereinbeore defined
The hydrolysis is conveniently performed in the
presence of an acid such as hydrochloric acid or sulfuric
acid or advantageously in the presence of a base such as
sodium hydroxide or potassium hydroxide. The reaction
is preferably carried out in the presence of a solvent,
e.g. ethanol, isopropanol, tert.-butanol, acetone or
dioxane, and at temperatures up to the boiling point of the
solvent used.
j) Reaction of a compound of formula
~ CH2 - OH
';~ 1 ~ (XIII)
(Hal)~ oR8
~ /
(wherein Rl, Hal and ~ are as hereinbefore defined and
R8 represents an organic acyl group)
with an amine of formula
~ 2
H - N \ (III)
R4
,~ .
(wherein R2 and R4 are as hereinbefore defined).
`:
- 15 -
.
~'

~ 0 ~ 2~ 1 3
The reaction is conveniently carried out in the
presenoe of a solvent, for example tetraline, or in an
excess of the amine of formula III used, at temperatures
from 100 to 220C, preferably, however, at temperatures
from 120 to 180C. The reaction may also be carried out
in the absence of a solvent.
The organic acyl group represented by R8 is preferably an
acetyl, butyryl, benzoyl or 4-chlorobenzoyl group.
k) For the preparation of compounds of general formula I
wherein the hydroxyl group is in the 2-position:
Reaction of a compound of formula
Ri ~ H2~1 (XIV)
0' 9
~ ( Hal )~, y
`:
(wherein Rl, Hal and ~ are as hereinbefore defined and
Rg represents an alkyl, aryl or aralkyl group)
with an amine of formula
/ R2
H - N (III)
\ R4
~w~lerein R2 and R4 are as hereinbefore defined) and
the subsequent hydrolysis of the reaction product.
- 16 -

~ Z ~'~3
The reaction is conveniently carried out in the
presence of a solvent such as tetraline or in an excess of
the amine of formula III used, and preferably at temperatures
from 100 to 2000Co, ideally, however, at temperatures from
120 to 180C. The reaction may, however, also be performed
in the absence of a solvent.
The subsequent hydrolysis is preferably carried out
in the presence of an acid such as sulfuric acid or
hydrochloric acid in a polar solvent, e.g~ ~ater, ethanol/
water or dioxane~water and at temperatures up to boiling
point of the solvent used.
The group R9 in the compound of formula XIV used is
preferably a methyl, phenyl or benzyl group.
1) For the preparation of compounds of general formula I
(wherein Rl, R2, Hal and ~ are as hereinbefore defined,
R4 represents a hydrogen atom and the hydroxyl group is in
the 2-position):
Hydrolysis of a compound of formula
(Hal y~3~C 2 Y1 - R2 (XV)
(wherein Rl, R2, Hal and ~ are as hereinbefore defined).
- 17 -

~3Zl~
The hydrolysis rnay if desired be carried out in the
presence of an acid such as hydrochloric acid, s~furic acid
or acetic acid, but is conveniently effected however, without
any acid, but in the presence of a polar solvent, e.g.
water, methanol/water or dioxane/water. The hydrolysis
is preferably effected at temperatures from 0 up to the
bo;ling point of the solvent used.
A m) For the preparation of compounds of general formula I
(wherein Rl, Hal and ~ are as hereinbefore defined, R2
represents a cyclohexyl group and R4 represents a methyl
group);
Reaction of a compound of formula
R ~ CH2 - OH
1 ~ (IIa)
(Hal)~ y OH
(wherein Rl, Hal and ~ are as hereinbefore defined)with
an amide of formula
R2~
O = P N I (XVI)
\ R4 / 3
- 18 -

~9 Z~ ~ 3
or with an amide of formula
0 R~
Rlo - C - N ~ (XVIa)
R~
(wherein R2 and R4 are as hereinbefore de~ined and
Rlo represents an alkyl, aryl or aralkyl group).
The reaction is conveniently carried out in the
presence of a solvent such as tetraline,and at
temperatures from 100 to 250C, preferably, however,
from 120 to 180C. The reaction may, if desired,
be performed in the absence of a solvent.
I The compounds of general formulae II - XVIa used
as starting materials in processes a - m are partly known
from the literature and may be prepared according to
processes known from the literature.
The benzyl halLdes of general formula II 9 for example,
may be prepared from the corresponding toluene derivatives
by reaction with halogen or with N-bromo-succinimide
under ultraviolet irradiation.
The benzyl alcohol derivatives of general formula II
may, for example, be obtained by reaction of the corresponding
benzyl alcohol with the corresponding acid in the presence
of hydrochloric acid, or by reaction of the corresponding
- 19 -

9Z~3
benzyl halide with the corresponding alcohol in the
presence of barium carbonateO A benzyl alcohol of
formula II may be prepared by halogenation of the
corresponding benzyl alcohol.
The aldehydes of general formula IV may be obtained,
for example, by halogenation of the corresponding
benzaldehydes and the imines of general formulae V and Va
may be obtained from the corresponding primary amines
and the corresponding carbonyl compounds. A compound of
ormula VI may be prepared by reduction of a compound of
formula V or Va, for example using sodium borohydride.
The benzylamines of general formula IX and X may for
example, be prepared by reaction of the corresponding
benzyl halides with the corresponding amines optionally
with subsequent acylation.
The benzamides of general formula XI used as
starting materials may for example, be prepared by
reaction of the corresponding acid halides with the
corresponding amines optionally with subsequent acylation~
The compounds of general formula XII used as
starting materials ma~ be obtained for example, by halogenation
of the corresponding benzoxazines.
- 20 -

~ 3
A compound of formula XIII may, for example, be
obtained by reduction of the corresponding benzaldehyde
with hydrogen and Raney nickel as catalyst.
A compound of formula XIV may be prepared, for
example by halogenation of the corresponding compound of
; fo~lula XIV wherein 1 is zero.
A compound of formula XV may for example be
obtained by condensation of the corresponding phenol
and an amine of formula III with an excess of formaldehyde.
An aSid amide of formula XVI or XVIa may be obtained
by reacting the corresponding acid halide with a
corresponding amine in the presence of pyridine,
The compounds of general formula I thus obtained may
if desired by converted into their acid addition salts,
preferably their physiologically compatible acid addition
salts, by means of inorganic or organic acids. Hydrochloric
acid, phosphoric acid, hydrobromic acid, sulfuric acid,
lactic acid, tartaric acid or maleic acid have proved
to be suitable for this purpose.
As stated above, the novel compounds of general
formula I in general possess valuable pharmacological
properties. Besides a stimulating efect on the production
of the surfactant or the antiatelectasis factor they particularly
show a secretolytic and antitussive activity.
- 21 -

3L~9Z1~3
The compounds
A = N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine
hydrochloride,
B = N-ethyl-N~cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine
hydrochloride 9
C = 3 9 5-dibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine
hydrochloride,
D = 3-bromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzylamine
hydrochlorideg
E = 3-bromo-5-chloro-N-cyclohexyl-4-hydroxy-N-methyl-benzylamine
hydrochloride,
F = 3,5-dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-
benzylamine hydrochloride,
G = 3,5~dibromo-N~dihydroxy-tert.-butyl)-2-hydroxy-
benzylamine hydrochloride,
H = 3,5-dichloro-N~(dihydroxy~tert.~butyl)-4-hydroxy-benzyl-
amine hydrochloride and
I = 3,5-dibromo-2-hydroxy-N-tert.~pentyl-benzylamine hydro-
chloride,
for example, have been invest;gated with regard to their
biological activities, and the results of these tests are
given hereinbelow.
- 22 -

~09~3
t i ~3 ~ V~
50 mg/kg of each of the substances to be investigated
were administered orally to several groups of 10 awake
white ratsO Coughing spasms were induced in these rats
by means of a spray containing 7.5% aqueous citric acid.
30 minutes after the application of the substance under
investigation the average percentage alteration in the
number of cough attacks was determined and compared with
the result from a control group of lO animals (see
Engelhorn and P~schmann In Arzneimittelforschung 13,
~74-480 (1963)).
:
Substance Average percentage alteration in the
number of cough attacks 30 minutes
` ~ g/kg
A -38
B -34
~ ,
2~ E~D5_ _~nt ~fe" ~
The expectoration tests were carried out on 8-10 narcotized
rabbits or 5 narcotized guinea pigs after oral application of
8 mg/kg of each of the substances to be investigated,
- 23 ~

~0 ~Z:1 ~ 3
The increase of secretion within 2 hours of application
of the substance was calculated (see Perry and Boyd in
Pharmakol. exp. Therap. 73, 65 (1941)).
The circulatory effect of the substances on cats was
determined under chloralose-urethane narcosis after
intravenous application of the compounds (size of test
group: 3 animals).
Tests in rabbits:
~, ~
Substance Increase of Circulatory effect
~c~tivn
A + 81 % 4 mg/kg:no change
B 8 mg/kg:slight fall of
blood-pressure
for a short time
B ~ ~7 ~ 8 mg/kg no change
Tests in guinea pigs:
,, . .. _ _ _
SubstanceIncrease o~ secretion
D + 66 %
E + 65 %
F + 70 %
G + 88 %
H ~ 88 %
l ______
- 24 ~

~Z~13
3) ~
The orientational acute toxicity was determined in groups of
5 white mice after oral applicati~n to each animal of a dose
ranging in size from 500 mg/kg to 5000 mg/kg (time of
observation: 72 hours).
Substance acute toxicity
A ~1000 mg/kg, p.o. (O of 5 animals dead)
B ~1000 mg/kg, p.o. (O of 5 animals dead)
C ~1000 mg/kg, p.o. (O of 5 animals dead)
D >500 mg/kg, p.o. (O of 5 animals dead)
E ~500 mg/kg, p.o. (O of 5 animals dead)
.~ F >5000 mg/kg, p.o. (O of 5 animals dead)
G ?5000 mg/kg, p.o. (O of 5 animals dead)
H
I ~5000 mg/kg, pOo. (O of 5 animals dead)
~ .
According to a further feature of the present invention
there are provided pharmaceutical compositions comprising
as active ingredient a compound of formula I as hereinbefore
defined or a physiologically compatible acid addition salt
thereof in association with a pharmaceutical carrier or
excipient.
- 25 -

~V ~ 2 ~ ~ 3
The compositions may, for example, be presented in a
form suitable for oral, rectal or parenteral administration.
Thus for example compositions for oral administration may be
solid or liquid and may take the form of juices, drops,
tablets or coated tablets, such compositions comprising
carriers or excipients conventionally used in the
pharmaceutical art.
For parenteral administration7 the carrier may be a sterile,
parenterally acceptable liquid such as sterile water, or a
parenterally acceptable oil, e.gO arachis oil, contained in
ampoules. Compositions for rectal administration may take
the form of suppositories, the carrier comprising a
suppository base.
Advantageously, the compositions may be formulated as
dosage units, each unit being adapted to supply a fixed
dose of active ingredientO Each dosage unit preferably
; ~ contains from 1 to 20 mg preferably however from 2 to 10 mg
of active ingredient.
The following Examples sense to illustrate the
preparation of compounds according to the invention and
also of pharmaceutical compositions containing the same.
- 26 -

'~)9Z1~3
Example 1
N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydro-
chloride
17 g of 3,5-dibromo-2-hydroxy-benzyl bromide and 12.7 g of N-
ethyl-cyclohexylamine were heated for 3 hours whilst refluxing
in 150 ml of ethanol. Subsequently the reaction mixture was
evaporated to dryness. The residue was shaken with 150 ml of
chloroform and 200 ml of water. The chloroform layer was sepa-
rated, filtered and evaporated to dryness. The residue was dis-
solved in ethanol and acidified with ethanolic hydrochloric acid.
In doing so the N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-
benzylamine hydrochloride crystallized out.
M.p.: 193 - 19~C ~decomposition).
Example 2
:
N-CycloheXyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine hydro-
chloride
--
21 g of 3,5-dibromo-salicylaldehyde, 56.5 g of N-methyl-cyclo-
hexylamine and 23 g of formic acid were heated for 6 hours at
70-80C. After cooling the reaction product was shaken with
chloroform and dilute ammonia. The chloroform layer was sepa-
rated and evaporated to dryness. The residue was purified by
means of chromatography over 800 g of silica gel with ethyl ace-
tate/chloroform ~1:1). The first 0.51 of eluent were discarded
and the remaining 0.51 were collected and evaporated to dryness.
The residue was dissolved in 50 ml of ethanol and acidified with
ethanolic hydrochloric acid. The N-cyclohexyl-3,5-dibromo-2-
hydroxy-N-methyl-benzylamine hydrochloride melting point: 189-
191C ~decomposition)) crystallized out.
-27-

Z113
Example 3
3,5-Dibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamino
hydrochloride
19 g of N-~3,5-dibromo-4-hydroxy-benzylidene)-cis-3-amino-cyclo-
hexanol (m.p.: 231-233~C, decomposition) were suspended in 0.51
of ethanol and mixed with 2 g of sodium borohydride. The mix-
ture was stirred for 1.5 hours at room temperature. Subsequently
200 ml of 2N sodium hydroxide solution were added to the mix-
ture and the ethanol was distilled off in vacuo. The remaining
solution was mixed with ammonium chloride. In doing so a cri-
stalline precipitate was obtained. The latter was sucked off,
washed with water and dissolved in 100 ml of 2N hydrochloric
acid whilst heating. After a short time the 3,5-dibromo-4-hyd-
roxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine hydrochloride
crystallized out and was then sucked off and washed with ace-
tone.
M.p.: 216-2183C ~decomp.)
Example 4
N-Cyclohexyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine hydro-
chloride
3.6 g o~ N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine, 3.6 g
of sodium hydrogen carbonate and 3.6 g of methyl iodide were re-
fluxed for 16 hours in 25 ml of tetrahydrofuran and 50 ml of
methanol. Subsequently the reaction mixture was filtered and
evaporated to dryness. The residue was shaken with chloroform
and dilute ammonia and the chloroform layer was evaporated to
dryness. The remaining residue was boiled with ethyl acetate
and after cooling the undissolved material was filtered off.
The filtrate was acidified with ethanolic hydrochloric acid,
thus precipitating the hydrochloride.
M.p.: 189-191C (decomposition)
-28-

~21~L3
Example 5
N-Cyclohexyl-3,5-dibromo-4-hydroxy-N-methy-l-benzylamine hydro-
chloride
7.2 g of N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine were
dissolved in 20 ml of formic acid and mixed with 2 ml of 40%
formaldehyde. The solution was heated for 3 hours over the boil-
ing water bath, subsequently diluted with water and made alkaline
with concentrated ammonia. The precipitated base was sucked off,
; washed with water and the hydrochloride recrystallized from
ethanol by addition of a little.
M.p.: 168-170C (decomposition~.
Example 6
N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine~hydro-
.. ... . ~
chloride
51 g of N-ethyl-cyclohexylamine and 12 g of paraformaldehyde
were dissolved whilst warming in 200 ml of ethanol. After cool-
ing 100 g of 2~4-dibromo-phenol were added. The reaction mix-
ture was left to stand for 1 hour at room temperature and was
then refluxed for 7 hours. The solution was evaporated to dry-
ness. The residue was dissolved in ether and shaken with 2N ammonia
solution and subsequently with water. The ether layer was mixed
with 2N hydrochloric acid whilst stirring vigorously un~il the mix-
ture showed a strong acid reaction. After a short time the hydro-
chloride crystallized. The latter was sucked off and washed in
turn with water and acetone. After recrystallization from me-
thanol/ether it had a melting point of 193-194C (decomposition).
-29-

~19~
Exam~e 7
N-~4-tert.-Butyl-cyclohexyl)-3~5-dibromo-4-hydroxy-benzylamine
M.p. of the hydrochloride: 229 - 231C (decomposition)
Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and 4-tert.-
butyl-cyclohexylamine analogously to Example 1.
Example 8
3,5-Dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzylamine
M.p. of the hydrochloride: 212 - 218C (decomposition)
Prepared from 3J5-dibromo-2-hydroxy-benzyl bromide and trans-4-
amino-cyclohexanol analogously to Example 1.
Example 9
3,5-Dibromo-2-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine
M.p. of the hydrochloride: 128 - 136C (decomposition)
Prepared from 3l5-dibromo-2-hydroxy-benzyl bromide and cis-3-
amino-cyclohexanol analogously to Example 1.
Example 10
3 9 5-Dibromo-?-hydroxy-N-(trans-3-hydroxy-cyclohexyl~-beniylamine
M.p.: 203 - 204.5C (decomposition)
Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and trans-3-
amino-cyclohexanol analogously to Example 1.
-30-

Example 11
3,5-Dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-N-methyl-
benzylamine
M.p. of the hydrochloride: 120C (decomposition)
Prepared analogously to Example 2 from 3,5-dibromo-salicylalde-
hyde, trans-4-methyl-amino-cyclohexanol and formic acid.
Example 12
3?5-Dibromo-2-hydroxy-N-~cis-3-hydroxy-cyclohexyl)-N-methyl-
benzylamine
M.p. of the hydrochloride: 80 - 83C ~decomposition)
Prepared analogously to Example 1 from 3,5-dibromo-2-hydroxy-
benzyl bromide and cis-3-methyl-amino-cyclohexanol.
Example 13
N-Ethyl-3,5-dibromo-2-hydroxy-N-~trans-4-hydroxy-cyclohexyl)-
benzylamine
M.p. of the hydrochloride as ethanolate: 135 - 137C ~decompo-
sition).
Prepared analogously to Example 1 from 3,5-dibromo-2-hydroxy-
benzyl bromide and trans-4-ethylamino-cyclohexanol.
Example 14
N-Cyclohexyl-3,5-dibromo-2-hydroxy-N-propyl-benzylamine
M.p. of the hydrochloride: 178 - 180C
Prepared analogously to Example 1 from 3,5-dibromo-2-hydroxy-
benzyl bromide and N-propyl-cyclohexylamine.
-31-

~O~ 3
Example 15
N-All_l-N-cyclohexyl-3,5-dibromo-2-hydroxy-beJizylamine
M.p. of the hydrochloride: 176 - 178C (decomposition)
Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-allyl-
cyclohexylamine analogously to Example 1.
Example 16
N-Cyclohexyl-3 _-dibromo-?-hydroxy-N-isopropyl-benzylamine
M.p.: 108 - 110C
Prepared analogously to Example 1 from 3,5-dibromo-2-hydroxy-
benzyl bromide and N-isopropyl-cyclohexylamine.
Example 17
N-Cyclo exyl-N-cyclopropyI-3,5-dibromo-2-hydroxy-benzylamine
M.p. of the hydrochloride: 204 - 208C (decomposition)
Prepared analogously to Example 1 from 3,5-dibromo-2-hydroxy-
benzyl bromide and N-cyclopropyl-cyclohexylamine.
Example 18
N-~4-tert.-Butyl-cycloheXyl)-3,5-dibromo-2-hydroxy-N-methyl-
benzylamine
M.p. of the hydrochloride: 209 - 211C (decomposition)
Prepared analogously to Example 1 from 3,5-dibromo-2-hydroxy-
benzyl bromide and N-methyl-4-tert.-butyl-cyclohexylamine.
-32-

~lt)S~Z 1~L3
Example L9
N-Ethyl-N-~trans-4~tert.-butyl-cyclohexyl)-3J5-dibromo-2-hydroxy-
benzylamine
M.p. of the hydrochloride: 175 - 176C (decomposition)
Prepared analogously to Example 1 from 3,5-dibromo-2-hydroxy-
benzyl bromide and N-ethyl-4-tert.-butyl-cyclohexylamine. The
mixture of isomers was separated by means of column chromato-
graphy.
Example 20
. .
; 10 N-Ethyl-N-~c_s-4-tert -butyl-cyclohexyl)-3,5-dibromo-2-hydroxy-
benzylamine
M.p. of the hydrochloride: 168 - 169C ~decomposition)
Prepared analogously to Example 19 from 3,5-dibromo-2-hydroxy-
benzyl bromide and N-ethyl-4-tert.-butyl-cyclohexylamine.
Example 21
N-~trans-4-tert~-~utyl-cyclohexyl)-3~5-dibromo-2-hydroxy-N-pr
pyl -benzyIamine
M.p. of the hydrochloride: 173 - 174C (decomposition)
Prepared analogously to Example 19 from 3,5-dibromo-2-hydroxy-
benzyl bromide and N-propyl-4-tert.-butyl-cyclohexylamine.
Example 22
N-~cis-4-tert.-~utyl-cycIohexyl)-3,5_dibromo-2-hydroxy-N-propyl-
benzylamine
M.p. of the hydrochloride: 148 - 150C Idecomposition).
Prepared analogously to Example 19 from 3,5-dibromo-2-hydroxy-
benzyl bromide and N-propyl-4-tert.-butyl-cyclohexylamine.

~IL09~ 3
Example 23
N-~4-tert.~ cyclohexyl~-3,5-dibromo-2-hydroxy-N-iso
benzylamine
M.p. of the hydrochloride: 152 ~ 154C (decomposition)
Prepared analogously to Example 1 from 3,5-dibromo-2-hydroxy-
benzyl bromide and N-isopropyl-4-tert.-butyl-cyclohexylamine.
Example 24
N-Cyclopentyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine
M.p.: 61 - 63C
Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-methyl-
cyclopentylamine analogously to Example 1.
Ex mple 25
N-Ethyl-N-cyclopentyl-3,5-dibromo-2-hyclroxy-benzylamine
M.p. of the hydrochloride: 124 - 128C ~decomposition)
Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-ethyl-
cyclopentylamine analogously to Example 1.
Example 26
N-Cyclopentyl-3,5-dibromo-2-hydroxy-N-propyl-benzylamine
M.p. of the hydrochloride: 113 - 120C
Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-propyl-
cyclopentylamine analogously to Example 1.
-34-

1(~9Z113
Example 2?
N-Cyclopentyl-3,5-dibromo-2-hydroxy N-isopropyl-ben~yl_mine
M.p. of the hydrochloride: 154 - 157C (decomposition)
Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-isopro-
pyl-cyclopentylamine analogously to Example 1.
Example 28
N-Cycloheptyl-3,5-dibromo-2-hydroxy-N_met y_-benzylamine
M.p. of the hydrochloride: 196 - 198C ~decomposition)
Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-methyl-
cycloheptylamine analogously to Example 1.
Example 29
N-Ethyl-N-cycloheptyl-3,5-dibromo-2-hydroxy-benzylami _
M.p. of the hydrochloride: 180 - 183C (decomposition)
Prepared from 3,5-dibromo-2-hydroxy~benzyl bromide and N-ethyl-
cycloheptylamine analogously to Example 1.
Example 30
N-Cycloheptyl-3,5-dibromo-2-hydroxy-N-propyl-benzylamine
M.p. of the hydrochloride: 134 - 139C
Prepared analogously to Example l from 3,5-dibromo-2-hydroxy-
benzyl bromide and N-propyl-cycloheptylamine.

~()92~'13
Example 31
N-Cycloheptyl-3~5-dibr-mo-2-hydroxy-N-isopropyl-benzylamine
M.p. of the hydrochloride: 156 - 159C (decomposition)
Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-isopro-
pyl-cycloheptylamine analogously ~o Example 1.
Example 32
3,5-Dibromo-4-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzylamine
.p. of the hydro~hloride: 220 - 225C Idecomposition)
Prepared analogously to Example 1 from 3,5-dibromo-4-hydroxy-
benzyl bromide and trans-4-amino-cyclohexanol.
Example 33
3,5-Dibromo-4-hydroxy-N-~trans-3-hydroxy-cyclohexyl~-benzylamine
M.p. of the hydrochloride: 215 - 215.5C ~decomposition)
Prepared analogously to Example 1 from 3,5-dibromo-4-hydroxy-
benzyl bromide and trans-3-amino-cyclohexanol.
Example 34
N-Cyclohexyl-3,5-dibromo-4-hydroxy-N-methyl-benzylamine
M.p. of the hydrochloride: 168 - 170C ~decomposition)
Prepared analogously to Example 1 from 3,5-dibromo-4-hydroxy-
benzyl bromide and N-methyl-cyclohexylamine.
-36-

3%1~L3
Example 35
3,5-Dibromo-4-hyd xy-N-(-trans-4-hydroxy-cyclohexyl)-N-methyl-
benzylamine
M.p. of the hydrochloride: 160 - 162C (decomposition)
Prepared analogously to Example 1 from 3,S-dibromo-4-hydroxy-
benzyl bromide and trans-4-methylamino-cyclohexanol.
Exam~le 36
3,5-Dibr _ ~ droxy-cyclohexyl)-N-methyl-
benzylamine
.
M.p.: 133 - 136C
Prepared analogously to Example 1 from 3,5-dibromo-4-hydroxy-
benzyl bromide and cis-3-methylamino-cyclohexanol.
Example 37
N-Ethyl-3,5-dibromo-4-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-
benzylamine
M.p. of the hydrochloride: 176 - 178C (decomposition)
Prepared analogously to Example 1 from 3,5-dibromo-4-hydroxy-
benzyl bromide and trans-4-ethylamino-cyclohexanol.
Exampla 38
N-Ethyl-3,5-dibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-
benzylamine
M.p.: 134 - 136C ~decomposition)
; Prepared analogously to Example 1 from 3~5-dibromo-4-hydroxy-
benzyl bromide and cis-3-ethylamino-cyclohexanol.
-37-

2~13
Example 39
N-Cyclohe~y~-3~5-dibromo-4--hydroxy-N-propyl-benzylamine
M.p.: 115 - 116C ~decomposition)
Prepared from 3,5-dibromo 4-hydroxy-benzyl bromide and N-propyl-
cyclohexylamine analogously to Example 1.
Example 40
N-Allyl-N-cyclohexyI-3,5-dibromo-4-hydroxy-benzylamine
M.p. of the hydrochloride: 184 - 186C (decomposition)
Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-allyl-
cyclohexylamine analogously to Example 1.
Example 41
N-Cyclohexyl-N-cyclopropyl-3,5-dibromo-4-hydroxy-benzylamine
M.p. of the hydrochloride: 197 - 198C (decomposition)
Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-cyclo-
propyl-cyclohexylamine analogously to Example 1.
Example 42
N-(4-tert.-Butyl-cyclohexyl)-3,5-dibromo-4-hydroxy-N-methyl-
benzylamine
M.p. of the hydrochloride: 158 - 159C ~decomposition)
Prepared analogously to Example 1 from 3,5-dibromo-4-hydroxy-
benzyl bromide and N-methyl-4-tert.-butyl-cyclohexylamine.
-38-

~2:113
Example 43
N-Ethyl-N-~4-tert.-but,y~-cyclohexyl)-3,5-dibromo-4-hydroxy-
benzylamine
M.p. of the hydrochloride: 170 - 170.5C ~decomposition)
Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-ethyl-
4-tert.-butyl-cyclohexylamine analogously to Example 1.
Example 44
_~4-tert.-Butyl-cyclohexyl)-3,5-dibromo-4-hydroxy-N-~ropyl-
benzylamine
_ __
M.p. of the hydrochloride: 159 - 160C (decomposition)
Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-propyl-
~-tert~-butyl-cyclohexylamine analogously to Example 1.
Example 45
N-Cyclopentyl-3,5-dibromo-4-hydroxy-N-methyl-benzylamine
M.p. of the hydrochloride: 185 - 188C ~decomposition)
Prepared analogously to Example 1 from 3,5-dibromo-4-hydroxy-
benzyl bromide and N-methyl-cyclopentylamine
Example 46
N-Ethyl-N-cyclopentyl-3,5-dibromo-4-hydroxy-benzylamine
M.p. of the hydrochloride: 164 - 165C ~decomposition)
Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-ethyl-
cyclopentylamine analogously to Example 1.
-39-

~6~92~13
Example 47
N-Cyclopentyl-3,5-dibromo-4-hydroXy-N-propyl-benzylamine
M.p. of the hydrochloride: 156 - 158C (decomposition)
Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-propyl-
cyclopentylamine analogously ~o Example 1.
Example 48
N-Cyclopentyl-3,5-dibromo-4-hydroxy-N-isopropyl-benzylamine
_ . . .
M.p. of the hydrochloride: 151 - 152C (decomposition)
Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-isopro-
pyl-cyclopentylamine analogously to Example 1.
Example 49
N-Cyc~l~oheptyl-3,5-dibromo-4-hydroxy-N-methyl-benzylamine
. . _ ~
M.p. of the hydrochloride: 175 - 179C (decomposition)
Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-methyl-
cycloheptylamine analogously to Example 1.
Example 50
N-Ethyl-N-cycloheptyl-3,5-dibromo-4-hydroxy-benzylamine
. . . _ _ _ . . _ _ _
M.p. of the hydrochloride: 176 - 177C ~decomposition)
Prepared analogously to Example 1 from 3,5-dibromo-4-hydroxy-
benzyl bromide and N-ethyl-cycloheptylamine.
-40-

Z1~3
Example 51
N-Cycloheptyl-3,5-dibromo-4-hydroxy-N-propyl-benzylamine
M.p. of the hydrochloride: 135 - 136C
Prepared analogously to Example 1 from 3,5-dibromo-4-hydroxy-
benzyl bromide and N-propyl-cycloheptylamine.
Example 52
N-(2-Bicyclo[2,2,1]heptyl)-3,5-dibromo-4-hydroxy-N-méthyl-ben-
zylamine
M.p. of the hydrochloride: 181 - 182C (decomposition)
Prepared analogously to Example 1 from 3,5-dibromo-4-hydroxy-
benzyl bromide and 2-methyl-amine-bicyclo[2,2,1]-heptane.
Example 53
_ _
N-Cyclohexyl-3,5-dichloro-2-hydroxy-N-methyl-benzylamine
M.p. of the hydrochloride: 174 - 178C
Prepared analogously to Example 1 from 3,5-dichloro-2-hydroxy-
benzyl bromide and N-methyl-cyclohexylamine.
Example 54
N-Ethyl-N-cyclohexyl-3,5-dichloro-2-hydroxy-benzylamine
_
M.p. of the hydrochloride: 185 - 188C ~decomposition)
Prepared analogously to Example 1 from 3,5-dichloro-2-hydroxy-
benzyl bromide and N-ethyl-cyclohexylamine.
-41-

~09Z~3
Example 55
N-Ethyl-3,5-dichloro-2-hydroxy-N-(tran-s-4-hydroxy-cyclohéxyl)-
benzylamine
M.p. of the hydrochloride: 147 - 152C
Prepared analogously to Example 1 from 3,5-dichloro-2-hydroxy-
benzyl bromide and trans-4-ethylamino cyclohexanol.
Example 56
N-Cyclohexyl-3,5-dichloro-2-hydroxy-N-propyl-benzylamine
M.p. of the hydrochloride: 168 - 170C
Prepared analogously to Example 1 from 3,5-dichloro-2-hydroxy-
banzyl bromide and N-propyl-cyclohexylamine.
Example 57
N-Cyclohexyl-3,5-dichloro-2-hydroxy-N-isopropyl-benzylamine
M.p.: 86 - 89C
Prepared analogously to Example 1 from 3,5-dichloro-2-hydroxy-
benzyl bromide and N-isopropyl-cyclohexylamine.
Example 58
N-Ethyl-N-cyclohexyl-3,5-dichloro-4-hydroxy-beniylamine
M.p. of the hydrochloride: 190 - 191C (decomposition)
Prepared from 3,5-dichloro-4-hydroxy-benzyl bromide and N-ethyl-
cyclohexylamine analogously to Example 1.
-42-

~Z~L~3
Example 59
N-Ethyl-3-bromo-5-chloro-~-cyclohexyl-2-hydroxy-benzylamine
M.p, of the hydrochloride: 194 - 197C (decomposition)
Prepared from 3-bromo-5-chloro-2-hydroxy-benzyl bromide and N-
ethyl-cyclohexylamine analogously to Example 1.
Example 60
N-E~hyl-S-bromo-3-chloro-N-cyclohexyl-2~hydroxy-benzylamine
. . = . . . ~
M.p, of the hydrochloride: 188 - 191C (decomposition)
Prepared from 5-bromo-3-chloro-2-hydroxy-benzyl bromide and N-
ethyl-cyclohexylamine analogously to Example 1.
Example 61
~: 5-Bromo-N-cyclohexyl-Z-hydroxy-N-methyl-benzylamine
M.p. of the hydrochloride: 194 - 197C
Prepared from 5-bromo-salicylaldehyde, N-methyl-cyclohexylamine
and formic acid analogously to Example 2.
::-
Example 62
N-Ethyl-5-bromo-N-cyclohexyl-2-hydroxy-benzylamine
M.p. of the hydrochloride: 175 - 178~C
Prepared from 5-bromo-salicylaldehyde, N-ethyl-cyclohexylamine
and formic acid analogously to Example 2.
-43-

Zl~L3
Example 63
N-Ethyl-5-bromo-2-hydroxy-N-(~rans-4-hydroxy-cyclohexyl~-ben-
. ~
zylamine
M.p. of the hydrochloride: 190 - 193C ~decomposition~
Prepared from 5-bromo-salicylaldehyde, trans-4-ethylamino-
cyclohexanol and formic acid analogously to Example 2.
Example 64
5-Bromo-N-cyclohexyl-2-hydroxy-N-propyl-benzylamine
M.p. of the hydrochloride: 166 - 169C (decomposition)
Prepared from 5-bromo-salicylaldehyde, N-propyl-cyclohexyl-
amine and formic acid analogously to Example 2.
Example 65
5-Bromo-N-cyclohexyl-2-hydroxy-N-isopropyl-benzylamine
M.p.: 90 - 93C
Prepared from 5-bromo-salicylaldehyde, N-isopropyl-cyclohexyl-
amine and formic acid analogously to E~ample 2.
Example 66
5 Chloro-N-cyclohe~yl-2-hydro-xy-N-methyl-benzylamine
M.p. of the hydrochloride: 194 - 19~C
Prepared from 5-chloro-salicylaldehyde, N-methyl-cyclohexyl-
amine and formic acid analogously to Example 2.
-44-

~lV9Z1~3
Example 67
N-Ethyl-S-chloro-N-cyclohexyl 2-hydroxy-benzylamine
M.p. of the hydrochloride: 169 - 171C
Prepared from 5-chloro-salicylaldehyde, N-ethyl-cyclohexyl-
amine and formic acid analogously to Example 2.
Example 68
5~-Chloro-N-cyclohexyl-2-hydroxy-N-propyl-benzylamine
M.p, of the hydrochloride: 140 - 142C
Prepared from 5-chloro-salicylaldehyde, N-propyl-cyclohexyl-
amine and ~ormic acid analogously to Example 2.
Example 69
S-Chloro-N-cyclohexyl-2-hydroxy-N-isopropyl-benzylamine
M.p.: 85 - 88C
Prepared from 5-chloro-salicylaldehyde, N-isopropyl-cyclohexyl-
amine and formic acid analogously to Example 2.
Exa~ple 70
3-Bromo-N-cyclohexyl-4-hydroxy-N-methyl-benzylamine
M.p. of the hydrochloride: 165 - 169C (decomposition)
Prepared analogously to Example 1 from 3-bromo-4-hydroxy-benzyl
bromide and N-methyl-cyclohexylamine.
-45-

1~)92~3
Example 71
N-(4-tert.-Butyl-cyclohexyl)-3~5-dibromo-2-hydroxy-benzylamin_
M.p.: 188 - 191C
Prepared analogously to Example 1 from 3,5-dibromo-2-hydroxy-
benzyl bromide and 4-t0rt.-bu~yl-cyclohexylamine.
Example 72
N-Ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine
. . _
M.p. of the hydrochloride: 180 - 181C (decomposition)
Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-ethyl-
cyclohexylamine analogously to Example 1.
Example 73
N-Ethyl-2-bromo-N-cyclohexyl-5-hydroxy-benzylamine
-
54 g of 2-bromo-5-hydroxy-benzyl bromide in 800 ml of carbon
tetrachloride were mixed with 51 g of N-ethyl-cyclohexylamine
and refluxed for 1 hour. Subsequently the reaction mixture was
shaken twice with water and the organic phase was dried
over sodium sulfate and evaporated. The residue was purified
by means of column chromatography over silica gel with ethyl
acetate as eluent. The crude base was dissolved in ethyl ace-
tate and acidified with absolute ethanolic hydrochloric acid.
In doing so the N-ethyl-2-bromo-N-cyclohexyl-5-hydroxy-benzyl-
amine hydrochloride crystallized out.
M.p.: 183 - 188C (decomposition)
-46-

~0 9 Z~ ~ 3
Example 74
~ ~droxAy-cyClhex~!l2~~
3~5 g o~ N-(2,4-dibromo-5-hydroxy-benzylidene)-trans-4-amino-
cyclohexanol in 70 ml of ethanol were added~ dropwise ~o a
solution of 0,74 g of sodium borohydride in 5 ml of water whilst
stirring. After stirring for 1 hour 10 ml of 2N sodium hydroxide
solution and 30 ml of water were added to the solution which
was then evaporated to half its volume. Subsequently the solu-
tion was mixed with saturated ammonium chloride solution thus
precipitating the 2,4-dibromo-5-hydroxy-N-(trans-4-hydroxy-cyclo-
hexyl)-benzylamin~. The precipitate was sucked off, suspended
in acetone, warmed and acidified with absolute ethanalic hydro-
ohloric acid~ In ddhg so the base dissol~ed and the hydrochloride
crystallized out immediately.
M,p.: 268 - 270~C (decomposition~
306 g of 3-bromo-N~cyclohexyl-4-hydroxy-N-methyl-benzylamine-
hydrochloride were dissolved in 50 ml of 90 % acetic acid and
mixed with a solution of 0,75 g of chlorine in 15 ml of glaclal
acetic acid whilst cooling with ice-water. After stirring for
a short time the solution was poured into a mixture of ice and
10N sodium hydroxide solution and extracted three times ~rith
methylene chloride. The organic phase was evaporated to dryness.
17he residue was purified by means of column chromatography o~er
silica gel with ethyl acetate as eluent. The 3-bromo-5-chloro-
N-cyclohexyl-4-hydroxy-N-methyl-benzylamine was recrystallized
from ethanol/ether.
M.p.: 136-138C.
- 47
.

~o~
N-E,thy -5-bromo N-cyclohex~ ro-4-h~dr~3~benzYlamine-
2,3 g of N-ethyl-3-chloro-N-cyclohexyl-4-hydroxy-benzylamine
were dissolved in 20 ml of 75% acetic acid and mixed dropwise
whilst stirring with 1,6 g of bromine. The solution was diluted
with water,made alkaline with concentrated ammonia and shaken
twice with chloroform. The organic phase was dried over so-
dium sulfate and evaporated. The residue was dissolved in ab-
solute ethanol and acidified with absolute ethanolic hydro-
chloric acid. On addition o~ ether the N-ethyl-5-bromo-N-cyclo-
hexyl-3-chloro-4-hydroxy-benzylamine hydrochloride crystal-
lized out.
M~p.: 165 - 168C (decomposition)
~.
13 g of N-ethyl-cyclohexylamine and 3 g of para~ormaldehyde were dis-
solved whilst heating' i~ 100 ml of ethanol. ~bQ ~xtur~ was ~hen cooled
mixed with 13 g o~ 2-chloro phenol, le~t to stand for 1,5 hours
at room temperature and finally refluxed for 3 hours. Subse-
~uently the solution was evaporated and the residue purified
with ethyl acetate over a column of silica gel. The crude base
was dissolved in absolute ethanol and acidified with absolute
ethanolic hydrochloric acid. The N-ethyl-3-chloro-N-cyclohexyl-
2-hydroxy-benzylamine-hydrochloride crystallized out on addition of
ethyl acetate.
M.p.: 177 - 17~C ~decomposition3
_ ~8

~O~Z~3
Example 78
3,5-Dichloro-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzyl-
amlne
M.p. of the hydrochloride: 216 - 222C (decomposition)
Prepared by reduction of N-(3,5-dichloro-2-hydroxy-benzylidene~-
trans-4-amino-cyclohexanol with sodium borohydride analogously
to Example 74.
Exam~l _ 9
3,5-Dichloro-4-hydroxy-N-(trans-4-hydroxy-cyclohexyl~-bénzyl-
am
M.p. of the hydrochloride: 222 - 225C (decomposition)
Prepared by reduction of N-~3~5-dichloro-4-hydroxy-benzylidene)-
trans-~-amino-cyclohexanol with sodium borohydride analogously
to Example 74.
Example 80
3-Bromo-5-chloro-2-hydroxy-N-~trans-4-hydroxy-cyclohexyl)-ben-
iylamine
M.p. of the hydrochloride: 214 - 221C ~decomposition)
Prepared analogously to Example 74 by reduction of N-(3-bromo-
5-chloro-2-hydroxy-benzylidene)-trans-4-amino-cyclohexanol with
sodium borohydride.
Example 81
5-Bromo-3-chloro-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-ben-
iylamine
M.p. of the hydrochloride: 193 - 197C (decomposition)
Prepared analogously to Example 74 by reduction of N-~5-bromo-
-49-

~ 3
3-chloro-2-hydroxy~benzylidene)-trans-4-amino-cyclohexanol with
sodium borohydride.
M.p. of the hydrochloride: 220 - 226C (decomposition)
Prepared analogously to Example 74 by reduction of N-(5-bromo-
3-chloro-4-hydroxy-benzylidene)-trans-4-amino-cyclohexanol with
sodium borohydride.
Example 8~
M.p. of the hydrochloride: 222 - 230C (decomposition)
Prepared analogously to Exampie 74 by reduction of N-(5-bromo-
2-hydroxy-benzylidene)-trans-4-amino-cyclohexanol with sodium
borohydride.-_
Example ~4
M.p. o~ the hydrochloride: 220 - 225C (decomposi~ on)
Prepared analogously to Example 73 from 2~bromo-5-hydr~xy-ben-
zy~ bromideand trans-4-amino-cyclohexanol.
- 50

,.`,> ~ 3
Example 85
M.p. of the hydrochloride: 225 - 227C (decomposition)
Prepared by reduction of N (3-bromo-4-hydroxy-benzylidene)-
trans-4-amino-cyclohexanol with sodium borohydride - analogous-
ly to Example 74.
Example 86
M.p. of the hydrochloride: 194 - 196C tdecomposition)
Prepared by reduction of N-(3 bromo-2-hydroxy-benzylidene)-trans-
4-amino-cyclohexanol with sodium bordhydride analogously to
Example 74.
.
~2a~
M.p. of the hydrochloride: 269 - 271C (decomposition)
Prepared by reduction of N-(2,6-dibromo-3-hydroxy-benzylidene)-
trans-4-amino-cyc~ohexanol analogously to Example 74.
Examp_e 88
M.p. of the hydrochloride: 209 - 214C (decompositbn)
Prepared analogously to Example 74 by reductio~ of N-(3,5-di-
chloro-2-hydroxy-benzylidene)-cis-3-amino-cyclohexanol.
- 51

lV~2113
Example 89
3 t 5-,Dichloro-4-hYdroxy-N- (cis-3-hYdrox~-c,~,Tclohexyl L-benz~!lamine
M.p. o~ the hydrochloride: 219 ~ 224C (decomposition)
Prepared by reduction of N-(3,5-dichloro-4-hydroxy-benzylidene)-
cis-3-amino-cyclohexanol analogously to Example 74.
~-Bromo-5-chloro-2 hYdroxy-N-(cis-~-h~droxy~cyclohex ~ -benzyl-
amine
M.p. of the hydrochloride: 197 - 201C (decomposition)
Prepared by reduction of N-~3-bromo-5-chloro-2-hydroxy-benzyli-
dene)~cis-3-amino-cyclohexanol analogously to Example 74.
Exa~
amine
M.p. o~ the hydroc~Dride: 219 - 222C (decomposition)
Prepared analogously to Example 74 by reduction of N-(5-bromo-
3-chloro-2 hydroxy-benzylidene)-cis-3-amino-cyclohexanol.
E~:Qm
amine
M.p. of the hydrochloride: 216 - 218C (decomposition)
Prepared analogously to EKample 74 by reduction of N-(5-bromo-
3-chloro-4-hydroxy-benzylidene)-cis-3-amino-cyclohexanol.
- 52

~0~3Z~3
E~æ~ 2~
~ ~clohexYl)-benz~lamine
M.p. of the hydrochloride: 148 - 151C (decomposition~
Prepared by reduction of N-~5-bromo-2-hydroxy-benzylidene)-cis-
3-amino-cyclohexanol analogously to Example 74.
Example 94
2-Bromo-5~d o3_y-N _ Le~LI9roxy-c~clohexyl)-benzylamine
M.p. of the hydrochloride: 245 - 250C (decomposition~
Prepared by reduction of N-(2-bromo-5-hydroxy-benzylidene)-cis-
3-amino-cyclohexanol analogously to Example 74.
Example 95
2,,4-Dibromo-5-hydrox~-N-(cis-3-hydroxy-c~clohexyl)-benzylamine
M.p. of the hydrochloride: 278 - 280C (decomposition)
Prepared by reduction of N-(2,4-dibromo-5-hydroxy-benzylidene)-
cis-3-amino-cyclohexanol analogously to Example 74.
Example 96
M.p. of the hydrochloride: 214 - 220C (decomposition)
Prepared by bromination of 4-hydroxy-N~(cis-3-hydroxy-cyclohexyl)-
benzylamine analogouæly to Example 76.
- 53

l~)9Z~L3
Example 97
3-Bromo-2-hydr ~ clohexyl ~ lamine
.M.p. of the hydrochloride: 163 - 167C (decomposition)
Prepared analogously to E~ample 74 by reduction of N-(3-bromo-
2-hydroxy-benzylidene)-cis-3-amino-cyclohexanol.
~ .
2L6-l~ibromo-3-h~rdroxy-N-(cis-3-h~,rdroxy-cyclohexYlL-benzYlamine
M.p. of the hydrochloride: 257 - 259C (decomposition)
Prepared analogously to Example 74 by reduction of N-(2,6-di-
bromo-3-hydroxy-benzylidene)-cis-3-amino-cyclohexanol.
~3~
M.p. of the hydrochloride: 132,5 - 137C (decomposition)
Prepared analogously to Example 76 by bromination of N-ethyl-
4-chloro-N-cyclohexyl-5-hydroxy-benzylamine.
N-Ethyl~4-chloro-N-c~clohex~ 3-hydroxY-benzylamire
M.p. of the hydrochloride: 128 - ~32C (decomposition)
Prepared analogously to Example 73 from 4-chloro-3-hydroxy-ben-
zy~ bromide and N-ethyl-cyclohexylamine.
- - 54

~ 3
ExamE_e 101
N-Ethyl-2-chloro-N-cyclohex~ -5-hydroxy-benz~rlamine
M.p. of the hydrochloride: 210 - 211C
Pr~pared analogously to Example 73 from 2-chloro-5-hydroxy-
benzyl bromideand N-ethyl-cyclohexylamine.
N~ yl N-cy~ohexyl-2 ? 4-dichloro-5~hydroxy-benzYlamine
M.p. of the hy~rochloride: 179 - 186C (decomposition)
Prepared analogously to E~ample 75 by chlorination of N-ethyl-
N-cyclohexyl-5-hydroxy-benzylamine.
x ~
xy-benzylamine
M.p~ of the hydrochloride: 185 - 190C (decomposition)
Prepared analogously to Example 77 from 2-bromophenol, !~ para-
formaldehyde and N-ethyl-cyclohexylamine.
M.p. of the hydrochloride: 144 - 146C
Prepared from 3-chloro~he~ol, paraformaldehyde and N-ethyl-
cyclohexylamine analogously to Example 77.
- 55

~ ~ Z ~ ~ 3
Example 105
- ~ ine
M.p. of the hydrochloride: 171 - 173C
Prepared analogously to ~ample 77 from 2-bromohydride para-
formaldehyde and N-e-thyl-cyclohexylamine.
N-E.thvl-4-bromo-N-cyclohexyl-2-hydroxy-benz~lamine
M.p. of the hydrochloride: 175 - 177C
Prepared ~rom 3-bromohydride paraformaldehyde and N-ethyl-
cyclohexylamine analogously to Example 77.
Example 107
N-Ethyl-3-chloro-N-cyclohexyl-4-hydroxy-benzylamine
M.p. of the hydrochloride: 181 - 183C
Prepared analo~ously to Example 75 by chlorination of N-ethyl-
N-cyclohexyl-4-hydroxy-benzylamine.
I~-Et ~ ro-N-cyclohcx~1-4-h~ b~393!LLLaLLD:
M.p. of the hydrochloride: 165 - 166,5C
Prepared analogously to Example 77 from 3-chlorophenol para-
formaldehyde and N-ethyl-cyclohexylamine~
- 56

~0~3Zl~L3
Example 109
N-Ethyl 2=bromo ~ s3sL~JcL__ohexyl-~-hy~droxY-benzy~amine
M.p. of the hydrochloride: 130 - 137C (decomposition)
Prepared analogously to Example 76 by bromination of N-ethyl-
4-chloro-N-cyclohexyl-3-hydroxy-benzylamine.
N-Eth~l-N-cyclohexx1-2,6-dibromo-3-hydro~Y-benzylamine
M.p.: 123 - 126C
Prepared analogously to Example 76 by bromination of N-ethyl-
N-cyclohexyl-3-hydroxy benzylamine.
d
M.p. o~ the hydrochloride: 127 - 132C (decomposition)
Prepared analogously to E.xample 75 by chlorination of N-e-thyl-
N-cyclohexyl-3-hydroxy-benzylamine.
Example 112
~ .
M.p. of the hydr~chloride: 196 - 20iC
Prepared analogously to Example 73 from 3,5-dibromo-2-hydroxy-
benzy~ brom We and sarcosine morpholide.

~ 9 Z~ ~ 3
Example 11~
æ~ ,
M.p. of the hydrochloride: 214 - 218C
Prepared analogously to Ekample 73 from 3,5-dibromo-4-hydroxy-
benzyl bromide and sarcosine morpholide.
Exam~le 114
4-Chloro-2-h~droxy~ meth~l-N-morpholinocarbonylmethYl-ben
amine
M.p. of the hydrochloride: 210 - 213C (deconposition)
Prepared analogously to Example 77 from 3-chlorophenol, para-
formaldehyde and sarcosine morphollde.
X~
2-Chloro-4-h~rdroxy-N-methyl-N-morpholinocarbonylmethyl-benzyl-
amine
M.p. of the hydrochloride: 216 - 217C tdecomposition)
Prepared analogously to-E~ample 77 ~r~om 3-chlorophenol, para-
formaldehyde and sarcosine morp~lolide.
Example 116
M.p. of the hydrochloride: 180 - 181C (decomposition)
Prepared analogously to E~ample 76 from M-ethyl-M-cyclohexyl-
4-hydroxy-benzylamine and bromine.
- 58 -

~L~9Z~L~3
Example 11?
N-Ethyl-6-chloro-N-cyclohexyl-2,4-dibromo-3-hydroxy-benzylamine
M.p.: 138 - 140C
Prepared analogously to Example 76 from N-ethyl-2-chloro-N-
cyclohexyl-5-hydroxy-benzylamine hydrochloride and bromine.
xample 118
N-Ethyl-4-chloro-N-cyclohexyl-2,6-dibromo-3-hydroxy-benzylamine
M.p. of the hydrochloride: 189 - 190C ~decomposition)
Prepared analogously to Example 76 from N-ethyl-4-chloro-N-
cyclohexyl-3-hydroxy-benzylamine hydrochloride and bromine.
Example 119
N-Ethyl-N-cyclohexyl-3-hydroxy-2,4,6-tribromo-benzylamine
.... .. _
M.p.: 172 - 175C
Prepared analogously to Example 76 from N-ethyl-2-bromo-N-
cyclohexyl-5-hydroxy-benzylamine and bromine.
Example 120
3-Hydroxy-N-(cis-3-hydroxy-cyclohexyl)-2,4~6-tribromo-benzyl-
amine
M.p. of the hydrochloride: 228 - 228.5C (decomposition)
Prepared analogously to Example 74 by reduction of N-~3-hydroxy-
2,4,6-tribromo-benzylidene)-cis-3-amino-cyclohexanol with so-
dium borohydride.
-59-

~L09Zl~L3
Example 121
3-Hydroxy-N-( rans-4-hydroxy-cyclohexyl)-2~4~6~tribromo-ben
amine
M.p. of the hydrochloride: 259 - 261C (decomposition)
Prepared analogously to Example 74 by reduction of N-(3-hydroxy-
2,4,6-tribromo-benzylidene)-trans-4-amino-cyclohexanol with so-
dium borohydride.
Example 122
N-Ethyl-5-chloro-N-cyclohexyl-2-hydroxy-benzylamine
3.5 g of N-ethyl-N-cyclohexyl-2-hydroxy-benzylamine hydrochlo-
ride were dissolved in 50 ml of glacial acetic acid. Whilst
stirring vigorously a solution of 0.85 g of chlorine in 10 ml of
glacial acetic acid was poured into the reaction mixture, which
was stirred for 1 minute and then poured onto ice. Subsequent-
ly lON sodium hydroxide solution was added until a slightly al-
kaline reaction could be observed and the mixture was extracted
twice with 100 ml of chloroform. The combined chloroform solu-
tions were washed with water, dried over sodium sulfate and eva-
porated to dryness in vacuo. The oily residue was dissolved in a
little absolute ethanol. On gradual addition of ether~ hydrochloric
acid until the solution was clearly acid colourless crystals pre-
cipitated. The hydrochloride was sucked off and recrystallized
twice from isopropanol.
M.p.: 169 - 171C
Example 123
N-Ethyl-N-cyclohexyl-3,5-dichloro-2-hydroxy-benzylamine
3.1 g of N-ethyl-N-cyclohexyl-2-hydroxy-benzylamine were dis-
solved in 100 ml of absolute tetrahydrofuran and 4 ml of py-
ridine. The solution was cooled to -5C. At that temperature
-60-

~9Z~
7.2 g of iodosobenzene dichloride were added portionwise to the
reaction mixture which was stirred for a further 2 hours at -5 -
0C. Subsequently the reaction mixture was evaporated to dryness
in vacuo and the residue was distributed between chloroform and
_
water. The chloroform solution was separated and the aqueous
solution was extracted further with chloroform. The combined
chloroform layers were dried over sodium sulfate and evaporated
to dryness in vacuo. The oily residue was dissolved in a little
absolute ethanol. On addition of ethereal hydrochloride acid
until an acid reaction could clearly be observed colourless
crystals precipitated which were then sucked off and recrystallized
from isopropanol.
M.p. of the hydrochloride: 185-188C ~decomposition)
Example 124
N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine
2.7 g of N-ethyl-N-cycloh~exyl -2-hydroxy-benzylamine were dissolved
in 50 ml of glacial acetic acid. Whilst stirring vigorously at
room temperature a solution of 1 ml of bromine in 10 ml of glacial
acetic acid was dropped slowly into the reaction mixture. The
reaction mixture was then poured onto ice, made alkaline with lON
sodium hydroxide solution and extracted three times with 100 ml
portions of chloroform. The combined chloroform solutions were
washed with water~ dried over sodium sulfate and evaporated
to dryness in vacuo. The oily residue was dissolved in
absolute ethanol. On addition~of ethereal hydrochloric acid until
an acid reaction could be observed clearly colourless crystals
precipitated which were sucked off and recrystallized from ab-
solute ethanol.
M.p. of the hydrochloride: 193 - 194C (decomposition)
Example 125
N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine
-61-

~3~
3 g of N-ethyl-N-cyclohexyl-2-hydroxy-benzylamine were dissolved
in 50 ml of mekhylene chloride. The solution was cooled ko -5C.
At that temperature a solution of 10.6 g of tribromophenol-
bromine in 200 ml of methylene chloride was slowly added dropwise
and with vigorous stirring to the reaction mixture which was then
stirred for a further 2 hours and evaporated to dryness in vacuo.
The residue was purified by means of column chromatography over
silica gel using chloroform as eluent. When the fractionation
was completed the solvent was evaporated in vacuo The residue
was dissolved in a little absolute ethanol. Ethereal hydrochloric
acid was added until a clearly acid reaction was observed and
colourless crystals precipitated which were sucked off and re-
crystallized from absolute ethanol.
M.p. of the hydrochloride: 193 - 194C (decomposition3
Example 126
N-Ethyl-N-cyclohexyl-3,~ droxy-benzy amine
0.15 g of 2-acetoxy-N-ethyl-N-cyclohexyl-3,5-dibromo-benzyl-
amine were boiled for 1 hour with 10 ml of 4N ethanolic hydro-
chloric acid. The reaction mixture was cooled, poured onto ice,
made alkaline with concentrated ammonia and shaken out with chlo-
roform. The chloroform extract was dried over sodium sulfate and
evaporated in vacuo. The residue was dissolved in ethanol, and
ethanolic hydrochloric acid was added thus crystallizing out
the hydrochloride.
M.p.: 193 - 194C (decomposition)
Example 127
3,5-Dibromo-2-hydroxy-N-~trans-4-hydroxy-cyclohexyl~-benzylamine
4.7 g of N-benzyl-3,5-dibromo-2-hydroxy-N-(trans-4~hydroxy-cyclo-
hexyl)-benzylamine were dissolved in 350 ml of methanol and 6 ml
of 2N hydrochloric acid and hydrogenated in the presence of 350 mg
of palladium (10%) on coal. The hydrogenation was stopped as soon
-62-

Z~L13
as 1 mol of hydrogen had been absorbed. The catalyst was filtered
off from the reaction mixture and the Eil~rate was evaporated in
vacuo. The residue was recrystallized from ethanol. 3,5-dibromo~
2-hydroxy-N-~trans-4-hydroxy-cyclohexyl)-benzylamine hydrochloride
was obtained with a melting point of 212 - 218C (decomposition).
Example 128
N-Ethyl-N-cyclohexyl-3~5-dibromo-2-hydroxy-benzylamine
0.2 g of N-ethyl-N-cyclohexyl-3,5-dibromo-2-methoxy-benzylamine
hydrochloride were boiled for 3 hours with 3 ml of a 40% solution
of hydrobromic acid in glacial acetic acid. The reaction mixture
was cooled, poured onto ice, made alkaline with ammonia and ex-
tracted with chloroform. The chloroform extract was dried over
sodium sulfate and evaporated in vacuo. The residue was dis-
solved in ethanol. By addition of ethanolic hydrochloric acid
the hydrochloride was crystallized out.
M.p.: 193 - 194C ~decomposition)
Example 129
N-(4-tert.-Butyl-cyclohexyl)-3,5-dibromo-2-hydroxy-benzylamine
., . .. . _ _
2.8 g of 3,5-dibromo-2-hydroxy-benzylamine and 1.6 g of 4-tert.-
butyl-cyclohexanone were refluxed for 4 hours in 250 ml of tolu-
ene. After cooling the reaction mixture was diluted with 250 ml
of methanoI and mixed portionwise whilst stirring with 2.8 g
of sodium borohydride. After one hour the mixture was evapo-
rated to dryness in vacuo. The residue was shaken with 2N sodium
hydroxide solution. The substance was sucked off, washed with
water and recrystallized from methanol. The mixture of isomers
could be separated by means of column chromatography over silica
gel with chloroform/ethyl acetate (2:1).
-63-

~09Zl~
M.p. of the cis-form: 159 - 160C
M.p. of the trans-form: 186 - 189C (decomposition)
Example 130
N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine
_ _
0.4 g of N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzamide
were boiled for 5 hours with 0.12 g of sodium borohydride in
20 ml of dry pyridine. In order to destroy the excess of sodium
borohydride, acetone was added and the pyridine was removed in
va . The residue was distributed between water and chloroform,
and the combined chloroform layers were dried over sodium sulfate
and evaporated in vacuo. The residue was purified over a column
of silica gel with ethyl acetate. An oil was obtained which was
dissolved in ethanol and converted into the N-ethyl-N-cyclohexyl-
3,5-dibromo-2-hydroxy-benzylamine hydrochloride by addition of
ethanolic hydrochloric acid.
M.p.: 193 - 194C ~decomposition).
Example 131
N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine
1 g of N-e*hyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzamide was
boiled for 1 hour with 0.17 g of lithium aluminium hydride in
80 ml of absolute tetrahydrofuran. The reaction product was
cooled and cautiously mixed with water. The precipitate was se-
parated and boiled with tetrahydrofuran. The combined tetra-
hydrofuran solutions were evaporated in vacuo, the residue was dis-
tributed between water and chloroform and the combined chloroform
layers were dried over sodium sulfate and evaporated in vacuo. An
oil was obtained which was dissolved in ethanol and converted into
the N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydro-
chloride by means of ethanolic hydrochloric acid.
M.p.: 193 - 194C (decomposition)
-64-

~2.1 13
Example 132
N-Ethyl-N-cyclohexyl-3,5-dibromo-~- _droxy-benzylamine
2.25 g of 2-acetoxy-N-ethyl-N-cyclohexyl-3,5~dibromo-benzamide
were dissolved in 30 ml of absolute tetrahydrofuran a-nd dropped
whilst stirring into a suspension of 0.8 g of lithium aluminium
hydride in 120 ml of absolute tetrahydrofuran. The mixture was
boiled for 75 minutes, then cooled to about 10C and mixed with
water. The precipitate was separated and washed once with tetra-
hydrofuran. The combined tetrahydrofuran solutions contain-
ing water were evaporated in order to remove the organic sol-
vent. The aqueous solution thus obtained was extracted three
times with chloroform and the combined chloroform extracts were
dried over sodium sulfate and evaporated. The N-ethyl-N-cyclo-
hexyl-3,5-dibromo-2-hydroxy-benzylamine was obtained an an oil
which was then dissolved in ethanol and converted into its hy-
drochloride with ethanolic hydrochloric acid.
M.p.: 193 - 194C (decomposition)
Example 133
N-Ethyl-N-cyclohexyI-3,5-dibromo-2-hydroxy-benzylamine
~ =
1.2 g of 2-acetoxy-N-acetyl-N-cyclshexyl-3,5-dibromo-benzyl-
amine were boiled for about 1 hour with 0.5 g of lithi~ alu-
minium hydride in 100 ml of absolute tetrahydrofuran. The excess
of lithium aluminium hydride was decomposed by cautious addi-
tion of water. The precipitate which formed was sucked off and
washed with tetrahydrofuran. The combined tetrahydrofuran solu-
tions containing water were evaporated and the remaining aqueous
residue was extracted with chloroform. The chloroform solution
was dried over sodium sulfate and evaporated. The oil thus ob-
tained was dissolved in ethanol and converted into the N-ethyl-
N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride
by addition of ethanolic hydrochloric acid.
M.p.: 193 - 194C (decomposition)
-65-

Z3~3
Example 134
3,5-~bromo=Z=~os~g~ L~ ns-4-hyclroxy-cyclohex~yl)-benz~lamine
100 g of 6,8-dibromo-3-(trans-4-hydroxy-cyclohexyl)-3,4-dihydro-
2H-1,3-benzoxazi~2-one was refluxed for 1 hour in a mixture
of 30 ml of tert.-butanol and 25 ml of 2 sodium hydroxide so-
lution. The reaction mixture was cooled and mixed in turn with
30 ml of 2N hydrochloric acid and as excess ~sodium hydrogen car-
bonate solution. The alcohol was distilled off ~ vacuo and the
aqucous phase was extracted twice with a mixture of tetrahydro-
furan and ether (1:1). The organic extracts were dried over
magnesium sulfate and evaporated in vacuo to a small volume.
Petroleum ether was added whilst heating until the reaction mix-
ture became turbid. The desired end product which melb~ at 191 -
193C was recrystallized whilst cooling.
M.p. of the hydrochloride: 212 - ~18C (decomposition)
N- h~l-5-bromo-N-cyclohexyl-2-hydroxy-benzylamine
--
M.p. of the hydrochloride: 175 - 178C
Prepared analogously to Example 124 from N-ethyl-N-cyclohexyl-
2-hydroxy-benzylamine hydrochloride ~nd bromine.
.
M.p. of the hydrochloride: 194 - 197C (decomposition)
Prepared analog~usly to Example 124 from N-ethyl-5-chloro-N-
cyclohexyl-2-hydroxy-benzylamine hydrochloride and bromine.
- 66

ao~z~3
N-Ethvl--M-cvclohex~l-3 5-dichl.oro-4-h~drox~-benzylamine
.p. of the hydrochloride: 19~ - 191C (decomposition)
Prepared analogously to Example 122 from N-ethyl-N cyclohexyl-
4-hydroxy-benzylamine and chlorine.
Example 138
3,5-Dibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl~-benzylamine
M.p. of the hydrochloride: 216 - 21~C (decomposition)
Prepared analogously to EY.ample 124 from 4-hydroxy-N-(cis-3-
hydroxy-cyclohexyl)-benzylamine hydrochloride and bromine.
Example 13g
.p. of the hydrochloride: 212 - 218~ (decomposition)
Prepared analogously to Example 124 from 2-hydroxy-N-(trans-4-
hyclroxy-cyclohexyl)-benzylamine hydrochloride and bromine.
Exam~le 140
.- ~
M.p. of the hydrochloride: 215 - 215,5C (decomposition)
Prepared analo~ously to Example 124 from 4-hydroxy-N-(trans-3-
hydroxy-cyclohexyl)-benzylamine hydrochloride and bromine,
- 67
,

~V~Zl~3
Example 141
3,5-Dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl~-benzylami-ne
M.p. of the hydrochloride: 212 - 218C (decomposition)
Prepared analogously to Example 128 by cleavage of 3,5-dibromo-
N-(trans-4-hydroxy-cyclohexyl)-2-methoxy-benzylamine hydrochlo-
- ride with 40% hydrobromic acid solution in glacial acetic acid.
Example 142
3,5-Dibromo-2-hydroXy-N-(t:rans-4-hydroxy-cyclohexyl~-benzylamine
M.p. of the hydrochloride: 212 - 218C ~decomposition)
Prepared analogously to Example 129 from 395-dibromo-2-hydroxy-
benzylamine, 4-hydroxy-cyclohexanone and sodium borohydride.
Example 143
3,5-Dib~ y~T~v~ A~ hydroxy-cyclohexyl~-benzyl _ine
M~po of the hydrochloride: 212 - 218C (decomposition)
Prepared analogously to Example 131 by reduction of 3,5-dibromo-
2-hydroxy-N-~rans-4-hydroxy-cyclohexyl)-benzamide with lithium
aluminium hydride.
Example 144
3,5-Dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl~-beniylamine
M.p. of the hydrochloride: 212 - 218C (decomposition)
Prepared analogously to Example 132 by reduction of 2-acetoxy-
3,5-dibromo-N-(trans-4-hydroxy-cyclohexyl)-benzamide with lithium
aluminium hydride.
-68-

Z~3
Example 145
3,5-Dibromo-4-hydroxy-N-~cis-3-hydroxy-cyclohexyl)-benzylamine
M.p. of the hydrochloride: 216 - 218C ~decomposition)
Prepared analogously to Example 127 by debenzylation of N-ben-
zyl-3,5-dibromo-4-hydroxy-N-~cis-3-hydroxy-cyclohexyl~-benzyl-
amine hydrochloride with hydrogen in the presence of palladium
on activated charcoal.
Example 146
3,5-Dibromo-4-hydroxy-N-~cis-3-hydroxy-cyclohexyl)-benzylamine
M.p. of the hydrochloride: 216 - 218C ~decomposition)
Prepared analogously to Example 128 by splitting of 3,5-dibromo-
N-~cis-3-hydroxy-cyclohexyl)-4-methoxy-benzylamine hydrochloride
with 40% hydrobromic acid solution in glacial acetic acid.
Example 147
_ _
3,5-Dibromo-4-hydroxy-N-~cis-3-hydroxy-cyclohexyl)-benzylamine
. .
M.p. of the hydrochloride: 216 - 218C (decomposition)
Prepared analogously to Example 129 from 3,5-dibromo-4-hydroxy-
benzylamine, 3-hydroxy-cyclohexanone and sodium borohydride.
Example 148
3,5-Dibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine
M.p. of the hydrochloride: 216 - 218C (decomposition)
Prepared analogously to Example 131 by reduction of 3,5-dibromo-
4-hydroxy-N-~cis-3-hydroxy-cyclohexyl)-benzamide with lithium
aluminium hydride.
-69-

~3Z.~
Example ]49
3,5-Dibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl~-benzylamine
. _ _ _ _ _
M.p. of the hydrochloride: 216 - 218C (decomposition)
Prepared analogously to Example 132 by reduction of 4-acetoxy-
3,5-dibromo-N-(cis-3-hydroxy-cyclohexyl)-benzamide with lithium
aluminium hydride.
Example 150
3,5-Dibromo-4-hydroxy-N-(trans-3-hydroxy-cyclohexyl)-benzylamine
M.p. of the hydrochloride: 215 - 215.5C (decomposition)
Prepared analogously to Example 127 by debenzylation of N-benzyl-
3 J 5-dibromo-4-hydroxy-N-(trans-3-hydroxy-cyclohexyl)-benzylamine
hydrochloride with hydrogen in the presence of palladium on acti-
vated charcoal.
Example 151
:
3,5-Dibromo-4-hydroxy-N-(trans-3-hydroxy-cyclohexyl~-benzylamine
M.p. of the hydrochloride: 215 - 215.5C ~decomposition)
Prepared analogously to Example 128 by cleavage of 3,5-dibromo-
N-(trans-3-hydroxy-cyclohexyl)-4-methoxy-benzylamine hydrochlo-
ride with 40% hydrobromic acid solution in glacial acetic acid.
Example 152
3,5-Dibromo-4-hydroxy-N-(trans-3-hydroxy-cyclohexyl)-benzylamine
M.p. of the hydrochloride: 215 - 215.5C (decomposition)
Prepared analogously to Example 129 from 3,5-dibromo-4-hydroxy-
benzylamine, 3-hydroxy-cyclohexanone and sodium borohydride.
-70-

2~3
Example 153
3,5-Dibromo-4-h droxy-cyclohexyl)-benzylamine
M.p. of the hydrochloride: 215 - 215.5C (decomposition~
Prepared analogously to Example 131 by reduction of 3,5-dibromo-
4-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzamide with lithium
aluminium hydride.
Example 154
3,5-Dibromo-4-hydroxy-N-~trans-3-hydroxy-cyclohexyl~-benzylamine
. . ............................ _ . _ _
M.p. of the hydrochloride: 215 - 215.5C ~decomposition)
Prepared analogously to Example 132 by reduction of 4-acetoxy-
3,5-dibromo-N-~trans-3-hydroxy-cyclohexyl)-benzamide with li-
thium aluminium hydride.
Example 155
3,5-Dibromo-4-hydroxy-N-(trans-4-hydroXy-cyclohexyl~-benzylamine
M.p. of the hydrochloride: 220 - 225C (decomposition)
Prepared analogously to Example 124 from 4-hydroxy-N-~trans-4-
hydroxy-cyclohexyl)-benzylamine hydrochloride and bromine.
Example 156
3,5-Dibromo-4-hydroxy-N-~trans-4-hydroxy-cyclohexyl~-N-methyl-
benzylamine
M.p. of the hydrochloride: 160 - 162C ~decomposition)
Prepared analogously to Example 124 from 4-hydroxy-N-~trans-4-
hydroxy-cyclohexyl)-N-methyl-benzylamine hydrochloride and bro-
mine.

~92~
Example 157
_
N-Ethyl-5-bromo-3-chlor _N-cyclohexyl-2-hydro-xy-beniylamine
M.p. of the hydrochloride: 188 - 191C (decomposition~
Prepared analogously to Example 122 from N-ethyl-5-bromo-N-cyclo-
hexyl-2-hydroxy-benzylamine hydrochloride and chlorine.
Example 158
N-Ethyl-3,5-dichloro-2-hydroxy-N-~trans-4-hydroxy-cyclohexyl)-
.
' 'benzylamine
M.p. of the hydrochloride: 147 - 152C
Prepared analogously to Example 123 from N-ethyl-2-hydroxy-N-
~trans-4-hydroxy-cyclohexyl~-benzylamine and iodosobenzene di-
chloride.
Example 159
N-~4-tert.-Butyl-cyclohexyl)-3,5-dibromo-4-hydroxy-benzylamine
M.p. of the hydrochloride: 158 - 159~C ~decomposition)
Prepared analogously to Example 124 ~rom N-~4-tert.-butyl-cyclo-
hexyl)-4-hydroxy-benzylamine hydrochloride and bromine.
Example 160
N-Ethyl-5-bromo-~-hydroxy-N-~trans-4-hydro-xy-cyclohexyl~-benzyl-
amine
M.p. of the hydrochloride: 190 - 193C ~decomposition)
Prepared analogously to Example 124 from N-ethyl-2-hydroxy-N-
~trans-4-hydroxy-cyclohexyl)-benzylamine hydrochloride and bro-
mine.
-72-

Example 161
5-Bromo-N-cyclohexyl-2-hydroxy-N-isopropyl-benzylamine
M.p : 90 - 93C
Prepared analogously to Example 124 from N-cyclohexyl-2-hydroxy-
N-isopropyl-benzylamine and bromine.
Example 162
N-Cyclopentyl-3,5-dibromo-4-hydroxy-N-methyl-~enzylamine
M.p. of the hydrochloride: 185 - 188C ~decomposition)
Prepared analogously to Example 124 from N-cyclopentyl-4-hydroxy-
N-methyl-benzylamine hydrochloride and bromine.
Example 163
N-Ethyl-N-cyclopentyI-3,5-dibromo-2-hydroxy-benzyIamine
Prepared analogously to Example 124 from N-ethyl-N-cyclopentyl-
2-hydroxy-benzylamine hydrochloride and bromine.
M.p. of the hydrochloride: 124 - 128C (decomposition)
Example 164
N-Cycloheptyl-3,5-dibromo-4-hydroxy-N-propyl-benzylamine
M.p. of the hydrochloride: 176 - 177C ~decomposition)
Prepared analogously to Example 124 from N-cycloheptyl-4-hydroxy-
N-propyl-benzylamine hydrochloride and bromine.

~2~L~L3
Example 165
N-Cycloheptyl-3,5-dibromo-2-hydroxy-N-isopropyl-benzylamine
M.p. of the hydrochloride: 156 - 159C (decomposition)
Prepared analogously to Example 124 from N-cycloheptyl-2-hydroxy-
N-isopropyl-benzylamine hydrochloride and bromine.
Example 166
-
N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-beniylamine
-
6 g of 3,5-dibromo-2-hydroxy-benzyl acetate and 7 g of N-ethyl-
cyclohexylamine were heated for 1 hour at 140C. 2N hydrochloric
acid and ether were added to the reaction mixture with stirring
thus crystallizing out the N-ethyl-N-cyclohexyl-3,5-dibromo-2-
hydroxy-benzylamine hydrochloride. The crystals were sucked off
and washed with water and acetone.
M.p.: lg3 - 194C ~decomposition)
Example 167
N-Ethyl-N-cyclohexyl-3~5-dibromo-2-hydroxy-benzylamine
7 g of 3,5-dibromo-2-hydroxy-benzyl alcohol and 2.8 g of sodium
hydride dispersion ~50% in oil) were refluxed for 6 hours in
150 ml of absolute tetrahydrofuran. Subsequently the reaction
mixture was cooled to -60 to -70C and 9.5 g of p-toluene-sul-
fonyl chloride in 100 ml of absolute tetrahydrofuran were
added dropwise with stirring. When the reaction mixture had
reached a temperature of -30C it was again cooled to ~70C.
Subsequen~ly 12.7 g of N-ethyl-cyclohexylamine in 100 ml of ether
were dropped into the reaction mixture whilst stirring. Slowly the
mixture was allowed to reach room temperature and was then extracted
-74-

~2~.3
twice with 200 ml of water. The combined aqueous phases were extrac-
ted once with chloroEorm. The chloroform layer was combinéd with
the ether-tetrahydrofuran layer and the mixture was evaporated to
dryness. Subsequently it was purified over a column of silica gel
with chloroform/ethyl acetate (9:1). The corresponding fractions
were combined and evaporated to dryness. The residue was stirred
with 2N hydrochloric acid and ether, thus crystallizing out the N-
ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride.
The crystals were sucked off and washed with water and acetone.
M.p.: 193 - 194C ~decomposition~
Example I68
N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-beniylamine
1.3 g of 2-benzoyloxy-3,5-dibromo-benzyl alcohol and 1.3 g of
N-ethyl-cyclohexylamine were heated for 1 hour at 140C. The
reaction product was stirred with 2N hydrochloric acid and ether
thus crystallizing out the N-ethyl-N-cyclohexyl-3,5-dibromo-2-
hydroxy-benzylamine hydrochloride. The crystals sucked off and
washed with water and acetone.
M.p.: 193 - 194C ~decomposition)
Example 169
N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine
2.8 g of 3,5-dibromo-2-hydroxy-benzyl alcohol and 3.8 g of N-
ethyl-cyclohexylamine were heated for 1 hour at 140C. The re-
action product was stirred with 2N hydrochloric acid and ether
thus crystallizing out the N-ethyl-N-cyclohexyl-3,5-dibromo-2-
hydroxy-benzylamine hydrochloride which was sucked off and washed
with water and acetone.
M.p.: 193 - 19~C ~decomposition~
-75-

~Z~.13
xample 170
N-Ethyl-N-cyclohexyl-3~5-dibromo-2-hydroxy-benzylamine
2.8 g of 3,5-dibromo-2-hydroxy-benzyl alcohol, 3.8 g of N-ethyl-
cyclohexylamine and 1.2 ml of 48% hydrobromic acid were heated
for 1 hour at 140C. The reaction mixture was shaken with chloro-
form and water. The chloroform layer was separated and evaporated
to dryness. The residue was stirred with 2N hydrochloric acid
and ether thus crystallizing out the N-ethyl-N-cyclohexyl-3,5-
dibromo-2-hydroxy-benzylamine hydrochloride which was sucked
off and washed with water and acetone.
M.p.: 193 - 194C (decompbsition)
Example 171
N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine
5.6 g of 3,5-dibromo-2-hydroxy-benzyl alcohol, 8.8 g of butyric
acid and 12.7 g of N-ethyl-cyclohexylamine were heated for one
hour at 140C, then cooled, dissolved in 200 ml of ether and
cxtracted four times with water. The organic phase was dried
over~;sodium sulfate and evaporated. The residue was dissolved in
a little absolute ethanol. This solution was acidified with
ethanolic hydrochloric acid and mixed with ether so that the
N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydro-
chloride crystallized out.
M.p.: 193 - 194C (decomposition)
Example 172
N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine
5.6 g of 3,5-dibromo-2-hydroxy-benzyl alcohol, 12.7 g of N-ethyl-
cyclohexylamine and 0.4 g of magnesium oxide were heated for 8 hours
at 120C. The reaction mixture was then mixed with ether and water
acidified with 2N hydrochloric acid and subsequently made alkaline with
-76-

3Zl~
with 2N hydrochloric acid and subsequently made alkaline with
concentrated ammonia. The mixture was shaken and the organic
phase was separated, washed four times with water, dried over
sodium sulfate and evaporated. The residue was dissolved in ab-
solute ethanol and acidified with ethanolic hydrochloric acid. On
addition of ether the N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-
benzylamine hydrochloride crystallized out.
M.p.: 193 - 194C (decomposition)
Example 173
3,5-Dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzylamine
-
0.9 g of 6,8-dibromo-2-methyl-1,3-benzdioxane and 1.0 g of trans-
4-amino-cyclohexanol were heated for 17 hours at 140C. Subse-
quently the reaction product was boiled with 100 ml of dilu~e
hydrochloric acid. The solution was treated with activated char-
coal and evaporated in vacuo to a volume of about 5 ml, thus crystal-
lizing out the 3,5-dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-
benzylamine hydrochloride. The crystals were sucked off, washed
with water and acetone and dried in vacuo at 80C.
M.p.: 212 - 218C (decomposition)
Example 174
N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine
2.9 g of 3,5-dibromo-~-methoxy-o-cresol and 3.8 g of N-ethyl-
cyclohexylamine were heated for 1 hour at 1~0C. The reaction
product was stirred with 2N hydrochloric acid and ether thus
crystallizing out the N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-
benzylamine hydrochloride which was sucked off and washed with
water and acetone.
M.p.: 193 - 194C (decomposition)

Z~3
175
N-Cyclohexyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine
1.4 g of 3,5-dibromo-2-hydroxy-benzyl alcohol and 11.5 g of
N,N'~N"-tricyclohexyl-N,N',N"-trimethyl-phosphoric acid tri-
amide were heated for 10 hours at 150C. The reaction product
was purified over a column of silica gel with chloroform/ethyl
acetate ~ . The corresponding fractions were combined and
evaporated. The residue was dissolved in petroleum ether, aci-
dified with ethanolic hydrochloric acid and shaken, the solu-
tion was decanted. The oily residue was dissolved in a littlé ab-
solute ethanol and mixed with ether thus crystallizing out the
N-cyclohexyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine hydro-
chloride.
M.p.: 189 - 191C
- Example 176
3,5-Dibromo-2-hydroxy-N-~trans-4-hydroxy-cyclohexyl)-benzylamine
2 g of 6,8-dibromo-3,4-dihydro-3-(trans-4-hydroxy-cyclohexyl)-
2H-1,3-benzoxazine were dissolved at room ~emperature in 20 ml
of methanol and mixed with 5 ml of water. After 15 minutes an-
other 10 ml of methanol were added forming a crystalline pre-
cipitate which was sucked off and washed with methanol. The base
was dissolved in absolute ethanol and acidified with ethanolic
hydrochloric acid. In doing so the 3,5-dibromo-2-hydroxy-N-~trans-
4-hydroxy-cyclohexyl)-benzylamine hydrochloride crystallized out.
M.p.: 212 - 218C ~decomposition)
-78-

2~L3
Example 177
3,5-Dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-ben
am
M.p. of the hydrochloride: 212 - 218C (decomposition)
Prepared analogously to Example 166 from 3,5-dibromo-2-hydroxy-
benzyl acetate and trans-4-amino-cyclohexanol.
Example 178
. .
N-Ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-beniylamine
M.p. of the hydrochloride: 180 - 181C (decomposition)
Prepared analogously to Example 166 from 3,5-dibromo-4-hydroxy-
benzyl acetate and N-ethyl-cyclohexylamine.
Example 179
3,5-Dibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-beniylamine
M.p. of the hydrochloride: 215 - 215.5C (decomposition)
Prepared analogously to Example 166 from 3,5-dibromo-4-hydroxy-
benzyl acetate and cis-3-amino-cyclohexanol.
Example 180
N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-beniylamine
M.p. of the hydrochloride: 193 - 194C ~decomposition)
Prepared analogously to Example 166 from 3,5-dibromo-2-hydroxy-
benzyl benzoate and N-ethyl-cyclohexylamine.
-79-

2:~.13
Example 181
3,5-Dibromo-2-hydroxy-N-(trans-4-hydroxy-cycl hexyl)-benzyl-
amine
M.p. of the hydrochloride: 212 - 218C (decomposition)
Prepared from 2-benzoyloxy-3,5-dibromo-benzyl alcohol and trans-
4-amino-cyclohexanol analogously to Example 168.
Example 182
N-F~thyl~N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine
M.p. of the hydrochloride: 180 - 181C (decomposition)
Prepared from 4-acetoxy-3,5-dibromo-benzyl alcohol and N-ethyl-
cyclohexylamine analogously to Example 168.
Example 183
3,5-Dibromo-4-hydroxy-N-(cis-3-hydroXy-cyclohexyl~-benzyIamine
M.p. of the hydrochloride: 215 - 215.5C (decomposition)
Prepared from 4-acetoxy-3,5-dibromo-benzyl alcohol and cis-3-
amino-cyclohexanol analogously to Example 168.
Example 184
3,5-Dibromo-2-hydroxy-N-(tràns-4-hydroxy-cyclohexyI~-benzyIamine
M.p. of the hydrochloride: 212 - 218C (decomposition)
Prepared from 3,5-dibromo-2-hydroxy-benzyl alcohol and trans-4-
amino-cyclohexanol analogously to Example 169.
-80-

2~3
Example 185
3,5-Dibromo-4-hydroXy-N-(cis-3-hydroxy-cyclohexyl~~benzylamine
M.p. of the hydrochloride: 215 - 215.5C (decomposition)
Prepared analogously to Example 169 from 3,5-dibromo-4-hydroxy-
benzyl alcohol and cis-3-amino-cyclohexanol.
Example 186
N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine
M.p. of the hydrochloride: 193 - 194C (decomposition)
Prepared analogously to Example 170 from 3,5-dibromo-2-hydroxy-
benzyl alcohol, N-ethyl-cyclohexylamine and p-toluene-sulfonic
acid.
Example 187
N-Ethyl-N~cyclohexyl-3,5-dibro -4-hydroxy-benzylamine
M.p. of the hydrochloride: 180 - 181C (decomposition)
Prepared analogously to Example 171 from 3,5-dibromo-4-hydroxy-
benzyl alcohol, N-ethyl-cyclohexylamine and butyric acid.
Example 188
3,5-Dibromo-2-hydroxy-N-~trans-4-hydroxy-cyclohexyl~-beniyl-
-
amine
M.p. of the hydrochloride: 212 - 218C ~decomposi-tion)
Prepared analogously to Example 171 from 3,5-dibromo-2-hydroxy-
benzyl alcohol, butyric acid and trans-4-amino-cyclohexanol.
-81

M.p. of the hydrochloride: 215 - 215,5C (decompo~ition)
Prepared analogously to Example 171 ~rom 3,5-dibromo-4-hydroxy-
benzyl alcohol~ cis-3-amino-cyclohexanol and butyric acid.
amine
__
M.p. of the hydrochlorlde: 212 - 218C (decomposition)
Prepared analogously to Example 172 from 3,5-dibromo-2-hydroxy-
benzyl alcohol, trans-4-amino cyclohexanol and magnesium oxide.
M.p. of the hydrochloride: 193 - 194C (decompo~ition)
Prepared analogously to E~ample 172 from 3,5-dibromo 2-hydroxy-
benzyl alcohol, N-ethyl-cyclohexylamine and potassium hydroxide.
, . . .
~ .
.p. of the hydrochloride: 215 - 215,5C (decompo~ition)
Prepared analogously to E~ample 172 from 3,5-dibromo-4hydroxy
benzyl aloohol, ciq-3-amino-cyclohexanol and magnesium oxide.
- 82 ~ .

~302~.3
.
M.p. of the hydrochloride: 19~ - 194C (decomposition)
Prepared analogously to E~ample 173 from 6,8-dibromo-2-methyl-
1,3-benzdioxane and N-ethyl~cyclohexylamine.
~2~ ,
amine
M.p. of the hydrochloride: 212 - 218C (decomposition)
Prepared analogously to Example 174 ~rom 3,5-dibromo-a-methoxy-
o-cresol and trans-4-amino-cyclohexanol.
_ aEe~
L:~ -
M.p. of the hydrochloride: 180 - 181C tdecomposition)
Prepared analogously to-Example 174 from 3,5-dibromo-a-methoxy-
p~cresol and N-ethyl-cyclohexylamine.
Mopo of the hydrochloride: 215 - 215,5C (decompo~ition)
Prepared analogously to Example 174 from 3,5-dibromo-~-methoxy-
p-cresol and cis-3-amino-cyclohexanol.
~ 83

:1(39~13
~a~
M~p. o~ the hydrochloride: 189 - 191~C
Prepared analogously to Example 175 ~rom 3,5-dibrom~-2-hydroxy-
benzyl alcohol and N-cyclohexyl-N-methyl-ace~amide. .
~
5J6 g of 3,5-dibromo-2-hydroxy-benzyl alcohol 2nd 6~3 g of di-
hydroxy-tert.-butylami~e were heated for 1 hour a~ 140Co
The molten ~as was th~n dissolved in absolute ethanol and aci-
dified with ethanolic hydrochloric acid~ The 3,5-dibromo-N-(di-
hydroxy~tert.-butyl~2-hydroxy-benzylamine hydrochloride cry-
~tallized out on addition of ether.
Recrystallization ~rom absolute ethanol, m.p.: 187-189C.
~a~
2106 g of 3,5-dibromo-2-hydroxy-benzyl bromi:de di~solved in 0"5 1
of carbon ~etrachloride were mixed with a solution of 26,4 g of
dihydrox~r-tert.-butylamine in 100.ml o~ ethanol and refluxed for 30
minutes. T~e precip~até w~ch ~ormed was sucked off and washed
with carbo~ tetrachloride and water. The crude product was dis-
solved in absolute ethanol and acidified with ethanolic hydro-
chloric acid. The 3,5-dibromo-N-(dihydroxy-tert.-butyl)-2-hydro-
xy~benzylami~e hydroc~loride crystallized out on addition
of ether.
M.p.: 187-189C. _ 84

~092~ ~L3
Example 200
3J5-Dibromo-N-(dihydroxy-tert.-butyl?-2-hydroxy-benzyl _ine
4.0 g of 3,5-dibromo-2-hydroxy-benzyl acetate and 4.0 g of di-
hydroxy-tert.-butylamine were heated for 1 hour at 140C. The
reaction product was dissolved in absolute ethanolJ acidified
with ethanolic hydrochloric acid and crystallized out on addi-
tion of ether.
M.p.: 187 - 189C.
Example 201
3,5-Dib-romo-2-hydroxy-N-tert.-pentyl-beniy amine
3.5 g of 3,5-dibromo-2-hydroxy-benzyl alcohol and 1.4 g of sodium
hydride dispersion ~50% in oil) were refluxed for 6 hours in 100 ml
of absolute tetrahydrofuran. Subsequently the reaction mixture
was cooled to -60 to -70C and 4.8 g of p-toluene-sulfonyl chloride
in 50 ml of absolute tetrahydrofuran were added dropwise. The
mixture was then left to stand until a temperature of -30C was
reached and was again cooled to -70C. 4.4 g of tert.-pentylamine
in 50 ml of ether were added dropwise to the stirred reaction mix-
ture until it slowly reached room temperature. Subsequently the
mixture was shaken twice with water, the aqueous layer was extracted
with chloroform and the combined organic phases were evaporated.
After purification over a column of silica gel with chloroform/
e~hyl acetate ~2/1~ the 3,5-dibromo-2-hydroxy-N-tert.-pentyl-
benzylamine hydrochloride was recrystalliæed from acetone/ether
after having been acidified with ethanolic hydrochloric acid.
Recrystallization from water, m.p.: 202-206C (decomposition).
Example 202
3,5-Dibromo-N-~dihydroxy-tert.-butyl~-2-hydroxy-benzylamine
-85-

10~3Z~3
2.9 g of 3,5-dibromo-2-hydroxy-benzyl methyl ether and 3.3 g of
dihydroxy-tert.-butylamine were heated for 1 hour at 140C. The
crude product was dissolved in absolute ethanol, acidified with
ethanolic hydrochloric acid and mixed with ether until the 3,5-
dibromo-N-~dihydroxy-tert.-butyl)-2-hydroxy-benzylamine hydro-
chloride crystallized out.
M. p.: 187 - 189C.
Example 203
3,5-Dibromo-N-(dihydroxy-tert.-butyl)-2-hydroxy-benzylamine
7 g of 3,5-dibromo-salicylaldehyde, 17.$ g of dihydroxy-tert.-
butylamine and 7.7 g of formic acid were heated for 6 hours at
70-80C. Subsequently the reaction mixture was mixed with 2N
ammonia and shaken vigorously. rne precipitate which formed was
sucked off. The residue was dissolved in ethanol, acidified with
ethanolic hydrochloric acid and mixed with ether whereby the pro-
duct crystallized~out.
Recrystallization from absolute ethanol/ether, m.p.: 187-189C.
Example 204
3,5-Dibromo-N-~dihydroxy-tert.-butyl)-2-hydroxy-beniylamine
7.3 g of N-~3,5-dibromo-2-hydroxy-benzylidene)-dihydroxy-tert.-
butylamine were stirred for 2 hours with 1 g of sodium borohy-
dride in 200 ml of ethanol. Some acetone was added to the reac-
tion mixture in order to decompose the excess of sodium boro-
hydride. The mixture was acidified with 2N hydrochloric acid
and evaporated to a small volume. After addition of 2N ammonia
until an alkaline reaction was observed the yellowish precipitate
was sucked off. The residue was dissolved in absolute ethanol
and acidified with ethanolic hydrochloric acid. Ether was added
to crystallize out the 3,5-dibromo-N-(dihydroxy-tert.-butyl)-2-
hydroxy-benzylamine hydrochloride.
M.p.: 187 - 189C.
-86-

~Z~3
Example 205
3~5-Dibromo-2-hydroxy-N-isopropyl-benzylamine
16 g of N-isopropylidene-~3,5-dibromo-2-hydroxy-benzylamine)
in 120 ml of ethanol were mixed with 2 g of sodium borohydride
the mixture was stirred f~r 3 hours, then filtered, mixed with
40 ml of 2N sodium hydroxide solution and 200 ml of water and
evaporated to about half the total volume. The solution was then
mixed with saturated ammonium chloride solution thus prccipitating
the crude base. The precipitate was sucked off and washed thoroughly
with water. The product was dissolved in acetone and acidified
with ethanolic hydrochloric acid. In doing so the 3,5-dibromo-2-
hydroxy-N-isopropyl-benzylamine hydrochloride crystallized out
immediat~ly.
M.p.: 195-199C (decomposition).
Example 206
3,5-Dibromo-N ~dihydroxy-tert.-butyl)-2-hydroxy-benz lamine
4.2 g of dihydroxy-tert.-butylamine and 1.2 g of paraformalde-
hyde were dissolved in 20 ml of absolute ethanol whilst warm-
ing. The solution was mixed at room temperature with 10.0 g of
2,4-dibromo-phenol and after standing for l hour was refluxed for
a further 7 hours. The reaction solution was subsequently acid-
ified with ethanolic hydrochloric acid and mixed with ether, thus
crystallizing out the 3,5-dibromo-N-(dihydroxy-tert.-butyl) 2-
hydroxy-benzylamine hydrochloride.
Recrystallization from absolute ethanol/ether; m.p.: 187-189C.
ExampIe 207
3,5-Dibromo-N-~dihydroxy-tert.-butyl?-2-hydroxy-benzyIamine
2.5 g of N-~dihydroxy-tert.-butyl)-2-hydroxy-benzylamine hydro-

10~3Z~.~3
chloride were dissolved in 50 ml of glacial acetic acid and 5 ml
of water and 3.2 g of bromine in 10 ml of glacial acetic acid were
added dropwise whilst stirring. Subsequently the reaction mix-
ture was diluted with water and made alkaline with concentrated
ammonia. The precipitated crude base was sucked off, dissolved
in absolute ethanol and acidified with ethanolic hydrochloric
acid. Ether was added until the 3,5-dibromo-N-(dihydroxy-tert.-
butyl)-2-hydroxy-benzylamine hydrochloride crystallized out.
Recrystallization from absolute ethanol/ether, m.p.: 187-189C.
Example 208
3,5-Dibromo-N-~dihydroxy-tert.-butyl)-2-hydroxy-benzylamlne
2.5 g of N-benzyl-3,5-dibromo-N-(dihydroxy-tert.-butyl~-2-hy-
droxy-benzylamine hydrochloride were dissolved in 200 ml of me-
thanol and hydrogenated in the presence of about 0.1 g of pal-
ladium ~10%) on coal. As soon as the calculated quantity of
hydrogen was absorbed the hydrogenation was stopped, the ca-
talyst filtered off and the solution evaporated. After recry-
stallizing twice from absolute ethanol/ether pure 3,5-dibromo-
N-~dihydroxy-tert.-butyl)-2-hydroxy-benzylamine hydrochloride
was obtained.
M.p.: 187-189C.
Example 209
3~5-Dibromo-2-hydroxy-tert.-pentyl-benzylamine
0.8 g of 3,5-dibromo-2-hydroxy-N-tert.-pentyl-benzamide were
refluxed for 5 hours with 0.3 g of sodium borohydride in 30 ml
of dry pyridine. In order to decompose the excess of sodium
borohydride, acetone was added and the pyridine was distillèd
off in vacuo. The residue was dissolved in hot 2N hydro-
chloric acid, filtered, made alkaline with 2N ammonia and shaken
three times with chloroform. The organic layer was dried

~0~%~ 3
over sodium sulfate and evaporated. Further purification was
effected by means of column chromatography over silica gel with
chloroform/ethyl acetate (2/1). The base obtained was dissolved in
a little acetone and acidified with ethanolic hydrochloric acid.
The 3,5-dibromo-2-hydroxy-tert.-pentyl-benzylamine hydrochloride
was crystallized out by addition of ether.
Recrystallization from water; m.p.: 202-206C ~decomposition).
Example 210
3,5-Dibromo-N-~dihydroxy-tert.-butyl)-2-hydroxy-benzylamine
1.8 g of 6.8-dibromo-3,4-dihydro-3-~dihydroxy-tert.-butyl)-
2H-1,3-benzoxazine-2-one in 50 ml of tert.-butanol and 40 ml
of 2N sodium hydroxide solution were refluxed for 1 hour. The
reaction mixture was cooled, mixed with 50 ml of 2N hydrochloric
acid and the alcohol was distilled off in vacuo. An excess of
sodium hydrogen carbonate solution was added, the precipitated
base was sucked off and washed with water. The residue was dis-
solved in absolute ethanol and acidified with ethanolic hydrochloric
acid. On addition of ether the 3,5-dibromo-N-(dihydroxy-tert.-
butyl)-2-hydroxy-benzylamine hydrochloride was crystallized out.
M.p.: 187-189C.
Example_11
3,5-Dibromo-N-(dihydroxy-tert.-butyl)-2-hydroxy-benzylàmine
0.9 g of 2-benzoyloxy-3,5-dibromo-benzyl alcohol and 0.6 g of
dihydroxy-tert.-butylamine were heated for 1 hour at 140C.
The reaction product was dissolved in absolute ethanol, acidi-
fied with ethanolic hydrochloric acid and mixed with ether in
order to crystallize out the 3,5-dibromo-N-(dihydroxy-tert.-
butyl)-2-hydroxy-benzylamine hydrochloride.
Recrystallization from absolute ethanol/ether; m.p.: 187-189C.
-89-

L3
Example 212
3,5-Dibromo-N-(dihydroxy-tert.-butyl~-2-hydroxy-benzylamine
1.8 g of 6,8-dibromo-2-methyl-1,3-benz-dioxane and 1,8 g of di-
hydroxy-tert.-butylamine were heated for 20 hours at 140C.
Subsequently the reaction product was boiled with 100 ml of 2N
hydrochloric acid, mixed with activated charcoal filtered and the
solvent was evaporated. The residue was recrystallized twice from
absolute ethanol/ether in order to purify the 3,5-dibromo-N-
~dihydroxy-tert.-butyl)-2-hydroxy-benzylamine hydrochloride.
M.p.: 187 - 189C.
Example 213
3,5-Dibromo-N-~dihydroxy-tert.-butyl)-2-hydroxy-benzylamine
3 g of 6,8-dibromo-3,4-dihydro-3-~dihydroxy-tert.-butyl)-2H-
1,3-benzoxazine were dissolved in 30 ml of methanol and mixed
with 10 ml of water. The precipitate which formed was sucked
off after 1 hour and washed with a little methanol. The base
was dissolved in a little absolute ethanol, acidified with
ethanolic hydrochloric acid and mixed with ether, thus crystal-
lizing out the 3,5-dibromo-N-(dihydroxy-tert.-butyl)-2-hydroxy-
ben~ylamine hydrochloride.
M.p.: 187-189~C.
Example 214
3,5-Dichloro-2-hydroxy-N-isopropyl-beniylamine
M.p. of the hydrochloride: 188-189.5C.
Prepared from 3,5-dichloro-2-hydroxy-benzyl bromide and iso-
propylamine analogously to Example 199.
-90 -

`` ~IL~9Z~.~3
M.p. of the hydrochloride: 234 236C (decomposition).
Prepared from 3,5-dibromo-4-hydroxy-benzyl bromlda and tert.-
butylamine analogously to E~ample 199.
M.p.: 172-174~. .
Prepared from 3,5~dichloro-2--hydroxy~benzyl bro~id~ and tert.-
butylamine analogously to Example 199.
X~
M~p. of the hydrochloride: 222-223C (decomposition)
Prepared from 395-dichloro-4-hydroxy-benzy~ bromide and tert.-
butylami~e analogously to E~am~le 19g.
M.p. of the hydrochloride: 176-180C (decompoRition).
Prepared from 3,5-dibromo-4-hydroxy benzyl:bromide and tert.-
pentylamine analogously to E~ample 199.
.. 91 ~ `

~0~2~13
M.p~ o~ the hydroohloride: 203-207C tdecomposition).
Prepared ~rom ~5-dichloro-4-hydroxy-benzyl ~romide and t0rt.-
pen~ylamine analogously to EKample 199.
E m~
Mop~ of the h~drochloride: 189-191C.
Prepared ~rom 3,5-dibromo-2-hydroxy-benzyl~brom~e and hydroxy-
tert.-butylamine analogou31y to Example 199.
~ ' ,
M.p. of the hydrochloride: 200-202C.
Prepared from 3,5-dibromo-4-hydroxy-benzy] bromi~ and hydroxy-
tertO~butylamine analogously to ~kample 199.
~.
~a~2 ,
M.p, of the hydrochloride: 208-212C ~decomposition)
: Prepared ~rom 3,5-dichloro-4-hydroxy-benzyl brom~de and hydroxy~
tert.-butylamine an~logously to .EKample 199.
- 92

~1~)9Z:~L3
M.p. of the hydrochlorid~: 182-183,5C.
Prepared ~rom 3,5~dibromo-4-hydroxy-benzyl bromide and dihydroxy-
tert.-butylamine analogously to Example 1990
M.p. o~ the hydrochloride: 1~9-191,,5C.
Prepared ~rom 3,5-dibromo-4-hydroxy-benzyl' bromi~e and trihydroxy-
tert.-~butylamine ~nalogously to Example 199.
.
Exa~
~h~
M.p. of the hydrochloride: 166-169C (decomposition).
Prepared from 3,5-d~hloro~4-hydroxy-benzyl bromi~e and dihydroxy-
~ert.-butylamine analo~ously to Example 199
''
~2~
;
M.p. o~ the hydrochloride: 185-187C (decompo3ition).
Prepared from 3,5-dibromo-2-hydroxy-benzy1 bromlde and trihydroxy-
tert.-butylEmine analogously to Example 199.
~ ~3

~2~13
~ t~3~_ ~y~ L,L~ L5
M.p. o~ the hydrochloride: 170-174C ~d~compo~ition).
Prepared from 3,5-dichloro-4-hydroxy-benzyl bromidb a~d trlhy-
droxy tert. butylamine analogou~ly to E~mpl~ ~99.
~2~
M.p. of the hydrochloxide: 216-220C (d~compo~ition).
Pr~pared from 3,5-dibromo-salicylaldehyde, t0rt. b~tylami~e and
~ormic acid analogously to Exa~pl~ 203
am~2~
~ ~.
M.p~ o~ th~ hydrochloride: 229-233C (~co~positlo~.
~repared by ~eduction o~ N-(3,5-dibromo-4-~y~roxy-benzyl~den~)-
isopropylamine with sodium borohydride analogously to Example 204.
~2~o
M.p. o~ th~ hydrochloride~ 223-231C (d~co~position).
Prepared by reduction o~ N-(3~5-dichloro-4-hydro~y-bffnz~lid~
isopropyla~ine with ~odium borohydride a~alogousl~ to E~mpl~ 204.
9~, ~

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Example 231
3,5-Dichloro-2-hydroxy-N-tert.-pentyl-benzylamine
M.p. of the hydrochloride: 211-213C (decomposition).
Prepared by reduction of N-~3,5-dichloro-2-hydroxy-benzylidene)-
tert.-pentylamine with sodium borohydride analogously to Example
204.
Example 232
3,5-Dichloro-2-hydroxy-N-(hydroxy-tert.-butyl)-benzylamine
M.p. of the hydrochloride: 200-204.5C (decomposition)
Prepared by reduction of N-(3J5-dichloro-2-hydroxy-benzylidene)-
hydroxy-tert.-butylamine with sodium borohydride analogously
to Example 204.
Example 233
3,5-Dichloro N-(dihydroxy-tert.-butyl)-2-hydroxy-benzylamine
M.p. of the hydrochloride: 184 - 188C (decomposition).
Prepared by reduction of N-~3,5-dichloro-2-hydroxy-benzylidene)-
dihydroxy-tert.-butylamine with sodium borohydride analogously
to Example 204.
Example-234
3,5-Dichloro-2-hydroxy-N-~trihydroxy-tert.-butyl)-beniylamine
M.p. of the hydrochloride: 172-176C ~decomposition).
Prepared by reduction of N-~3,5-dichloro-2-hydroxy-benzylidene)-
trihydroxy-tert.-butylamine with sodium borohydride analogously
to Example 204.
-95-

~(~9Z~L3
Example 235
5-Bromo-N-tert.-butyl-2-hydroxy-benzylam
M.p. of the hydrochloride: 255-258C (decomposition).
Prepared by reduction of N-(5-bromo-2-hydroxy-benzylidene)-
tert.-butylamine with sodium borohydride analGgously to Example
204.
Example 236
Juice containing 4 mg of N-ethyl-N-cyclohexyl-3,5-dibromo-4-
hydroxy-benzylamine hydrochloride per 10 ml.
_ . . .
Composition:
100 ml of juice contain
active ingredient 0 04 g
tartaric acid 0 50 g
benzoic acid 0.20 g
ammonium chloride 0.40 g
glycerine 10.00 g
sorbitol 50 00 g
naphthol red S 0.01 g
raspberry flavouring 4824 0.25 g
(Messrs. Boake, Roberts ~ ~o.~
ethanol 10.00 g
distilled water ad 100.00 ml
Preparation:
45 g approximately of distilled water were heated to 80C.
The tartaric acid, benzoic acid, active substance, naphthol
red S and sorbitol were then dissolved in turn in the water
which was subsequently mixed with glycerine and a 20% solution
of the ammonium chloride. After cooling to room temperature,
ethanol and the raspberry flavouring were stirred into the
mixture. The juice was filled up to the indicated volume and
filtered in an appropriate manner.
-96-

13
Composition:
1 tablet contains
active ingredient 4.0 mg
lactose 60.0 mg
potato starch 41.0 mg
polyvinylpyrrolidone 4.0 mg
- magnesium stearate 1.0 mg
110.0 mg
Preparation:
The active ingredient was mixed with lactose and with potato
starch and granulated through a screen of 1 mm mesh-size with
a 20% aqueous solution of polyvinylpyrrolidone. The moist
granulate was dried at 40C, again passed through the above men-
tioned screen and mixed with magnesium stearate. The mixture
was pressed into tablets.
Weight of tablet: 110 mg
Punch: 7 mm
Example 239
Coated tablets containing 4 mg of N-ethyl-N-cyclohexyl-3,5-di-
bromo-4-hydroxy-benzylamine hydrochloride
.
The tablets prepared according to Example 238 were coated accord-
ing to conventional methods with a shell consisting essentially
of sugar and talcum. The finished coated tablets were polished
with beeswax.
Weight of coated tablet: 200 mg
Example 2~0
Suppositories containing 4 mg of N-ethyl-N-cyclohexyl-3,5-di-
bromo-4-hydroxy-benzylamine hydrochloride
. . _
-97-

Z~ L.3
10 ml of juice contain 4 mg of N-ethyl-N-cyclohexyl-
3,5-dibromo-4-hydroxy-benzylamine-hydrochloride.
Example 237
Drops containing 4 mg of N-ethyl-N-cyclohexyl-3,5-dibromo-4-
hydroxy-benzylamine hydrochloride per ml.
..... _ _ _ . ,, , _ _ _
Composition:
100 ml of drop solution contain
active ingredient 0.40 g
- methyl p-hydroxy-benzoate 0.07 g
propyl~p-hydroxy benzoate 0.03 g
polyvinylpyrrolidone 5.00 g
aniseed oil 0.01 g
fennel oil 0.001 g
ethanol - 10.00 g
distilled water ad 100.00 ml
Preparation:
The p-hydroxy-benzoic acid esters, polyvinylpyrrolidone and
active ingredient were dissolved in turn in the distilled water
warmed to 80C. The solution was cooled and subsequently mixed
- 20 with a mixture of the aromatic substances and ethanol. The
solution was made up to the indicated volume with distilled
water and filtered through an appropriate screen.
1 ml of drop solution contain 4 mg of N-ethyl-N-cyclo-
hexyl-3,5-dibromo-4-hydroxy-benzylamine hydrochloride.
Example 238
Tablets containing 4 mg of N-ethyl-N-cyclohexyl-3,5-dibromo-4-
hydroxy-benzylamine hydrochloride
-98-

~L~9Z~13
Composition:
l suppository contains
active ingredient 4.0 mg
suppository mass (e.g. Witepsol W 45) 1696.0 mg
1700.0 mg
Preparation:
The finely pulverized active ingredient was stirred into the molten
suppository mass cooled to 40C and homogenized. The mass was
poured into slightly pre-cooled moulds at about 35C.
Example 241
Ampoules containing 4 mg of N-ethyl-N-cyclohexyl-3,5-dibromo-
4-hydroxy-benzylamine hydrochloride
Composition:
1 ampoule contains
active ingredient 4.0 mg
tartaric acid 2.0 mg
glucose 95.0 mg
distilled water ad 2.0 ml
Preparation:
The distilled water was heated to 80C and the tartaric acid
and active ingredient were dissolved therein whilst stirring.
After cooling to room temperature the glucose was dissolved and
the solution was made up to the indicated volume. The solution
was then filtered sterile.
Filling: into white 2 ml-ampoules
Sterilisation: 20 minutes at 120C
_99 _