BENZIMIDAZOLE DERIVATIVES

DERIVES DE BENZIMIDAZOLE

English Abstract

ABSTRACT OF THE DISCLOSURE:
The invention is concerned with new benzimidazole
derivatives of the general formula:
<IMG>
wherein R1 represents a hydrogen atom, an alkyl group con-
taining from 1 to 6 carbon atoms (which may be substituted by
one or more than one of the same type of substituent selected
from the hydroxy group, alkenyl groups containing from 2 to 5
carbon atoms and alkanoyloxy groups containing from 2 to 7
carbon atoms), and R2 represents an alkyl group containing
from 7 to 20 carbon atoms, the group R1OOC- being attached to
the 4- or 5-position of the benzimidazole ring system, and
pharmaceutically acceptable salts thereof. The compounds of the
invention possess useful pharmacological properties, for
example hypolipidaemic activity.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for the preparation of benzimidazole deri-
vatives having the general formula:
<IMG> (I)
wherein R1 represents a hyarogen atom, a straight- or branched-
chain alkyl group containing from 1 to 6 carbon atoms (which
may be substituted by one or more than one of the same type of
substituent selected from the hydroxy group, alkenyl groups
containing from 2 to 5 carbon atoms and alkanoyloxy groups con-
taining from 2 to 7 carbon atoms), and R2 represents a straight-
or branched-chain alkyl group containing from 7 to 20 carbon
atoms, the group R1OOC- being attached to the 4- or 5-position
of the benzimidazole ring system, and of the pharmaceutically
acceptable salts thereof, which comprises:
a) cyclising a compound of the general formula:
<IMG>
(II)
wherein R0 represents a hydrogen atom or a group -COR2, and
R1 and R2 are as hereinbefore defined; or
b) reacting a compound of the general formula:
(V)
<IMG>

wherein R1 is as hereinbefore defined, with a compound of
general formula:
R2CHO (VI)
wherein R2 is as hereinbefore defined, and a copper (II) salt
in the presence of an aqueous inert organic solvent medium at
between ambient temperature and the reflux temperature of the
reaction mixture, followed by converting the resulting copper
salt into the corresponding compound of general formula (I); or
c) for preparing benzimidazole derivatives of general
formula (I) wherein R1 represents a hydrogen atom and R2 is as
hereinbefore defined, hydrolysing a corresponding ester of
general formula (I) wherein R1 represents a straight- or
branched-chain alkyl group containing from 1 to 6 carbon atoms,
which may be substituted by one or more than one of the same
type of substituent selected from the hydroxy group, alkenyl
groups containing 2 to 5 carbon atoms or alkanoyloxy groups containing from
2 to 7 carbon atoms, and R2 is as hereinbefore defined; or
d) for preparing benzimidazole derivatives of general
formula (I) wherein R1 represents a straight- or branched-
chain alkyl group containing from 1 to 6 carbon atoms, which
may by substituted by one or more than one of the same type of
substituent selected from the hydroxy group, alkenyl groups con-
taining from 2 to 5 carbon atoms or alkanoyloxy groups con-
taining from 2 to 7 carbon atoms and R2 is as hereinbefore
defined, esterifying a corresponding carboxylic acid of general
formula (I) wherein R1 represents a hydrogen atom, and R2 is as
hereinbefore defined; and
e) where desired, converting the benzimidazole derivative
of general formula (I) thus obtained into a pharmaceutically
acceptable salt.
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2. A process according to claim 1, wherein a compound of
the general formula:
<IMG> (II)
wherein R0 represents a hydrogen atom or a group -COR2, and R1
and R2 are as hereinbefore defined, is cyclised.
3. A process according to claim 2, wherein the compound
is cyclised by reaction with an inorganic acid in the presence
of water and in an organic solvent.
4. A process according to claim 3, wherein the cyclisation
is carried out at an elevated temperature.
5. A process according to claim 2, wherein R0 represents
a hydrogen atom and the compound is cyclised by reaction with
an organic acid in water or an organic solvent.
6. A process according to claim 5, wherein the compound
is cyclised at an elevated temperature.
7. A process according to claim 2, wherein the compound
is cyclised either (a) in the absence of an organic solvent
and at an elevated temperature, or (b) in the presence of water
and an inorganic acid and in a suitable organic solvent.
8. A process according to claim 2, wherein R1 represents
a hydrogen atom or a straight- or branched-chain alkyl group
containing from 1 to 6 carbon atoms,
9. A process according to claim 2, wherein R1 represents
a hydrogen atom.
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10. A process according to claim 2, wherein R1 represents
the methyl group.
11. A process according to claim 2, wherein R1 is an n-butyl,
2,3-dihydroxyprop-1-yl, allyl or pivaloyloxymethyl group.
12. A process according to claim 2, wherein R2 represents
a straight-chain alky] group containing from 7 to 20 carbon
atoms.
13. A process according to claim 2, wherein R2 represents
an alkyl group containing from 10 to 18 carbon atoms.
14. A process according to claim 2, wherein the group R1OOC-
is attached to the 5-position of the benzimidazole ring system.
15. A process according to claim 1, wherein a compound of
the general formula:
<IMG>
(V)
wherein R1 is as hereinbefore defined, is reacted with a com-
pound of general formula:
R2CHO (VI)
wherein R2 is as hereinbefore defined, and a copper (II) salt
in the presence of an aqueous inert organic solvent medium at
between ambient temperature and the reflux temperature of the
reaction mixture, and the resulting copper salt is converted
into the corresponding compound of general formula (I).
16. A process according to claim 15, wherein R1 represents a
hydrogen atom or a straight- or branched-chain alkyl group con-
taining from 1 to 6 carbon atoms.
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17. A process according to claim 15, wherein R1 represents
a hydrogen atom.
18. A process according to claim 15, wherein R1 represents
the methyl group.
19. A process according to claim 15, wherein R1 is an n-
butyl, 2,3-dihydroxyprop-1-yl, allyl or pivaloyloxymethyl group.
20. A process according to claim 15, wherein R2 represents
a straight-chain alkyl group containing from 7 to 20 carbon
atoms.
21. A process according to claim 15, wherein R2 represents
an alkyl group containing from 10 to 18 carbon atoms.
22. A process according to claim 15, wherein the group
R1OOC- is attached to the 5-position of the benzimidazole ring
system.
23. A process according to claim 1, which comprises:
a) cyclising a compound of the general formula:
<IMG> (II)
wherein R0 represents a hydrogen atom or a group -COR2, R1
represents a straight- or branched-chain alkyl group containing
from 1 to 6 carbon atoms, which may be substituted by one or
more than one of the same type of substituent selected from
the hydroxy group, alkenyl groups containing from 2 to 5 carbon
atoms or alkanoyloxy groups containing from 2 to 7 carbon atoms,
and R2 is as hereinbefore defined; or
74

b) reacting a compound of the general formula:
<IMG> (V)
wherein R1 represents a straight- or branched- chain alkyl
group containing from 1 to 6 carbon atoms, which may be sub-
stituted by one or more than one of the same type of substi-
tuent selected from the hydroxy group, alkenyl groups con-
taining from 2 to 5 carbon atoms or alkanoyloxy groups con-
taining from 2 to 7 carbon atoms, with a compound of the
general formula:
R2CHO (VI)
wherein R2 is as hereinbefore defined, and a copper (II) salt
in the presence of an aqueous inert organic solvent medium at
between ambient temperature and the reflux temperature of the
reaction mixture, followed by converting the resulting copper
salt into the corresponding compound of general formula (I);
and
c) hydrolysing the resulting ester of general formula (I)
to provide a benzimidazole derivative of general formula (I)
wherein R1 represents a hydrogen atom.
24. A process according to claim 23, wherein R2 represents
a straight-chain alkyl group containing from 7 to 20 carbon
atoms.
25. A process according to claim 23, wherein R2 represents
an alkyl group containing from 10 to 18 carbon atoms.
26. A process according to claim 23, wherein the group
RlOOC- is attached to the 5-position of the benzimidazole ring

system.
27. A process according to claim 1, which comprises:
a) cyclising a compound of the general formula:
<IMG> (II)
wherein R° represents a hydrogen atom or a group -COR2, R1
represents a hydrogen atom and R2 is as hereinbefore defined; or
b) reacting a compound of the general formula;
<IMG> (V)
wherein R1 represents a hydrogen atom, with a compound of
general formula:
R2CHO (VI)
wherein R2 is as hereinbefore defined and copper (II) salt in
the presence of an aqueous inert organic solvent medium at
between ambient temperature and the reflux temperature of the
reaction mixture, followed by converting the resulting copper
salt into the corresponding compound of general formula (I);
and
c) esterifying the resulting carboxylic acid of general
formula (I) by reaction of the acid, or an acyl chloride or
salt thereof, with an excess of an alcohol of the general for-
mula:
R3OH (VII)
wherein R3 represents a straight- or branched-chain alkyl
76

group containing from 1 to 6 carbon atoms, which may be substi-
tuted by one or more than one of the same type of substituent
selected from the hydroxy group, alkenyl groups containing from
2 to 5 carbon atoms or alkanoyloxy groups containing from 2 to
7 carbon atoms or by reaction with the corresponding alkyl halide.
28. A process according to claim 27, wherein R3 represents
a straight- or branched-chain alkyl group containing from 1
to 6 carbon atoms.
29. A process according to claim 27, wherein R3 represents
the methyl group.
30. A process according to claim 27, wherein R3 is an n-
butyl, 2,3-dihydroxyprop-1-yl, allyl or pivaloyloxymethyl group.
31. A process according to claim 27, wherein R2 represents
a straight-chain alkyl group containing from 7 to 20 carbon
atoms.
32. A process according to claim 27, wherein R2 represents
an alkyl group containing from 10 to 18 carbon atoms.
33. A process according to claim 27, wherein the group
RlOOC- is attached to the 5-position of the benzimidazole ring
system.
34. Benzimidazole derivatives of the general formula:
<IMG> (I)
wherein R1 represents a hydrogen atom, a straight- or branched-
chain alkyl group containing from 1 to 6 carbon atoms (which
77

may be substituted by one or more than one of the same type of
substituent selected from the hydroxy group, alkenyl groups
containing from 2 to 5 carbon atoms and alkanoyloxy groups
containing from 2 to 7 carbon atoms), and R2 represents a
straight- or branched-chain alkyl group containing from 7 to
20 carbon atoms, the group RlOOC- being attached to the 4-
or 5-position of the benzimidazole ring system, and pharma-
ceutically acceptable salts thereof, whenever prepared by a
process according to claim 1 or its obvious chemical equivalents.
35. Benzimidazole derivatives according to claim 34, when-
ever prepared by a process according to claims 2 or 7, or their
obvious chemical equivalents.
36. Benzimidazole derivatives according to claim 34, wherein
R1 represents a hydrogen atom or a straight- or branched-chain
alkyl group containing from 1 to 6 carbon atoms, whenever
prepared by a process according to claim 8 or its obvious
chemical equivalents.
37. Benzimidazole derivatives according to claim 34, wherein
R1 represents a hydrogen atom, whenever prepared by a process
according to claim 9 or its obvious chemical equivalents.
38. Benzimidazole derivatives according to claim 34, wherein
R1 represents the methyl group, whenever prepared by a process
according to claim 10 or its obvious chemical equivalents.
39. Benzimidazole derivatives according to claim 34, wherein
R1 is an n-butyl, 2,3-dihydroxyprop-1-yl, allyl or pivaloyloxy-
methyl group, whenever prepared by a process according to
claim 11 or its obvious chemical equivalents.
40. Benzimidazole derivatives according to claim 34, wherein
78

R2 represents a straight-chain alkyl group containing from 7 to
20 carbon atoms, whenever prepared by a process according to
claim 12 or its obvious chemical equivalents.
41. Benzimidazole derivatives according to claim 34, wherein
R2 represents an alkyl group containing from 10 to 18 carbon
atoms, whenever prepared by a process according to claim 13 or
its obvious chemical equivalents:
42. Benzimidazole derivatives according to claim 34, wherein
the group R1OOC- is attached to the 5-position of the benzimi-
dazole ring system, whenever prepared by a process according to
claim 14 or its obvious chemical equivalents.
43. Benzimidazole derivatives according to claim 34, whenever
prepared by a process according to claim 15 or its obvious
chemical equivalents.
44. Benzimidazole derivatives according to claim 34, wherein
R1 represents a hydrogen atom or a straight- or branched-chain
alkyl group containing from 1 to 6 carbon atoms, whenever pre-
pared by a process according to claim 16 or its obvious
chemical equivalents.
45. Benzimidazole derivatives according to claim 34, wherein
R1 represents a hydrogen atom, whenever prepared by a process
according to claim 17 or its obvious chemical equivalents.
46. Benzimidazole derivatives according to claim 34, wherein
R1 represents the methyl group, whenever prepared by a process
according to claim 18 or its obvious chemical equivalents.
47. Benzimidazole derivatives according to claim 34, wherein
R1 is an n-butyl, 2,3-dihydroxyprop-1-yl, allyl or pivaloyloxy-
methyl group, whenever prepared by a process according to claim
79

19 or its obvious chemical equivalents.
48. Benzimidazole derivatives according to claim 34, wherein
R2 represents a straight-chain alkyl group containing from 7 to
20 carbon atoms, whenever prepared by a process according to
claim 20 or its obvious chemical equivalents.
49. Benzimidazole derivatives according to claim 34, wherein
R2 represents an alkyl group containing from 10 to 13 carbon
atoms, whenever prepared by a process according to claim 21 or
its obvious chemical equivalents.
50. Benzimidazole derivatives according to claim 34, wherein
the group RlOOC- is attached to the 5-position of the benzimi-
dazole ring system, whenever prepared by a process according to
claim 22 or its obvious chemical equivalents.
51. Benzimidazole derivatives according to claim 34, wherein
R1 represents a hydrogen atom, whenever prepared by a process
according to claim 23 or its-obvious chemical equivalents.
52. Benzimidazole derivatives according to claim 34 r wherein
R1 represents a hydrogen atom and R2 represents a straight-chain
alkyl group containing from 7 to 20 carbon atoms, whenever pre-
pared by a process according to claim 24 or its obvious chemical
equivalents.
53. Benzimidazole derivatives according to claim 34, wherein
R1 represents a hydrogen atom and R2 represents an alkyl group
containing from 10 to 18 carbon atoms, whenever prepared by a
process according to claim 25 or its obvious chemical equivalents.
54. Benzimidazole derivatives according to claim 34, wherein
the group R1OOC- is attached to the 5-position of the benzimi-
dazole ring system and R1 represents a hydrogen atom, whenever
prepared by a process according to claim 26 or its obvious
chemical equivalents.

55. Benzimidazole derivatives according to claim 34, wherein
R1 represents a straight- or branched-chain alkyl group con-
taining from 1 to 6 carbon atoms, which may be substituted by
one or more than one of the same type of substituent selected
from the hydroxy group, alkenyl groups containing from 2 to 5
carbon atoms or alkanoyloxy groups containing from 2 to 7 car-
bon atoms, whenever prepared by a process according to claim 27
or its obvious chemical equivalents.
56. Benzimidazole derivatives according to claim 34, wherein
R1 represents a straight- or branched-chain alkyl group con-
taining from 1 to 6 carbon atoms, whenever prepared by a process
according to claim 28 or its obvious chemical equivalents.
57. Benzimidazole derivatives according to claim 34, wherein
R represents the methyl group, whenever prepared by a process
according to claim 29 or its obvious chemical equivalent.
58. Benzimidazole derivatives according to claim 34, wherein
R1 is an n-butyl, 2,3-dihydroxyprop-l-yl, allyl or pivaloyloxy-
methyl group, whenever prepared by a process according to claim
30 or its obvious chemical equivalents.
59. Benzimidazole derivatives according to claim 34, wherein
R1 represents a straight- or branched-chain alkyl group con-
taining from 1 to 6 carbon atoms, which may be substituted by
one or more than one of the same type of substituent selected
from the hydroxy group, alkenyl groups containing from 2 to 5
carbon atoms or alkanoyloxy groups containing from 2 to 7
carbon atoms, and R2 represents a straight-chain alkyl group
containing from 1 to 20 carbon atoms, whenever prepared by a
process according to claim 31 or its obvious chemical equivalents.
60. Benzimidazole derivatives according to claim 34, wherein
81

R1 represents a straight- or branched-chain alkyl group
containing from 1 to 6 carbon atoms, which may be substituted
by one or more than one of the same type of substituent
selected from the hydroxy group, alkenyl groups containing
from 2 to 5 carbon atoms or alkanoyloxy groups containing
from 2 to 7 carbon atoms, and R2 represents an alkyl group
containing from 10 to 18 carbon atoms, whenever prepared by
a process according to claim 32 or its obvious chemical
equivalents.
61. Benzimidazole derivatives according to claim
34, wherein the group RlOOC- is attached to the 5-position
of the benzimidazole ring system and R1 represents a straight-
or branched-chain alkyl group containing from 1 to 6 carbon
atoms, which may be substituted by one or more than one of
the same type of substituent selected from the hydroxy group,
alkenyl groups containing from 2 to 5 carbon atoms or alka-
noyloxy groups containing from 2 to 7 carbon atoms, whenever
prepared by a process according to claim 33 or its obvious
chemical equivalents.
82

62. A process according to claim 1 for the prepara-
tion of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid and
its pharmaceutically acceptable salts, comprising hydrolysing
methyl 2-(n-pentadecyl )-benzimidazole-5-carboxylate or an
acid addition salt thereof under alkaline conditions and, when
desired, converting the so obtained derivative into a
pharmaceutically acceptable salt.
63. A process according to claim 3 for the prepara-
tion of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid and
its pharmaceutically acceptable salts, comprising cyclising
3,4-bis(n-hexadecanamido)-benzoic acid with an inorganic acid
in the presence of water in an organic solvent, and, when
desired, converting the so obtained derivative into a
pharmaceutically acceptable salt.
64. A process according to claim 2 for the prepara-
tion of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid and
its pharmaceutically acceptable salts, comprising reacting
3,4-diaminobenzoic acid with palmitic acid in the presence of
water and an inorganic acid and in a suitable solvent,
allowing the resulting product to cyclise in situ and, when
desired, converting the so obtained derivative into a
pharmaceutically acceptable salt.
65. A process according to claim 2 for the prepara-
tion of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid and
its pharmaceutically acceptable salts, comprising treating
3,4-diaminobenzoic acid or a salt thereof with n-hexadecanoyl
chloride, cyclising to resulting product in situ and, when
desired, converting the so obtained derivative into a
pharmaceutically acceptable salt.
83

66. A process according to claim 3 for the prepara-
tion of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid and its
pharmaceutically acceptable salts, comprising cyclising
3-amino-4-(hexadecanamido)-benzoic acid with an inorganic
acid in the presence of water in an organic solvent and, when
desired, converting the so obtained derivative into a
pharmaceutically acceptable salt.
67. 2-(n-Pentadecyl)benzimidazole-5-carboxylic acid
and its pharmaceutically acceptable salts, whenever prepared
by a process according to claim 62, 63 or 64 or its obvious
chemical equivalents.
68. 2-(n-Pentadecyl)benzimidazole-5-carboxylic acid
and its pharmaceutically acceptable salts, whenever prepared
by a process according to claim 65 or 66 or its obvious
chemical equivalents.
69. A process according to claim l for the preparation
of 2-(n-undecyl)benzimidazole-5-carboxylic acid and its
pharmaceutically acceptable salts, comprising hydrolysing
methyl 2-(n-undecyl)-benzimidazole-5-carboxylate and, when
desired, converting the so obtained derivative into a
pharmaceutically acceptable salt.
70. 2-(n-Undecyl)benzimidazole-5-carboxylic acid and
its pharmaceutically acceptable salts, whenever obtained by a
process according to claim 69 or its obvious chemical
equivalents.
71. A process according to claim l for the prepara-
tion of n-butyl 2-(n-pentadecyl)benzimidazole-5-carboxylate
and its pharmaceutically acceptable salts, comprising
84

esterifying 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride
or a salt thereof with n-butanol and when desired, converting
the so obtained derivative into a pharmaceutically acceptable
salt.
72. n-Butyl 2-(n-pentadecyl)benzimidazole-5-carboxylate
and its pharmaceutically acceptable salts, whenever obtained
by a process according to claim 71 or its obvious chemical
equivalents.
73. A process according to claim 1 for the prepara-
tion of 2,3-dihydroxyprop-1-yl 2-(n-pentadecyl)-benzimidazole-
5-carboxylate and its pharmaceutically acceptable salts,
comprising esterifying 2-(n-pentadecyl)benzimidazole-5-carboxylic
acid or a salt thereof with glycerol in the presence of sodium
hydroxide and, when desired, converting the so obtained
derivative into a pharmaceutically acceptable salt.
74. 2,3-Dihydroxyprop-l-yl 2-(n-pentadecyl)-benzimi-
dazole-5-carboxylate and its pharmaceutically acceptable salts,
whenever obtained by a process according to claim 73 or its
obvious chemical equivalents.
75. A process according to claim 3 for the prepara-
tion of 2-(n-tridecyl)benzimidazole-5-carboxylic acid and its
pharmaceutically acceptable salts, comprising cyclising
2,3-bis(n-tetradecanamido)-benzoic acid with an inorganic acid
in the presence of water in an organic solvent, and, when
desired, converting the so obtained derivative into a
pharmaceutically salt.
76. 2-(n-Tridecyl)benzimidazole-5-carboxylic acid
and its pharmaceutically acceptable salts, whenever obtained by
a process according to claim 75 and its obvious chemical
equivalents.

77. A process according to claim 1 for the prepara-
tion of 2-(n-dodecyl)benzimidazole-5-carboxylic acid and its
pharmaceutically acceptable salts, comprising hydrolysing
methyl 2-(n-dodecyl)-benzimidazole-5-carboxylate or a salt
thereof and, when desired, converting the so obtained derivative
into a pharmaceutically acceptable salt.
78. 2-(n-Dodecyl)benzimidazole-5-carboxylic acid
and its pharmaceutically acceptable salts, whenever obtained by
a process according to claim 77 or its obvious chemical
equivalents.
79. A process according to claim 3 for the prepara-
tion of (RS)-2-(tetradec-2-yl)benzimidazole-5-carboxylic acid
and its pharmaceutically acceptable salts, comprising cyclising
3,4-bis [2-methyltetradecanamido] benzoic acid with an inorganic
acid in the presence of water and an organic solvent and, when
desired, converting the so obtained derivative into a
pharmaceutically acceptable salt.
80. (RS)-2-(tetradec-2-yl)benzimidazole-5-carboxylic
acid and its pharmaceutically acceptable salts, whenever
obtained by a process according to claim 79 or its obvious
chemical equivalents.
81. A process according to claim 3 for the prepara-
tion of 2-(n-hexadecyl)benzimida]ole-5-carboxylic acid and
its pharmaceutically acceptable salts, comprising cyclising
3,4-bis(n-heptadecanamido)-benzoic acid with an inorganic acid
in the presence of water and an organic solvent, and, when
desired, converting the so obtained derivative into a
pharmaceutically acceptable salt.
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82. 2-(n-Hexadecyl)benzimidazole-5-carboxylic acid
and its pharmaceutically acceptable salts, whenever obtained
by a process according to claim 81 and its obvious chemical
equivalents.
83. A process according to claim 3 for the prepara-
tion of 2-(n-octadecyl)benzimidazole-5-carboxylic acid and
its pharmaceutically acceptable salts, comprising cyclising
4-amino-3-(n-nonadecanamido)-benzoic acid with an inorganic
acid in the presence of water and an organic solvent, and,
when desired, converting the so obtained derivative into a
pharmaceutically acceptable salt.
84. 2-(n-Octadecyl)benzimidazole-5-carboxylic acid
and its pharmaceutically acceptable salts, whenever obtained by
a process according to claim 83 or its obvious chemical
equivalents.
85. A process according to claim 1 for the prepara-
tion of 2-(n-heptadecyl)benzimidazole-5-carboxylic acid and
its pharmaceutically acceptable salts, comprising hydrolysing
methyl 2-(n-heptadecyl)benzimidazole-5-carboxylate or a salt
thereof and, when desired, converting the so obtained
derivative into a pharmaceutically acceptable salt.
86. 2-(n-Heptadecyl)benzimidazole-5-carkoxylic acid
and its pharmaceutically acceptable salts, whenever obtained
by a process according to claim 85 or its obvious chemical
equivalents.
87. A process according to claim 3 for the prepara-
tion of methyl 2-(n-heptyl)benzimidazole-5-carboxylate acid
and its pharmaceutically acceptable salts, comprising cyclising
87

methl 3,4-bis(n-octanamido)benzoate with an inorganic acid
in the presence of water and an organic solvent, and, when
desired, converting the so obtained derivative into a
pharmaceutically acceptable salt.
88. Methyl 2-(n-heptyl)benzimidazole-5-carboxylate
acid and its pharmaceutically acceptable salts, whenever
obtained by a process according to claim 87 or its obvious
chemical equivalents.
88

Description

This invention relates to new therapeutically useful
benzimidazole derivatives and their pharmaceutically acceptable
salts, as well as to processes for preparing them and pharma-
ceutical compositions containing them.
The benzimidazole derivatives of the present invention are
represented by the general ormula:
RlOOC ~ ¦ ~ R2 (I)
H
wherein Rl represents a hydrogen atom, a straight- or branched-
chain alkyl group containing from 1 to 6 carbon atoms (which may
be substituted by one or more than one of the same type of
substituent selected from the hydroxy group, alkenyl groups
containing from 2 to 5 carbon atoms and alkanoyloxy groups con-
taining from 2 to 7 carbon atoms), and R2 represents a straight-
or branched-chain alkyl group containing from 7 to 20 carbon
atoms, the RlOOC- being attached to the 4- or 5-position of
the benzimidazole ring system.
Preferably, Rl represents a hydrogen atom, or a methyl
group, or a n-butyl, 2,3-dihydroxyprop-1-yl, allyl or pival-
oyloxymethyl group. Preferably also, R2 is a straight-chain
alkyl group and contains from 10 to 18 carbon atoms.
The group RlOOC is preferably attached to the 5-position
of the benzimidazole ring system.
It will be understood by those skilled in the art that
the compounds of general formula (I) exhibit tautomerism such
that the hydrogen atom which is depicted as residing on one of
the nitrogen may reside on either nitrogen atom, and that both
the forms thus described may be present to a greater or lesser
degree and are in a state of dynamic equilibrium with each
- 1 -

76S
other. In the tauto~ers the 4- and 5~positions become the 7-
and 6-positions respectively. Furthermore, in certain cases the
substituents Rl and R contribute to optical isomerism. A11
such forms are embraced by the present invention.
By the term "pharmaceutically acceptable salt" is meant a
salt formed by reaction with an acid or, when Rl represents a
hydrogen atom, by reaction with a base, so that the anion (in the
case of an acid addition salt) or the cation (in the case of a
salt formed by a compound of formula ~I) wherein Rl represents
a hydrogen atom) is relatively innocuous to the animal organism
when used in therapeutic doses so that the beneficial pharmacolo-
gical properties of the parent compound of general formula I
are not vitiated by side-effects ascribable to the said anion
or cation.
Suitable acid addition salts include salts derived from
inorganic acids, for example hydrochlorides, hydrobromides,
phosphates, sulphates and nitrates, and organic salts, for
example methanesulphonates, 2-hydroxyethanesulphonates, oxalates,
lactates, tartrates, acetates, salicylates, citrates, propionates,
succinates, fumarates, maleates, methylene-bis-~-hydroxy-
naphthoates, gentisates and di-p-toluoyltartrates.
Suitable salts formed by compounds of general formula (I)
wherein Rl represents a hydrogen atom include the alkali metal
(e.g. sodium and potassium), alkaline earth metal (e.g. calcium
and magnesium) and ammonium salts, and salts of amines known in
the art to be pharmaceutically acceptable, e.g. ethylenediamine,
choline, diethanolamine, triethanolamine, octadecylamine,
diethylamine, triethylamine, 2-amino-2-(hydroxymethyl)propane-
1,3-diol and 1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol.
It is to be understood that, where in this specification
reference is made to compounds of general formula (I), it is

S
intended to refer also to their pharmaceutically acceptable
salts, where the context so permits.
The new compounds of general ormula (I) are prepared in
accordance with this invention by any of the following process
(1) through (5).
1. According to a feature of the present invention, the
compounds of general formula (I) are prepared by the cyclisation
of a compound of the general formula:
1 ~ ~NHCOR2
R OOC ~ ll (II)
NHR
wherein R represents a hydrogen atom or a group -COR2, and
and R are as hereinbefore defined, optionally prepared ln
situ, for example as hereinafter described for the cyclisation
of compounds of general formula (III) or (IV).
(i) Thus, when R is a group -COR2, a compound of the
geneFal formula: ~ 2
NHCOR
RlOOC ~ (III~
HCOR2
wherein Rl and R2 are as hereinbefore defined, is cyclised,
preferably at an elevated temperature, for example between 60
and 100C, e.g. at or near 8~C, by reaction wi.h an inorganic
acid, for example hydrochloric acid, in the presence of water
and in an organic solvent, for example an alcohol such as
methanol or ethanol, or a ketone such as acetone or, preferably,
methyl ethyl ketone~ or
(ii) when RO is a hydrogen atom (especially in respect of
those compounds wherein Rl represents a straight- or branched-

chain alkyl group containing from 1 to 6 carbon atoms), a
compound of the geneLal formula:
NHCOR
R1OOC ~ (IV)
\NH2
wherein Rl and R2 are as hereinbefore defined, is cyclised,
either under conditions similar to those described hereinbefore
under (i) or, alternatively, by reaction with an organic acid,
e.g. p-toluenesulphonic acid, in water or an organic solvent,
e.g. toluene, preferably at an elevated temperature, for
example between 60 and 10~C, e.g. at or near 80C, or
(iii) (especially ;n respect of those compounds wherein Rl
represents a straight- or branched-chain alkyl group containing
from l to 6 carbon atoms) cyclisation usually without isolation
of an acylated intermediate of formula (III) or (IV) either
(a) in the absence of an organic solvent and at an elevated
temperature, for example at between 150 and 250C, or (b) in
the presence of water and an inorganic acid, for example
hydrochloric acid, and in a suitable organic solvent, for example
diglyme.
2. According to a further feature of the present invention,
the compounds of general formula (I) are prepared by the reaction
of a compound of the general formula:
~NH2
RlOOC ~ ll ( V )
~,
NH2
wherein Rl is as hereinbefore defined, with a compound of
general formula:
R CHO (VI)

6S
wherein R2 is as hereinbefore defined, and a copper (II) salt,
fo~ example c~pric acetate~ in the presence of an a~ueous inert
organic solvent medium, for example a mixture of water and
methanol, at between ambient temperature and the reflux tem-
perature of the reaction mixture, followed by converting the
resulting copper salt into the corresponding compound of for~
mula (I).
3. According to another feature of the present inventionl
carboxylic acids of genera~ formula (I) (wherein R2 is as here-
inbefore defined and Rl represents a hydrogen atom) are pre-
pared by hydrolysis o a corresponding ester of general formula
(I) wherein R2 is a hereinbefore defined and Rl represents a
straight- or branched-chain alkyl group containing from 1 to 6
carbon atoms, which may be substituted by one or more than one
of the same type of substituent selected from the hydroxy group,
alkenyl groups containing from 2 to 5 carbon atoms or alkanoyloxy
groups containing from 2 to 7 carbon atoms. Preferably, the
hydrolysis is carried out under alkaline conditions, for example
in the presence of an alkali metal hydroxide in an aqueous
organic solvent system and at an elevated temperature, e.g. in
the presence of sodium hydroxide, in a~ueous ethanol and at the
reflux temperature.
4. According to a still further feature of the present
invention, esters of general formula (I) (wherein R is as
hereinbefore defined and Rl represents a straight- or branched-
chain alkyl group containing from 1 to 6 carbon atoms, which may
be substituted by one or more than one of the same type of sub-
stituent selected from the hydroxy groupt alkenyl groups con-
taining from 2 to 5 carbon atoms or alkanoyloxy groups con-
taining from 2 to 7 carbon atoms) are prepared by esterificationof a corresponding acid of general formula (I) wherein R2 is as

6S
hereinbefore deined and Rl represents a hydrogen atom. The
esterification may be carried out by the application or adapta~
tion of known methods, or example by reaction of the acid with
an excess of the appropriate alcohol of the general formula:
~ OH (VII)
wherein R3 represents a straight- or branched-chain alkyl group
containing from 1 to 6 carbon atoms (which may be substituted
by one or more than one of the same type of substituent selected
from the hydroxy groupl alkenyl groups containing from 2 to 5
carbon atoms or alkanoyloxy groups containing from 2 to 7
carbon atoms) optionally as the solvent medium, and in the pre-
sence of an inorganic acid, e.g. hydrochloric acid, preferably
at an elevated temperature, e.g. between 60 and 100C; or by
reaction with the corresponding alkyl halide.
Acid chlorides formed by reaction with thionyl chloride,
or salts of the acids may be used.
5. According to a further feature of the present invention,
compounds of general formula (I) may be converted into pharma-
ceutically acceptable salts, and vice versa, by the application
or adaptation of known methods. As well as being useful in
itself, this process is useful for the purification of compounds
of general formula (I) and their salts by taking advantage of
differences in solubility in water and various organic solvents
of the compounds and their salts and of any impurities, by means
of known methods such as crystallisation.
(i) Compounds of general formula (I) may be converted to
their pharmaceutically acceptable acid addition salts, for
example, by reaction with the appropriate acid in solution or
suspension in a suitable solvent, e.g. acetone, methanol or
ethanol, followed if necessary by evaporation of part or all of
the solvent, and collection of the solid salt.
\ - 6 -
, .

(ii) On ~he othe~ hand, the acid addition salts may be
converted to the parent compounds of general formula (I), for
example by reaction with aqueous ammonia in the presence of a
suitable solvent, e.g. ethanol, followed by treatment with a
weak acid, for example glacial acetic acid.
(iii) Acids ~ general formula (I) wherein R represents a
hydrogen atom (R2 being as hereinbefore defined) may be con-
verted to salts of pharmaceutically acceptable bases, for
example, by reaction with the appropriate base, for example the
appropriate amine or a compound of the general formula:
MloR4 (VIII)
wherein Ml represents an alkali metal, e.g. sodium or potassium,
and R4 represents an alkyl group containing up to 4 carbon
atoms, e.g. methyl or ethylt or a hydrogen atom, in a suitable
solvent, e.g. methanol or ethanol, or a mixture of water and
acetone, followed if necessary by evaporation of part or all of
the solvent, a~d collection of the solid salt.
(iv) These salts may be converted to the parent compounds
of formula (I), for example by reaction with a suitable acid,
e.g. glacial acetic acid, in solution in a suitable solvent, e.g.
water or ethanol, followed if necessary by evaporation of part
or all of the solvent, and collection of the solid compound
of formula (I).
By the term "known methods" as used in this specification
is meant methods heretofore used or described in the literature.
It will be understoad by those skilled in the art that in
the performance o the processes of the present invention it
may be desirable to introduce chemical protecting groups into
the reactants in order to avoid secondary reactions taking
place; for example~ in process (1) hereinbefore described,
hydroxy groups in the substituent Rl depicted in general for-

7f~5
mula (II) may have been converted into benzyloxy groups beforereaction as described with subsequent remo~al of the benzyl
group. Furthermore~ one process of preparation may be selected
in preference to others as a means of making certain envisaged
compounds of general formula tI).
Compounds of general formula (II) wherein R represents a
hydrogen atom may be prepared from compounds of the general
formula:
NHCOR2
~
R ^~ W (IX)
N2
wherein Rl and R2 are as hereinbefore defined, by reduction, for
example by catalytic hydrogenation, using for example palladium
on charcoal.
Compounds of general formula (II) wherein R represents a
group of the formula -COR2 (R2 being as hereinbefore defined)
may be prepared from compounds of general formula (II) wherein
R represents a hydrogen atom by reaction with compounds of
general formu~a IXI) depicted hereinafter.
Compounds of general formula (IX) may be prepared by the
reaction of a compound of the general formula:
NH2
~\ '''-- (X)
2
wherein Rl is as hereinbefore defined, with a compound of general
formula XI, in a similar manner to that hereinafter described in
method A (i).
-- 8 --
,~

S
Compounds of general formula (Il) in which the substituent
group -NHCOR2 is meta to the substituent group -COORl and in
which R represents a hydrogen atom rnay be prepared by the
reaction of a compound of general formula (V) with a compound of
general formula (XI) as hereinaEter described in method A (ii).
Compounds of general formula (II) wherein R represents a
group of the formula -COR2 (R2 being as hereinbefore described)
may also be prepared by the reaction of a compound of general
formula V with a compound of general formula (XI) as herein-
after described in method A (i).
Compounds of general formula (II) wherein Rl represents astraight- or branched chain alkyl group containing from 1 to -6
carbon atoms (which may be substituted by one or more than one of
the same type of substituen~ selected from the hydroxy group,
alkenyl groups containing from 2 to 5 carbon atoms and
alkanoyloxy groups containing from 2 to 7 carbon atoms) may be
prepared by esterification o the corresponding compounds of
general formula (II) wherein Rl represents a hydrogen atom by the
application or adaptation of known methods, for example by
reaction with the corresponding diazoalkane in the presence of
an inert organic solvent.
Method A
The compounds of general formula (II) may be prepared by
the reaction of a compound of the general formula:
,~IH2
RlOOC l ll (V)
V~
~H2
wherein Rl is as hereinbefore defined, with an acylating agent
of the general formula:

765
R COX (XI)
wherein R2 is as hereinbefore defined and Xl represents a halogen,
preferably chlorine, or a hydroxy group. (According to pro-
cess (1) hereinbefore described, there follows cyclisation of
the resulting product optionally in situ). Particularly
suitable conditions are as follows:
(i) Compounds of general formula (V) wherein Rl is as
hereinbeEore defined may be reacted with acyl halides of general
formula (XI) wherein R2 is as hereinbefore defined and Xl
represents a halogen, preferably chlorine, in an inert organic
solvent, for example dichloromethane or dimethylformamide, pre-
ferably under anhydrous conditions and preferably in the pre-
sence of an acid binding agent, or example a trialkylamine,
e.g. triethylamine, or an alkali metal carbonate or bicarbonate,
e.g. anhydrous sodium or potassium carbonate.
(ii) Compounds of general formula (V), especially those
wherein Rl represents a straight- or branched-chain alkyl
group containing from 1 to 6 carbon atoms, may be reacted with
acyl halides ~f general formula (XI) wherein R2 is as herein-
~0 before defined and Xl represents a halogen, preferably chlorine,
under conditions similar to those described hereinbefore under
(i) but using a lesser quantity of the acyl halide and con-
trolling the temperature, preferably at between 0C and room
temperature.
By using a set o conditions between those described here-
inbefore under (i) and those described hereinbefore under (ii)
there would be obtained a mixture of intermediates of general
formula (III) and (IV)~ which would be cyclised under the con-
ditions described hereinbefo~e under (1) (i) and (1) (ii).
(iii) Compounds of general formula (V), especially those
wherein Rl represents a straight- or b~anched-chain alkyl group
-- 10 --

~417fi~i
containing fr~m 1 to 6 carbon atams, may be reacted with the com-
pounds of general ormula (XI) wherein R2 is as hereinbefore
defined and Xl represents a hydroxy group or a chlorine atom, to
form compounds o general ormula (I), usually without isolation
of acylated intermediates, either (a) in the absence of solvent
at an elevated temperatures, for example at between 150 and
250C, or (b) in the presence o water and an inorganic acid,
for examFle hydrochloric acid, and in a suitable solvent, for
example diglyme~
The compounds of general formula (I) possess useful pharma-
cological properties, in particular, hypolipidaemic activity.
For example~ they lower the concentrations of cholesterol and of
triglycerides in the blood. Furthermore, they hinder or prevent
the development of atheromatous lesions, and in addition they
reduce the proliferation of arterial smooth muscle cells which
is a major feature o atheromatous plaques. The compounds of
general formula (I) also lower blood glucose levels in mice
suffering from diabetes mellitus. The compounds of general
formula (I) also suppress lymphocyte transformation as do anti-
rheumatic drugs. Thus~ they are of utility in the prevention or
treatment of diabetes mellitus, hyperlipoproteinaemic states,
of atherosclerosis, and of associated conditions such as angina,
myocardial infarction, cerebral vascular occlusion, arterial
aneurism, peripheral vascular disease, recurrent pancreatitis
and xanthomas; as well as arthritis, immunological disease,
cancer and graft rejection.
Compounds of general formula (I) which are of particular
interest include the following compounds, their optically active
forms and their salts:
methyl 2-(n-pentadecy~)benzimidazole~5-carboxylate A
2-(n-pentadecyl)benzimidazole-5-carboxylic acid B
A

1141~7~S
methyl 2-(n-undecyl)benzimidazole-5-carboxylate C
2-(n-undecyl)benzimidazole-S-carboxylic acid D
methyl 2-(n-tridecy])benzimidazole-5-carboxylate E
2-(n-tridecyl)benzimidazole-5-carboxylic acid F
methyl 2-(n-dodec~l)benzimidazole-5-carboxylate G
2-(n-dodecyl)benzimidazole-5-carboxylic acid H
methyl 2-(n-decyl)benzimidazole-5-carboxylate
2-(n-decyl)benzimidazole-5-carboxylic acid J
methyl 2-(n-heptadecyl)benzimidazole-5-carboxylate 1~
2-(n-heptadecyl)benzimidazole-5-carboxylic acid L
methyl 2-(n-nonyl)benzimidazole-5-carboxylate M
2-(n-nonyl)benzimidazole-5-carboxylic acid N
methyl 2-(n-heptyl)benzi.midazole-5-carboxylate O
2-(n-heptyl)benzimidazole-5-carboxylic acid P
2-(n-tetradecyl)benzimidazole-5-carboxylic acid Q
2-(n-octyl)benzimidazole-5-carboxylic acid R
methyl 2-(n-tetradecyl.)benzimidazole-5-carboxylate S
methyl 2-(n-hexadecyl)benzimidazole-5-carboxylate T
2-(n-hexadecyl)benzimidazole-5-carboxylic acid U
methyl 2-(n-eicosyl)benzimidazole-5-carboxylate V
2-(n-eicosyl)benzimidazole-5-carboxylic acid W
methyl 2-(n-nonadecyl)benzimidazole-5-carboxylate X
2-(n-nonadecyl)benzimidazole-5-carboxylic acid Y
2-(n-octadecyl)benzimidazole-5-carboxylic acid Z
(RS)-2-(tetradec-2-yl)benzimidazole-5-carboxylic acid AA
(RS)-2-(tridec-3-yl)benzimidazole-5-carboxylic acid BB
2-(tridec-7-yl)benzimidazole-5-carboxylic acid CC
(RS)-2-(tridec-5-yl)benzimidazole-5-carboxylic acid DD
ethyl 2-(n-pentadecyl)benzimidazole-5-carboxylate EE
n-hexyl 2-(n-pentadecyl)benzimidazole-5-carboxylate FF
n-butyl 2-(n-pentadecyl)benzimidazole-5-carboxylate GG

Ii~s'i
isopropyl 2-(n-pentadecyl)benzimidazole-5-carboxylate HH
methyl 2-(n-octadecyl)benzimidazole-5-carboxylate II
pivaloyloxymethyl 2-(n-pentadecyl)benzimidazole-5-
carboxylate JJ
2,3 dihydroxyprop-1-yl 2-(n-pentadecyl)-benzimidazole-
5-carboxylate KK
2-(n-tridecyl)benzimidazole-4-carboxylic acid LL
tert-butyl 2-(n-pentadecyl)benzimidazole-5-carboxylate MM
allyl 2-(n-pentadecyl)benzimidazole-5-carboxylate NN
and
2-(n-pentadecyl)benzimidazole-4-carboxylic acid PP
The letters A to PP are assigned to the compounds for easy
reference later in the specification, for example in the Tables.
The properties of the compounds of general formula (I)
-were demonstrated in the following tests:
Hypolipidaemic Activity in Rats
Male Wistar rats each weighing between 120 and 150 g were
caged in groups af eight and fed a powdered diet for 10 days.
For the last 7 days cf that period the test compound was
administered orally by mixing the compound in the diet and
allowing the animals to feed no~mally. Food consumption was
measured on day 9 for each group.
At noon on day 10 the animals were killed by inhalation
of carbon dioxide from solid carbon dioxide. A sample of
blood was removed by cardiac puncture and the sc-rum cholestero]
and serum triglycerides were analysed by means of an auto-
analyser.
Control groups (receiving only the normal, unmedicated
diet) were included with each test.
The percentage reductions in the concentrations of serum
cholesterol and serum triglycerides were calculated by com-
- 13 -

~1765
parison with the simultaneous controls, for each concentra-
tion of the test compound used.
The results obtained are shown in following Table I.
TABI,E I
. .
ompound Form ~ w/w % change in serum
dose compared witl I control
. in diet cholesterol triglycerides
~ . _
A HCl 0.2 +7 -1
salt
B HCl a . 2 -50 -44
salt 0.2 -50 -64
0.2 -39 -40
a . 2 -22 -45
0.2 -21 -46
. 0.4 -61 -63
0.2 _ -55 -60
0.2 -42 -69
0.1 -3~ -3~
0.1 -14 -51
0 03 -2 -44
B mono- 0.2 +4 +19
hydrate 0.2 -10 _9
. 0.4 -63 -76
s sodium 0.2 -51 -64
salt 0.1 -24 -44
mono- 0.4 -62 -79
hydrate 0.2 -55 -62
C parent 0.2 -30 -57
compound 0.2 -13 -54
- 14 -

~1~17fi5
TABLE I (continued)
~ompound Form % w/w % change in serum
dose compared with control
in diet cholesterol triglyceridec
D HCl 0.2 -34 -60
salt 0.2 -24 -50
0.2 -40 -~0
E HCl 0.2 -23 -58
_ _ salt ~ __ . _
F HCl 0.2 _ ___ .
salt 0.2 -36 -47
0.03 -17 -10
G salt 0.2 -18 -41
H HCl 0.2~ -33 -52
salt 0.03 -4 -26
I HCl 0.2 -3 -36
. salt
J HCl -1~ .~
L HCl 0.2 -3 -36
salt 0.2 -20 -26
N HCl 0.2 -14 -3
_ salt . .
. O HCl 0.2 -4 +24
salt .
P 5 alt -18 -10
- 15 -

11'~1~6S
TABLE I (continued)
-
~ompound Form ~ w/w % change in serum
dose compared with control
in diet cholesterol triglycerldes
Q HCl 0.2 -41 -62
salt 0.2 -35 -69
. 0.03 -4 -20
R HCl 0.2 -2 -10
sal t
S HCl 0.2 ~9 -28
sal t
T HCl 0.2 +6 -20
salt
U HCl 0.2 -20 -50
salt
. .
V HCl 0~2 +2 -12
salt
W HCl 0.2 +5 -15
salt
.
X HC1 0.2 -10 -3
salt
_
Y HCl 0.2 -17 -14
sal t
Z HC1 0.2 0 -20
sal t
_
AA HG1 0.2 -35 -75
sal t
- 16 -

11~17t~5
TABLE I (continued)
~ompound Form ~ w/w % change in serum
dose compared wit~ control
in diet cholesterol triglycerides
.
BB HCl 0 . 2 -lg -46
salt
. _
CC H2SO4 0.2 -6 +9
half
salt
.
DD H2SO4 0.2 +11 -15
half
salt
_
EE HCl 0 . 2 -27 -47
salt
.
FF HCl 0 . 2 -16 -51
salt
GG HCl 0 . 2 -40 -54
salt 0.2 -33 -60
. .
HH HCl 0 . 2 -5 -32
salt l
II HCl 0 . 2 -1 -20
salt
JJ parent 0. 2 -40 -51
compound 0.1 -1 -33
KK HCl 0 . 2 -72 --73
salt 0.1 -28 -21
- 17 -

TABLE I (continued~
_
Compound Form % w/w % change in serum
dose compared wit ~ control
in diet cholesterol I triglycerides
MV HCl +4 I -8
~U salt 0.2 -19
~. u5Clt L
Anti-atheroma activity in Rabbits.
Male New Zealand White rabbits each weighing 2.2-2.8 kg
were subjected to de-endothelialisation of the abdominal aorta
and of one femoral artery by balloon catheter. After recovery
from the anaesthetic, they were each administered a diet to
which had been added 1% w/w cholesterol and a certain concen-
tration of the test compound, for 14 days. At the end of that
time the animals were killed and the concentration of the
serum cholesterol was determined. The aorta and femoral
arteries were removed, the intima-media were stripped from the
adventitia/ and the cholesterol concentrations were determined.
Portions of the femoral arteries were examined histologically.
A control yroup, not receiving the test compound, was
included with each test.
The percentage reductions in the concentrations of serum
cholesterol and arterial cholesterol were calculated by com-
parison with the simultaneous controls.
The results obtained are shown in following Table II.
- 18 -

~ _
a
E~
~ o a~ ~r a~
~ . l i
tJ ~'~I
~
O o o
o~ O O
.
Femoral artery ~ ~ o
aJ ~ ~ ~D r~
without prior de-
endothelialisation
o ~ .
~ ~ Femoral artery ~ ~ ~
H ~ 8 wi th prior de- l l
.~ endothelialisation
o
.~ Abdo.~inal aorta
c ~ o with prior de- ~ o
o o endotheliallsation
0~o~ __
~ ~ , ~r
3 0 ~ o o o
o\ ~ ,~
.. .,, ,~, o r~d~ .,~ ~
O '~ ~ C ~ r
O 1~ 0 :>~ O
u~ ~ ~
.~ _ .
o a:
~) __ _
-- lg --

~141i7~5
Hypoglycaemia Activity in Diabetic Mice
Diabetic mice (strain C 57, black, MRI derived Obese/
Obese) of either sex each weighing between 45 and 70 g were
fed a powdered diet for a period of 1 week preceding the test.
Treated animals were than given the test compound mixed in
the diet at a certain concentration for several days. The
animals were then weighed, anaesthetised with carbon dioxide
and bled by cardiac puncture.
The following serum parameters were assessed:
1. Glucose - by the glucose-oxidase method of God-Perid
2. Cholesterol and trigl~cerides - these were measured by an
auto-analyser after removal of phospholipids by
means of activated zeolite and extraction by
isopropanol,
Control groups (receiving only the normal, unmedicated
diet) were included with each test.
The percentage reductions in the concentrations of serum
glucose, and serum cholesterol and serum triglycerides were
calculated by comparison with the simultaneous controls, for
each concentration of the test compound used.
The results obtained are shown in following Table III.
_ . /
- 20 -

;5
,~,
.
o
C ~
o ~ ~ Ln
c ;) a~ ~ o
~ S: o
O~o 3 ~
. .
~s ~a
a
tn Q~ ,~
.,~ O ~ Ln ~ ~D
H ~ tlJ O
H ~ t) 5
~ O ~
m O~o ~ 3
o ~ u~
.,~ ~ ~ ~ ~ :~
,~
~o l~
J~
3 .a) ~
a) 3 ~ o o o o
C: o\'' ,~
___.
a
~ ~ E L) E
Li rl ~J O ~ ~ ~ OS~ ~ ~ O
o ~ ~1 C ~ro ~ I c
O ~ O ~ O ~ O ~ O ~ O
u~ ~n E Su~
_ ._
~C
O
m .
E
_. __
-- 21 --

7~
Aortic smooth muscle cell proliferation
inhibiting activity.
Smooth muscle cells were grown in culture from explants of
pig thoracic aorta, using Dulbeccc's Modified Eagles (DME)
Medium containing 2G ~ foetal calf serum (ECS) and antibiotics.
The cells were incubated at 37C ln an atmosphere of 95 % air
and 5 % carbon dioxide. At confluency the cells were routinely
subcultured by trypsinising and replating at approximately one
third of their confluent density in DME Medium containing 10 %
FCS and antibiotics.
The smooth muscle cells were plated out at densities of
100,000 - 200,000 cells per 35 x 10 mm Falcon dish in 2 ml
DME Medium, containing 10 % FCS and antibiotics. After 24
hours, when the cells had attached to the dishes, the medium
was replaced with 2 ml DME Medium containing 1 % FCS and
antibiotics. The cultures were incubated for a further three
days to allow the cells to become quiescent (i.e. no longer
undergoing cell division). The medium was then replaced by
2 ml control or test medium. The test medium consisted of DME
Medium (containing 10 % FCS and antibiotics) and the compound
to be tested at a concentration of 5 ,ug/ml medium. The com-
pounds were pre-dissolved in water, acetone or glycofurol such
that the final concentration of solvent in the medium was 0.2
(v/v). The controlmedium consisted of DME Medium ~containing
10 % FCS and antibiotics) and appropriate solvent at 0.2 %
(v/v) concentration. After three days incubation in test or
control medium, the medium was replaced with fresh test or
control medium and the cells incubated for a further three or
four days. ~t the end of the six or seven day incubation
period cell numbers were determined by trypsinising the cells
and counting the cell suspension in a Coulter counter.
- 22 -

6S
All results in ~'able IV hereafter represent the mean
value for our dishes of cells. Percentage inhibition of pro-
liferation was calcu]ated using the following formula:
Percentage inhibition of proliferat;on
= 100 - (C S)x 100
Where S = Mean cell number per dish at start of experiment
(upon addition of control or test medium).
T = Mean cell number per dish in test cultures at
completion of experiment.
C = Mean cell number per dish in control cultures
at completion of experiment.
_
Compound Form Solvent % inhibition
L HCl H2O 48
salt 2 31
. -
O HClacetone 33
saltacetone 38
glycofurol 54
acetone 23
A HClacetone 21
saltacetone 16
acetone 41
Mitoqen-stimulated lymph node cell lymphocyte
transformation inhibiting activity in Guinea Pigs
Guinea pigs were sensitised to Mycobacterium tuberculosum
by footpad injections of Freund's Complete Adjuvant (FCA)
(0.05 ml; 0.05 mg/ml of 50 ~ v/v FCA solution in sterile
physiological saline).
- 23 -

1~17~5
After L4 days lymph node cells were obtained and suspended
in Eagles Minimal Essential (EME) Medium~ containing 10 %
foetal cal serum (FCS) and bufered with Earle's salts~ at a
concentration of 2.5 x 10~ ~ells/ml.
For 24 hours, 0.1 ml o cell suspension was incubated at
37C in an atmosphere of 95 % air and 5 % carbon dioxide in the
presence o 0.15 ml o mitogen or of mitogen plus the compound
to be tested in E~ Medium (containing 10% FCS and buffered
with Earle's salts).
Eighteen hours befo~e harvestingr 3H-th~midine (l ul of
lO0 ~Ci/ml solution in 0~9 ~ sterile saline) was added.
As an index of DNA synthesis, the level of 3H-thymidine
incorporation by the cells was measured, with comparison with
the mitogen control.
The results are given below in Table V.
TABLE V
Compound Dose in % inhibition of
incubation 3H-thymidine incorporation
medium into cell DNA compared
~g/ml with mitogen control
L 3 83
98
O Cl
The utility of the compounds is enhanced by the fact that
they are of only very low toxicity, as demonstrated in the
following test:
L - 24 -

11~1 1~65
Oral Toxicity in ~lice
Groups of mice were dosed orally with graded doses o~ the
test compound (in a 0.5 % w/v aqueous suspension of tragacanth
mucilage) and observed or 3 days thereafter. The percentages
of animals which died during that period at each dose ]evel
were used to construct a graph, from which the LD50, that is to
say the dose in mg/kg animal body weight, necessary to kill
50 ~ of the mice, was calculated.
Compounds of formula (I) specified in the list above were
tested and the LD50 f each compound was greater than 1000 mg/kg
animal body weight.
Preferred compounds of the invention are those hereinbefore
identified by the letters B, D, GG, KK, F, H, AA, U, Z, L and O.
The present invention therefore includes within its scope
pharmaceutical compositions which comprise at least one of the
compounds of general formula (I) or a pharmaceutically
acceptable salt thereof in association with a pharmaceutically
acceptable carrier or coating. In clinical practice, the com-
pounds of the present invention may be administered parenterally,
but are preferably administered rectally or, more preferably,
orally.
Solid compositions for oral administration include com-
pressed tablets, pills, powders and granules. In such solid
compositions, one or more of the active compounds is, or are,
admixed with at least one inert diluent such as starch, sucrose
or lactose. The compositions may also comprise, as is normal
practice, additional s~bstances other than inert di]uents, e.g.
lub~icating agents, such as magnesium stearate.
Liquid compositions for oral administration include pharma-
ceutically acceptable emulsions, solutionsr suspensions,syrups and elixirs containing inert diluents commonly used in

7~5
the art such as water and liquid paraffin. Besides inert
diluents such compositions may comprise adjuvants, such as
wetting, and suspending agents, and sweeteniny, flavouring,
perfuming and preserving agents. The compositions according to
the invention for oral administration also include capsules of
absorbable material such as gelatin, containing one or more of
the active substances with or without the addition of diluents
or excipients.
Preparation according to the invention for parenteral
administation include sterile aqueous, aqueous-organic, and
organic solutions, suspensions and emulsions. Examples of
organic solvents or suspending media are propylene glycol, poly-
ethylene glycol, vegetable oils such as olive oil and injectable
organic esters such as ethyl oleate. These compositions may
also contain adjuvants such as stabilising, preserving, wetting,
emulsifying and dispersing agents. They may be sterilized by,
for example, filtration through a bacteria-retaining filter, by
incorporation in the compositions of sterilizing agents, by
irradiation or by heating. They may also be manufactured in the
form of sterile solid compositions, which can be dissolved in
sterile water or some other sterile injectable medium immediately
before use.
Solid compositions for rectal administration include sup-
positories formulated in accordance with known methods and con-
taining one or more o the compounds of formula I or a pharma-
ceutically acceptable salt thereo.
The percentage of active ingredient in the compositions of
the invention may be varied, it being necessary that it should
constitute a proportion such that a suitable dosage shall be
obtained. Obviously several unit dosage forms may be adminis-
tered at about the same time. The dose employed will be
- 26 -

11~17t~S
determined by the physician, and depends upon the desirecl
therapeutic effect, the route of administration and the dura-
tion o the treatment, and the condition of the patient. In
the adult, the doses are generally between 0.1 and 50 mg/kg
body weight per day by oral administration, for example as
hypolipidaemic and anti-atheroma agents and in associated car-
diovascular diseases, between 10 and 50 mg/kg body weight per
day by oral administration; in the treatment of diabetes,
between 5 and 40 mg/kg bod~ weight per day by oral administration
and in the treatment of arthritis and associated diseases, bet-
- ween 0.1 and 10 mg/kg body weight per day by oral administration.
The following Examples and Reference Examples illustrate
the preparation of the compounds of the present invention.
EXAMPLE 1
Compound A
A solution of methyl 4-amino-3-(n-hexadecanamido)benzoate
(46 g) and p-toluenesulphonic acid (lS g) in toluene (1000 ml)
was stirred and heated at reflux for 2 hours, with the water
produced being removed continuously by means of a Dean and
Stark apparatus. The solution was cooled to 60C and was
washed with aqueous sodium carbonate solution (2N; 2 x 200 ml).
The toluene layer was dried over magnesium sulpha~e and was
then concentrated in vacuo, to give an oil. The oil was tri-
turated with petroleum ether (b.p. 40 - 60C) to yield a buff
solid which, on recrystailisation rom petroleum ether
(b.p. 40 - 60C), gave methyl 2-(n-pentadecyl)benzimidazole-
5-carboxylate (24.6 g) in the form of a white solid, m.p. 96 -
98C.
The methyl 4-amino-3-(n-hexadecanamido)-benzoate, used
as starting material, was prepared by either of the following
methods:
- 2

i5
(i) A stirred solution o~ methyl 3,4-diaminobenzoate (35 g)
in dry dimethylormami~e (12aO ml)f containing anhydrous sodium
carbonate (11.~ g), was treated dropwise with n-hexadecanoyl
chloride (58 g) during one hour. The rate of addition of the
n-hexadecanoyl chloride was such as to allow the temperature of
the reaction mixture to rise from an initial value of 10C to
room temperature. The mixture was then stirred at room tem-
perature for a further period of 3 hours and was then poured
into water (5 litres). The resulting solid was collected and
was boiled in acetone (1000 ml) and the boiling mixt~re was
then filtered. The filtrate was cooled to 0C and the resulting
buff solid was filtered off, to give methyl 4-amino-3-(n-hexa-
decanamido)benzoate (48.2 g), m.p. 112 - 114C.
(ii) A stirred solution o methyl 3,4-diaminobenzoate (16.6 g)
in dry dichloromethane (270 ml), containing triethylamine
(10.3 g) t was treated dropwise with a solution of n-hexadecanoyl
chloride (27.5 g) in dry dichloromethane (30 ml) during 45
minutes. The temperature during the addition was maintained
between 16 and 20~C. The mixture was stirred for a further
period of 2 hours. The resulting solid was then collected and
boiled in a mixture o acetone (1000 ml) and methanol (150 ml)
and the insoluble material was removed by filtration. The
filtrate was cooled to 25C and treated with water (800 ml) to
give methyl 4-amino-3-(n-hexadecanamido)-benzoate in the form
of a buff solid, m.p. 112~ - 114C.
EXAMPLE 2
Compound A
A solution of meth~l 4-amino-3-(n-hexadecanamido)benzoate
(34 g; prepared as described hereinbefore in Example 1) in a
mixture of ethanol and water (200 ml; 9:1 v/v) was treated with
an excess o a saturated solution of hydrogen chloride in
- 28 -

765
ethanol. The mixture was heated at ref]ux for 2 hours and was
then cooled. The resulting solid was collected and recrystallised
from a mixture of ethanol and water (9:1 v/v) to give methyl
2-~n-pentadecyl)benzimidazole-S-carboxylate hydrochloYide
(24.2 g) in the form of a white solid, m.p. 230 - 232C (with
decomposition).
EXAMPLE 3
Compound A
Methyl 3r4-diaminobenzoate (8.8 g) and hexadecanoic acid
(12.8 g) were ground together to form an intimate mixture.
The mixture was heated at 200C for 150 minutes. The mixture
was then cooled to 60C and was extracted with boiling petroleum
ether (b.p. 60 - 80C; 2~ ml). The extract was concentrated
n vacuo to give a brown oil. The oil was dissolved in ethanol
(100 ml) and the solution was treated with a solution of
potassium hydroxide in ethanol (10 ~ w/w) until the pH of the
mixture was 7. The mixture was then cooled to OOC and filtered
and the filtrate was concentrated _ vacuo to give a brown oil
(ln.2 g). The oi] was dissolved in chlorofo~m (15 ml) and
chromatographed on silica gel (275 g). Elution with ¢hlorofo~m
gave an of-white solid (6.0 g), which was recrystallised from
petroleum ether (b.p. 40~ - 60C), to give meth~l 2-(n-penta-
decyl)benzimidazole-5-carboxylate (5.3 g) in the form of a
white solid, m.p. 96 - 98C.
EXAMPLE 4
Compound B
A stirred solution of methyl 2-(n-pentadecyl)-benzimidazole-
5-carboxylate (36 g; prepared as described hereinbefore in
Example 1 or 3) in a mixture of ethanol and water (500 ml; 4:1
v/v) containing sodium hydroxide (8 g) was heated at reflux for
90 minutes. The mixture was cooled to 0C and was acidified by
- 29 -

il~l7~iS
treatment with concentrated hydrochloric acid. The resulting
off-white so]id was collected and was recrystallised (with treat-
ment with charcoal) from a mixture o ethanol and water (800 ml;
4:1 v/v) to give 2-(n-pelltadecyl)benzimidazole-5-carboxylic
acid hydrochloride (32 g) in the form of a white solid, m.p.
289 - 291C (with decomposition).
EXAMPLE 5
Compound B
A solution of methyl 2-(n-pentadecyl)-benzimidazole-5-
carboxylate hydrochloride (24.2 g; prepared as described here-
inbefore in Example 2) in a mixture of ethanol and water
(250 ml; 4:1 v/v), containing sodium hydroxide (7 g) was
treated in a manner similar to that described hereinbefore in
Example 4 to yive 2-(n-pentadecyl)benzimidazole-5-carboxylic
acid hydrochloride (22.4 g), m.p. 289 - 291C (with decom-
position).
EXAMPLE 6
Compound C
A solution o methyl 4-amino-3-(n-dodecanamido)benzoate
(41.0 g) in toluene (1000 ml) containing p-toluenesulphonic
acid (25 g) was treated in a manner similar to that described
hereinbefore in Example 1 to give methyl 2-(n-undecyl)-ben-
zimidazole-5-carboxylate (27.0 g) in the form of a white
solid, m.p. 93 - 95C
~he methyl 4-amino-3-(n-dodecanamido)-benzoate, used as
starting material, was prepared as follows:
A solution of methyl 3,4-diaminobenzoate (25.0 g) in dry
dimethylformamide (1120 ml), containing anhydrous sodium car-
bonate (7.7 g), was treated with n-dodecanoyl chloride (30.5 g)
in a manner similar to that hereinbefore described in Example
l(i) to give crude methyl 4-amino-3-(n-dodecanamido)benzoate
- 30 -

(41 g) in the form o~ a buf solid.
EXAMPLE 7
Compound C
Methyl 3,4-diaminobenzoate (33 g) and dodecanoic acid
(40 g) were ground together to form an intimate mixture and the
mixture was heated at 200C for 3 hours. The mixture was
then treated in a manner similar ta that described hereinbefore
in Example 3 to give methyl 2-(n-undecyl)benzimidazole-5-car-
boxylate (19 g) in the form of a white~solid, m.p. 92 - 94C.
EXAMPLE 8
Compound D
A solution of methyl 2-(n-undecyl)-benzimidazole-5-carboxy-
late (28.6 g; prepared as described hereinbefore in Example 7)
in a mixture of ethanol and water (350 ml; 4:1 v/v) containing
sodium hydroxide (6.93 g) was treated in a manner similar to
that described hereinbefore in Example 4 to give 2-(n-undecyl)
benzimidazole-5-carboxylic acid hydrochloride (22.3 g) in the
form of a white solid, m.p. 289 - 294C (with decomposition).
EXAMPLE 9
Compound E
Methyl 3,4-diaminobenzoate (33.0 g) and n-tetradecanoic
acid (45.6 g) were ground together to form an intimate mixture
and the mixture was heated at 200C for 6 hours. The mixture
was cooled to 60C and was then extracted with petroleum ether
(b.p. 60 - ~0C), and the petroleum ether extracts were com-
centrated ln vacuo to give a brown oil. The oi] was dissolved
in ethanol (500 m]) and the solution was treated with a
solution of potassium hydroxide in ethanol (10 % w/v) until
the pH of the mixture was 7. The mixture was cooled to 0C
and filtered and the filtrate was concentrated in vacuo to
give a brown oil. The oil was partitioned between a hot mix-

~1~17~5
ture of petroleum ether (b.p. 60 - 80C) and toluene (300 ml;
4:1 v/v~, and water (3~0 ml)~ The organic layer was concentrated
in vacuo to give an oil which was then dissolved in hot toluene
(100 ml) and treated with an excess of a saturated solution of
hydrogen chloride in ethanol. The resulting solid was collected
and recrystallised from ethanol (with treatment with charcoa')
to give methyl 2-(n-tridec~l)benzimidazole-5-carboxylate hydro-
chloride (16 g) in the form of a white solid, m.p. 228 - 236 C
(with decomposition).
EXAMPLE 10
_
Compound E
Methyl 4-amino-3-(n-tetradecanamido)-benzoate (40 g) was
treated in a manner similar to that described hereinbefore in
Example 2 to give methyl 2-(n-tridecyl)benzimidazole-5-car-
boxylate hydrochloride (33 g) in the form of a white solid,
m.p. 228 - 234C (with decomposition).
The methyl 4-amino-3-(n-tetradecanamido)-benzoate, used as
starting material, was prepared as follows:
A stirred solution of methyl 3,4-diaminobenzoate (25.0 g)
in dry dichloromethane (5aO ml), containing triethylamine
(15.5 g), was treated dropwise with a solution of n-tetradecanoyl
chloride (37.12 g) in dry dichloromethane (50 ml) in a manner
similar to that described hereinbefore in Example l(ii) to give
crude methyl 4-amino-3-(n-tetradecanamido)-benzoate (40 g) in
the form of a buff solid.
EXAMPLE 11
Compound F
A solution of methyl 2-(n-tridecyl)-benzimidazole-5-car-
boxylate (7.9 g) in a mixture of ethanol and water (200 ml;
4:1 v/v) containing sodium hydroxide (2.4 g) was treated in a
manner similar to that described hereinbefore in Example 4 to
- 32 -

11~1765
give 2-(n-tridecyl)benzimidazole-5-carboxylic acid hydrochloride
(5.7 g) in the form of a white solidt m.p. 299 - 305C
(with decomposition).
EXAMPLE ]2
Compound B
2-(n-Pentadecyl)benzimidazole-5-carboxylic acid hydro-
chloride ( 15~0 g; prepared as described hereinbefore in
~xample 4) was dissolved in a hot mixture of ethanol and water
(1000 ml; 6:1 v/v). The hot solution was treated with aqueous
ammonia solution (2N) until the solution was alkaline. Glacial
acetic acid was then added to the mixture until the solution
was acidic, and the solution was cooled to 0C to give a white
solid (12.3 g). This solid was recrystallised from a mixture of
ethanol and water (4:1 v/v) to give 2-(n-pentadecyl)benzimida-
zole-5-carboxy]ic acid ~12.0 g) in the form of a white solid,
m.p. 113 - 115C, thought to be the monohydrate.
EXAMPL~ 13
Compound G
Methyl 4-amino-3-(n-tridecanamido~benzoate (prepared as
described hereinafter from 17.8 g of methyl 3,4-diaminobenzoate
and used without further purification) was dissolved in hot
ethanol (500 ml) containing an excess of hydrochloric acid, and
was treated in a manner similar to that described hereinbefore
in Example 2 to give methyl 2-(n-dodecyl)-benzimidazole-5-
carboxylate hydrochloride (25.5 g) in the form of a white solid,
m.p. 221 - 225 C (with decomposition).
The methyl 4-amino-3-(n-tridecanamido)benzoate, used as
starting material, was prepared as follows:
A solution of methyl 3,4-diaminoben20ate (17.8 g) in
dichloromethane (350 ml) containing triethylamine (10.8 g)
was treated with n-tridecanoyl chloride (25 g) in a manner

11417f~5
similar to that described hereinbefore in Example l(ii) to give
crude methyl 4-amino-3-(n-tridecanamido)benzoate (40 g).
EXAMPLE 14
Compound H
A solution of methyl 2-(n-dodecyl)-benzimidazole-5-car-
boxylate (15.5 g) in a mixture of ethanol and water (100 ml;
4:1 v/v) containing sodium hydroxide (50 g) was treated in a
manner similar to that described hereinbefore in Example 4 to
give 2-(n-dodecyl)benzimidazole-5-carboxylic acid hydrochloride
(11.7 g) in the form of a white solid, m.p. 276 - 290C (with
decomposition).
EXAMPLE lS
Compound B
A solution of 3,4-bis(n-hexadecanamido)-benzoic acid (20 g)
in methyl ethyl ketone (400 ml) was treated with concentrated
hydrochloric acid (35 ml of strength 36.5 % w/v). The mixture
was heated at reflux far 5 hours and was then cooled. The
resulting solid-was collected and washed with boiling petro-
leum ether (b.p. 60 - 80C), and recrystallised from ethanol
to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydro-
chloride (15 g) in the form of a white solid, m.p. 289 - 291C
(with decomposition).
The 3,4-bis(n-hexadecanamido)benzoic acid, used as
starting material, was prepared as follows:
A solution of 3,4-diaminobenzoic acid (7.5 g) in dichloro-
methane (100 ml) containing triethylamine (15 g) was treated
with n-hexadecanoyl chloride (27.5 g) in a manner similar to
that described hereinbefore in Example l(ii). A solid was
collected and was recrystallised from glacial acetic acid and
was then recrystallised from methyl ethyl ketone (with filtra-
tion o the hot solution) to give 3,4-bis(n-hexadecanamido)ben-
- 34 -
. i
... ..,~

zoic acid (20 g) in the orm of a buf solid/ m.p. 198-202C.
EXAMPLE ]6
Compound A
A solution of methyl 3,4-bis(n-hexadecanamido)benzoate
(10.0 g) in methyl ethyl ketone (100 ml) was treated in a manner
similar to that described hereinbefore in Example 15 to give
methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride
(5.7 g) in the form of a white solid, m.p. 230-232C (with
decomposition).
The methyl 3,4-bis(n-hexadecanamido)-benzoate, used as
starting material, was prepared as follows:
A solution of methyl 3,4-diaminobenzoate (5.0 g) in
dichloromethane (50 ml)~ containing triethylamine (6.2 g), was
treated with n-hexadecanoyl chloride (16.5 g) in a manner
similar to that described hereinbefore in Example l(ii) (the
temperature of the reaction mixture during the addition being
allowed to rise from 20C to 30C). A solid was collected and
recrystallised from chloroform to give methyl 3,4-bis(n-hexa-
decanamido)benzoate (14.9 g) in the form of a white solid,
m.p. 129-132C.
EXAMPLE 17
Compound I
A stirred solution of methyl 3,4-bis(n-undecanamido)
benzoate (33.0 g) in methanol (400 ml) containing concentrated
hydrochloric acid (50 ml of strength 36.5 % w/v) was heated at
. . .
reflux for 3 hours. The mixture was then cooled to 0C and
filtered, and the solid obtained was combined with the residue
resulting from evaporation of the filtrate in vacuo. The com-
bined solids were washed with hot petroleum ether (b.p. 60-
80C; 200 ml) and recrystallised from ethanol (with filtration
of the hot solution) to give methyl 2-(n-decyl)benzimidazole-5-
- 35 -

765
carboxylate hydrochloride in ~he form o a white solid (13.7 g),
m.p. 230-240C (with decomposition).
The methyl 3~4-bis(n-undecanamido)-benzoate, used as
starting material, was prepared as follows:
A solution of methyl 3,4-diamin~benzoate (17.9 g) in
dichloromethane (300 ml) containing triethylamine (21.8 g) was
treated with n-undecano~l chloride (44.3 g) in a manner similar
to that described hereinbefore in Example 16. A solid was
collected and recrystallised twice from ethanol (with filtra-
tion of the hot so]ution) to give methyl 3,4-bis(n-undecanamido)
benzoate (40.2 g) in the form of a white solid, m.p. 139-141C.
EXAMPLE 1
Compound J
- A solution of methyl 2-(n-decyl)-benzimidazole-5-carboxy-
late hydrochloride (13.7 g; prepared as described hereinbefore
in Example 17) in a mixture o~ ethanol and water (250 ml; 4:1
v/v) containing sodium hydroxide (4.6 g) was treated in a manner
similar to that described hereinbefore in Example 4 to give 2-
(n-decyl)benzimidazole-5-carboxy]ic acid hydrochloride (9.4 g)
in the form of a white solid, m.p. 270-282C (with decomposition).
EXAMPLE 19
Compound B
A solution of 2-(n-pentadecyl)benzimidazole-5-carboxy]ic
acid monohydrate (11.16 g; prepared as described hereinbefore
in Example 12) in methanol (150 ml) was heated to 60C and
treated with a solution of sodium methoxide ~prepared by
carefully dissolving sodium (0.6~ g) in anhydrous methanol
(40 mll7 and the mixture was then cooled. The solvent was
evaporated in vacuo and the residue was recrystallised from
water to give sodium 2-(n-pentadecyl)benzimidazole-5-calboxy-
late monohydrate (9.7 g) in the form of a white solid, which
_ - 36 -

114~765
darkens at 250C and decomposes at above 300C.
EXAMPLE 20
Compound B
A stirred suspension of 2-(n-pentadecyl)-benzimidazole-5-
carboxylic acid monohydrate (1.00 g; prepared as described
hereinbefore in Example 12) in acetone (30 ml) was treated
dropwise with a solution of methanesulphonic acid (0.25 g) in
methanol (15 ml) at room temperature. The mixture was heated
to 40C to obtain a solution, and then the solvent was evaporated
in vacuo. The white solid residue was triturated with acetone
~30 ml) and the resulting solid was collected and washed with
acetone (10 ml) to give 2-(n-pentadecy])benzimidazole-5-car-
boxylic acid methanesulphonate (1.19 g) in the form of a white
solid~ m.p. 115-117C.
EXAMPLE 21
Compound B
A stirred suspension of 2-(n-pentadecyl)-benzimidazole-~-
carboxylic acid monohydrate (1.00 g; prepared as described here-
inbefore in Example 12) in acetone (30 ml) was treated with an
excess of a solution of 2-hydroxyethylsulphonic acid (10 % w/v)
in a mixture of methanol and water (19:1 v/v). The solution
was evaporated in vacuo and the residue was triturated with
acetone (30 ml). The resulting solid was collected and washed
with acetone (10 ml) to give 2-(n-pentadecyl)benzimidazole-5-
carboxylic acid 2-hydroxyethylsulphonate (1.24 g) in the form
of a white solid, m,p. 93-95C.
EXAMPLE 22
Com~ound A
2-(n-Pentadecyl)benzimidazole-5-carboxylic acid hydro-
chloride (10.0 g, prepared as described hereinbefore in Example4) was dissolved in boiling methanol (250 ml) in a reflux
-

~41765
apparatus and then was treated with concentrated hydrochloric
acid (2G ml of strength 3G.5 % w/v). The mixture was heated at
reflux for 3 hours and was then cooled to 0C. The resulting
white solid was collectedl washed with water, and recrystallised
from ethanol to give methyl 2-(n-pentadecyl)benzimidazole-5-
carboxylate hydrochloride (3.2 g) in the form oE a white solid,
m.p. 230-232C (with decomposition).
EXAMPLE 23
Compound K
Methyl 3t4-diaminobenzoate (33.0 g) and n-octadecanoic
acid (56.8 g) were ground together to form an intimate mixture
and the mixture was heated at 200C for 210 minutes. The mixture
was then treated in a manner similar to that described here-
inbefore in Example 9. The brown oil obtained after partition
between the hot mixture of petroleum ether, toluene and water
was dissolved in chloroform (25 ml) and subjected to chromato-
graphy on a column of silica gel (750 g). Elution with a mix-
ture of chloroform and methanol (19:1 v/v) gave a light
brown solid (40 g)~ This solid was dissolved in hot toluene
(200 ml) and treated with an excess o~ a saturated solution of
hydrogen chloride in ethanol. The resulting solid was collected
and recrystallised (with treatment with charcoal) Erom a mix-
ture of ethanol and water (9:1 v/v), to give methyl 2-(n-hepta-
decyl)benzimidazole-5-carboxylate hydrochloride (19.9 g) in the
form of a white solid~ m.p. 22g-234C (with decomposition).
EXAMPLE 24
Compound L
A solution of methyl 2-(n-heptadecyl) benzimidazole-5-
carboxylate hydrochloride (11.5 g; prepared as described herein-
before in Example 23) in a mixture of ethanol and water (200 ml;
1:1 v/v) containing sodium hydroxide (14.35 g) was treated in a
- 3~ -

7~5
manner similar to that described hereinbefore in Example 4 to
give 2-(n-heptadecyl)benzimidazole-5-carboxylic acid hydro-
chloride (8.8 g) in the form of a white solid, m.p. 279-
284C (with decomposition).
EXAMPLE 25
Compound M
A mixture of methyl 4-amino-3-(n-decanamido)benzoate
(16.7 g) and toluene ~60G ml) containing p-toluenesulphonic acid
(5.0 g) was treated in a manner similar to that described here-
inbefore in Example 1 to give methyl 2-(n-nony]) benzimidazole-
5-carboxylate (14.0 g) in the form of a white solid, m.p 101-
103C.
The methyl 4-amino-3-(n-decanamido)-benzoate, used as
starting material, was prepared as follows:
A stirred solution of methyl 3,4-diaminobenzoate (16.6 g)
in dry dimethylformamide (600 ml) containing anhydrous sodium
carbonate (5.3 g) was treated dropwise with n-decanoyl chloride
(19.1 g) in a manner similar to that described hereinbefore in
Example l(i) to give methyl 4-amino-3-(n-decanamido) benzoate
(18.8 g) in the form of a buff solid, m.p. 96-98C.
EXAMPLE 26
Compound N
A solution of methyl 2-(n-nonyl)benzimidazo]e-5-carboxylate
(13.5 g; prepared as described hereinbefore in Example 25) in a
mixture of ethanol and water (400 ml; 4:1 v/v) containing
sodium hydroxide (3.6 g) was treated in a manner similar to
that described hereinbefore in Example 4 to give 2-(n-nonyl)
benzimidazole-5-carboxylic acid hydrochloride (8.6 g) in the form
of a white solid, m.p~ 275-280C.
EXAMPLE 27
Compound O
- 39 -

1~41~7~i$
A stirred solution of methyl 3,4-bis(n-octanamido)benzoate
(81.8 g) in methanol (~0~ ml) containing concentrated hydro-
chloric acid (100 ml of strength 36.5 ~ w/v) was heated at reflux
for 4 hours. The mixture was then c~oled and treated in a
manner similar to that described hereinbeore in Example 17 to
give methyl 2~(n-hepty])benzimidazole-5-carboxylate hydrochloride
(33.8 g) in the form of a white solid, m.p. 140-142C (with
decomposition).
The methyl 3,4-bis(n-octanamido)benzoate, used as starting
material, was prepared as follows:
A solution of methyl 3,4-diaminobenzoate (41.2 g) in
dichloromethane (412 ml) containing triethylamine (51.0 g) was
treated with a solution of n-octanoyl chloride (80.6 g) in
dichloromethane (330 ml) in a manner similar to that described
hereinbefore in Example 16, recrystallising from methanol
(with treatment with charcoal), to give methyl 3,4-bis(n-octan-
amido)benzoate (81.8 g) in the form of a white solid, m.p. 138-
140C.
EXAMPLE 28
-
Compound P
A stirred solution of methyl 2-(n-heptyl)-benzimidazole-
5-carboxylate hydrochloride (23.0 g; prepared as described
hereinbefore in Example 27) in a mixture of ethanol and water
(200 ml; 12:1 v/v) containing sodium hydroxide (8.9 g) was
heated at reflux for 5 hours. The mixture was treated in a
manner similar to that described hereinbefore in Example 4 to
give 2-(n-heptyl)-benzimidazole-5-carboxylic acid hydrochloride
(14.4 g) in the form of a white solid, m.p. 310-313C (with
decomposition).
EXAMPLE 29
-
Compound Q
- 40 -

A stirred sol~tion o 3,4-bis~n-pentadeeanamido)benzoie
aeid (49.3 g) in a mixture ~ methy] ethyl ketone and eoncen-
trated hydroehlorie acid (560 ml 10:1 v/v) was heated at reflux
for 3 hours. The mixture was then cooled. The resulting solid
was eolleeted and washed with methyl ethyl ketone (200 ml)
and then washed with boiling petroleum ether (200 ml; b.p. 60-
80C). It was recrystallised rom a mixture of ethanol and
water (4 1 v/v) (with treatment with charcoal and with filtra-
tion of the hot solution) to give 2-(n-tetradecyl)benzimidazole-
5-earboxylic aeid hydrochloride (15.7 g), m.p. above 300C
(with decomposition).
The 3,4-bis(n-pentadeeanamido)benzoie aeid, used as
starting material, was prepared as follows:
A solution of 3,4-diaminobenzoie acid (13.85 g) in
dimethylformamide (180 ml) containing triethylamine (27.6 g)
was treated with n-pentadeeanoyl chloride (47.4 g) in a manner
similar to that deseribed hereinbefore in Example l(i). The
resulting solid was colleeted and reerystallised from methyl
ethyl ketone (with treatment with ehareoal and with filtra-
tion of the hot solution) to give 3,4-bis(n-pentadeeanamido)
benzoie aeid (49.3 g), m.p. 178- 180C.
EXAMPLE 30
Compound R
(a) A stirred solution of methyl 3,4-bis(n-nonanamido)ben-
zoate (23.3 g) in methanol (300 ml) was treated with eoneen-
trated hydrochloric acid (40 ml of strength 36.5 % w/v). The
mixture was heated at reflux for 3 hours and the solvent was
removed in vacuo to give a white solid. The solid was washed
with hot petroleum ether (100 ml b.p. 40-60C) and was
recrystallised from water (700 ml) with hot filtration to give
methyl 2-n-octy].benzimidazo]e-5-carboxylate hydrochloride in
- 41 -

7~;5
the form of a white so~id, m.~. 238-243C (12.0 g).
lb) A stirred solution o~ methyl 2-n-octylbenzimidazole-5-
carboxylate hydrochloride (11 g; prepared as described above)
in a mixture of ethanol and water (240 ml; 12:1 v/v) containing
sodium hydroxide (4.0 g) was heated at reflux for 4 hours.
The mixture was treated in a manner similar to that described
hereinbefore in Example 4 to give 2-(n-octyl)benzimidazole-5-
carboxylic-acid hydrochloride (7.8 g) in the form of a white
solid, m.p. 280-300C (with decomposition).
The methyl 3,4-bis(n-nonanamido)benzoate, used as starting
material, was prepared as follows:
(c) A stirred solution of methyl 3,4-diamino-benzoate (2G g)
in dry dichloromethane 1250 ml), containing triethylamine (24.2 g),
was treated dropwise with a solution of nonanoyl chloride
(44.12 g) in dry dichloromethane (50 ml) in a manner similar to
that hereinbefore described in Example l(ii). The resulting
pink solid was recrystallised from methanol, with treatment
with charcoal, to give methyl 3,4-bis-(n-nonanamido)benzoate
(30.3 g) in the form of a white solid, m.p. 142-145C.
EXAMPLE 31
Compound S
2-(n-Tetradecyl)benzimidazole-5-carboxylic acid hydro-
chloride ~8.5 g; prepared as described hereinbefore in Example
29) was dissolved in boiling methanol (96 ml) in a reflux
apparatus and was then treated with concentrated hydrochloric
acid (22 ml,of strength 36.5 % w/v). The mixture was refluxed
for 3 hours, and was then treated in a manner similar to that
described hereinbefore in Example 22 to give methyl 2-(n-tetra-
decyl)benzimidazole-5-carboxylate hydrochloride (6.2 g) in
the form of a white solid, m.p. 233-235C.
- 42 -

11~1765
EXAMPLE 32
Compound T
2-(n-Hexadec~l)benzimidazole-5-carboxylic acid hydro-
chloride (9.0 g; prepared as described hereinafter in Example
33) was dissolved in boiling methanol (400 ml) in a reflux
apparatus and then was treated with'concentrated hydrochloric
acid (100 ml of strength 36~5 % w/v). The mixture was heated
at reflux for 8 hours and was then treated in a similar manner
to that described hereinbefore in Example 22 to give methyl
2-(n-hexadecyl)benzimidazole-5-carboxylate hydrochloride (7.4 g)
in the form of a white solidj m.p. 225-230C (with decompo-
sition).
EXAMPLE 33
Compound U
A solution of 3,4-bis(n-heptadecanamido)-benzoic acid
(250 g) in methyl ethyl ketone (1500 ml) was treated with con-
centrated hydrochloric acid (180 ml, of strength 36.5 ~ w/v).
The mixture was refluxed for 8 hours and was treated in a
similar manner to that described hereinbefore in Example 15 to
give 2-(n-hexadecyl)benzimidazole-5-carboxylic acid hydro-
chloride (44.9 g) in the form of an off-white solid, m.p. 296-
306C (with decomposition).
The 3,4-bis(n-heptadecanamido)benzoic acid, used as
starting material, was prepared as follows:
A stirred solution o 3,4-diaminobenzoic acid (45.6 g) in
dimethylformamide (400 ml), containing triethylamine (75.8 g),
was treated dropwise with n-heptadecanoyl chloride (130 g)
during 1.5 hours. The rate of addition of n-heptadecanoyl
chloride was such as to allow the temperature of the reaction
mixture to rise from room temperature to 35 -40 C. The mixture
was then stirred at room temperature for'a further period of 2
- 43 -

1~1'7~5
hours and was then poured in~o hot water (3500 ml kept at 70C~
containing concentrated hydrochloric acid (50 ml of strength
36.5 ~ w/v) to give crude 3,4-bis(n-heptadecanamido)-benzoic
acid (140 g) in the form of a pink solid.
EXAMPLE 34
Compound V
2-n-Eicosylbenzimidazole-5-carboxylic acid hydrochloride
(12 g; prepared as described hereinafter in Example 35) in
chloroform (300 ml) was treated dropwise with stirring with
thionyl chloride (100 ml). The mixture was refluxed for 4
hours and was then cooled and the excess thionyl chloride and
the solvent was removed in vacuo to give a white solid. The
solid was suspended in anhydrous methanol (300 ml) and the
mixture was stirred and refluxed for 8 hours and then cooled.
The solid was collected and washed with methanol to give
methyl 2-(n-eicosyl)benzimidazole-5-carboxylate hydrochloride
(9.2 g) in the form of a white solid, m.p. 220-226C.
EXAMPLE 35
Compound W
A solution of 3,4-bis(n-heneicosanamido)-benzoic acid
(126.5 g) in methyl ethyl ketone (1000 ml) was treated with
concentrated hydrochloric acid (100 ml, of strength 3~.5
w/v). The mixture was refluxed for 10 hours and was then
treated in a similar manner to that described hereinbefore in
Example 15 to give a white solid which was recrystallised from
n-butanol (1200 ml) to give 2-(n-eicosyl)benzimidazole-5-
carboxylic acid hydrochloride (45.1 g) in the form of a white
solid, m.p. 294-298C (with decomposition).
The 3,4-bis(n-heneicosanamido)benzoic acid, used as
starting material, was prepared as follows:
A stirred solution of 3,~-diaminobenzoic acid (21.9 g) in
- 44 -

7f~5
dimethylformamide (175 ml), containing triethylamine (43.6 g),
was treated dropwise with n-heneicosanoyL chloride (99.2 g) in
a manner similar to that described hereinbefore in Example 33
to give crude 3,4-bis(n-heneicosanamido)-benzoic acid (126.5 g)
in the form of a light brown solid.
EXAMPLE 36
~ .
2-(n-Nonadecyl)benzimidazole-5-carboxylic acid hydro-
chloride (14.6 9; prepared as described hereinafter in Example
37) was suspended in thionyl chloride (350 ml) and the mix-
ture was stirred and refluxed for 6 hours. The excess thionyl
chloride was removed _ vacuo to give a yellow-brown solid.
The solid was suspended in anhydrous methanol (500 ml) and the
mixture was stirred and refluxed for 3 hours. The mixture
was then treated in a similar manner to that described in
Example 34 to give methyl 2-(n-nonadecyl)benzimidazole-5-carboxy-
late hydrochloride (12.2 g) in the form of a white solid,
m p 219 227C
EXAMPLE 37
ComPound Y
A suspension of 3~4-bis(n-eicosanamido)-benzoic acid
(89.1 g) in methyl ethyl ketone (1200 ml) was heated with con-
centrated hydrochloric acid (120 ml, of strength 36.5 ~ w/v).
The mixture was stirred and refluxed for 8 hours and then
treated in a similar manner to that described hereinbefore in
Example 15 to give a white solid. The solid was boiled with
n-butanol (100 ml) and the mixture was cooled to give 2-(n-
nonadecyl)benzimidazole-5-carboxylic acid hydrochloride (36.5 g)
in the form of a white solid, m,p. 290-300C (with decompo-
sition).
The 3,4-bis(n-eicosanamido)benzoic acid, used as starting
- 45 -
k~
~ .

material~ was prepared as ollows:
A stirred solution o 3,4-diaminobenzoic acid (18.3 g) in
dimethylformamide (200 ml), containing triethylamine (36.5 g),
was treated dropwise with n-eicosanoyl chloride (79.4 g) in a
manner similar to that described hereinbefore in Example 33 to
give crude 3,4-bis(n-eicosanamido)benzoic acid (93 g) in the
form of a pale brown solid~ m.p~ 16a-170C.
EXAMPLE 38
Compound Z
A suspension of 4-amino-3-(n-nonadecanamido)-benzoic acid
(107 g) in methyl ethyl ketone (1500 ml) was treated with con-
centrated hydrochloric acid (100 ml, of strength 36~5 % w/v).
The mixture was stirred and refluxed for 3 hours. The mixture
was cooled to 10C and the solid was collected, washed with
methyl ethyl ketone (2 x S00 ml) and suspended in water
(500 ml). Sodium hydroxide solution (50 g in water (150 ml))
was added to the mixture and the mixture was stirred and
warmed to 60C to effect solution. Glacial acetic acid was
added to the stirred mixture until the mixture was pH 5, and
the resultant solid was collected, washed with water (2 x 500 ml)
and dried. The solid was recrystallised from ethanol, with
treatment with charcoal, to give a white solid which was care-
fully dried and then suspended in methyl ethyl ketone (500 ml)
containing concentrated hydrochloric acid (100 ml, of strength
36.5 % w/v). The mixture was stirred and refluxed for 1 hour
and then cooled to give 2-~n-octadecy])ben~imidazole-5-carboxylic
acid hydrochloride (33.8 g) in the fo~m of a white solid,
m.p. 292-297C (with decomposition).
The 4-amino-3-(n-nonadecanamido)benzoic acid, used as
starting material, was prepared as follows:
A stirred solution of 3,4-diaminobenzoic acid (38 g) in
- 46 -

114~7~;5
dimethylormamide (500 ml), containi~g triethylamine (50.5 g),
was treated dropwise with n-nonadecano~l chloride (79.1 g) in a
similar manner to that described hereinbeore in Example 33 to
give an orange solution, which was poured into water (3000 ml),
containing concentrated h~drochloric ac d (100 ml, of strength
36.5 % w/v). The solid was collected, washed with water (2 x
100 ml) and then dried to give crude 4-amino-3-(n-nonadecanamido)-
benzoic acid (107 g), m.p. 103-;13C.
EXAMPLE 3g
Compound II
2-(n-Octadecyl)benzimidazole-5-carboxylic acid hydro-
chloride (12 g; prepared as described hereinbefore in Example
38) in thionyl chloride (L00 ml) was stirred and refluxed for
3 hours and then treated in a manner similar to that described
hereinbefore in Example 36 to give methyl 2-(n-octadecyl)ben-
zimidazole-5-carboxylate hydrochloride (11.6 g) in the form
of a white solid, m.p 224-230C.
~XAMPLE 40
Compound AA
A suspension of 3,4-bis~2-methyltetradecanamido7benzoic
acid (53.1 g) in methyl ethyl ketone (250 ml) was treated with
concentrated hydrochloric acid (37.6 ml, of strength 36.5 %
w/v). The mixture was stirred and refluxed for 16 hours. The
mixture was cooled to 0C and the solid was collected (11.17 g)
and washed with methyl ethyl ~etone (2 x 25 ml). The solid
was suspended in water (50 ml), and sodium hydroxide solution
~20 g in water (50 ml)7 was added to the suspension. The
mixture was stirred and warmed to 60C to effect solution, and
then glacial acetic acid was added to the stirred mixture until
the mixture was pH 5. The resulting solid was collected,
washed with water and recrystallised from ethanol with treatment
- 47 -
'~

ll~i7~5
with charcoal, and then treated'in a similar manner to that
described hereinbeore in Example 38 to give (RS)-2-(tetradec-2-
yl)-benzimidazole-5-carb~xylic acid hydrochloride (11 g) in
the form of a white solid, m,p. 214-21~C.
The 3,4-bis~2-methyltetradecanamido7-benzoic acid, used
as starting material, was prepared as follows:
A stirred solution of 3,4-diaminobenzoic acid (17.5 g) in
dimethylformamide (1~0 ml), containing triethylamine (34.8 g),
was treated dropwise with pentadecan-2-oyl chloride (59.7 g) in
a similar manner to that described hereinbefore in ~xample 33
to give crude 3,4-bis~2-methyltetradecanamido7-benzoic acid
(68 g).
EXAMPLE 41
Compound CC
A solution of 4-amino-3-~2-hexyloctanamido7-benzoic acid
(15.2 g) in methyl ketone (78 ml) was treated with concentrated
hydrochloric acid (18.2 ml~ of strength 36.5 % w/v). The mix-
ture was stirred and refluxed for 12 hours and the methyl
ethyl ketone was then removed in vacuo. The residue was suspended
in water (200 ml) and sodium hydroxide solution (50 % w/v in
water) was added to the mixture until it was pH 11. The mix-
ture was heated to 90C and then diluted with water to a total
volume of 1500 ml. The solution was treated with charcoal and
then treated with an excess of acetic acid (25 % w/v in water)
to give an off-white solid. The solid was collected, washed
with water and recrystallised from ethyl acetate to give 2-
(tridec-7-yl)benzimidazole-5-carboxylic acid (8.89 g), m.p.
157-158C.
The solid was dissolved in acetone (350 ml) and the solution
treated with concentrated sulphuric acid (1.55 ml, of strength
98 % w/w). On cooling, a white solid was obtained, which was
- 48 -

~1417fi5
recrystallised rom methyl ethyl ketone to give 2-(tridec-7-yl)-
benzimidazole-5-carboxylic acid hemisulphate (6.8 g), in the
form of a white solid, m.p. 202-205C.
The 4-amino-3-~2-hexyloctanamido7benzoic acid, used as
starting material, was prepared as ollows:
A stirred solution of 3t4-diaminobenzoic acid (20.7 g) in
dimethylformamide (165 ml), containing triethylamine (56.5 ml),
was treated dropwise with 2-hexyloctanoyl chloride (67 g) in a
similar manner to that described in Example 33. The waxy solid
was collected and dissolved in diethyl ether (500 ml), and the
ether solution was dried and evaporated to give a red brown oil.
This oil was extracted with hot methanol, using a continuous
extraction apparatus, for 5 hours. The methanol solution was
evaporated on a rotary evaporator to give a brown solid, which
was recrystallised from acetone to give 4-amino-3-~2-hexyloctan-
amido7benzoic acid (15.2 g) in the form of a white solid, m.p.
219-222C.
EXAMPLE 42
Compound BB
A solution of 4-amino-3-(2-ethyldodecanamido)-benzoic acid
(24.7 g) in methyl ethyl ketone (125 ml) was treated with con-
centrated hydrochloric acid (29 ml, of strength 36.5 % w/v).
The mixture was stirred and refluxed for 12 hours and was then
treated in a similar manner to that described hereinbefore in
Example 41 to give a white solid, which was recrystallised from
a mixture of acetone (20a ml) and water (200 ml) to give (RS)-
2-(tridec-3-yl)benzimidazole-5-carboxylic acid hemisulphate
(14.2 g) in the form of a white solid, m.p. 185-187C.
The 4-amino-3-(2-ethyldodecanamido)benzoic acid, used as
starting material, was prepared as follows:
A stirred solution of 3,4-diaminobenzoic acid (22.8 g) in
- 49 -

7~5
dimethylormamide (2~0 ml), containing triethylamine (22.7 g),
was treated dropwise with 2-ethyldodecanoyl chloride (37 g) in
a similar manner to that described hereinbefore in Exanlple 41
to give a solid, which was recrystallised from ethyl acetate
with treatment with charcoal to give 4-amino-3-(2-ethyldodecan-
amido)benzoic acid (22.2 g) in the form of a white solid, m.p.
188- 191C.
EXAMPLE 43
Compound DD
A solution of 4-amino-3-~2-butyldecanamido7-benzoic acid
(9.8 g) in methyl ethyl ketone (50 ml) was treated with con-
centrated hydrochloric acid (11.5 ml, strength 36.5 % w/v) in
a manner similar to that described hereinbefore in Example 41
to give (RS)-2-(tridec-5-yl)benzimidazole-5-carboxylic acid
hemisulphate (4.7 g) in the orm of a white solid m.p. 161-
164C.
The 4-amino-3-~2-butyldecanamido7benzoic acid, used as
starting material, was prepared as follows:
A stirred solution of 3,4-diaminobenzoic acid (15.8 g) in
dimethylformamide (130 ml), containing triethylamine (43.4 g),
was treated dropwise with 2-butyldecanoyl chloride (51.4 g) in
a similar manner to that described hereinbefore in Example 41
to give 4-amino-3-~2-butyldecanamido7benzoic acid (9.8 g) in
the form of a white solid~ m.p. 178-182C.
EXAMPLE 44
Compound EE
A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl
chloride hydrochloride (10 g) in ethanol (250 ml) was stirred
and refluxed for 2 hours. The mixture was cooled to room tem-
perature and the solid was collected and washed with ethanol
(50 ml) and then with diethyl ether (2 x 50 ml). The solid
- 50 -

~l~lt7~;5
was dissolved in boiling ethanol (25 ml) and the solution treated
with concentrated hydrochloric acid (0.5 ml of strength 36.5
w/v). The solution was cooled t~ 0C and the resulting solid
was collected to give ethyl 2-(n-pentadecyl)benzimidazole-5-
carboxylate hydrochloride (7.8 g) in the form of a white solid,
m.p. 207-213C.
The 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride, used
as starting material, was prepared as follows:
2-(n-Pentadecyl)benzimidazole-5-carboxylic acid mono-
hydrate (32 g) was added portionwise to a stirred solution of
thionyl chloride (250 ml) at room temperature. The mixture was
stirred and refluxed for 2 hours and theh the thionyl chloride
was removed in vacuo to give 2-(n-pentadecyl)benzimidazole-5-
carbonyl chloride hydrochloride (33 g) in the form of a cream
solid, m.p. 286-288C (with decomposition).
EXAMPLE 45
Compound FF
A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl
chloride hydrochloride (10 g; prepared as described herein-
before in Example 44) in n-hexyl alcohol (300 ml) was treated
in a similar manner to that described hereinbefore in Example
44 to give hexyl 2-(n-pentadecyl)benzimidazole-5-carboxylate
hydrochloride (9.3 g) in the orm of a white solid m.p.
166-170C.
EXAMPLE 46
Compound GG
A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl
chloride hydrochloride (10 g; prepared as described herein-
before in Example 44) in n-butyl alcohol (300 ml) was treated
in a similar manner to that described hereinbefore in Example
44 to give butyl 2-(n-pentadecyl)benzimidazole-5-carboxylate
-- 51 --

i765
hydrochloride (8.9 g) in the form of a white solid, m.p, 170-
174C
EXAMPLE 47
Compound HH
A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl
chloride hydrochloride (10 g; prepared as described herein-
before in Example 44) in isopropyl alcohol (300 ml) was treated
in a similar manner to that described hereinbefore ln Example
44 to give isopropyl 2-(n-pentadecyl)benzimidazole-5-carboxy-
late hydrochloride (6.4 g) in the form of a white solid,m p 184 186C
EXA~PLE 48
ComPound JJ
A stirred mixture o sodium 2-(n-pentadecyl)-benzimidazole-
5-carboxylate (13.7 g; prepared as described hereinbefore in
Example 19) and chloromethyl pivalate (5 g) in hexamethyl-
phosphoramide (35 ml) was heated to 50C or 3 hours. After
coolingl the mixture was poured into water (250 ml) and
extracted with diethyl ether (3 x 75 ml). The organic layer
was washed with water (3 x 100 ml)-and dried over magnesium
sulphate. The organic solvent was removed in vacuo to give
a brown oil, which was chromatographed on silica gel (400 g)
using chloroform as the eluent. Fractions (100 ml) were
collected and fractions 14 to 22 on evaporation of the solvent
gave a colourless oil. The oil was dissolved in diethyl ether
and was treated with a saturated solution of hydrochloric acid
in ethanol until the pll of the mixture was pll 1. The white
solid was collected and washed with diethyl ether (3 x 100 ml)
to give pivaloyloxymethyl 2-n-pentadecylbenzimidazole-5-
carboxylate hydrochloride (1~ g) in the form of a white solidm p. 165-175C.
- 52 -
,, ~

11~17~
EXAMPLE 49
Compound KK
Sodium hydride (12 g o~ a 50 ~ oil dispersion) was added
during 15 minutes to a stirred mixture of glycerol (100 g) and
dry tetrahydrofuran (100 ml). ~hen the addition was complete,
the mixture was stirred vigorously for a further 30 minutes
and then 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydro-
chloride (20 g; prepared as described hereinbefore in Example 4)
was added to the mixture during 5 minutes. The mixture was
stirred vigorously for 2 hours and was then allowed to stand
overnight. The brown mixture was poured into water (800 ml)
containing glacial acetic acid (g.4 g) and the oily product
was extracted into chloroform (2 x 400 ml). The combined
extracts were washed with water (2 x 500 ml) and dried over
sodium sulphate. The solvent was evaporated 1n vacuo, the
residual oil was dissolved in toluene (300 ml) and the solution
was filtered and cooled to give a brown gum. The toluene was
decanted, diethyl ether (100 ml) was added and the mixture was
warmed until the gum dissolved. On rapid cooling to -30C, a
white solid precipitated out and was collected and washed with
diethyl ether (2 x 100 ml) to give 2,3-dihydroxyprop-l-yl 2-
(n-pentadecyl)-benzimidazole-5-carboxylate (6.6 g) in the form
of a white solid, m.p. 109-112C.
EXAMPLE 50
Compound B
3,4-Diamillobenzoic acid (10 g) and palmitic acid (168 g) in
diglyme containing concentra-ted hydrochloric acid (10 ml, of
strength 36.5 % w/v) (100 ml) were heated at reflux for 10 hours.
The cooled mixture was poured into water (300 ml) and the solid
was collected. The solid was washed with dilute hydrochloric
acid (2 x 100 ml, of strength 2N) and then boiling petroleum

11~176S
ether (4 x lOa ml, b.p. 40-60C). The solid was recrystallised
from ethanol, with treatment with charcoal, to give 2-(n-penta-
decyl)benzimidazole-5-carboxylic acid hydrochloride (50 mg),
m.p. 295-300C (with decomp~sition).
EXAMPLE 5 1
Compound B
3,4-Diaminobenzoic acid monohydrochloride (1.88 g) and n-
hexadecanoyl chloride (2.74 g) were mixed together intimately
and the mixture was heated at 130C or 2 hours. The mixture
was then cooled to room temperature and was triturated with
water (100 ml) to give 2-~n-pentadecyl)benzimidazole-5-car-
boxylic acid hydrochloride (0.1 g), m.p. 29~-300C (with
decomposition).
EXAMPLE 5 2
_ompound B
A stirred solution o 3,4-diaminobenzoic acid (9 g) in
dimethylformamide (19a ml) was treated with n-hexadecanoyl
chloride (16.3 g) during 30 minutes. The mixture was then
refluxed for 6 hours and was poured into water (100 ml). The
solid was collected and suspended in dilute hydrochloric acid
(100 ml, of strength 2N). The solid was again collected and
washed with water to give 2-(n-pentadecyl)benzimidazole-5-
carboxylic acid hydrochloride (3 g), m.p. 295-300C (with
decomposition).
EXA~IPLE 53
Compound B
A solution of 2-(n-pentadecyl)benzimidazole-5-carboxylic
acid monohydrate (390 g; prepared as described hereinbefore in
Example 12) in a mixture of acetone (2000 ml) and water
(1000 ml) was heated to 60C and then treated with an aqueous
solution of sodium hydroxide (40 g, in water 50 ml). The
- 54 -

7~5
mixture was stirred fo~ ~ hour with refluxing and was then cooled
to 0C. The solid was collected and recrystallised from a
mixture of acetone (1000 ml) and water (500 ml) to give sodium
2-(n-pentadecyl)benzimidazole-5-carboxylate monoh~drate (345 g),
m.p. above 300C with decomposition.
EXAMPLE 54
Compound LL
A solution of 2,3-bis(n-tetradecanamido)-benzoic acid
(17.6 g) in methyl ethyl ketone (250 ml) was treated with con-
centrated hydrochloric acid (25 ml, strength 36.5 % w/v). The
mixture was refluxed for 5 hours, then coo]ed and treated in a
similar manner to that described hereinbe-fore in Example 15 to
give 2-(n-tridecyl)benzimidazole-4-carboxylic acid hydro-
chloride (6.5 g) in the form of a buff solid, m.p. 192-200C.
The 2,3~bis(n-tetradecanamico)benzoic acid, used as
starting material, was prepared as follows:
A solution of 2,3-diaminobenzoic acid (20 g) in dimethyl-
formamide (200 ml)~ containing triethylamine (39.9 g), was
treated with n-tetradecanoyl chloride (65.0 g). The rate of
addition of the n-tetradecanoyl chloride was such as to allow
the temperature of the reaction mixture to rise from room
temperature to 45-50C. The mixture was then stirred foL a
further 2 hours and allowed to stand at room temperature over-
night. Methanol (20 ml) was added to the mixture, and the
- resulting mixture was stirred for 20 minutes and afterwards
treated with concentrated hydrochloric acid (strength 36.5 %
w/v) until the pE~ was 2. The resultant mixture was poured
into water (1000 ml) and the black solid was collected, washed
with water (2 x 500 ml) and then with hot light petroleum
(b.p. 60-80C; 500 ml), and was finally recrystallised from
ethanol, with treatment with charcoal, to give 2,3-bis(n-tetra-

11~176S
decanamido)benzoic acid (17.7 g) in the form of a buff solid,
m p 150 158C
EX~MPIE 55
Compound B
A suspension of 3-amina-4-(hexadecanamido)-benzoic acid
(2.0 g) in methyl ethyl ketone (60 ml) containing hydrochloric
acid (1.5 ml, of strength 36.S ~ w/v) was refluxed for 5 hours.
The resul'ing solid was collected, washed with boiling petro-
leum ether (b.p. 60-80C) and recrystallised from ethanol to
give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydro-
chloride (2.0 g) in the form of a white solid m.p. 288-290C
(with decomposition).
The 3-amino-4 (n-hexadecanamido)benzoic acid, used as
starting material, was prepared as follows:
A solution of 3-nitro-4-(n-hexadecanamido)-benzoic acid
(22 g) in n-butanol (500 ml) was hydrogenated by shaking in the
presence of 5 ~ w/w palladium on charcoal (2.5 g) at 70C and
atmospheric pressure for 6 hours. The mixture was filtered
hot and the filtrate allowed to cool. The resulting solid was
collected and washed with ethanol (100 ml) to give 3-amino-4-
(hexadecanamido)benzoic acid (11.6 g) in the form of a cream
solid m.p. 160-162C.
The 3-nitro-4-(n-hexadecanamido)benzoic acidr used as
starting material, was prepared as follows:
A solution of 4-amino-3-nitrobenzoic acid (18.2 g) and
hexadecanoyl chloride (33.0 g) in dry dimethylformamide (100 ml)
was heated for 90 minutes at 97C. The solution was cooled and
then poured onto crushed ice (300 g). The resulting solid was
collected, washed with water (3 x 100 ml), dried and recrystal-
lised from a mixture of acetone and water (5:1) (with treat-
ment with charcoal~ to give 3-nitro-4-(n-hexadecanamido)benzoic
- 56 -

7i5
acid (31.7 g) in the ~rm of a pale yellow solidt m.p. 153-
15~C.
EXAMPLE 56
Compound ~lM
A suspension of 2-(n-pe~tadecyl)benzimidazole-5-carboxylic
acid hydrochloride (9.6 g; prepared as described hereinbefore in
Example 4) in thionyl chloride (75 ml) was refluxed for 2
hours. The excess thionyl chloride was removed by vacuum dis-
tillation leaving a brown solid. The solid was triturated with
toluene (200 ml) and the toluene was evaporated in vacuo. The
residue was added to a solution of triethylamine (3.64 ml) in
tert-butanol (250 ml) and the mixture was refluxed for 3 hours.
After cooling, the excess tert-butanol was evaporated ln vacuo
and the residue was suspended in ethyl acetate (150 ml). The
suspension was refluxed for 1~ minutes and was filtered hot.
The filtrate was cooled and the resulting solid was collected.
The solid was washed with ethanol (2 x S0 ml) and then with
diethyl ether (2 x 50 ml), and dried to give tert-butyl 2-(n-
pentadecyl')benzimidazole-5-carboxylate hydrochloride (5.5 g)
as an off-white solid, m~p. 16$-lG8C.
EXA~lPLE 57
ComPound NN
A mixture of 2-(n-pentadec~l)benzimidazole-5-carbonyl
chloride (lS g; prepared as described hereinbefore in Example
44) in allyl alcohol (300 ml) was treated in a similar manner
to that described hereinbefore in Example 44 to give allyl 2-
(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (10.4 g)
in the form of a white solid, m.p. 198-200C.
EXAMPLE 58
Compound ~l
To a stirred solution o~ methyl 3,4-diaminobenzoate (9.8 g)
- 57 -

11~1765
in methanol (200 ml) was added a solution of cupric acetate
(23.6 g) in water (300 ml) followed by a solution of n-decanal
(10 g) in methanol (40 ml). The mixture was refluxed for one
hour and allowed to cool~ and the purple solid was collected.
The solid was dissolved in 75 ~ v/v aqueous methanol (600 ml)
and hydrogen sulphide gas was passed into the solution until
the precipitation of copper sulphide ceased. The copper sul-
phide was collected and the filtrate was concentrated to give
a red oil. The oil was dissolved in methanol (100 ml) containing
concentrated hydrochloric acid (15 ml, of strength 36.5 ~ w/v)
and the solution was refluxed for 4 hours. After Gooling the
greyish-green solid was collected and was dissolved in tetra-
hydrofuran (100 ml) containing aqueous ammonia (5 ml, of
strength 33 ~ w/w). The solution was diluted with water (400 ml)
and the pink solid was collected. The solid was chromatographed
on silica with a mixture o chloroform and methanol (25:1 v/v)
as eluent. The isolated material was dissolved in methyl ethyl
ketone (25 ml) and concentrated hydrochloric acid (2.3 ml, of
strength 36.5 ~ w/v) was added with stirring. The resulting
solid was collected and washed with diethyl ether (2 x 50 ml)
yielding methyl 2-(n-nonyl)-benzimidazole-5-carboxylate hydro-
chlori~e (5.3 g) in the form of white solid, m.p. 234-237C
(with decomposition).
EXAMPLE 59
Compound PP
Concentrated hydrochloric acid (120 ml, of strength 36.5
w/v) was added during 20 minutes to a refluxing solution of
crude 2,3-bis(n-hexadecanamido)-benzoic acid (165.3 g) in
methyl ethyl ketone (1200 ml), and the mixture was refluxed for
6 hours. The resulting solution was cooled and the solvent was
removed by vacuum distillation. After triturating the residue
- 58 -

1~1765
with water (2000 ml), the granular solid was collected and
washed with hot petroleum ether (b.p. 60-~0C; 2 x 500 ml) and
then with diethyl ether (500 ml). The solid was dissolved in
boiling methyl ethyl ketone (250 ml), and the solution was
treated with charcoal and filtered hot. The filtrate was evapo-
rated ln vacuo leaving a buff solid. The solid was chromato-
graphed on silica with a mixt~re of chloroform and methanol
(9:1 v/v) as eluent. The resulting product was recrystallised
from ethyl acetate to give 2-(n-pentadecyl)benzimidazole-4-
carboxylic acid (5.4 g) as a buff solid, m.p. 160-166C.
The 2,3-bis(n-hexadecanamido)benzoic acid, used as
starting material, was prepared as follows:
A solution of 2t3-diaminobenzoic acid (40 g) in dimethyl-
formamide (600 ml), containing triethylamine (79.7 g, 109.5 ml),
was treated with n-hexadecanoyl chloride (144.5 g). The rate
of addition was such as to allow the temperature of the reaction
mixture to rise from room temperature to 45-50C. The mix-
ture was then stirred for a further 3 hours and was allowed to
stand at room temperature overnight. The mixture was added to
water (1200 ml) containing concentrated hydrochloric acid
(50 ml, of strength 36.5 % w/v), and the resulting solid was
collected and washed with water (1200 ml). The solid was
stirred with hot water (4000 ml; 65C) for 30 minutes and was
collected and dried at 70C in vacuo. The resulting product
2,3-bis(n-hexadecanamido)benzoic acid was used without further
purification in the above preparation.
REFERE;NCE EXA~IPLE~ 1
A stirred solution of 3,4-diaminobenzoic acid (152 g) in
dimethylformamide (1500 ml), containing triethylamine (303 g),
was treated dropwise with n-hexadecanoyl chloride (549.0 g)
during 1.5 hours. The rate of addition of n-hexadecanoyl
-- S9 --

11~176S
chloride was such as to allow the temperature of the reaction
mixture to rise rom r~om temperature to 35-40 C. The
mixture was then stirred at room temperature for a further
period of 2 hours and was then poured into hot water (10 litres
kept at 70C) containing concentrated hydrochloric acid (150 ml
of strength 36.5 ~ w/v). The resulting solid was collected
and gave crude 3,4-bis(n-hexadecanamido)benzoic acid (600 g) in
the Eorm of a buff solid, m.p. 180-190C, suitable for use in
the preparation hereinbefore described in Example 15.
REFERENCE EXAMPLE 2
By proceeding in a similar manner to that hereinbefore
described in Example 38 for the preparation of 4-amino-3-(n-
nonadecanamido)benzoic acid but replacing n-nonadecanoyl chloride
by n-octanoyl chloride, there was prepared 4-amino-3-(n-octan-
amido)benzoic acid in the form of an off-white solid, m.p.
202-203C after recrystallisation from methanol.
REEERENCE EXAMPLE 3
By proceeding in a similar manner to that hereinbefore
described in Example 38 for the preparation of 4-amino-3-(n-
nonadecanamido)benzoic acid but replacing n-nonadecanoyl chloride
by n-dodecanoyl chloride, there was prepared 4-amino-3-(n-
dodecanamido)benzoic acid in the form of a white solid, m.p.
183-185 C.
REFERENCE EXAMPLE 4
By proceeding in a similar manner to that hereinbefore des-
cribed in Example 38 for the preparation of 4-amino-3-(n-nona-
- decanamido)benzoic acid but replacing n-nonadecano~l chloride
by n-octadecanoyl chloride, there was prepared 4-amino-3-(n-
octadecanamido)benzoic acid in the form of a light brown solid,
m.p. 185-187C after recrystallisation from methyl ethyl
ketone.
- 60 -

il9~1765
REFERENCE EXAMPLE 5
A solution of methyl 3,4-diaminobenzoate (83.1 g) in dry
dimethylfo~mamide (900 ml) containing triethylamine (50.8 g)
was treated dropwise with n-octanoyl chloride (81.3 g) during
30 minutes at a temperature maintained between 5 and 8C.
The mixture was stirred for a further period of 2 hours. The
solid was removed by filtration and the filtrate was poured
into water (800~ ml). The resulting solid was collected and
was recrystallised twice from methanol to give methyl 4-amino-
3-(n-octanamido)-benzoate (65.S g) in the form of a white solid,
m.p. 120C.
REFERENCE EXAMPLE 6
By proceeding in a similar manner to-that hereinbefore des-
cribed in Reference Example 5 for the preparation of methyl
4-amino-3-(n-octanamido)-benzoate but replacing n-octanoyl
chloride by n-dodecanoyl chloride, there was prepared methyl
4-amino-3-(n-dodecanamido)benzoate in the form of an off-white
solid, m.p. 102-105C after recrystallisation from methanol.
- REFERENCE EXAMPLE 7
By proceeding in a similar manner to that hereinbefore
described in Reference Example 5 for the prepa~ation of methyl
4-amino-3-(n-octanamido)benzoate but replacing n-octanoyl
chloride by n-tridecanoyl chloride, there was prepared methyl
4-amino-3-(n-tridecanamido)benzoate in the form of a light
brown solid, m.p. 101-104C after recrystallisation from
metharol.
REFERENCE EXAMPLE 8
By proceeding in a similar manner to that hereinbefore
described in Reference Example 5 for the preparation of methyl
4-amino-3-(n-octanamido)benzoate but replacing n-octanoyl
chloride by n-tetradecanoyl chloride, there was prepared methyl
- 61 -

1141~7~i5
4-amino-3-(n-tetradecanamido)benzoate in the form o~ a light
brown solid, m.p. 108-lOgC after recrystallisation from
methanol.
REFERENCE EXAMPLE 9
By proceeding in a similar manner to that hereinbefore
described in Reference Example 5 for the preparation of methyl
4 amino-3-(n-octanamido)-benzoate but replacing n-octanoyl
chloride by n-hexadecanoyl chloride, there was prepaLed methyl
4-amino-3-(n-hexadecanamido)benzoate in the form of a white
solid, m.p. 109-110C after recrystallisation from methanol.
REFERENCE EXAMPLE 10
A stirred solution of methyl 3,4-diaminobenzoate (5 g)
in dry dimethylformamide (50 ml), containing triethylamine
(6.1 g), was treated dropwise with a solution of hexadecanoyl
chloride (16.54 g) in dry dimethylformamide (40 ml) during 5
minutes. The temperature was allowed to rise from 20C to 50C.
The mixture was stirred for a further period of 3 hours. The
resulting suspension was poured into water (800 ml) containing
hydrochloric acid (10 ml~ 36.5 ~ w/v). The resulting solid was
collected and recrystallised from a mixture of chloroform and
acetone (1:1) to give methyl 3,4-bis(n-hexadecanamido~benzoate
(12. 1 g) in the form of a white solid, m.p. 129-132C, which
is identical to the starting material used in Example 16.
REFERENCE EXA~PLE 11
By proceeding in a similar manner to that hereinbefore
described in Reference Example 10 for the preparation of methyl
3,4-bis(n-hexadecanamido)-benzoate but replacing n-hexadecanoyl
chloride by n-octanoyl chloride, there was prepared methyl
3,4-bis(n-octanamido)benzoate in the form of a white solid,
m.p. 145-147C after recrystallisation from acetone.
- 62 -

6~
RE~ERENCE EXAMPLE 12
By proceeding in a similar manner to that hereinbefore des-
cribed in Reference Example 10 for the preparation of methyl
3,4-bis(n-hexadecanamido)-benzoate but replacing n-hexadecanoyl
chloride by n-dodecanoyl chloridel there was prepared methyl
3,4-bis(n-dodecanamido)benzoate in the form of an off-white
solid, m.p. 129-131C after recrystallisation from acetone.
REFERENCE EXAMPLE 13
By proceeding in a similar manner to that hereinbefore
described in Reference Example 10 for the preparation of ;nethyl
3,4-bis(n-hexadecanamido)-benzoate but replacing n-hexadecanoyl
chloride by n-tridecanoyl chloride, there was prepared methyl
3,4-bis(n-tridecanamidojbenzoate in the form of a white solid,
m.p. 132-134C after recrystallisation from acetone.
REFERENCE EXAMPLE 14
By proceeding in a similar manner to that hereinbefore
described in Reference Example 10 for the preparation of methyl
3,4-bis(n-hexadecanamido)-benzoate but replacing n-hexadecanoyl
chloride by n-tetradecanoyl chloridel there was prepared methyl
3t4-bis(n-tetradecanamido)benzoate in the form of a white solid,
m.p. 132-133C after recrystallisation from acetone.
REFERENCE EXArfilPLE 15
By proceeding in a similar manner to that hereinbefore
described in Reference Example 10 for the preparation of methyl
3,4-bis(n-hexadecanamido)-benzoate but replacing n-hexadecanoyl
chloride by n-octadecanoyl chloride, there was prepared methyl
3,4-bis(n-octadecanamido)benzoate in the form of a white solid,
m.p. 120C after recrystallisation from a mixture of acetone
and methanol (1:1).
REFERENCE EXAMPLE 16
3-Amino-4-(n-octanamido)bellzoic acid (12.1 g) in methanol
- 63 -

1~4~65
(200 ml) was treated with ethereal diazomethane until the
reaction had gone to completion (as shown by thin layer chromato-
graphy on silica, using methanol: chloroform: glacial acetic
acid; 10:90:0.5). Acetic acid (~.2 ml) was then added and the
reaction mixture concentrated under reduced pressure. The
resulting solid was recrystallised from ethyl acetate to give
methyl 3-amino-4-(n-octanamido)benzoate (9.2 g) in the form of
a cream solid, m.p. 128-131C.
REEERENCE EXA~PLE 17
-
3-Nitro-4-(n-octanamido)benzoic acid (25 g) dissolved in
ethanol (500 ml) at 50C was hydrogenated by shaking in the
presence of 5 % w/w palladium on charcoal (2.5 g) at 50C and
atmospheric pressure for 3 hours. The mixture was filtered hot
and the filtrate was evaporated in vacuo. The residue was
recrystallised from a mixture of ethanol and water (1:1) to
give 3-amino-4-(n-octanamido)benzoic acid (8 g) in the form of
a yellow solid, m.p. 155-156C.
The 3-nitro-4-(n-octanamido)benzoic acid, used as
starting material, was prepared as follows:
A solution of 4-amino-3-nitrobenzoic acid (l8.2 g) and n-
octanoyl chloride (19.4 g) in dry dimethylformamide (100 ml) was
treated for 90 minutes at 97C. The solution was cooled and
poured onto ice (300 g). The resulting solid was collected and
washed with water (3 x 100 ml), dried and recrystallised from
a mixture of methanol and water (8:1)(with treatment with
charcoal) to gi~e 3-nitro-4-(n-octanamido)benzoic acid (22 g) in
the form of a pale yellow solid, m.p. 153C-154C.
REFERENCE EXAMPLE 18
3-Nitro-4-(n-dodecanamido)benzoic acid (21 g) dissolved in
ethyl acetate (500 ml) was hydrogenated by shaking in the pre~ence
of 5 % w/w palladium on charcoal (2.5 g) at 50C and atmospheric
- 64 -

1~1765
pressure. The resulting mixture was iltered hot to yield a
cream solid on cooling. This product was ~ecrystallised from
methanol to give 3-amino-4-(n-dodecanamido)benzoic acid (7.4 g)
as a beige solid m.p. 158-16a~C.
REFERENCE EXAMPLE 19
By proceeding in a similar manner to that hereinbefore
described in Reference Example 5 for the preparation of methyl
4-amino-3-(n-octanamido)benzoate but replacing n-octanoyl
chloride by n-decanoyl chloride, there was prepared methyl 4-
amino-3-(n-decanamido)benzoate in the form of a white solid, m.p.
96-100C.
REFERENCE EXAMPLE 20
By proceeding in a similar manner to that hereinbefore
described in Reference Example 10 for the preparation of methyl
3,4-bis(n-hexadecanamido)-benzoate but replacing n-hexadecanoyl
chloride by n-decanoyl chloride, there was prepared methyl 3,4-
bis(n-decanamido)benzoate in the form of a white solid, m.p.
139-141C after recrystallisation from ethanol.
REFERENCE EXAMPLE 21
A stirred solution of 3,4-diaminobenzoic acid (10 g) in
dry dimethylformamide (laO ml) containing potassium carbonate
(28 g) was treated dropwise with a solution of n-dodecanoyl
chloride (33.1 g) in dry dimethylformamide (30 ml) during 5
minutes. The temperature was allowed to rise from 20 to 50C.
The mixture was stirred for a further period of 3 hours. The
resulting suspension was filtered and the filtrate poured into
water (700 ml) containing hydrochloric acid (10 ml, 36.5 ~
w/v). The resulting solid was collected and recrysta]lised
from glacial acetic acid; the product was then washed with
water and recrystallised from methyl ethyl ketone to give 3,4-
bis(n-dodecanamido)-benzoic acid (12.5 g) in the form of a white
- 65 -

1'765
solidI m.p. 195-197C.
REFERENCE EXAMPLE 22
By proceeding in a similar manner to that hereinbefore
described in Reference Example 21 for the preparation oi 3,4-
bis~n-dodecanamido)benzoic acid but replacing n-dodecanoyl
chloride by n-hexadecanoyl chloride and potassium carbonate
by sodium carbonate, there was prepared 3,4 bis(n-hexadecanamido)-
benzoic acid in the form of a white solid, m.p. 198-202 C
after successive recrystallisation from glacial acetic acid and
methyl ethyl ketone. .-
REFERENCE EXAMPLE 23
By proceeding in a similar manner to that hereinbefore
described in Reference Example 21 for the preparation of 3r4~
bis(n-dodecanamido)-benzoic acid but replacing n-dodecanoyl
chloride by n-octanoyl chloride there was prepared 3,4-bis(n-
- octanamido)benzoic acid in the form of a white solid, m.p.
195-197C after successive recrystallisation from glacial
acetic acid and methyl ethyl Icetone.
REEERENCE EXAMPLE 24
By proceeding in a similar manner to that hereinbefore
described in Reference Example 21 for the preparation of 3,4-
bis(n-dodecanamido)-benzoic acid but replacing n-dodecanoyl
chloride by n-tetradecanoyl chloride, there was prepared 3,4-
bis(n-tetradecanamido)benzoic acid in the form of a white
solid, m.p. 201-206C after successive recrystallisation from
glacial acetic acid and methyl ethyl ketone.
REFERENCE EXAMPLE 25
Methyl 4-(n-dodecanamido)-3-nitrobenzoate (21 g) dissolved
in warm ethyl acetate (500 ml) (50-55C) was hydrogenated by
shaking in the presence of 5 % w/w palladium on charcoal (2.0 g)
at 60C and atmospheric pressure for 2 hours. The mixture was
- 66 -

11~1765
filtered hot and the ~iltrate was allowed to cool. The solid was
collected to give methyl 3-amina-4-(n-dodecanamido)benzoate
(14.1 g) in the form o a white solidf m.p. 134-137C.
The methyl 4-(n-dodecanamido)-3-nitrobenzoate, used as
starting material, was prepared as follows:
Methyl 4-amino-3-nitrobenzoate (19.6 g) and n-dodecanoyl
chloride (23 g) in dimethylformamide (100 ml) were heated for
2 1/2 hours at 97C with occasional shaking. 'rhe resulting
solution was poured onto crushed ice (30a g) and the solid
collected and recrystallised from a mixture of methanol and
chloroform (5:1) to give methyl 4-(n-dodecanamido)-3-nitroben-
zoate (31 g) in the form of a yellow solid, m.p. 78 -80C.
The methyl 4-amino-3-nitrobenzoate was prepared as follows:
4-Amino-3-nitrobenzoic acid (70 g) was added to a solution
of anhydrous hydrogen chloride in methanol ~made from acetyl
chloride (78 g) and dry methanol (300 ml~7. The resulting mix-
ture was refluxed for 10 hours, cooled in ice and the solid
collected to give methyl 4-amino-3-nitrobenzoate (62 g) in the
form of a yellow solid, m.p. 193-195C.
REFERENCE EXAMPLE 26
By proceeding in a similar manner to that hereinbefore
described in Reference Example 25 for the preparation of methy]
3-amino-4-(n-dodecanamido)-benzoate but replacing methyl 4-(n-
dodecanamido)-3-nitrobenzoate by methyl 4-(n-hexadecanamido)-3-
nitrobenzoate, there was prepared methyl 3-amino-4-(n-hexade-
canamido)benzoate in the Eorm of a white slolid, m.p. 135-
137C.
REFERE~ICE EXAMPLE 27
By proceeding in a similar manner to that hereinbefore
described in Reference Example 25 for the preparation of methyl
3-amino-4-(n-dodecanamido)-benzoate but replacing methyl 4-(n-

dodecanamido)-3-nitrobenzoate by methyl 4-(n-decanamido)-3-
nitrobenzoate~ there was prepared methyl 3-amino-4-(n-decan-
amido)benzoate in the form of a white solidr m.p. 131-133C.
REFERENCE EXAMPLE 28
A stirred solution of 3,4-diaminobenzoic acid (8.4 g) in
dry dimethylformamide (1~0 ml) containing potassium carbonate
(15.27 g) was treated dropwise with a solution of n-hexadecanoyl
chloride (15.17 g) in dry dimethylformamide (30 ml) during 30
minutes at 0-5C. The mixture was stirred for a further 2
hours at 0-5C and allowed to warm to room temperature in 30
minutes.
The solution was then poured into water (700 ml) containing
hydrochloric acid (10 ml, 36.5 ~ w/v). The solid was collected,
heated with acetone (300 ml) at 50C, and recrystallised from
methyl ethyl ketone giving 4-amino-3-(n-hexadecanamido)benzoic
acid (9.4 g) in the form of a white solid, m.p. 197-199C.
REFERENCE EXAMPLE 29
By proceeding in a similar manner to that hereinbefore
described in Reference Example 21 for the preparation of 3,4-
bis(n-dodecanamido)benzoic acid but replacing n-dodecanoyl
chloride by n-decanoyl chloride, there was prepared 3,4-bis
(n-decanamido)-benzoic acid, in the form of a white solid,
m.p. 194-196C after successive recrystallisation from
glacial acetic acid and methyl ethyl ~etone.
REFERENCE EXAMPLE 30
By proceeding in a similar manner to that hereinbefore
described in Reference Example 21 for the preparation of 3,4-
bis(n-dodecanamido)benzoic acid but replacing n-dodecanoyl
chloride by n-tridecanoyl chloride there was prepared 3,4-
bis(n~tridecanamido)-benzoic acid in the form of an off-white
solid, m.p. 192-194C after successive recrystallisation
- 68 -
. ,,. ~
. .

765
from glacial acetlc acid and methyl ethyl ketone.
REFERENCE EXAMPLE 31
By proceeding in a similar manner to that hereinbefore
described in Reference Example 21 f~r the preparation of 3,4-bis
(n-dodecanamido)benzoic acid but replacing n-dodecanoyl chloride
by n-octadecanoyl chloride there was prepared 3,4-bis(n-octade-
canamido)benzoic acid in the form of a white solid, m.p~ 193-
196C after successive recrystallisation from glacial acetic
acid and methyl ethyl kctone.
The following Example illustrates a pharmaceutical com-
position according to the present invention.
EXAMPLE 60 .
No. 2 size gelatin capsules each containing:
sodium 2-(n-pentadecyl)benzimidazole-5-carboxylate 20 mg
lactose , 100 mg
starch 60 mg
dextrin -' 40 mg
magnesium stearate 1 mg
were prepared in accordance with the usual procedure.
_ .,
, 69
.