CARBAZOLE DERIVATIVES AND PROCESS FOR THEIR MANUFACTURE

DERIVES DU CARBAZOLE ET PROCEDE POUR LEUR FABRICATION

English Abstract

ABSTRACT OF THE DISCLOSURE
New carbazole derivatives of the formula
<IMG> (I)
which are topical anti-inflammatory agents, are produced by
dehydrogenating a tetrahydrocarbazole derivative of the
formula
<IMG>
(II) (III)
in the above formulae, R1 represents a hydroxymethyl group; an
alkanoyloxymethyl, tetrazolyl, cyano, oximinocarbonyl, amino-
carbonyl or carboxyl groups R2 to R4 each represents a hydrogen
atom, a halogen atom, a lower alkyl group, a trifluoromethyl
group or a lower alkoxy group, R2 being in the 3-position or
the 4-position; R5 and R6 have the same meanings as R2 to R4
or together represent the residue of a five- or six-membered
isocyclic ring; and R7 represents a hydrocarbon residue con-
taining 3 to 8 carbon atoms or, when at least one of the
residues R2 to R6 is a substituent different from hydrogen, a
hydrogen atom a methyl group or an ethyl group.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing a carbazole derivative
of the general formula I
(I)
<IMG>
in which R1 represents a hydroxymethyl group; a alkanoyloxymethyl
having 1 to 8 carbon atoms in the alkanoyl group, tetrazolyl,
cyano, oximinocarbonyl, aminocarbonyl or carboxyl group which
may be free or in the form of a salt with a physiologically
tolerable base, an ester with a physiologically unobjectionable
alcohol or an amide with a physiologically unobjectionable
amine; R2 to R4 each represents a hydrogen atom, a halogen
atom, a lower alkyl group, a trifluoromethyl group or a lower
alkoxy group, R2 being in the 3-position or the 4-position; R5
and R6 have the same meanings as R2 to R4 or together represent
the residue of a five- or six-membered isocyclic ring; and R7
represents a hydrocarbon residue containing 3 to 8 carbon atoms
provided that when at least one of the residues R2 to R6 is a
substituent different from hydrogen, R7 may also be a hydrogen
atom, a methyl group or an ethyl group which process comprises
dehydrogenating a tetrahydrocarbazole derivative of the general
formula II or III
<IMG>
(II) (III)

in which R1 to R7 have the above meanings and when required
in the product obtained, the secondary amino group in the 9-
position is lower alkylated, a free hydroxyl group is esterified
or etherified, an ester group is hydrolyzed and a free carboxyl
group or an chloride or an hydride derivative thereof is
converted into a salt,ester, amide, oximinocarbonyl group,
cyano group, hydroxymethyl group or tetrazolyl group.
2. A process as claimed in claim 1 wherein the
dehydrogenation is effected by means of a catalyst of the
platinum group.
3. A process as claimed in claim 1 wherein the
dehydroqenation is effected by means of a quinone.
4. A process as claimed in claim 1 wherein the
dehydrogenation is effected by means of lead dioxide, manganese
dioxide, or sulphur.
5. A carbazole derivative of the general formula I
(I)
<IMG>
in which R1 represents a hydroxymethyl group, an alkanoyloxy-
methyl having 1 to 8 carbon atoms in the alkanoyl group or
alkoxymethyl group, a tetrazolyl group, a cyano group, an
oximino carbonyl group, an amino-carbonyl group, or a carboxyl
group which may be free or in the form of a salt with a
physiologically tolerable base, an ester with a physiologically
unobjectionable alcohol or an amide with a physiologically
unobjectionable amine; R2 to R4 may be the same or different
and each represents a hydrogen atom, a halogen atom, a lower
alkyl group, a trifluoromethyl group or a lower alkoxy qroup,
36

R2 being either in the 3-position or 4-position; R5 and R6
have the same meanings as R2 to R4 or together represent the
residue of a five- or six-membered isocyclic ring; and R7
represents a hydrocarbon residue containing 3 to 8 carbon
atoms, provided that, when at least one of the residues R2 to
R6 is a substituent other than hydrogen, R7 may also be a
hydrogen atom, a methyl group or an ethyl group whenever pre-
pared or produced by the process as claimed in claim 1, 2 or
3 or an obvious chemical equivalent thereof.
6. A process as claimed in claim 1 in which in the
reactants R1 is ethoxy carbonyl, methoxy carbonyl, isomethoxy
carbonyl, hydroxy methyl, acetoxy methyl, tetrazolyl, oximino
carbonyl, cyano amino carbonyl, carboxyl, amino carbonyl,
morphorino carbonyl, 2-dimethylamino ethyl oxycarbonyl; R2 is
hydrogen, methyl, chlorine, or methoxy; R3 is hydrogen or
chlorine, R4 is hydrogen, methyl, fluorine or methoxy; R5 is
hydrogen, fluorine, trifluoromethyl, chlorine, or methyl; R6
is hydrogen, methoxy, methyl, chlorine or ethyl or R5 and R6
together form a benzene ring and R7 is hydrogen methyl or benzyl.
7. A carbazole derivative of formula I given in
claim 1 or a pharmaceutically acceptable salt, thereof whenever
prepared or produced by the process as claimed in claim 6 or
an ohvious chemical equivalent thereof.
8. A process as claimed in claim 1 which comprises
refluxing 6-methoxy-1,2,3,4-tetrahydrocarbazole-1-carboxylic
acid ethyl ester in xylene in the presence of a palladium-
carbon catalyst.
9, 1-Ethoxycarbonyl-6-methoxy-carbazole whenever
prepared or produced by the process as claimed in claim 8 or
an obvious chemical equivalent thereof.
10. A process as claimed in claim 1 which comprises
refluxing 8-methoxy-1,2,3,4-tetrahydrocarbazole-1-carboxylic
37

acid ethyl ester in chlorobenzene in the presence of a pallad-
ium-carbon catalyst.
11. A process as claimed in claim 1 which comprises
refluxing 5-chloro-8-methoxy-1,2,3,4-tetrahydrocarbazole-1-
carboxylic acid ethyl ester in xylene in the presence of a
palladium-carbon catalyst.
12. 1-Ethoxycarbonyl-8-methoxy-carbazole whenever
prepared or produced by the process as claimed in claim 10 or
11 or an obvious chemical equivalent thereof.
13. A process as claimed in claim 1 which comprises
refluxing 8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic
acid ethyl ester in cumene, in the presence of a palladium-
carbon catalyst.
14. A process as claimed in claim 1 which comprises
refluxing 7-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-1-
carboxylic acid ethyl ester in xylene in the presence of a
palladium-carbon catalyst.
15. 1-Ethoxycarbonyl-8-methyl-carbazole whenever
prepared or produced by the process as claimed in claim 13 or
14 or an obvious chemical equivalent thereof.
16. A process as claimed in claim 1 which comprises
refluxing 7-fluoro-1,2,3,4-tetrahydrocarbazole-1-carboxylic
acid ethyl ester in chlorobenzene in the presence of a
palladium-carbon catalyst.
17. 1-Ethoxycarbonyl-7-fluoro-carbazole whenever
prepared or produced by the process as claimed in claim 16
or an obvious chemical equivalent thereof.
18. A process as claimed in claim 1 which comprises
refluxing 6-fluoro-1,2,3,4-tetrahydrocarbazole-1-carboxylic
acid ethyl ester in xylene in the presence of a palladium-
carbon catalyst and ortho-dichlorobenzene.
19. 1-Ethoxycarbonyl-6-fluoro-carbazole whenever
prepared or produced by the process as claimed in claim 18 or
38

an obvious chemical equivalent thereof.
20. A process as claimed in claim 1 which comprises
refluxing 7-trifluoro-methyl-1,2,3,4-tetrahydrocarbazole-1-
carboxylic acid ethyl ester in xylene in the presence of a
palladium-carbon catalyst and ortho-dichlorobenzene.
21. 1-Ethoxycarbonyl-7-trifluoromethyl-carbazole
whenever prepared or produced by the process as claimed in
claim 20 or an obvious chemical equivalent thereof.
22. A process as claimed in claim 1 which comprises
refluxing 5-chloro 8-methyl-1,2,3,4-tetrahydrocarbazole-1-
carboxylic acid ethyl ester in chlorobenzene in the presence
of a palladium-carbon catalyst.
23. 1-Ethoxycarbonyl-5-chloro-8-methyl-carbazole
whenever prepared or produced by the process as claimed in
claim 22 or an obvious chemical equivalent thereof.
24. A process as claimed in claim 1 which comprises
refluxing 7-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-1-
carboxylic acid ethyl ester in chlorobenzene in the presence
of a palladium-carbon catalyst.
25. A process as claimed in claim 1 which comprises
refluxing 7-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-1-
carboxylic acid ethyl ester in xylene with chloranil.
26, 1-Ethoxycarbonyl-7-chloro-8-methyl-carbazole
whenever prepared or produced by the process as claimed in
claim 24 or 25 or an obvious chemical equivalent thereof.
27. A process as claimed in claim 1 which comprises
refluxing 5-chloro-8-methoxy-1,2,3,4-tetrahydrocarbazole-1-
carboxylic acid ethyl ester in chlorobenzene in the presence
of a palladium-carbon catalyst.
28. 1-Ethoxycarbonyl-5-chloro-8-methoxy-carbazole
whenever prepared or produced by the process as claimed in
claim 27 or an obvious chemical equivalent thereof,
39

29. A process as claimed in claim 1 which comprises
refluxing 7-chloro-3,8-dimethyl-1,2,3,4-tetrahydrocarbazole-
1-carboxylic acid ethyl ester in chlorobenzene in the presence
of a palladium-carbon catalyst.
30. 1-Ethoxycarbonyl-7-chloro-3,8-dimethyl-carbazole
whenever prepared or produced by the process as claimed in
claim 29 or an obvious chemical equivalent thereof.
31. A process as claimed in claim 1 which comprises
refluxing 7,8-dichloro-1,2,3,4-tetrahydro-carbazole-1-carboxylic
acid ethyl ester in xylene in the presence of a palladium-
carbon catalyst and ortho-dichlorobenzene.
32. 1-Ethoxycarbonyl-7,8-dichloro-carbazole whenever
prepared or produced by the process as claimed in claim 31 or
an obvious chemical equivalent thereof.
33. A process as claimed in claim 1 which comprises
refluxing 7,8-dichloro-1,2,3,4-tetrahydrocarbazole-1-carhoxylic
acid ethyl ester in xylene in the presence of a palladium-
carbon catalyst and ortho-dichlorobenzene.
34. 1-Isoamyloxycarbonyl-7,8-dichloro-carbazole
whenever prepared or produced by the process as claimed in
claim 33 or an obvious chemical equivalent thereof.
35. A process as claimed in claim 1 which comprises
refluxing 7,8-dimethyl-1,2,3,4-tetrahydro-carbazole-1-carboxylic
acid ethyl ester in xylene in the presence of a palladium-
carbon catalyst.
36. A process as claimed in claim 1 which comprises
refluxing 7,8-dimethyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic
acid ethyl ester in xylene with chloranil.
37. 1-Ethoxycarbonyl-7,8-dimethyl-carbazole whenever
prepared or produced by the process as claimed in claim 33 or
36 or an obvious chemical equivalent thereof.
38. A process as claimed in claim 8 which comprises
reflux of the 6-methoxy-carbazole-1-carboxylic acid ethyl ester,

so obtained in methanolic aqueous potassium hydroxide.
39. 6-Methoxy-carbazole-1-carboxylic acid whenever
prepared or produced by the process as claimed in claim 38
or an obvious chemical equivalent thereof.
40. A process as claimed in claim 10 which comprises
reflux of the 8-methoxy-carbazole-1 carboxylic acid ethyl ester
so obtained in methanolic aqueous potassium hydroxide,
41. 8-Methoxy-carbazole-l-carboxylic acid whenever
prepared or produced by the process as claimed in claim 40 or
an obvious chemical equivalent thereof,
42. A process as claimed in claim 13 which comprises
refluxing 8-methyl-carbazole-1-Carboxylic acid ethyl ester,
so obtaincd in methanolic aqueous potassium hydroxide.
43. 8-Methyl-carbazole-1-carboxylic acid whenever
prepared or produced by the process as claimed in claim 42
or an obvious chemical equivalent thereof.
44. A process as claimed in claim 16 which comprises
refluxing 7-fluoro-carbazole-1-carboxylic acid ethyl ester
so obtained in methanolic aqueous potassium hydroxide.
45. 7-Fluoro-carbazole-1-carboxylic acid whenever
prepared or produced by the process as claimed in claim 44
or an obvious chemical equivalent thereof.
46, A process as claimed in claim 24 in which the
7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester is refluxed with
a mixture of aqueous potassium hydroxide and dimethyl sulphoxide.
47. 7-Chloro-8-methyl-carbazole-1-carboxylic acid
whenever prepared or produced by the process as claimed in
claim 46 or an obvious chemical equivalent thereof.
48. A process as claimed in claim 22 in which the
5-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester is refluxed with
a mixture of aqueous potassium hydroxide and dimethyl sulphoxide.
49. 5-Chloro-8-methyl-carbazole-1-carboxylic acid
whenever prepared or produced by the process as claimed in
41

claim 48 or an ohvious chemical equivalent thereof.
50. A process as claimed in claim 29 in which the
7-chloro-3,8-dimethyl carbazole-1-carboxylic acid ethyl ester
is refluxed with a mixture of aqueous potassium hydroxide and
dimethyl sulphoxide.
51. 7-chloro-3,8-dimethyl-carbazole-1-carboxylic
acid whenever prepared or produced by the process as claimed
in claim 50 or an obvious chemical equivalent thereof.
52. A process as claimed in claim 27 in which the
5-chloro-8-methoxy-carbazole-1-carboxylic acid ethyl ester is
refluxed with a mixture of aqueous potassium hydroxide and
dimethyl sulphoxide.
53. 5-chloro-8-methoxy-carbazole-1-carboxylic acid
whenever prepared or produced by the process as claimed in claim
52 or an obvious chemical equivalent thereof.
54. A process as claimed in claim 31 in which the
7,8-dichloro-carbazole-1-carboxylic acid ethyl ester is refluxed
with a mixture of aqueous potassium hydroxide and dimethyl sul-
phoxide.
55. 7,8-dichloro-carbazole-1-carboxylic acid whenever
prepared or produced by the process as claimed in claim 54 or an
obvious chemical equivalent thereof.
56, A process as claimed in claim 35 in which the
7,8-dimethyl-carbazole-1-carboxylic acid ethyl ester is refluxed
with a mixture of agueous potassium hydroxide and dimethyl sul-
phoxide.
57. 7,8-dimethyl-carbazole-1-carboxylic acid whenever
prepared or produced by the process as claimed in claim 56 or an
obvious chemical equivalent thereof.
58, A process as claimed in claim 18 in which the 6s
fluoro-carbazole-l-carboxylic acid ethyl ester is refluxed with
a mixture of aqueous potassium hydroxide and dimethyl sulphoxide.
42

59. 6-fluoro-carbazole-1-carboxylic acid whenever pre-
pared or produced by the process as claimed in claim 58 or an
obvious chemical equivalent thereof.
60. A process as claimed in claim 20 in which the 7-
trifluoromethyl-carbazole-1-carboxylic acid ethyl ester is
refluxed with a mixture of aqueous potassium hydroxide and
dimethyl sulphoxide.
61. 7-trifluoromethyl-carbazole-1-carboxylic acid
whenever prepared or produced by the process as claimed in claim
60 or an obvious chemical equivalent thereof.
62. A process as claimed in claim 24 in which the
7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester so
obtained in tetrahydrofurane is stirred with a suspension of
lithium-aluminium hydride in absolute tetrahydrofurane and the
mixture tRen refluxed.
63, 7-chloro-1-hydroxymethyl-8-methyl-carbazole when-
ever prepared or produced by the process as claimed in claim 62
or an obvious chemical equivalent thereof.
64. A process as claimed in claim 46 in which the
7-chloro-8-methyl-carbazole-1-carboxylic acid so obtained is
treated with phosphorous pentachloride in diethyl ether with
cooling and the reaction mixture treated with gaseous ammonia.
65. 7-chloro-8-methyl-carbazole-1-carboxylic acid
amide whenever prepared or produced by the process as claimed
in claim 64 or an obvious chemical equivalent thereof.
66, A process as claimed in claim 56 in which the
7,8-dimethyl-carbazole-1-carboxylic acid so obtained is treated
with phosphorous pentachloride in diethyl ether with cooling
and the reaction mixture treated with excess morpholine.
67, 7,8-dimethyl-carbazole-1-carboxylic acid morpho-
lide whenever prepared or produced by the process as claimed
in claim 66 or an obvious chemical equivalent thereof.
43

68. A process as claimed in claim 46 in which the
7-chloro-8-methyl-carbazole-1-carboxylic acid so obtained is
added with cooling to a solution of hydroxyl amine in ethanol
and sodium ethylate containing sodium.
69. A process as claimed in claim 96 in which the
7-chloro-8-methyl-carbazole-1-carboxylic acid so obtained is
treated with thionyl chloride and dimethylformamide and then
the mixture heated in chloroform and the 7-chloro-8-methyl-
carbazole-1-carboxylic acid chloride so obtained treated with
hydroxyl amine.
70. 7-chloro-8-methyl-carbazole-1-carbohydroxamic
acid whenever prepared or produced by theprocess as claimed in
claim 68 or 69 or an obvious chemical equivalent thereof.
71. A process as claimed in claim 1 which comprises
refluxing 7-chloro-6-methyl-1,2,3,4-tetrahydrocarbazole-1-
carboxylic acid ethyl ester in chlorobenzene in the presence
of a palladium-carbon catalyst.
72. 7-chloro-6-methyl-carbazole-1-carboxylic acid
ethyl ester whenever prepared or produced by the process as
claimed in claim 71 or an obvious chemical equivalent thereof.
73. A process as claimed in claim 71 in which the
7-chloro-6-methyl-carbazole-1-carboxylic acid ethyl ester so
obtained is refluxed with a mixture of aqueous potassium hydrox-
ide and dimethyl sulphoxide,
74, 7-chloro-6-methyl-carbazole-1-carboxylic acid
whenever prepared or produced by the process as claimed in claim
73 or an obvious chemical equivalent thereof.
75. A process as claimed in claim 1 which comprises
refluxing 5-chloro-6-methyl-1,2,3,4-tetrahydrocarbazole-1-car-
boxylic acid ethyl ester in chlorobeznene in the presence of a
palladium-carbon catalyst.
76. 5-chloro-6-methyl-carbazole-1-carboxylic acid
44

ethyl ester whenever prepared or produced by the process as
claimed in claim 75 or an obvious chemical equivalent thereof.
77. A process as claimed in claim 71 in which the
5-chloro-6-methyl-carbazole-1-carboxylic acid ethyl ester so
obtained in refluxed with a mixture of aqueous potassium hydrox-
ide and dimethyl sulphoxide.
78. 5-chloro-6-methyl-carbazole-1-carboxylic acid
whenever prepared or produced by the process as claimed in claim
77 or an obvious chemical equivalent thereof.
79. A process as claimed in claim 1 which comprises
refluxing 8-chloro-7-methyl-1,2,3,4-tetrahydrocarbazole-1-
carboxylic acid ethyl ester in chlorobenzene in the presence
of a palladium-carbon catalyst.
80. 8-chloro-7-methyl-carbazole-1-carboxylic acid
ethyl ester whenever prepared or produced by the process as
claimed in claim 79 or an obvious chemical equivalent thereof.
81. A process as claimed in claim 71 in which the
8-chloro-7-methyl-carbazole-1-carboxylic acid ethyl ester so
obtained is refluxed with a mixture of aqueous potassium hydrox-
ide and dimethyl sulphoxide.
82. 8-chloro-7-methyl-carbazole-1-carboxylic acid
whenever prepared or produced by the process as claimed in
claim 81 or an obvious chemical equivalent thereof.
83. A process as claimed in claim 1 which comprises
refluxing 7-chloro-8-ethyl-1,2,3,4-tetrahydrocarbazole-1-carbox-
ylic acid ethyl ester in chlorobenzene in the presence of a
palladium-carbon catalyst.
84. 7-chloro-8-ethyl-carbazole-1-carboxylic acid
ethyl ester whenever prepared or produced by the process as
claimed in claim 83 or an obvious chemical equivalent thereof.
85. A process as claimed in claim 71 in which the
7-chloro-8-ethyl-carbazole-1-carboxylic acid ethyl ester so

obtained is refluxed with a mixture of aqueous potassium hydrox-
ide and dimethyl sulphoxide.
86. 7-chloro-8-ethyl-carbazole-1-carboxylic acid
whenever prepared or produced by the process as claimed in
claim 85 or an obvious chemical equivalent thereof.
46

87. A process as claimed in claim 1 which comprises
refluxing benzo[a]-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid
ethyl ester in xylene in the presence of a palladium-carbon
catalyst.
88. Benzo[a]-carbazole carboxylic acid ethyl ester
whenever prepared or produced by the process as claimed in claim
87 or an obvious chemical equivalent thereof.
89. A process as claimed in claim 71 in which the
benzo[a]-carbazole-1-carboxylic acid ethyl ester so obtained is
refluxed with a mixture of aqueous potassium hydroxide and
dimethyl sulphoxide.
90. Benzo[a]-carbazole-1-carboxylic acid whenever
prepared or produced by the process as claimed in claim 88 or
an obvious chemical equivalent thereof.
91. A process as claimed in claim 54 in which the
7,8-dichloro-carbazole-1-carboxylic acid so obtained is treated
with triethyl-amine in absolute dimethyl glycol with cooling
and then isobutyl chloroformate and after removal of the precip-
itate the filtrate treated with dimethylamine and ethanol in
dimethyl glycol with cooling.
92. 7,8-Dichloro-carbazole-1-carboxylic acid (2'-
dimethylaminoethyl) ester whenever prepared or produced by the
process as claimed in claim 91 or an obvious chemical equivalent
thereof.
93. A process as claimed in claim 46 in which the
7-chloro-8-methyl-carbazole-1-carboxylic acid is treated with
phosphorous pentachloride in diethyl ether with cooling and the
reaction mixture treated with 2-dimethylamino ethanol.
94. 7-Chloro-8-methyl-carbazole-1-carboxylic acid
(2'-dimethylaminoethyl) ester whenever prepared or produced by
the process as claimed in claim 93 or an obvious chemical
equivalent thereof.
47

95. A process as claimed in claim 24, in which the
7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester so
obtained in dimethyl formamide is treated with a sodium hydride
suspension and to the reaction mixture methyl iodide is added.
96. 7-chloro-8,9-dimethyl-carbazole-1-carboxylic acid
ethyl ester whenever prepared or produced by the process as
claimed in claim 95 or an obvious chemical equivalent thereof.
97. A process as claimed in claim 95 in which the
7-chloro-8,9-dimethyl carbazole-1-carboxylic acid ethyl ester
so obtained is refluxed with a mixture of aqueous potassium
hydroxide and dimethyl sulphoxide.
98. 7-chloro-8,9-dimethyl-carbazole-1-carboxylic
acid whenever prepared or produced by the process as claimed
in claim 97 or an obvious chemical equivalent thereof.
99. A process as claimed in claim 24 in which the
7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester so
obtained in dimethyl formamide is treated with a sodium hydride
suspension and to the reaction mixture benzyl iodide is added.
100. 7-chloro-8-methyl-9-benzyl-carbazole-1-carboxylic
acid ethyl ester whenever prepared or produced by the process as
claimed in claim 99 or an obvious chemical equivalent thereof.
101. A process as claimed in claim 24 in which the
7-chloro-8-methyl-9-benzyl-carbazole-1-carboxylic acid ethyl
ester so obtained is refluxed with a mixture of aqueous potassium
hydroxide and dimethyl sulphoxide.
102. 7-chloro-8-methyl-9-benzyl-carbazole-1-carboxylic
acid whenever prepared or produced by the process as claimed in
claim 101 or an obvious chemical equivalent thereof.
48

103. A process as claimed in claim 64 in which the
7-chloro-8-methyl-carbazole-1-carboxylic acid amide so obtained
is treated portion wise with phosphorus oxychloride and the mixture
obtained heated.
104. 7-Chloro-8-methyl-carbazole-1-carbonitrile
whenever prepared or produced by the process as claimed in
claim 103 or an obvious chemical equivalent thereof.
105. A process as claimed in claim 103 in which the
7-chloro-8-methyl-carbazole-1-carbonitrile so obtained is
admixed with hexamethyl-phosphoric acid triamide and sodium
azide and subsequently formic acid is added to the reaction
mixture.
106. 7-Chloro-8-methyl-1-(5-tetrazolyl)-carbazole
whenever prepared or produced by the process as claimed in
claim 105 or an obvious chemical equivalent thereof.
107. A process as claimed in claim 1 which comprises
refluxing 4-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic
acid methyl ester in chlorobenzene in the presence of a
palladium-carbon catalyst.
108. 4-Chloro-carbazole-1-carboxylic acid methyl
ester whenever prepared or produced by the process as claimed
in claim 107 or an obvious chemical equivalent thereof.
109. A process as claimed in claim 107 in which
the 4-chloro-carbazole-1-carboxylic acid methyl ester so
obtained is a mixture of aqueous potassium hydroxide and
dimethyl sulphoxide.
110. 4-Chloro-carbazole-1-carboxylic acid whenever
prepared or produced by the process as claimed in claim 109
or an obvious chemical equivalent thereof.
111. A process as claimed in claim 1 which comprises
refluxing 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic
acid methyl ester in chlorobenzene in the presence of a
palladium-carbon catalyst.
49

112. 3-Chloro-carbazole-1-carboxylic acid methyl
ester whenever prepared or produced by the process as claimed
in claim 111 or an obvious chemical equivalent thereof.
113. A process as claimed in claim 111 in which
the 3-chloro-carbazole-1-carboxylic acid methyl ester so
obtained is refluxed with a mixture of aqueous potassium hydroxide and
dimethyl sulphoxide.
114. 3-Chloro-carbazole-1-carboxylic acid whenever
prepared or produced by the process as claimed in claim 113
or an obvious chemical equivalent thereof.
115. A process as claimed in claim 1 which comprises
refluxing 4-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic
acid methyl ester in xylene in the presence of a palladium-
carbon catalyst.
116. 4-Methyl-carbazole-1-carboxylic acid methyl
ester whenever prepared or produced by the process as claimed
in claim 115 or an obvious chemical equivalent.
117. A process as claimed in claim 115 in which the
4-methyl-carbazole-1-carboxylic acid methyl ester so obtained
is refluxed with a mixture of aqueous potassium hydroxide and dimethyl
sulphoxide.
118. 4-Methyl-carbazole-1-carboxylic acid whenever
prepared or produced by the process as claimed in claim 117
or an obvious chemical equivalent.
119. A process as claimed in claim 1 which comprises
refluxing 3-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic
acid methyl ester in chlorobenzene in the presence of a
palladium-carbon catalyst.
120. 1-Methoxycarbonyl-3-methyl-carbazole whenever
prepared or produced by the process as claimed in claim 119
or an obvious chemical equivalent thereof.
121. A process as claimed in claim 119 in which
the 3-methyl-carbazole-1-carboxylic acid methyl ester so

obtained is refluxed with a mixture of aqueous potassium hydrox-
ide and dimethyl sulphoxide.
122. 3-methyl-carbazole-1-carboxylic acid whenever
prepared or produced by the process as claimed in claim 121 or
an obvious chemical equivalent thereof.
123. A process as claimed in claim 62 in which the
7-chloro-1-hydroxymethyl-8-methyl-carbazole so obtained is
treated with acetic anhydride in the presence of pyridine.
124. 7-chloro-1-acetoxymethyl-8-methyl-carbazole
whenever prepared or produced by the process as claimed in claim
123 or an obvious chemical equivalent thereof.
51

Description

` 105368Z
This invention relates to new carbazole derivatives of
the general formula I
R3
4 = 1 2 (I)
in which Rl represents a hydroxymethyl group, an alkanoyloxy-
methyl group, with 1 to 8 carbon atoms in the alkanoyl group,
a tetrazolyl group, a cyano group, an oximinocarbonyl group, an
aminocarbonyl group, a carboxyl group, its salts with physio-
logically tolerable bases, its esters of physiologically accep-
i table alcohols or its amides of physiologically acceptable
amines; R2 to R4 represent hydrogen atoms, halogen atoms, lower
1 alkyl groups, trifluoromethyl groups or lower alkoxy groups;
; R5 and R6 have the same meanings as R2 to R4 or together repre-
' sent the residue of a five- or six- membered isocyclic ring;
and R7 represents a hydrocarbon radical containing 3 to 8 carbon
~ 20 atoms or, when at least one of the radicals R2 to R6 is a sub-
j~ stituent different from hydrogen, a hydrogen atom, a methyl group
3 or an ethyl group.
; The new carbazole derivatives are pharmacologically
~- ~ctive substances, which are distinguished especially by their
strong anti~inflammatory activity when used topically. As is
explaàned more fully below, the new carbazole derivatives differ
advantageously in their activity from the known structurally
-~ analogous N~phenyl-anthranilic acid derivatives~ which when used
~` topically possess a very low anti~inflammatory activity.
As sfiown by the results of pharmacological tests given
hereinafter, the new carbazole deri~vatives may contain various
.,- ~
.:
, . ~ 1 --
, . ~ .
.

lOS368Z
substituents Rl to R7 without losing their anti-inflammatory
activity when used topically.
Rl substituents include, in addition to hydroxymethyl
groups, tetrazolyl groups, cyano groups, oximinocarbonyl groups
and aminocarbonyl groups, especially carboxyl groups, their
salts with physiologically tolerable bases, their esters with
physiologically acceptable alcohols and their amides with
physiologically acceptable amines. Suitable physiologically
tolerable salts of carboxyl groups include, for example, alkali
or alkaline earth metal salts, such as the sodium salt or the
calcium salt.
Physiologically acceptable alcohols, with which the
carboxyl groups may be esterified, are, for example, straight-
chained or branched or cyclic, saturated or unsaturated hydro-
carbon radicals, which are optionally interrupted by an oxygen
atom or a nitrogen atom or substituted by hydroxyl groups, amino
; groups or carboxyl groups, for example, alkanols, alkenols,
alkinols, cycloalkanols, cycloalkenols, cycloalkyl-alkanols,
phenylalkanols, phenylalkenols, alkandiols, hydroxy-carboxylic
acids, aminoalkanols or alkylaminoalkanols and dialkylamino-
alkanols containing 1 to 4 carbon atoms in the alkyl radical.
Alcohols suitable for esterifying the carboxyl group
in the l-position are, for example, those containing a methyl,
carboxymethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-amino-
ethyl, 2-dimethylaminoethyl, 2-carboxyethyl, propyl, allyl, -
cyclopropylmethyl, isopropyl, 3-hydroxypropyl, propinyl, 3-
aminopropyl, butyl, sec.-butyl, t-butyl, butyl-t2), cyclobutyl,
pentyl, isopentyl, t-pentyl, 2-methylbutyl, cyclopentyl, hexyl,
cyclohexyl, cyclohex-2-enyl, cyclopentylmethyl, heptyl, benzyl,
2-phenylethyl, octyl, bornyl, isobornyl, menthyl, nonyl, decyl,
3-phenylpropyl, 3-phenyl-prop-2-enyl, undecyl or dodecyl radical.

l~S36B'~:
Physiologically acceptable amines, with which the
carboxyl group in the l-position may be amidated, preferably
include alkylamines, dialkylamines, alkanolamines, dialkanol~
amines containing 1 to 6 carbon atoms in the alkyl or alkanol
residue, or five- or six-membered N-heterocycles. Suitable
amines are, for example, methylamine, ethylamine, isopropyl-
amine, ethanolamine, dimethylamine, diethylamine, diethanol-
amlne, pyrrolidine, piperidine, morpholine and N-methyl- piper-
azlne .
The substituent Rl may also be an alkanoyloxymethyl
~A~ group, of which the alkanoyl group prcferably contains 1 to 8carbon atoms. Suitable alkanoyl radicals include, for example,
the formyl, acetyl, propionyl, butyryl and the hexanoyl radical.
As lower alkyl groups R2 to R6 there are preferably used
alkyl groups containing 1 to 4 carbon atoms such as the methyl,
ethyl, propyl, isopropyl, butyl and t-butyl groups.
A halogen atom R2 to R6 is preferably a fluorine, chlo-
rine or bromine atom.
The radical of a five- or six-membered isocyclic ring
formed by the substituents R5 and R6 is cyclopentene, cyclo-
hexene or benzene.
; Suitable hydrocarbon radicals R7 containing 1 to 8
carbon atoms are, for example, straight-chained or branched
alkyl residues, which are optionally substituted by three- to
six-membered cycloalkyl groups or by phenyl groups. As hydro-
'` carbon radicals R7 there are mentioned, for example, the methyl,
e~hyl, propyl, isopropyl, butyl, hexyl, 3-cyclopropyl-propyl,
cyclopentyl-methyl and the benzyl radical.
The present invention also includes a process for pro-
ducing the new carbazole derivatives of the general formula I,which is characterized in that tetrahydrocarbazole derivatives
of the general formula II or III
-- 3
.. . . . . . .
. .

~S36~Z
4 ~ 4~
R5 N R5 N
R6 R7 Rl R6 R7 Rl -
in which Rl to R7 have the meanings given for formula I, are
dehydrogenated in a known manner, and optionally a secondary
amino group in the 9-position is alkyla~e-d~ free hydroxyl
groups are esterified or etherified, ester groups are hydrolyzed,
and free carboxyl groups or reactive derivatives thereof are
converted into salts, esters, amides, cyano groups, oximino~
carbonyl groups, hydroxymethyl groups or tetrazolyl groups.
The dehydrogenation of the tetrahydrocarbazole deriva-
tives of the general formulae II and III is carried out by
known methods. Thus, for example, it is possible to dehydro-
genate the compounds of the formula II or III with noble metal
catalysts of the platinum group. Suitable noble metal catalysts
include, for example, platinum oxide catalysts or especially -
palladium-carbon catalysts.
The reaction is preferably carried out in a high boiling
` aromatic solvent, for example, toluene, xylene, cumene, anisole,
! chlorobenzene, dichlorobenzene or chlorotoluene. The reaction
temperature is determined by the choice of the solvent and is
approximately lO0 to 200C, and preferably 130 to 180C. ~1hen
the tetrahydrocarbazole derivatives of the general formula II
or III contain halogen atoms, the latter can be split off if a
halogen-free solvent is used for the reaction. If the reaction -
is carried out in a halogen-containing solvent (which contains
the same halogen atom as the compound to be dehydrogenated) the
splitting off of halogen atoms can be avoided.
Additional oxidizing agents for use in the process
:-. .. .
... . ~ , . .
.~
.:.~ : . . . .

1053,~8Z
include quinones, such as para-benzoquinone, chloranil, tetra-
chlor-ortho-benzoquinone and dichloro-cicyano-benzoquinone, or
inorganic oxidizing agents, such as lead dioxide, manganese
dioxide and sulphur. The solvents are high-boiling solvents
such as xylene, cumene, chlorobenzene and dichlorobenzene. The
reaction temperature is 100 to 200C, and preferably 130 to
160C
The optional subse~uent alkylation of a secondary amino
group in the 9-position is also carried out by known methods
that are customarily used for the N-alkylation of indole deriva-
tives.
Thus, for example, the nitrogen atom of the carbazole
ring may be metallized by reaction with metal hydrides or metal
amides such as sodium hydride or sodamide, and the reactive
compounds thus obtained reacted with the halides (chlorides,
bromides or iodides) of the finally desired hydrocarbon residue.
For this reaction, which is carried out at a reaction temperature
of about 0 to 120C, there are preferably used polar aprotic
solvents, such as dimethylformamide, N-methyl-pyrrolidone or
hexamethylphosphoric acid triamide.
The subsequent esterification of the free hydroxymethyl
group, as an optional measure, is also carried out by methods
known for this purpose. A possible method of esterification
is, for example, the esterification of the hydroxy compounds
with acid anhydrides or acid chlorides in the presence of
aromatic N-heterocycles such as pyridine, collidine or lutidine,
or in the presence of aqueous solutions of basic alkali metal
compounds, such as sodium bicarbonate, potassium bicarbonate,
sodium carbonate, sodium hydroxide or potassium hydroxide.
The optional subsequent hydrolysis of the esters is
carried out by known methods, for example, the hydrolysis of

105368Z
the esters in water or aqueous alcohol in the presence of acid
catalysts, such as hydrochloric acid, sulphuric acid, para-
toluene sulphonic acid, or of basic catalysts, such as potassium
hydrogen carbonate, potassium carbonate, sodium hydroxide or
potassium hydroxide.
The optional subsequent esterification of the free
acids is also carried out by known methods. The acids may be
reacted, for example, with diazomethane or diazoethane, whereby
the corresponding methyl or ethyl esters are obtained. A method
lQ that is generally applicable is the reaction of the acids with
the alcohols in the présence of carbonyl-diimidazole or dicyclo-
hexyl-carbodiimide. It is possible to react the acids with
alkyl halides in the presence of copper (I) chloride or silver
oxide~
Another method consists of converting the free acids
with the corresponding dimethylformamide-alkylacetals into the
corresponding acid alkyl esters. Moreover, the acids may be
reacted in the presence of strongly acid catalysts, such as
hydr~gen chloride, sulphuric acid, perchloric acid, trifluoro-
2a methyl sulphonic acid or para-toluene sulphonic acid, with the
alcohols or lower-alkane carboxylic acid esters of the alcohols.
~ However, it is also possible to convert the carboxylic
,~ acids into the acid chlorides or mixed anhydrides, and to react~,~
~ ~ the 1-tter with the alcohols in the presence of basic catalytts
I -.
~ 30
i~
~ ~ 6 -
.. ... . . . .
.. . : . . . ~ .

~OS3682
such as pyridine, collidine, lutidine or 4-dimethylaminopyridine.
The salts of the carboxylic acids are formed, for
example by hydrolyzing the esters with basic catalysts, or by
neutralizin~ the acids with alkali carbonates or alkali hydrox-
ides, for example, sodium carbonate, sodium hydrogen carbonate,
sodium hydroxide, potassium carbonate, potassium hydrogen car-
bonate or potassium hydroxide.
- 6a -
.

105368;~ ~
It is also possible to react esters of the general
formula I in the presence of acid or basic catalysts with the
alcohol finally desired. For this purpose, there are preferably
used, as acid or basic catalysts, hydrogen chloride, sulphuric
acid, phosphoric acid, para-toluene sulphonic acid, trifluor-
acetic acid or, for example, alkali, alkaline earth or alumin-
ium alcoholates.
The optional subsequent amide formation of hydroxamic
acid formation from the free carboxylic acids or their reactive
derivatives is also carried out by methods known for this
purpose. Thus, for example, the carboxylic acids are reacted
under known conditions with the amines or hydroxylamine in the
presence of dicyclohexyl-carbodiimide, and the corresponding ~-
aminocarbonyl compounds are obtained.
It is also possible, for example, to convert the acid
chlorides, mixed anhydrides or esters of the corresponding
carboxylic acids under known conditions by treatment with
ammonia, amines or hydroxylamine into the corresponding amides
or hydroxamic acids.
The optional subsequent conversion of reactive carboxy-
lic acid derivatives into nitriles is also carried out by methods
known for such purpose, for example, by causing dehydrating
agents, such as, for example, dicyclohexyl-carbodiimide,
carbonyl-diimidazole, polyphosphoric acid, thionyl chloride or
phosphorus oxychloride, to act on the corresponding aminocar-
bonyl compounds under known conditions.
Known methods are also used to obtain from reactive
derivatives of the carboxylic acids the corresponding hydroxy-
methyl compounds. Thus, for example, the carboxylic acid ester
in an aprotic halogen-free solvent, e.g., an ether (such as
diethyl ether, diisopropyl ether, tetrahydrofurane or glycol
- 7
.
~: ., .~ . , -

~53682
dimethyl ether), may be reduced with a complex metal hydride
such as lithium-aluminium hydride, diisobutyl-aluminium hydride
or diethyl-aluminium hydride to form the corresponding hydroxy-
methyl compound.
Known methods may also be used for preparing the tetra-
zolyl compounds, for example, the nitriles in aprotic solvents
such as dimethylformamide, N-methylacetamide, N-methylpyrro-
lidone or hexamethyl-phosphoric acid triamide, may be reacted
under known conditions with alkali azides, such as sodium azide,
to form the corresponding tetrazolyl compounds.
It has already been mentioned that the new carbazole
derivatives are pharmacologically active compounds, which are
distinguished especially by a strong anti-inflammatory activity
when applied topically. The inflammation-inhibiting activity of
the new carbazole derivatives in local application can be de-
termined by the method of Tonelli as follows:
The substance to be tested is dissolved in an irritant
consisting of 4 parts of pyridine, 1 part of distilled water, ~ -
5 parts of ether and 10 parts of an ethereal solution of 4%
strength of croton oil. Felt strips fixed to the inner sides
of forceps, such as used for microscope slides, are impregnated
with the test solution, and are pressed under light pressure
for 15 seconds on the right ears of male rats weighing from
100 to 160 grams.
The left ears remain untreated and serve as controls.
Three hours after the application, the animals are killed and
discs 9 mm in diameter are stamped out of their ears. The
difference in weight between a disc from the right ear and a
disc from the left ear is a measure of the oedema formed.
Control animals are treated in the same manner, except
that the irritant solution used contains no test substance.
. - . ~
.: ... ...

- 1053682
The anti-inflammatory activity is determined by dividing
the average difference in the ear weights of the treated group
by the average difference in the ear weights of the control
group.
The following table demonstrates the activity of the
carbazole derivatives as compared with that of the known anti-
inflammatory substances I and II.
Table
.
No. Substance Concentration Anti-inflamm.
mg/ml activity
in%
I N-(3-trifluoromethyl-phenyl)-3.75 0%
anthranilic acid 7.5 0%
15.0 20%
. _
II hydrocortisone acetate 7.5 19%
15.0 41%
III 9-methyl-carbazole-1- 7.5 33%
carboxylic acid
_ _ .
IV 6-fluoro-carbazole-1- 7.5 24%
carboxylic acid 15.0 41%
V 7-trifluoromethyl-carbazole-1-7.5 40%
carboxylic acid 15.0 56%
_
VI 7,8-dichloro-carbazole-1- 7.5 37%
carboxylic acid (2'-dimethyl- 15.0 40%
aminoethyl) ester
VII 7-chloro-8-methyl-carbazole-1- 3.75 42%
carboxylic acid 7.5 59%
15.0 85%
VIII 5-chloro-8-met`hyl-carbazole-1- 7.5 26%
carboxylic acid 15.0 52%
IX 8-chloro-7-carbazole-1- 3.75 38%
carboxylic acid 7.5 62%
15.0 83%
. . _
X 7-chloro-3,8-dimethyl-carbazole 7.5 2%
-l-carboxylic acid 15.0 56%
XI 7-chloro-8,9-dimethyl-carbazole 7.5 46
-l-carboxylic acid 15.0 69%
XII 7-chloro-8-methyl-carbazole-1- 7.5 31%
carboxylic acid amide 15.0 54%
g
- -
. : . .
: . . . , :. :

iO5368Z
No. Substance Concentration Anti-inflamm.
mg/ml activity
in%
XIII 7-chloro-8-methyl-carbazole-1- 3.75 28%
carbo-hydroxamic acid 7.5 50%
15.0 70%
XIV 7-chloro-1-hydroxymethyl-8- 7.5 36%
methyl-carbaæole 15.0 41
XV 7,8-dimethyl-carbazole-1- 7.5 36%
carboxylic acid morpholide
XVI benzo[a]-carbazole-l- 3.75 22%
carboxylic acid 7.5 46%
XVII carbazole-l-carboxylic acid 7.5 40%
15.0 50%
1 0
It can be seen from the table that the new carbazole de-
rivatives, as compared with the structurally analogous known N-
phenyl-anthranilic acid derivatives, are distinguished by a
superior anti-inflammatory activity. The anti-inflammatory
activity of the new carbazole derivatives when applied locally
is approximately as strong as that of the known anti-inflamma-
torily active corticoids.
Surprisingly, not only the new carbazole derivatives,
bu~ also known carbazole derivatives that differ from those of
the general f~rmula I in that the substituents R2 to R7 are all
hydrogen atoms exhibit a pronounced topical anti-inflammatory
activity, as can be seen from the above table. Accordingly
these compounds are also suitable for the production of topical
anti-inflammatorily active medicinal preparations.
Thus, within the scope of the present invention there
have been prepared non-steroidal compounds that possess an
excellent topical inflammation-inhibiting activity.
The corticoids hitherto used for the treatment of inflam- ~ -
mation of the skin possess, in addition to the topical action,
a systemic action. Such corticoids, even when topically
-- 10 --

1053619Z
applied, are able, because of absorption through the inflamed
skin or because of skin lesions, to pass into the blood stream
where, as hormone-active substances, they influence the body
functions in various ways.
The topically active carbazole derivatives of the pre-
sent invention do not have such a disadvantage.
Moreover, the carbazole derivatives have the advantage
that they possess a low toxicity and display a certain anti-
bacterial and antifungal activity, which is wholly desirable
in the topical treatment of inflammations.
The new compounds are suitably used in conjunction with
the carriers usual in galenical pharmacy for the local treat-
ment of allergies, contact dermatitis, eczemas of very many
types, neurodermatitis, erythrodermia, burns, Pruritis vulvae
et ani, rosacea, Erythematodes cutaneus, psoriasis, Lichen
ruber planus et verrucosus and like skin diseases.
The preparation of medicinal specialities is carried
out in the usual manner by converting the active substances
with suitable additives into the desired forms for application,
for example, solutions, lotion, salves, creams, inhalant pre-
parations or plasters. The concentration of active substance
in the preparations thus formulated depends on the form of
application. In the case of lotions and salves it is preferable
to use a concentration of active substance of 0.005% to 5%.
The starting compounds for the process of the invention
are known or can easily be prepared in accordance with the
following scheme of the formulae
.

1053682
4~0Br ~ R4 ~ ~î
R5HN ~ R5 ~ ~ N
R6 R7 OOR8 6 R7 COOR8
(IV) (V) (III')
R5\~ ~ 2 ~ R2
R6 COOR8 6 H COOR8
(VI) (VII) (II' )
R $o N2N~ R ' ~r
( IV ' ) (V) ( I I I
in which R2 to R7 have the above meanings, and R8 represents
a lower alkyl group, by heating the components at 50 to 200C, ~
for example, under an inert gas in the presence of a Lewis .. :.
acid such as zinc chloride, and optionally with the addition of
a lower alcohol, such as ethanol, or a lower carboxylic acid,
such as acetic acid, as solvent.
In the esters obtained, it is possible, under the con-
ditions already described, optionally to alkylate a secondary
amino group present in the 9-position, esterify or etherify
free hydroxy groups,hydrolyze ester groups, and to convert free
- 12 -

lOS3682
carboxyl groups or reactive derivatives thereof into salts,
esters, amides, oximinocarbonyl groups, cyano groups, hydroxy-
methyl groups or tetrazolyl groups.
In principle the condensation may also be carried out
using other ~-halogen-cyclohexanone derivatives, for example,
~-chloro- or ~-iodo-cyclohexanone derivatives. It is also
possible to carry out the reaction without using Lewis acids
or to use other catalysts such as boron trifluoride, phosphoric
acid or hydrogen chloride.
When the reaction is carried out using substituted
anilines, the substituted aniline is advantageously used in
excess preferably with a 2.2 to 2.5 molar excess. The reaction
may be carried out with or without solvents. Preferred sol-
vents are alcohols such as ethanol and butanol, or ethers such
as dioxane and dimethoxy-ethane. In working without solvents,
the excess of the aniline component may serve as solvent. In
both cases a catalyst, for example, zinc chloride, may be added.
The reaction is preferably carried out under an atmos-
phere of a protective gas, for example, nitrogen or an inert
gas.
The reaction temperature, which is determined by the
choice of the solvent, is 80 to 200C, and preferably, when
working without solvents or when solid aniline components are
used, 140 to 150C.
The reaction is carried out under atmospheric pressure
or reduced pressure, preferably at 100 mm of mercury.
When substituted phenyl-hydrazines (IV) are used as
starting materials,the reaction is preferably effected at a
temperature of 50 to 150C, and may be carried out using cata-
lysts known from the Fischer indole synthesis, for example,zinc chloride, hydrogen chloride, sulphuric acid, phosphoric
- 13 -

lOS368Z
acid, polyphosphoric acid and boron trifluoride. Preferred
solvents are acetic acid, glacial acetic acid and alcohols.
However, the reaction may also be carried out without solvents
in molten zinc chloride or in polyphosphoric acid and phos-
phoric acid.
The hitherto unknown compounds of the general formula
II, 5,6,7,8-tetrahydrocarbazole-1-carboxylic acid itself, and
esters and amides thereof are, surprisingly, also distinguished
by a pronounced anti-inflammatory activity upon local applica-
tion, and can be used as medicinally active substances in the
same manner as the carbazole derivatives.
Accordingly, the invention also includes the unknown
5,6,7,8-tetrahydrocarbazole-1-carboxylic acid derivatives, and
their preparation and use.
The following examples illustrate the process of the
invention.
Example 1 -
(a) 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid
ethyl ester are mixed with 10 g of 3-methoxyaniline, and the
mixture is heated at 140C under a light vacuum (about 100 torr),
while stirring, for 7 hours. After cooling, the mixture is
diluted with carbon tetrachloride, filtered, the organic phase
is washed, concentrated in vacuo, and the residue is purified
by chromatography over silica gel with cyclohexane-benzene as
eluent, and 6-methoxy-1,2,3,4-tetrahydrocarbazole-1-carboxylic
acid ethyl ester is obtained.
(b) 2.05 g of 6-methoxy-1,2,3,4-tetrahydrocarbazole-
l-carboxylic acid ethyl ester are dissolved in 20 ml of xylene,
2 g of 10% strength palladium-carbon catalyst are added, and
the whole is heated for 4 hours under reflux. After cooling
the reaction mixture, the catalyst is filtered, the solution
', , : ' : . ' '

l~S36t~Z
is concentrated in vacuo, the residue is recrystallized from
benzene, and 1.5 g of 6-methoxy-carbazole-1-carboxylic acid
ethyl ester melting at 107C are obtained.
Example 2
(a) Under the conditions given in Example l(a), 10 g
of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are
reacted with 2-methoxyaniline to form 3-methoxy-1,2,3,4-tetra-
hydrocarbazole-l-carboxylic acid ethyl ester.
(b) The 8-methoxy-1,2,3,4-tetrahydrocarbazole-1-
carboxylic acid ethyl ester is dissolved in chlorobenzene, and,
after the addition of 10% strength palladium-carbon, dehydro-
genated as described in Example l(b), and, after recrystalliza-
CR r~ z~k
A tion from ethanol there is obtained a 73% yield of ~-methoxy-~
l-carboxylic acid ethyl ester melting at 76C.
Example 3
(a) Under the conditions given in Example l(a), 10 g
of 3-bromo-2-oxo-cylcohexane carboxylic acid ethyl ester are
reacted with 2-methyl-aniline to form 8-methyl-1,2,3,4-tetra-
hydrocarbazole-l-carboxylic acid ethyl ester.
(b) The 8-methyl-1,2,3,4-tetrahydrocarbazole-1-car-
boxylic acid ethyl ester is dissolved in cumene, and, after
the addition of 10% strength palladium-carbon, dehydrogenated
as described in Example l(b), and, after recrystallization
from methanol, a 75% yield of 8-methyl-carbazole-1-carboxylic
acid ethyl ester melting at 68C is obtained.
Example 4
(a) Under the conditions given in Example l(a), 10 g
of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are
reacted with 3-fluoraniline to form 7-fluoro-1,2,3,4-tetra-
hydrocarbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared
- 15 -

1053682
is dissolved in chlorobenzene, 10~ strength palladium-carbon is -
added, and the derivative is dehydrogenated as in Example l(b),
and, after recrystallization from isopropyl alcohol, a 77%
yield of 7-fluoro-carbazole-1-carboxylic acid ethyl ester melt-
ing at 132C is obtained.
Example 5
(a) Under the conditions given in Example l(a), 10 g
of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are
reacted with 4-fluoraniline to form 6-fluoro-1,2,3,4-tetra-
hydrocarbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared
is dissolved in ortho-dichlorobenzene, 10% strength palladium-
carbon is added, and the derivative is dehydrogenated as des-
cribed in Example l(b), and, after recrystallization from
isopropyl alcohol, a 60% yield of 6-fluoro-carbazole-1-carboxy-
lic acid ethyl ester melting at 130C is obtained.
Example 6
(a) Under the conditions given in Example l(a), 10 g
of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are
reacted with 3-trifluoromethyl-aniline to form 7-trifluoro-
methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared
is dissolved in ortho-dichlorobenzene, 10% strength palladium-
carbon is added, and the derivative is dehydrogenated as des-
cribed in Example l(b), and, after recrystallization from
isopropyl alcohol, a 55% yield of 7-trifluoromethyl-carbazole-
l-carboxylic acid ethyl ester melting at 80C is obtained.
Example 7
(a) Under the conditions given in Example l(a), but
with the addition of 0.5 g of zinc chloride after 2 hours, 10
g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are
- 16 -
. :. . - : .

1()5368Z
reacted with 5-chloro-2-methyl-aniline to form 5-chloro-8-
methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl
ester.
(b) The tetrahydrocarbazole derivative thus prepared
is dissolved in chlorobenzene, 10% strength palladium-carbon
is added, and the derivative is dehydrogenated as described in
Example l(b), and, after recrystallization from isopropyl
alcohol-methanol, an 85% yield of 5-chloro-8-methyl-carbazole-
l-carboxylic acid ethyl ester melting at 102C is obtained.
Example 8
(a) Under the conditions given in Example 7(a), 10 g
of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are
reacted with 3-chloro-2-methyl-aniline to form 7-chloro-8-
methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl
ester.
(b) The tetrahydrocarbazole derivative thus prepared
is dissolved in chlorobenzene, 10% strength palladium-carbon
is added, and the derivative is dehydrogenated as described
in Example l(b), and, after recrystallization from isopropyl
alcohol-methanol, a 70% yield of 7-chloro-8-methyl-carbazole-
l-carboxylic acid ethyl ester melting at 98C is obtained.
Example 9
l g of chloranil and 15 ml of xylene are added to
600 mg of 7-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-l-
carboxylic acid ethyl ester, and the whole is heated under
reflux for 25 hours. The solvent is then distilled, sodium
dithionite and a dilute solution of sodium hydroxide are added
to the residue, and the mixture is extracted several times
with benzene. The organic phase is washed and concentrated,
and the residue is recrystallized from isopropyl alcohol-
methanol to yield 350 mg (61%) of 7-chloro-8-methyl-carbazole-

1~5368Z
l-carboxylic acid ethyl ester melti~ng at 97C.
Example 10
(a) Under the conditions given in Example 7(a), 10 g of
3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted
with 5-chloro-2-methoxy-aniline to form 5-chloro-8-methoxy-
1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is
dissolved in chlorobenzene, 10~ strength palladium-carbon is
added, and the derivative is dehydrogenated as described in
Example l(b), and, after recrystallization from isopropyl alcohol,
a 52% yield of 5-chloro-8-methoxy-carbazole-1-carboxylic acid
ethyl ester melting at 113C is obtained.
Example 11
(a) Under the conditions given in Example 7(a), 10 g
of 3-bromo-2-oxo-5-methyl-cyclohexane carboxylic acid ethyl
ester are reacted with 3-chloro-2-methyl-aniline to form 7-
chloro-3,8-dimethyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic
acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is
dissolved in chlorobenzene, 10% strength palladium-carbon is
added, and, the derivative is dehydrogenated as described in
Example l(b), and, after recrystallization from isopropyl alcohol,
a 70% yield of 7-chloro-3,8-dimethyl-carbazole-1-carboxylic
acid ethyl ester melting at 137C is obtained.
Example 12
(a) Under the conditions given in Example 7(a), 10 g
of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are
reacted with 2,3-dichloro-aniline to form 7,8-dichloro-1,2,3,4-
tetrahydro-carbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared
is dissolved in ortho-dichlorobenzene, 10% strength palladium-
- 18 -

105366~
carbon is added, and the derivative is dehydrogenated as de-
scribed in Example l(b~, and, after recrystallization from
isopropyl alcohol, a 60% yield of 7,8-dichloro-carbazole-1-
carboxylic acid ethyl ester melting at 107C is obtained.
Example 13
- (a) Under the conditions given in Example 7(a), 10 g
of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are
reacted with 2,3-dichloro-aniline to form 7,8-dichloro-1,2,3,4-
tetrahydrocarbazole-l-carboxylic acid ethyl ester.
tb) The tetrahydrocarbazole derivative thus prepared
is dissolved in ortho-dichlorobenzene, 10% strength palladium-
carbon is added, and the derivative is dehydrogenated as
described in Example l(b), and, after recrystallization from
methanol, a 45% yield of 7,8-dichloro-carbazole-1-carboxylic
acid isoamyl ester melting at 66C is obtained.
Example 14
(a) Under the conditions given in Example 7(a), 10 g
of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are
reacted with 2,3-dimethyl-aniline to form 7,8-dimethyl-1,2,3,4-
tetrahydro-carbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared
i8 dissolved in xylene, 10% strength palladium-carbon is added,
and the derivative is dehydrogenated as in Example l(b), and,
after recrystallization from isopropyl alcohol, a 66% yield of
7,8-dimethyl-carbazole-1-carboxylic acid ethyl ester melting
at 93C is obtained.
Example 15
Under the conditions given in Example 9, 7,8-dimethyl-
1,2,3,4-tetrahydxocarbazole-1-carboxylic acid ethyl ester is
-- 19 --

lOS368Z
dehydrogenated with chloranil, and, after recrystallization
from isopropyl alcohol, a 50% yield of 7,8-dimethyl-carbazole-
l-carboxylic acid ethyl ester melting at 92C is obtained.
Example 16
3.1 g of 5-chloro-8-methoxy-1,2,3,4-tetrahydrocarbaz-
ole-l-carboxylic acid ethyl ester are heated under reflux with
20 ml of xylene and 3 grams of 10% strength palladium-carbon
for 6 hours. The mixture is allowed to cool, the catalyst is
filtered, the solution is concentrated in vacuo and the resi-
due is recrystallized from ethanol to yield 2.0 g ~66%) of
8-methoxy-carbazole-1-carboxylic acid ethyl ester melting at
75C.
Example 17
Under the conditions given in Example 16, 7-chloro-
8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl
ester is dehydrogenated, and, after recrystallization from
methanol, a 60% yield of 8-methyl-carbazole-1-carboxylic acid
ethyl ester melting at 68C is obtained.
Example 18
2 ml of methanol and a solution of 2.5 g of potassium
hydroxide in 10 ml of water are added to 1.2 g of 6-methoxy-
carbazole-l-carboxylic acid ethyl ester, and the whole is heated
under reflux for 4 hours, while stirring. The mixture is then
poured into water, filtered, the filtrate is acidified drop-
wise with hydrochloric acid and the crude product that separ-
ates is recrystallized from acetone-ethyl acetate to yield 0.8
gram (80%) of 6-methoxy-carbazole-1-carboxylic acid melting at
262C.
Example 19
-
Under the conditions given in Example 18, 8-methoxy-
carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and,
- 20 -

105368~
after recrystallization from methanol, a 65% yield of 8-
methoxy-carbazole-l-carboxylic acid melting at 252C is ob-
tained.
Exa~le 20
Under the conditionsgiven in Example 18, 8-methyl-
carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and,
after recrystallization from acetic acid, a 70~ yield of 8-
methyl-carbazole-l-carboxylic acid melting at 286C is obtained.
Example 21
Under the co~ditionsgiven in Example 18, 7-fluoro-
carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and,
after recrystallization from dioxane-water, a 70% yield of 7-
fluoro-carbazole-l-carboxylic acid melting at 260C is
obtained.
Example 22
A solution of 4.2 grams of potassium hydroxide, 50 ml
of water and 5 ml of dimethyl sulphoxide, is added to 212 grams
of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester,
and the whole is heated under reflux for 6 hours. Then the
mixture is diluted with 50 ml of hot water, filtered, the fil-
trate is acidified dropwise with hydrochloric acid and the
product that separates is recrystallized from dioxane-water
to yield 1.5 g (77%) of 7-chloro-8-methyl-carbazole-
carboxylic acid melting at 249C.
xample 23
Under the conditionsgiven in Example 22, 5-chloro-8-
methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed,
and, after recrystallization from dioxane-water, a 55% yield
of 5-chloro-8-methyl-carbazole-1-carboxylic acid melting at
303C is obtained.
Example 24
- 21 -

lOS368Z
Under the conditions given in Example 22, 7-chloro-
3,8-dimethyl carbazole-l-carboxylic acid ethyl ester is hydro-
lyzed, and, after recrystallization from dioxane-water, an 85%
yield of 7-chloro-3,8-dimethyl-carbazole-1-carboxylic acid
melting at 294C is obtained.
Example 25
Under the conditio~ given in Example 22, 5-chloro-8-
methoxy-carbazole-l-carboxylic acid ethyl ester is hydrolyzed,
and, after recrystallization from dioxane, a yield of 70% of
5-chloro-8-methoxy-carbazole-1-carboxylic acid melting at 328C
is obtained.
Example 26
Under the conditionsgiven in Example 22, 7,8-dichlorD-
carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and,
after recrystallization from dioxane-water, an 83% yield of
7,8-dichloro-carbazole-1-carboxylic acid melting at 290C is
obtained.
Example 27
Under the conditionsgiven in Example 22, 7,8-dimethyl-
carbazole-l-carboxylic acid ethyl ester is hydrolyzed,and,
after recrystallization from dioxane, a 65~ yield of 7,8-
dimethyl-carbazole-l-carboxylic acid melting at 239C is
obtained.
Example 28
Under the co~ditionsgiven in Example 22, 6-fluoro-
carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and,
after recrystallization from dioxane-water, a yield of 92% of
6-fluoro-carbazole-1-carboxylic acid melting at 254C is
obtained.
Example 29
Under the conditions given in Example 22, 7-trifluoro-
- 22 -
.,

~0~
methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and
after recrystallization from dioxane-water, an 83% yield of 7-
trifluoro-methyl-carbazole-l-carboxylic acid melting at 266C
- is obtained.
Example 30
(a) To a suspension of 0.3 g of lithium-aluminium
hydride in 5 ml of absolute tetrahydrofurane is added dropwise
0.560 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl
ester dissolved in lOml of absolute tetrahydrofurane, and the
mixture is stirred for one hour at room temperature. The mixture
is then heated under reflux for one hour, allowed to cool,
diluted with 20 ml of ethyl acetate, hydrochloric acid is
added dropwise to the mixture while cooling, and the organic
phase is separated, washed and concentrated in vacuo. The
residue is recrystallized from toluene, and a 95% yield of
7-chloro-1-hydroxymethyl-8-methyl-carbazole melting at 187C is
obtained.
(b) Pyridine and acetic anhydride are added to the
hydroxymethyl compound thus obtained, the mixture is allowed
to 9tand for 30 minutes at room temperature and is taken up in
chloroform. The chloroform solution is washed, concentrated
in vacuo, and an 85% yield of 7-chloro-1-acetoxymethyl-8-methyl-
carbazole that solidifies as a glassy mass is obtained.
Example 31
7.8 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid
are mixed with 200 ml of diethyl ether and cooled to -10C. 8.7
g of phosphorous pentachloride are introduced into the suspen-
sion while stirring, and the mixture is stirred for 2 hours at
about 0C. Dry ammonia is then introduced for one hour while
stirring, and the mixture is further stirred for 10 hours at
room temperature. The reaction mixture is then poured into water,
extracted with ethyl acetate, and the extract is washed and
-23-
, ~ ,

1053~Z
concentrated. The residue is recrystallized from dioxane, and
7.1 g (91%) of 7-chloro-8-methyl-carbazole-1-carboxylic acid
amide melting at 223C are obtained.
Example 32
Under the conditions given in Example 31, but with the
difference that, instead of ammonia, an excess of morpholine is
added to the reaction mixture, 7,8-dimethyl-carbazole-1-carboxylic
acid is converted into the carboxylic acid morpholide, and, after
recrystallization from dioxane-water, a 75% yield of 7,8-dimethyl-
carbazole-l-carboxylic acid morpholide melting at 183C is
obtained.
Example 33
(1) To a solution of 200 mg of hydroxylamine in 15 ml of
ethanol are added 10 ml of a sodium ethylate solution containing
1% of sodium and, in portions, 1.0 g of 7-chloro-8-methyl-
carbazole-l-carboxylic acid ethyl ester, while cooling. The
mixture is stirred for one hour at 0C and for a further 12 hours
at room temperature, and is then concentrated ln vacuo. The
re~idue is taken up in water, acidified to a pH of 1 with
hydrochloric acid, extracted with ethyl acetate, the extract is
washed and concentrated and the residue is recrystallized from
ethanol-water to give a 20% yield of 7-chloro-8-methyl-carbazole-
l-carbo-hydroxamic acid melting at 200C.
(2) 1.8 g of 7-chloro-8-methyl-carbazole-1-carboxylic
acid are introduced into 13 g of thionyl chloride, 0.5 ml of
dimethylformamide is added, and the mixture is stirred for one
hour at room temperature. 10 ml of absolute chloroform are then
added to the mixture, which is heated for two hours at 60C and
concentrated ln vacuo. In order to remove the thionyl chloride,
the residue is taken up several times in chloroform, and the
solution thus obtained is concentrated ln vacuo. The resulting
crude product is recrystallized from benzine-chloroform to
-24-

yield 7-chloro-8-methyl-carbazole-1-carboxylic acid chloride
melting at 130C.
15 ml of ether and 1.3 g of crystalline hydroxylamine
are added to the acid chloride thus obtained, and the whole is
stirred for 16 hours at room temperature. The precipitate is
filtered with suction, washed with ether and dissolved in water.
The aqueous solution is acidified with 2N hydrochloric acid
to a pH of 1, extracted with ethyl acetate, the extract is
concentrated, the residue is recrystallized from dioxane-water
and 0.72 g (40%) of 7-chloro-8-methyl-carbazole-1-carbo-
hydroxamic acid melting at 200C is obtained.
Example 34
(a) Under the conditions given in Example 7(a), 10 g of
3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted
with 3-chloro-4-methyl-aniline to form 7-chloro-6-methyl-1,2,3,
4-tetrahydrocarbazole-1-carboxylic acid ethyl ester and 5-chloro-
6-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl
ester which are separated by chromatography.
(b) ~he 7-chloro-6-methyl-tetrahydrocarbazole derivative
thus prepared is dissolved in chlorobenzene, 10% strength
palladium-carbon is added, the derivative is dehydrogenated as in
Example l(b), and, after recrystallization from isopropyl
alcohol, a 75% yield of 7-chloro-6-methyl-carbazole-1-carboxylic
acid ethyl ester melting at 155C is obtained.
Example 35
Under the conditions given in Example 18, 7-chloro-6-
methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed,
and, after recrystallization from ethanol-dioxane, and 85% yield
of 7-chloro-6-methyl-carbazole-1-carboxylic acid melting at
310C is obtained.
Example 36
The 5-chloro-tetrahydrocarbazole derivative prepared
-25-
.. . : . : . ' -:

105;~68Z
3~
A ~ according to Example ~(a) is dissolved in chlorobenzene, 10~
strength palladium-carbon is added, the derivative is dehydro-
genated as described in Example l(b), and, after recrystalliz-
ation from isopropyl alcohol, an 80% yield of S-chloro-6-
methyl-carbazole-l-carboxylic acid ethyl ester melting at 160C
is obtained.
Example 37
Under the conditions given in Example 18, 5-chloro-6-
methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed,
and, after recrystallization from dioxane-water, a 70% yield
of 5-chloro-6-methyl-carbazole-1-carboxylic acid melting at
305C is obtained.
Example 38
(a) Under the conditions given in Example 7(a), 10 g of
3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are
reacted with 2-chloro-3-methyl-aniline to form 8-chloro-7-methyl-
1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared
is dissolved in chlorobenzene, 10% strength palladium-carbon
is added, the derivative is dehydrogenated as described in
Example l(b), and, after recrystallization from isopropyl alcohol,
a 60% yield of 8-chloro-7-methyl-carbazole-1-carboxylic acid
ethyl ester melting at 73C is obtained.
Example 39
Under the conditions given in Example 18, 8-chloro-7- ~
methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, ;;
and, after recrystallization from dioxane, a 75% yield of 8-chloro-
7-methyl-carbazole-1-carboxylic acid melting at 266C is obtained.
Example_40
(a) Under the conditions given in Example 7(a), 10 g of
3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are
reacted with 3-chloro-2-aniline to form 7-chloro-8-ethyl-1,2,3,4-
-26-
:, ' ' ' ' '

~0s~6~z
tetra hydrocarbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is
dissolved in chlorobenzene, 10% strength palladium-carbon is
added, the derivative is dehydrogenated as described in Example
l(b), and 7-chloro-8-ethyl-carbazole-1-carboxylic acid ethyl
ester is obtained.
Example 41
Under the conditions given in Example 18, 7-chloro-8-
ethyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed,
and 7-chloro-8-ethyl-carbazole-1-carboxylic acid is obtained.
Example 42
(a) Under the conditions given in Example 7(a), 10 g of
3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester is reacted
with -naphthylamine to form benzo[a]-1,2,3,4-tetrahydrocarbazole-
l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared
is dissolved in xylene, 10~ strength palladium-carbon is added,
the derivative is dehydrogenated as described in Example l(b),
and, after recrystallization from isopropyl alcohol, a 70
yield of benzo[a]-carbazole-l-carboxylic acid ethyl ester
melting at 93C is obtained.
Example 43
Under the conditions given in Example 18, benzo[a]-
carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after
recrystallization from methanol-dioxane, an 80% yield of benzo[a]-
carbazole-l-carboxylic acid melting at 343C is obtained.
Example 44
1.3 g of 7,8-dichloro-carbazole-1-carboxylic acid are
dissolved in 30 ml of absolute dimethyl glycol, and 0.6 g of
triethylamine is added. The mixture is cooled to -10C, 0.63
g of isobutyl chloroformate is added, and the mixture is stirred
for 20 minutes at -10C. The resulting precipitate is rapidly
-27-
.. - , . : .

1~536~
filtered with suction, to the filtrate is added 0.5 g of
dimethylamino-ethanol in 2 ml of dimethyl glycol, the mixture is
stirred for 10 minutes at -10C and allowed to stand for about
16 hours at about 0C.
The reaction mixture is then concentrated ln vacuo, the
residue is taken up in ether, filtered, and the filtrate is
washed, dried and concentrated in vacuo. There are obtained 1.6 g
(99%) of 7,8-dichloro-carbazole-1-carboxylic acid (2'-dimethyl-
amino-ethyl) ester in the form of an oil.
Example 45
Under the conditions given in Example 31, the reaction is
carried out with 2-dimethylamino-ethanol, instead of ammonia, to
yield 7-chloro-8-methyl-carbazole-1-carboxylic acid (2'-dimethyl-
amino-ethyl) ester melting at 91C (from cyclohexane).
Example 46
0.2 g of a sodium hydride suspension of about 50% strength
is added to 1.0 g of 7-chloro-8-methyl-carbazole-1-carboxylic
acid ethyl ester in 20 ml of dimethylformamide, and the mixture
is stirred for 4 hours at room temperature. Then 0.8 g of
methyl iodide i8 added to the mixture, and the whole is stirred
for a further 12 hours. The solvent is then distilled in vacuo,
the residue is taken up in chloroform, and the chloroform phase
is washed and concentrated. The residue is purified with
cyclohexane-toluene over a column of silica gel, and there is
obtained 0.74 g (70~) of 7-chloro-8,9-dimethyl-carbazole-1-
carboxylic acid ethyl ester in the form of an oil.
Example 47
Under the conditions given in Example 18,7-chloro-8,9-
dimethyl carbazole-l-carboxylic acid ethyl ester is hydrolyzed,
and, after recrystallization from dioxane-water, a 75% yield of
7-chloro-8,9-dimethyl-carbazole-1-carboxylic acid melting at
237C is obtained.
-28-

'~ ~0~3~Z
Example 48
4 Under the conditions given in Example ~, but using
benzylchloride instead of methyl iodide, 7-chloro-8-methyl-
carbazole-l-carboxylic acid ethyl ester is converted with a
65% yield into 7-chloro-8-methyl-9-benzyl-carbazole-1-caxboxylic
acid ethyl ester melting at 81C (from methanol).
Example 49
Under the conditions given in Example 18, 7-chloro-8-
methyl-9-benzyl-carbazole-1-carboxylic acid ethyl ester is
hydrolyzed, and, after recrystallization from methanol, a 75%
yield of 7-chloro-8-methyl-9-benzyl-carbazole-1-carboxylic acid
melting at 190C is obtained.
Example 50
3.9 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid
amide are introduced in portions into 15 ml of phosphorus
oxychloride, while stirring. The mixture is then slowly heated
to 120C and maintained for 2 hours at such temperature. The
reaction mixture is allowed to cool and poured while stirring
vigorously into a solution of 100 ml of ice-water and 25 ml of
an aqueous solution of ammonia, and the precipitate formed is
filtered with suction and recrystallized from isopropyl alcohol
to yield 2.7 g (75%) of 7-chloro-8-methyl-carbazole-1-
carbonitrile melting at 267C.
Example 51
2.1 g of 7-chloro-8-methyl-carbazole-1-carbonitrile are
dissolved in 50 ml of hexamethyl-phosphoric acid triamide and
5.2 g of sodium azide are added while stirring. The mixture
is stirred for 20 minutes and 6.1 ml of formic acid of 98%
strength are added dropwise while cooling, and the mixture is
stirred for 3 days at 60 to 70C. The whole is then poured into
a mixture of 50 g of ice and 200 ml of an 0.5N solution of
sodium hydroxide and further quantities of sodium hydroxide
-29-

10536~
solution are added until a pH of 10 is reached.
The mixture is extracted with chloroform, the chloroform
phase is discarded, and the aqueous phase is acidified with hydro-
chloric acid to a pH of 3 and extracted with ether. The ether
phase is dried and concentrated. The residue is recrystallized
from isopropyl alcohol to yield 2.5 g (98~) of 7-chloro-8-
methyl-l-(5-tetrazolyl)-carbazole melting at 279C.
Example 52
(a) Methanol-containing hydrogen chloride is added to
4-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid, and the
mixture is maintained for 16 hours at room temperature. The
mixture is diluted with methanol, the solution is neutralized
by agitation with Amberlite IR 4B (trade mark), concentrated
in vacuo, the residue is recrystallized from isopropyl alcohol,
and 4-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid
methyl ester is obtained.
(b) The tetrahydrocarbazole derivative thus prepared is
dissolved in chlorobenzene, 10% strength palladium-carbon is added,
the derivative is dehydrogenated as described in Example l(b), and,
after recrystallization from isopropyl alcohol, a 65% yield of
4-chloro-carbazole-1-carboxylic acid methyl ester melting at
136C is obtained.
Example 53
Under the conditions given in Example 18, 4-chloro-
carbazole-l-carboxylic acid methyl ester is hydrolyzed, and,
after recrystallization from isopropyl alcohol, a 70% yield of
4-chloro-carbazole-1-carboxylic acid melting at 280C is obtained.
Example 54
(a) Under the conditions given in Example l(a), 10 g of
5-chloro-anthranilic acid methyl ester are reacted with 2-bromo-
cyclohexanone to form 3-chloro-5,6,7,8-tetrahydrocarbazole-1-
carboxylic acid methyl ester.
-30-

1053682
(b) The tetrahydrocarbazole derivative thus prepared is
dissolved in chlorobenzene, 10% strength palladium-carbon is
added, the derivative is dehydrogenated as described in Example
l(b), and, after recrystallization from isopropyl alcohol, a 65%
yield of 3-chloro-carbazole-1-carboxylic acid methyl ester melting
at 169C is obtained.
Example 55
Under the conditions given in Example 18, 3-chloro-
carbazole-l-carboxylic acid methyl ester is hydrolyzed, and,
after recrystallization from ethyl acetate, an 85% yield of 3-
chloro-carbazole-l-carboxylic acid melting at 245C is obtained.
Example_56
(a) Under the conditions given in Example 7(a), 10 g of
4-methyl-anthranilic acid methyl ester are reacted with 2-bromo-
cyclohexanone to form 4-methyl-5,6,7,8-tetrahydrocarbazole-1-
carboxylic acid methyl ester.
(b) The tetrahydrocarbazole derivative thus prepared
is dissolved in xylene, 10% strength palladium-carbon is added,
the derivative is dehydrogenated as described in Example l(b),
and 4-methyl-carbazole-1-carboxylic acid methyl ester is obtained.
Example 57
Under the conditions given in Example 18, 4-methyl-
carbazole-l-carboxylic acid methyl ester is hydrolyzed, and
4-methyl-carbazole-1-carboxylic acid is obtained.
Example 58
(a) Under the conditions given in Example l(a), 10 g of
5-methyl-anthranilic acid methyl ester are reacted with 10 g of
2-bromo-cyclohexanone to form 3-methyl-5,6,7,8-tetrahydrocarbazole
l-carboxylic acid methyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is
dissolved in xylene, 10% strength palladium-carbon is added, the
derivative is dehydrogenated as in Example l(b), and 3-methyl-
-31-
.
- - . . ~, ~

~OS;~682
carbazole-l-carboxylic acid methyl ester is obtained.
Exam~le 59
Under the conditions given in Example 18, 3-methyl-
carbazole-l-carboxylic acid methyl ester is hydrolyzed, and 3-
methyl-carbazole-l-carboxylic acid is obtained.
Example 60
0.5 g of zinc chloride and 7.1 g of 2-bromo-cyclohexanone
are added to 15.7 g of 2-amino-5-chloro-benzoic acid methyl ester,
and the mixture is heated for 5 hours at 160C~ The mixture
is then allowed to cool,is diluted with toluene, and the toluene
phase is washed with dilute hydrochloric acid and water, dried
and evaporated in vacuo. The residue is recrystallized from
isopropyl alcohol-cyclohexanone to yield 4.5 g (42%) of 3-chloro-
5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester.
Example 61
` 1.2 g of 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic
acid methyl ester are stirred for 10 minutes in a mixture of
15 ml of isopropyl alcohol and an aqueous sodium hydroxide
solution of 35% strength in a hot ~110C) bath. The isopropyl
alcohol is then slowly distilled, and the sodium salt of
3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid is
filtered, washed with ether and dried.
The salt is taken up in dilute hydrochloric acid and
extracted with ethyl acetate, the extract is concentrated, the
residue is recrystallized from ethyl acetate, and 0.9 g (80%) of
3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid melting at
251C is obtained.
Example 62
Under the conditions given in Example 59, 2-bromo-
cyclohexanone is reacted with 2-amino-5-methyl-benzoic acid methyl
ester, and, after recrystallization from cyclohexane, a 55% yield
of 3-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl
-32-
.: - , : :
. , .. ~ -

-` 1053682
ester melting at 111C is obtained.
Example 63
Under the conditions given in Example 60, 3-methyl-5,6,7,
8-tetrahydrocarbazole-1-carboxylic acid methyl ester is hydrolyzed,
and, after recrystallization from isopropyl alcohol, a 75% yield
of 3-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid melting
at 225C is obtained.
Example 64
(1) Under the conditions given in Example 59, 2-bromo-
cyclohexanone is reacted with N-methyl-anthranilic acid methyl
ester, and, after recrystallization from methanol, a 15% yield
of 9-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl
ester melting at 56C is obtained.
(2) Under the conditions given in Example 45,5,6,7,8-
tetrahydrocarbazole-l-carboxylic acid methyl ester is methylated,
and a yield of 65% of 9-methyl-5,6,7,8-tetrahydrocarbazole-1-
carboxylic acid methyl ester is obtained.
Example 65
Under the conditions given in Example 60, 9-methyl-5,6,7,8-
tetrahydrocarbazole-l-carboxylic acid methyl ester is hydrolyzed,
and, after recrystallization from ethanol, a 75% yield of 9-methyl-
5,6,7,8-tetrahydrocarbazole-1-carboxylic acid melting at 180C
is obtained.
Example 66
The composition for a salve:
0.05% of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester
2.50% of Allercur hexachlorophenate, micronized, particle size
about 8 ~ (Allercur is a registered Trade Mark for
l-para-chlorobenzyl-2-pyrrolidyl-methylbenzimidazole)
6.00% of ~ostapdat KW 340 (a registered trade mark for tertiary
ester of 0-phosphoric acid and wax alcohol
tetraglycol ether)
-33-

lOS36~
0.10% of sorbic acid
10.00% of neutral oil (migloyol 812 - registered trade mark)
3.50% of stearyl alcohol
1.50~ of wool fat, anhydrous DAB 6
76.35~ of desalted water.
Example 67
The composition for a salve:
0.05 g of 8-chloro-7-methyl-carbazole-1-carboxylic acid ethyl
ester
5.00 g of white wax DAB 6
5.00 g of wool fat DAB 6
20.00 g of white petroleum jelly DAB 6
25.00 g of Amphocerin K "Dehydag"
14.95 g of paraffin oil, liquid DAB 6
30.00 g of water, desalted
0.02 g of Crematest perfume oil No. 6580 "Dragee"
Example 68
1.000 g of micronized 7-chloro-8-methyl-carabazole-1-
carboxylic acid ethyl ester (average particle size: smaller
than 7 ~) and 39.000 g of ground lactose are mixed. Quantities
of 40 mg of the mixture are charged into plug capsules. The
inhalant preparation can be administered, after opening the
capsule, by inhaling, preferably by sniffing, or a Spinhaler
(trade mark) may be used for administering the inhalant preparation.