Note: Descriptions are shown in the official language in which they were submitted.
69785-28
DESCRIPTION 1 3 3 7 7 6 7
The present invention is concerned with new indolo-
carbazole derivatives, processes for the preparation thereof and
pharmaceutical compositions containing them.
The new indolocarbazole derivatives according to the
present invention are compounds of the general formula I:
H
X
y
(\ /~\-~ Cl~
l1 l2
wherein R1 and R2, which can be the same or different, are
hydrogen atoms, straight-chained or branched alkyl radicals
containing up to 6 carbon atoms; benzyl radicals; aminoalkyl
radicals containing up to 12 carbon atoms, which radicals are
unsubstituted or are substituted on a carbon atom by a hydroxy
group, a C1-C4 alkyl group or a C1-C4 alkoxy group or are
substituted on the amino nitrogen atom by C1-C4 alkyl or benzyl,
or the amino nitrogen atom forms part of a pyrrolidino,
piperidino, piperazino or morpholino group; alkoxycarbonylalkyl
radicals containing up to 6, preferably up to 4 carbon atoms,
-CH2-CO-NR R radicals, wherein R and R4 are the same or
different and signify hydrogen atoms, alkyl radicals containing
up to 4 carbon atoms or benzyl radicals; or R1 and R2 are
haloalkyl; hydroxyalkyl or alkoxyalkyl radicals with, in each
case, up to 6 carbon atoms; a benzoylalkoxyalkyl-, acetyloxy-
D 2 ~
1 3 3 7 7 6 7 69785-28
alkoxyalkyl- or hydroxyalkoxyalkyl radicals with, in each case,
up to 11 carbon atoms or acyl radicals containing up to 4 carbon
atoms, or R1 and R2 together signify an alkylene radical
containing 2 to 4 carbon atoms which may be unsubstituted or
substituted by hydroxy, C1 4-alkoxy or amino and X and Y are the
same and both signify hydrogen atoms or X and Y are different,
one of them being a hydrogen atom and the other being a hydroxyl
group or an alkoxy radical containing up to 4 carbon atoms, with
the provisos that (i) not all of the symbols R1, R2, X and Y do
not simultaneously stand for hydrogen atoms, and tii) if one of
X and Y is other than hydrogen, then R and R are both
hydrogen; as well as the pharmacologically acceptable salts
thereof.
The present invention also provides processes for the
preparation of compounds of general formula (I) and of regio-
isomeric mixtures of two of these compounds of general formula
(I), as well as pharmaceutical compositions containing at least
one compound of general formula (I).
The preparation of the compounds of general formula
(I) takes place, depending upon the substitution, according to
one of the processes described hereinafter:
A) when X and Y are hydrogen atoms and R and R are the
same but are not hydrogen atoms or one of the symbols R1 and R2
stands for a hydrogen atom, a compound of general formula (I)
can be obtained by alkylating or acylating the indolocarbazole
of the formula II:
1 3 3 7 7 6 7 69785-28
~ Cll)
b H
on one or both indole nitrogen atoms with one or two equivalents
of a compound of the general formula III:
R - T (III)
in which R5 is a straight-chained or branched alkyl radical
containing up to 6 carbon atoms; a benzyl radical; an aminoalkyl
radical containing up to 12 carbon atoms, which radical is
unsubstituted or is substituted on a carbon atom by a hydroxy
group, a C1-C4 alkyl group or a C1-C4 alkoxy group or are
substituted on the amino nitrogen atom by C1-C4 alkyl or benzyl,
or the amino nitrogen atom forms part of a pyrrolidino,
piperidino, piperazino or morpholino group; an alkoxycarbonyl-
alkyl radical containing up to 6, preferably up to 4 carbon
atoms; a haloalkyl or alkoxyalkyl radical containing, in each
case, up to 6 carbon atoms; a benzoyloxyalkoxyalkyl or
acetyloxyalkoxyalkyl radical with, in each case up to 11 carbon
atoms; or an acyl radical containing up to 4 carbon atoms and T
represents a leaving group and preferably stands for a halogen
atom, especially an iodine, bromine or chlorine
D 3a
1 337767
atom, in the PL~-enCe of one or two equivalents of a base,
for example an alkali metal or alkaline earth metal hydride,
carbonate, hydroxide, oxide or alkoxide, or of an organo-
lithium com~ou-.d, in per se known manner; or by modifying
an already introduced radical R5 by conventional methods of
preparative organic chemistry (see, for example, Houben-
Weyl, Methoden der Org~isçhen Chemie, pub. Georg Thieme
Verlag, Stuttgart, 1966) to one of the radicals Rl or R2,
for example by hydrolysis, ether cleavage, amide formation
or reduction.
Thus, compounds of general formula (I), in which R1 and/or
R2 is a -CH2-Co-NR3R4 radical, are preferably prepared by
reacting com~oul.ds of general formula (I), in which Rl
and/or R2 is an alkoxycarbonylmethyl radical, with an amine
of general formula HNR3R4, wherein R3 and R4 have the above-
given meanings.
Compounds of general formula (I), wherein R1 and/or R2 are
hydroxyalkyl radicals, are preferably prepared by
hydrolysing com~uul,ds of general formula (I), wherein R1
and/or R2 is a haloalkyl radical and especially bromoalkyl
or chloroalkyl radical, or by ether cleavage of com~u~--ds of
general formula (I), wherein Rl and/or R2 is an alkoxyalkyl
radical.
Compounds of general formula (I), wherein Rl and/or R2 are
hydroxyalkoxyalkyl radicals, are preferably prepared by
methods known per se from com~oul.ds of general formula (I),
wherein Rl and/or R2 is a benzoyloxyalkoxyalkyl or
acetyloxyalkoxyalkyl radical. Preferred hydroxyalkoxyalkyl
radicals are 2-hydroxyethoxymethyl and 3-
hydroxypropoxymethyl radicals.
Compounds of general formula (I), wherein R1 and/or R2 are
N,N-disubstituted 3-amino-2-hydroxypropyl radicals, are
preferably prepared by alkylation of indolocarbazole
compounds of general formula (II) with 1,1-disubstituted 3-
hydroxyazetidinium halogenides (J. Org. Chem. 1968, 523).
1 3377C~7
69785-28
The substituents at the 1,1-positions of the 1,1-
disubstituted azetidine ring become the substituents on the
amino nitrogen atom of the N,N-disubstituted 3-amino-2-
hydroxypropyl radical. Hence the substituents at the 1,1-
positions of the azetidine ring can be C1-C4 alkyl or benzyl
groups or the 1,1-substituents are linked to form, with the
nitrogen atom of the azetidine ring, a pyrrolidino, piperidino,
piperazino or morpholino group.
D
- 4a
-
1 337767
Compo~ln~c of general formula (I), in which Rl and R2
together form an alkylene radical -(CH2)n -, wherein n is 2,
3 or 4, are ob~A i n^~ by reacting the indolocarbazole of
formula (II) with two equivalentD of one of the above-
mentioned bases and one equivalent of a dihaloAlkAn- and
preferably of a dibromoAl~Ane.
Com~ounds of general formula (I), wherein Rl and R2 together
form a propylene radical of general formula V:
-CH2 -CH-CH2-
R (V)
wherein R is hydroxy, Cl_4-alkoxy or amino, are prepared by
reaction of the indolocarbazole of general formula (II) with
two equivalents of one of the above mentioned bases and
epichlorohydrin or epibromohydrin, whereby the primarily
obtained hydroxy substituted propylene radical is reacted by
methods known per se into Cl_4-alkoxy or amino substituted
propylene radicals.
Compounds of general formula (I), wherein Rl and/or R2 are
methyl or ethyl radicals, can also be prepared by alkylating
with dimethyl or diethyl sulphate in known manner.
The above-described process of alkylating or acylating the
indolocarbazole of formula (II) in the presence of a base
with an alkylating or acylating agent is surprising because
it was not to have been foreseen that the introduction of
one or two radicals R5 would take place selectively on the
indole nitrogen atom but not on the nitrogen atom of the
lactam ring.
B) When X and Y both signify hydrogen atoms and Rl and R2 are
different and neither of them is a hydrogen atom, compounds
of general formula (I) can be prepared by reacting a
compo~ln~ of general formula (I), which has been prepared
according to process A) in which either Rl or R2 has one of
the meanings given for R5 and the other is a hydrogen atom,
_ ~ 337767
with a com~oul.d of general formula (III), in which R5 has
another meAn~ ng given for R5, in the presence of a base in a
manner analogous to that described for process A) and, if
desired, one or both of the radicals with the meaning of R5
is modified, as described in process A), to give one of the
radicals Rl or R2.
C) Com~oul.ds of general formula (I), wherein X or Y is a
hydroxyl group and the other one of two symbols is a
hydrogen atom, can be prepared by reduction of the imide of
the formula IV:
H
=~ N~=
(IV)
H H
Preferred reducing agents include zinc amalgam/gaseous
hydrogen chloride in a C1-C4-alcohol and zinc amalgam in
glacial acetic acid.
Compounds of general formula (I), wherein X or Y is a Cl-C4-
alkoxy radical and the other one is a hydrogen atom, can be
prepared either by reduction of the imide of formula (IV) in
a Cl-C4-alcohol, preferably with zinc amalgam/gaseous
hydrogen chloride, or by acid-catalysed reaction of a
compound of general formula (I), wherein X or Y is a
hydroxyl group and the other one is a hydrogen atom, with a
Cl-C4-alcohol in an anhydrous medium.
If, in the case of the reduction with zinc amalgam/gaseous
hydrogen chloride in a Cl-C4- alcohol, a mixture of compounds of
general formula (I) is obtained, wherein X or Y is either a
hydroxyl group or a Cl-C4-alkoxy radical and the other one is a
hydrogen atom, these can be separated by conventional proce~ce
for example crystallisation or chromatography.
1 337767
A so obtained compound of general formula (I), wherein X or Y is
a hydroxyl group or a Cl-C4-alkoxy radical and Rl and R2 are
hydrogen atoms, can, if desired, be alkylated or acylated
according to process A) or B) to give a com~ou~-d of general
formula (I), wherein X or Y is a hydroxyl group or a Cl-C4-
alkoxy radical and the other one is a hydrogen atom and Rl and
R2 have the meAnings given above except that they are not both
hydrogen atoms.
Unsubstituted and substituted aminoAlkyl radicals contAining up
to 12 carbon atoms which are especially preferred for Rl and/or
R2 include unsubstituted aminoAl~yl radicals, such as 2-
aminoethyl, 3-aminopropyl and 1-amino-2-propyl radicals, N,N-
dialkylamino and N,N-alkylbenzylaminoalkyl radicals with Cl-C4-
alkyl substituents on the nitrogen atoms and up to 4 carbon
atoms in alkyl chain, in which the alkyl chains can be
substituted by further Cl-C4-alkyl radicals or by a hydroxyl
group, especially a dimethylaminoethyl, 3-dimethylamino-1-
propyl, 3-dimethylamino-2-propyl, 2-diethylaminoethyl, 2-tN-
benzyl-N-methylamino]-ethyl, 3-tN-benzyl-N-methylamino]-propyl
or 3-dimethylamino-2-hydroxy-1-propyl radical, a 3-diethylamino-
2-hydroxy-1-propyl, 3-piperidino-2-hydroxy-1-propyl, 3-
dimethylamino-2-methoxy-1-propyl, 3-diethylamino-2-methoxy-1-
propyl, 3-piperidino-2-methoxy-1-propyl, 3-(N-benzyl-N-
methylamino)-2-methoxy-1-propyl, 3-(N-benzyl-N-methylamino)-2-
hydroxy-l-propyl, 3-(N-methylamino)-2-methoxy-1-propyl, 3-(N-
methylamino)-2-hydroxy-1-propyl, 4-dimethylamino-3-methoxy-2-
butyl radical or a 2-piperidinoethyl, 3-piperidinopropyl, 2-
pyrrolidinoethyl, 3-pyrrolidinopropyl, 2-morpholinoethyl, 3-
morpholinopropyl, pyrrolidin-3-ylmethyl, N-methyl-pyrrolidin-2-
ylmethyl, piperidin-2-ylmethyl, N-methyl-piperidin-2-ylmethyl
radical or a piperazinoalkyl radical with 1 to 4 carbon atoms in
the alkyl chain, unsubstituted or substituted at the nitrogen
atom by Cl_4-alkyl.
Further radicals which are especially preferred for Rl and/or R2
include straight-chained and branched alkyl radicals contAining
up to 4 carbon atoms, especially methyl, ethyl, n-propyl,
isopropyl and n-butyl radicals, methoxycarbonylmethyl radicals,
1 337767
benzyl radicals, 2-methoxyethyl radicals, acetyl radicals and
also alkylene radicals containing 2 to 4 carbon atoms and
especially a butylene or hydroxysubstituted propylene radical
which Rl and R2 form together.
Com~oullds of general formula (I) obtAine~ according to proces~e~
A), B) and C), in which R1 and R2 are different, can be used as
regioisomeric mixtures. By means of known separation procesFer,
such as crystallisation or chromatography, the two regioisomers
can be separated.
Compounds of general formula (I) which have a chiral centre can
be used as stereoisomeric mixtures or in the form of the
enantiomers. The enantiomers can be obtained according to the
prores~^C normally employed for the optical separation of
stereoisomers.
Basic compounds of general formula (I) which have a basic centre
on R1 or R2 are, for the ~UL~ of purification and for
galenical reasons, preferably converted into crystalline,
pharmacologically acceptable salts, The salts are obtained in
the usual way by neutralisation of the bases with appropriate
inorganic and organic acids.
As acids for this purpose, there can be used, for example,
hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic
acid, acetic acid, tartaric acid, lactic acid, citric acid,
malic acid, salicylic acid, ascorbic acid, malonic acid and
succinic acid.
The preparation of the indolocarbazoles used as starting
materials of formulae (II) and (IV) is described in the
literature or can be carried out in an analogous way (see
Heterocycles, 20, 469/1983; and Tetrahedron Letters, 1983,
1441).
The compounds according to the present invention are potent
inhibitors of protein kinAces~ such as protein kinAFe C. Thus,
for example, the compound of Example la, in the enzyme assay of
1 3 3 7 7 6 7 69785-28
protein kinase C activated with phosphatidylserine and diacyl-
glycerol, shows a 50% inhibition at a concentration of 66
nanomole/litre. The experiment was carried out according to
European Patent Specification No. 0,255,126 (inhibition of protein
kinase C). Indolocarbazoles have admittedly already been
described as inhibitors of protein kinase C ~see J. Antibiot. 30,
275/1977; Biochem. Biophys. Res. Commun. 135, 397/1986). However,
they are mainly indolocarbazole-N,N-glycosides of microbial or
semisynthetic origin.
Protein kinase C plays an important key role for intra-
cellular signal transduction and is closely connected with the
regulation of contractile, secretory and proliferative processes.
On the basis of these properties, the compounds according to the
present invention can be used for the treatment of heart and blood
vessel diseases, such as thromboses, arteriosclerosis, hyper-
tension, inflammatory processes, allergies, cancers and certain
degenerative damage of the central nervous system. The compounds
can be administered, in the formulation appropriate for a partic-
ular use, enterally or parenterally in dosages of from 1 to 50
mg/kg.
The invention extends to pharmaceutical compositions
containing a compound of the invention, together with a suitable
adjuvant or carrier material. It also extends to a commercial
package containing a compound of the invention, together with
instructions for its use for the treatment of the above-mentioned
conditions.
The following examples are given for the purpose of
illustrating the present invention:
C 9
... .. .....
1 337767
Example 1
6.7.12.13-Tetrahydro-5-oxo-12.13-dipropyl-5H-in~olo-~2.3-a]-
pyrrolor3.4-c~carbazole.
20 mg, (0.67 mmole) sodium hydride (80% in mineral oil) are
suspended in 10 ml dry dimethylformamide and 100 mg (0.32 mole)
6,7,12,13-tetrahydro-5-oxo-5H-indolo~2,3-a]pyrrolot3,4-
c]carbazole are added portionwise thereto at ambient
temperature. After subsidence of the gas evolution, the reaction
mixture is further stirred for 1 hour at ambient temperature and
then 120 mg (0.71 mmole) n-propyl iodide are added thereto and
stirring continued for 16 hours at ambient temperature. The
solvent is removed by rotary evaporation in a vacuum and the
residue is chromatographed on silica gel with toluene/ethyl
acetate (1:1 v/v). The fraction with the Rfof 0.4 is isolated
and stirred with diisopropyl ether. The crystals formed are
filtered off with suction.
6.7.12.13-Tetrahydro-5-oxo-12.13-dipropyl-5H-indolor2.3-
alpYrrolo~3.4-c]carbazole is obtained in the form of beige
crystals; m.p. 180 - 185-C. (decomp.), yield 43%.
In an analogous manner, there is obtained 12.13-diethyl-
6.7 12.13-tetrahydro-5-oxo-5H-indolo~2.3-a~-pyrrolor3.4-
c~carbazole (l.a): m.p. > 225 C (decomp.), after
crystallisation from diisopropyl ether, yield 32%.
With the use of two equivalents of sodiumhydride and one
equivalent of 1,4-dibromobutane, there is obtained, in an
analogous manner, 12.13-butano-6.7.12.13-tetrahydro-5-oxo-5H-
indolor2.3-alpYrrolor3.4-c]carbazole (l.b~: m.p. > 300 C, after
crystallisation from diisopropyl ether, yield 53%.
In an analogous manner, there is obtained
12.13-~ibenzyl-6.7.12.13-tetrahydro-5-oxo-5H-indolo r 2.3-a
pyrrolo-r3.4-clcarbazole (l.c~
m.p. > 250- C (decomp.) from diisopropyl ether, yield 33%;
1 337767
11
Example 2
6.7.12.13-Tetrahydro-5-oxo-l~-propyl-5H-indolor2.3-al-
pyrrolo r 3.4-c~carbazole and
6.7.12.13-tetrahydro-5-oxo-13-propyl-5H-indolo r 2.3-
a~pyrrolo r 3.4-c~carbazole
The crude product obtained by the reaction of 100 mg (0.32
mmole) 6,7,12,13-tetrahydro-5-oxo-5H-indol[2,3-a]pyrrolo[3,4-
c]carbazole with 10 mg (0.33 mmole) sodium hydride (80% in
mineral oil) and 60 mg (0.35 mmole) n-propyl iodide analogously
to Example 1 is separated chromatographically on silica gel with
toluene/ethyl acetate (1:1 v/v), The fraction with the Rf of
0.3 i8 isolated and stirred with diisopropyl ether, The beige
crystals formed are filtered off.
There is obtained an approximately 3:1 regioisomeric mixture of
6.7.12.13-tetrahydro-5-oxo-12-pro~yl-5H-indolo~2.3-a]-
pyrrolo r 3.4-c~carbazole and 6.7.12.13-tetr~ydro-5-oxo-13-
~ro~yl-5H-indolo~2.3-a~pyrrolo r 3.4-c]carbazole: m.p. about 300C
(decomp.), yield 44%.
In analogous manner, there is obtained:
6.7.12.13-tetrahydro-12-(2-methoxyethyl)-5-oxo-5H-indolor2 3-a~
pyrrolo[3.4-c~ carbazole and 6.7.12.13-tetrahydro-13-(2-
methoxyethyl~-5-oxo-5H-indolo~2.3-a~-pyrrolo~3.4-cl-carbazole
(2.a~, m.p. > 250- C (decomp.) from diisopropyl ether, in a 5:1
regioisomeric mixture, yield 26%;
with one equivalent sodium hydride and one equivalent acetic
anhydride and chromatographic separation of the regioisomers
there is obtained:
13-acetyl-6.7.12.13-tetrahydro-5-oxo-5H-indolo r 2.3-a1-
pyrrolo~3.4-c~-carbazole (2.b), m.p. > 315C (decomp.) from
diisopropyl ether, yield 14%;
1 337767
12
Example 3
12-Ethyl-6.7,12.13-tetrahydro-5-oxo-5H-indolo~2.3-a~-
pYrrolo[3.4-c~-carbazole
The crude product obtained by the reaction of 200 mg (0.64
mmole) 6,7,12,13-tetrahydro-5-oxo-5H-indolot2,3-a]pyrrolo[3,4-
c]carbazole with 20 mg (0.66 mmole) sodiumhydride (80~ in
mineral oil) and 110 mg (0.71 mmole) ethyl iodide analogously to
Example 1 is separated chromatographically on silica gel with
toluene/ethyl acetate (1:1 v/v). The fraction with the Rf of
0.25 is isolated, stirred with toluene/ethanol (9:1 v/v) and the
crystals formed are filtered off. The approximately 3:1
regioisomeric mixture obtained of 12-ethyl-6,7,12,13-tetrahydro-
5-oxo-5H-indolot2,3-a]pyrrolot3,4-c]carbazole and 13-ethyl-
6,7,12,13-tetrahydro-5-oxo-5H-indolot2,3-a]pyrrolot3,4-
c]carbazole is boiled up with acetone and the crystals are
filtered off after cooling.
There is obtained 12-etbLYl-6.7.12.13-tetrahYdro-5-oxo-5H-
indolo~2.3-a~pyrrolo~3.4-c~carbazole in the form of beige
crystals; m.p. > 290C (decomp.), yield 27%.
1 337767
13
Example 4
12-(3-DimethylaminoproDyl)-6.7.12.13-tetrahYdro-5-oxo-5H-
indolor2~3-a~pyrrolo r 3.4-clcarbazole and
13-(3- di~ethYl~minQpropyl)-6~7~l2~l3-tetrahydro-5-oxo-5H
indolo~2.3-a~pyrrolor3.4-c~carbazole
The crude product obtained by the reaction of 150 mg (0.48
mmole) 6,7,12,13-tetrahydro-5-oxo-5H-indolo~2,3-a]pyrrolo[3,4-
c]carbazole with 18 mg (0.60 mmole) sodium hydride (80% in
mineral oil) and 73 mg (0.60 mmole) 3-dimethylaminopropyl
chloride analogously to Example 1 is separated
chromatographically on silica gel with ethyl acetate/acetone
(1:1 v/v). The fraction with the Rf of 0.1 is isolated and
stirred with diisopropyl ether. The crystals formed are
filtered off.
There is obtained an approximately 6:1 regioisomeric mixture of
12-(3-dimethylaminopropyl)-6.7.12.13-tetra-hydro-5-oxo-5H-
indolo r 2.3-~l~yrrolo r 3.4-c~carbazole and 13-(3-
dimethylaminopropyl)-6.7.12.13-tetrA~ydro-5-oxo-5H-indolor2.3-
alpyrrolor3.4-clcarbazole in the form of beige crystals; m.p.
265-C (decomp.), yield 48%.
There is obtained in analogous manner:
6.7.12.13-tetrahydro-12-(2-morpholinoethyl)-5-oxo-5H-indolo-
r 2.3-alpyrrolo[3.4-c~)carbazole and 6.7.12.13-tetrahydro-13-(2-
morpholinoethyl)-5-oxo-5H-indolo- r 2.3-a ~ Dyrrolo r 3.4-c~~carbazole
(4.a), m.p. > 230 C (decomp.) from diisopropyl ether, 3:1
regioisomeric mixture, yield 30%;
6.7.12.13-tetrahydro-5-oxo-12-(2-~YrrolidinoethYl)-5H-indolo-
~2.3-a~pyrrolo r 3.4-c~)carbazole and 6,7.12.13-tetrahydro-5-oxo-
13-(2-pyrrolidinoethyl)-5H-indolo- r 2.3-al~yrrolo r 3.4-cl-
carbazole ~4.b), m.p. 239-243 C from diisopropyl
ether/ethylacetate, yield 28%;
1 337767
14
(+)-12-~3-diethyl~ino-2-methoxy-1-propyl)-6.7.12 13-tetrahydro-
S-oYn-5~-inAolor2~3-a~yrrolor3~4-c~-carbazol and (+~-13-(3-
diethyl~ino-2-methoxY-l-propyl)-6.7.12.~3-tetrahydro-S-oYo-5H-
indolo-r2.3-a~pyrrolo~3.4-c~ rbazol (4.c), m.p. 240-260- C
(decomp.) from diisopropyl ether/ethylacetate, 3:1 regioisomeric
mixture, yield 54%;
(+)-12-(3-dimethylamino-2-methoxy-1-Dropyl~-6.7.12.13-
tetrahy~ro-5-oxo-5H-indolo~2 3-a~pYrrolo~3.4-c~-sarbazole and
(+)-13-(3-dimethylamino-2-methoxY-l-~ropyl)-6.7.12.13-
tetrahydro-5-oxo-5H-indolo r 2.3-a~pyrrolor3.4-cl-carbazole (4.d),
m.p. > 190 C (decomp.) from diisopropyl ether/ethylacetate, 7:3
regioisomeric mixture, yield 21%;
(+)-12-r3-(N-benzyl-N-methylamino)-2-methoxy-1-propyl1-
6.7.12.13-tetrahYdro-5-oxo-5H-indolor2.3-a~pyrrolor3.4-c~-
carbazole and (+~-13-~3-(N-BenzYl-N-methylamino)-2-methoxY-l-
propyl~-6.7.12.13-tetrahydro-5-oxo-5H-indolor2,3-a~pyrrolo~3.4-
c~-carbazole (4.e), m.p. > 150- C (decomp.) from diisopropyl
ethere/ethylacetate, 5:3 regioisomeric mixture, yield 32%;
6.7.12.13-tetrahydro-5-oxo-12-(3-piperidinopropyl~-5H-indolo-
r2.3-a~pyrrolor3.4-c~-carbazole and 6.7.12.13-tetrahydro-5-oxo-
13-(3-piperidinopropYl)-5H-indolo-r2.3-a~pyrrolor3.4-c~-
carbazole (4.f), m.p. > 230- C (decomp.) from diisopropyl ether,
7:4 regioisomeric mixture, yield 17%.
1 337767
~YAmple 5
6.7.12.13-TetrahYdro-12-methyl-5-oxo-5H-indolor2.3-a~-
pyrrolo r 3.4-c~carbazole and
6.7.12.13-tetrahydro-13-methyl-5-oxo-5H-indolo r 2.3-
alpyrrolo r 3.4-c~carbazole
29 mg (0.97 mmole) sodium hydride (80% in mineral oil) are
pen~ in 20 ml dry dimethylformamide and 200 mg (0.64 mmole)
6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolot3,4-
c]carbazole added portionwise thereto at ambient temperature.
After subsidence of the gas evolution, 0.09 ml (0.95 mmole)
dimethyl sulphate are added thereto and the reaction mixture is
stirred for 72 hours at ambient temperature. The solvent is
distilled off in a vacuum and the residue mixed with 20 ml
aqueous sodium carbonate solution. It is extracted twice with,
in each case, 20 ml ethyl acetate. The ethyl acetate solutions
are dried over anhydrous sodium sulphate and subsequently
evaporated in a vacuum. The residue is chromatographed on
silica gel with dichloromethane/ methanol (95:5 v/v). The
fraction with the Rf of 0.4 is isolated and stirred with
diisopropyl ether/acetone (9:1 v/v). The crystals formed are
filtered off.
There is obtained an approximately 7:1 regioisomeric mixture of
6 7 12 13-tetrahydro-12-methyl-5-oxo-5H-indolor2 3-a~-
pyrrolo r 3 4-c~carbazole and 6 7 12 13-tetrahydro-13-methYl-5-
oxo-5H-indolo~2 3-alpYrrolor3 4-c~carbazole in the form of beige
crystals; m.p. > 300 C (decomp.), yield 38%.
With 2 equivalents of sodium hydride and dimethyl sulphate,
there i8 obtA i ne~, in an analogous way, 6 7 12 13-tetrahydro-
12 13-dimethyl-5-oxo-5H-indolo r 2 3-a~-pyrrolo r 3 4-c~carbazole
(5.a); m.p. 248 - 251-C, after crystallisation from diisopropyl
ether, yield 56%.
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Example 6
6.7.12.13-TetrahYdro-7-hydroxv-5-oxo-5H-in~olor2~3-a]
pyrrolo[3.4-c~carbazole (6.a) and
7-ethoxy-6.7.12.13-tetrahydro-5-oxo-5H-indolo r 2.3-a]pYrrolor3.4-
c~-carbazole (6.b)
To a stirred suspension of 10 g (153 mmole) zinc dust and 1 g
(3.7 mmole) mercuric chloride in 10 ml water is added 0.5 ml
concentrated hydrochloric acid. After about 5 minutes, the
supernatant liquid is decanted off, The zinc amalgam thus
obt~ine~ is first washed with water and s~h~equently repeatedly
washed with ethanol. After the addition of 30 ml dry ethanol,
the mixture is cooled in an ice-bath and 330 mg (1.01 mmole)
6,7,12,13-tetrahydro-5,7-dioxo-5H-indolot2,3-a]-pyrrolot3,4-
c]carbazole are added thereto. Dry gaseous hydrogen chloride is
then slowly pAcee~ in over the course of 1 hour, with further
cooling. The reaction mixture i8 filtered, the filtrate is
evaporated and the residue is chromatGy.a~hed on silica gel with
toluene/ ethyl acetate (1:1 v/v). The fraction with the Rf of
0.3 i8 isolated and crystallised from ethyl acetate.
There are obtained beige crystals of 7-ethox y-6 . 7.12.13-
tetrahydro-5-oxo-5H-indolo r 2.3-a1-~yrrolo r 3.4-clcarbazole (6.b);
m.p. > 300C, yield 22%.
The fraction with the Rf of 0.2 is isolated and stirred with
diisopropyl ether. There are obtained beige crystals of
6 . 7.12.13-tetrahydro-7-hYdroxy-5-oxo-5H-indolor2.3-
a1pyrrolor3.4-c~carbazole (6.A~; m.p. > 300C, yield 23%.
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Example 7
6,7,12,13-Tetrahydro-12-methoxycarbonylmethyl-5-oxo-5H-
indolo r 2,3-a ~ pYrrolo r 3,4-c~carbazole and
6,7,12,13-tetrahydro-13-methoxycarbonylmethyl-5-oxo-5H-indolo-
[2,3-a~DYrrolo~3.4-c~carbazole
The crude product obtained by the reaction of 150 mg (0.48
~ole) 6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-
c]carbazole with 18 mg (0.60 mmole) sodium hydride (80% in
mineral oil) and 115 mg (0.75 mmole) methyl bromoacetate
analogously to Example 1 is separated chromatographically on
silica gel with dichloromethane/methanol (95:5 v/v). The
fraction with the Rf of 0.35 is isolated and stirred with
diisopropyl ether. The crystals formed are filtered off.
There is obtained an approximately 3:1 regioisomeric mixture of
6,7,12,13-tetrahydro-12-methoxycarbonylmethyl-5-oxo-5H-
indolo~2.3-a~pyrrolo~3,4-c~carbazole and 6,7,12,13-tetrahydro-
13-methoxycarbonylmethyl-5-oxo-5H-indolo~2,3-a~pyrrolo[3,4-
clcarbazole in the form of beige crystals; m.p. > 300C, yield
51%.
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~A~ple 8
(+)-6,7.12.13-tetrA~ydro-12,13-(2-hydroxypropano)-5-oxo-5H-
indolo r 2,3-a~pyrrolo- r 3,4-c~carbazole
The crude product obtained by the reaction of 300 mg (0,96 mmol)
6,7,12,13-tetrahydro-5-oxo-5H-indolot2,3-a~pyrrolot3,4-c]-
carbazole with 33 mg (1,1 mmol) sodium hydride (80% in mineral
oil) and 0,1 ml (1,2 mmol) epibromohydrine in 30 ml dry
dimethylformamide analogously to Example 1 (reaction time 72 h
at ambient temperature) is separated chromatographically on
silica gel with cyclohexane/tetrahydrofuran (1:1 v/v). The
fraction with the Rf of 0.15 in toluene/ethylacetate (1:1 v/v)
is isolated and stirred with diisopropyl ether/ methanol. The
crystals formed are filtered off.
There is obtained 6,7,12,13-tetrahydro-12,13-(2-hydroxypropano)-
5-oxo-5H-indolot2,3-a]pyrrolot3,4-c]carbazole in the form of
beige crystals; m.p. > 300 C (decomp.), yield 19%.
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19
Example 9
(+)-12-(3-diet~ylamino-2-hydro~y-1-propyl~-6.7 12.13-tetrahydro-
5-oxo-5H-indolo[2.3-a]pyrrolor3.4-c~carbazole and (+)-13-(3-
diethylamino-2-hYdroxy-l-propyl)-6.7 12 13-tetrahydro-5-oxo-5H-
indolo~2 3-alpyrrolo r 3.4-c~carbazole
The crude product obtained by the reaction of 500 mg (1,61
mmole) 6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-
c]carbazole with 58 mg (1.92 mmole) sodium hydride (80% in
mineral oil) and 447 mg (2.70 mmole) 1,1-diethyl-3-
hydroxyazetidiniumchloride in 50 ml dry dimethylformamide
analogously to Example 1 is extracted with 200 ml ethylacetate
and 50 ml water. The organic phase is separated, dried with
sodium sulfate and evaporated. The residue is separated
chromatographically on silica gel with dichloromethane/methanol
(95:5 v/v). The fraction with the Rf of 0.1 is isolated and
stirred with diisopropyl ether/ethylacetate. The crystals
formed are filtered off.
There i8 obtained an approximately 1:1 regioisomeric mixture of
(+)-12-(3-diethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-
5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole and (+)-13-(3-
diethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-5-oxo-5H-
indolo[2,3-a]pyrrolo[3,4-c]carbazole in the form of pale beige
crystals; m.p. > 195C (decomp.), yield 44%.
There is obtained in an analogous manner:
(+)-12-(3-piperidino-2-hydroxy-1-proDyl)-6.7.12.13-tetrahydro-5-
oxo-SH-indolo[2.3-a]pyrrolo[3.4-c]carbazole and (+)-13-(3-
piperidino-2-hydroxy-1-propyl)-6,7.12.13-tetrahydro-5-oxo-5H-
indolo~2.3-a~pyrrolo[3.4-c~carbazole (9.a), m.p. > 205-C
(decomp.) from diisopropyl ether, yield 28%.
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Example 10
I+)-6.7.12,13-TetrahYdro-12-(3-N-methylamino-2-methoxy-1-
propyl)-5-oxo-5H-in~olor2.3 -A ~ pyrrolo-~3.4-c~carbazole and 1+)-
6.7.12.13-tetrahy~ro-13-(3-N-methylamino-2-methoxy-l-propyl)-5-
oxo-5H-indolo~2.3-a~pyrrolo- r 3.4-c~carbazole
100 mg (0,2 mmol) (+)-12-[3-(N-benzyl-N-methylamino)-2-methoxy-
-propyl]-6~7~12~13-tetrahydro-5-oxo-5H-indolo~2~3-a]pyrrolo-
t3,4-c]carbazole and (+)-13-t3-(N-benzyl-N-methylamino)-2-
methoxy-l-propyl]-6,7,12,13-tetrahydro-5-oxo-5H-indolot2,3-a]-
pyrrolot3,4-c]carbazole (Example 4.e) in 30 ml glacial acetic
acid are hydrogenated 5 h with 100 mg Palladium on charcoal (10%
Pd / 50% water) at 55-60 C. The catalyst will be filtered off,
the solution evaporated and the residue partitioned between
sodium hydrogen carbonate solution (50 ml) and ethyl acetate
(100 ml). The organic phase is separted off, dried over sodium
sulphate and evaporated. The residue is stirred with diisopropyl
ether/ethyl acetate (4:1, v:v), the crystals filtered off and
dried.
One obtains (+)-6,7,12,13-tetrahydro-12-(3-N-methylamino-2-
methoxy-l-propyl)-5-oxo-5H-indolot2,3-a]pyrrolot3,4-c]carbazole
and (+)-6,7,12,13-tetrahydro-13-(3-N-methylamino-2-methoxy-1-
propyl)-5-oxo-5H-indolot2,3-a]pyrrolot3,4-c]carbazole in the
form of pale beige crystals of the m.p. > 170-C (decomp.), yield
62%, as 3:1 regioisomeric mixture.
