CA1337767C - Indolocarbazole derivatives, processes for the preparation thereof and pharmaceutical compositions containing them - Google Patents
Indolocarbazole derivatives, processes for the preparation thereof and pharmaceutical compositions containing themInfo
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- CA1337767C CA1337767C CA000590001A CA590001A CA1337767C CA 1337767 C CA1337767 C CA 1337767C CA 000590001 A CA000590001 A CA 000590001A CA 590001 A CA590001 A CA 590001A CA 1337767 C CA1337767 C CA 1337767C
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Abstract
The present invention provides indolocarbazole deriva-tives of the general formula I:
(I) 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 substi-tuted on the amino nitrogen atom by C1-C4 alkyl or benzyl, or the amino nitrogen atom forms part of a heterocyclic ring that can optionally contain an oxygen atom or a further nitrogen atom;
alkoxycarbonylalkyl radicals containing up to 6 carbon atoms;
-CH2-CO-NR3R4 radicals, wherein R3 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-, acetyloxyalkoxyalkyl- or hydroxyalkoxyalkyl radical 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 contain-ing up to 4 carbon atoms, with the proviso that all of the symbols R1, R2, X and Y do not simultaneously signify hydrogen atoms; as well as the pharmacologically acceptable salts thereof. The com-pounds are potent inhibitors of protein kinases and can be used, for example, for the treatment of heart and blood vessel diseases, such as thromboses, arteriosclerosis, hypertension, inflammatory processes, allergies, cancers and certain degenerative diseases of the central nervous system. The present invention also provides processes for the preparation of these compounds and pharmaceu-tical compositions containing them.
(I) 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 substi-tuted on the amino nitrogen atom by C1-C4 alkyl or benzyl, or the amino nitrogen atom forms part of a heterocyclic ring that can optionally contain an oxygen atom or a further nitrogen atom;
alkoxycarbonylalkyl radicals containing up to 6 carbon atoms;
-CH2-CO-NR3R4 radicals, wherein R3 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-, acetyloxyalkoxyalkyl- or hydroxyalkoxyalkyl radical 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 contain-ing up to 4 carbon atoms, with the proviso that all of the symbols R1, R2, X and Y do not simultaneously signify hydrogen atoms; as well as the pharmacologically acceptable salts thereof. The com-pounds are potent inhibitors of protein kinases and can be used, for example, for the treatment of heart and blood vessel diseases, such as thromboses, arteriosclerosis, hypertension, inflammatory processes, allergies, cancers and certain degenerative diseases of the central nervous system. The present invention also provides processes for the preparation of these compounds and pharmaceu-tical compositions containing them.
Description
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 ~
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:
~ 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 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 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 -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:
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.
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, 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 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:
... .. .....
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%;
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%;
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%.
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%;
(+)-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%.
~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%.
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%.
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%.
~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%.
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%.
-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.
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 ~
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:
~ 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 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 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 -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:
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.
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, 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 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:
... .. .....
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%;
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%;
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%.
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%;
(+)-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%.
~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%.
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%.
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%.
~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%.
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%.
-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.
Claims (46)
1. Indolocarbazole derivatives of the general formula I:
(I) 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 carbon atoms; -CH2-CO-NR3R4 radicals, wherein R3 and R4 are the same or different and are hydrogen atoms, alkyl radicals containing up to 4 carbon atoms or benzyl radicals; or R1 and R2 are haloalkyl; hydroxyalkyl or alkoxyalkyl radicals containing, in each case, up to 6 carbon atoms; benzoylalkoxyalkyl-, acetyloxyalkoxyalkyl- or hydroxyalkoxyalkyl radicals with, in each case, up to 11 carbon atoms or acyl radicals containing up to 4 carbon atoms; or R
and R2 together form 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 either the same and 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
simultaneously stand for hydrogen atoms, and (ii) if one of X
and Y is other than hydrogen, then R1 and R2 are both hydrogen;
as well as the pharmacologically acceptable salts thereof.
(I) 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 carbon atoms; -CH2-CO-NR3R4 radicals, wherein R3 and R4 are the same or different and are hydrogen atoms, alkyl radicals containing up to 4 carbon atoms or benzyl radicals; or R1 and R2 are haloalkyl; hydroxyalkyl or alkoxyalkyl radicals containing, in each case, up to 6 carbon atoms; benzoylalkoxyalkyl-, acetyloxyalkoxyalkyl- or hydroxyalkoxyalkyl radicals with, in each case, up to 11 carbon atoms or acyl radicals containing up to 4 carbon atoms; or R
and R2 together form 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 either the same and 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
simultaneously stand for hydrogen atoms, and (ii) if one of X
and Y is other than hydrogen, then R1 and R2 are both hydrogen;
as well as the pharmacologically acceptable salts thereof.
2. Indolocarbazole derivatives of general formula I
according to claim 1 wherein R1 or R2 is 2-aminoethyl, 3-amino-propyl or 1-amino-2-propyl radicals, a dimethylaminoethyl, 3-dimethylamino-1-propyl, 3-dimethylamino-2-propyl, 2-diethylamino-ethyl, 2-[N-benzyl-N-methylamino]-ethyl, 3-[N-benzyl-N-methyl-amino]-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-1-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 or N-methyl-pyrrolidin-2-ylmethyl, a 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 C1-4-alkyl, or R1 or R2 is methyl, ethyl, n-propyl, isopropyl or n-butyl radicals, methoxycarbonylmethyl radicals, benzyl radicals, 2-methoxyethyl radicals, acetyl radicals or a butylene or a propylene radical, unsubstituted or hydroxysubstituted, which R1 and R2 form together.
according to claim 1 wherein R1 or R2 is 2-aminoethyl, 3-amino-propyl or 1-amino-2-propyl radicals, a dimethylaminoethyl, 3-dimethylamino-1-propyl, 3-dimethylamino-2-propyl, 2-diethylamino-ethyl, 2-[N-benzyl-N-methylamino]-ethyl, 3-[N-benzyl-N-methyl-amino]-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-1-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 or N-methyl-pyrrolidin-2-ylmethyl, a 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 C1-4-alkyl, or R1 or R2 is methyl, ethyl, n-propyl, isopropyl or n-butyl radicals, methoxycarbonylmethyl radicals, benzyl radicals, 2-methoxyethyl radicals, acetyl radicals or a butylene or a propylene radical, unsubstituted or hydroxysubstituted, which R1 and R2 form together.
3. The compound 6,7,12,13-tetrahydro-5-oxo-12,13-dipropyl-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharm-acologically acceptable salt thereof.
4. The compound 12,13-diethyl-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
5. The compound 12,13-butano-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
6. The compound 12,13-dibenzyl-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharm-acologically acceptable salt thereof.
7. The compound 6,7,12,13-tetrahydro-5-oxo-12-propyl-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
8. The compound 6,7,12,13-tetrahydro-5-oxo-13-propyl-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
9. The compound 6,7,12,13-tetrahydro-12-(2-methoxyethyl)-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacolog-ically acceptable salt thereof.
10. The compound 6,7,12,13-tetrahydro-13-(2-methoxyethyl)-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacolog-ically acceptable salt thereof.
11. The compound 13-acetyl-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
12. The compound 12-ethyl-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
13. The compound 12-(3-dimethylaminopropyl)-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
14. The compound 13-(3-dimethylaminopropyl)-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
15. The compound 6,7,12,13-tetrahydro-12-(2-morpholino-ethyl)-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
16. The compound 6,7,12,13-tetrahydro-13-(2-morpholino-ethyl)-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
17. The compound 6,7,12,13-tetrahydro-5-oxo-12-(2-pyrrolidinoethyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
18. The compound 6,7,12,13-tetrahydro-5-oxo-13-(2-pyrrolidinoethyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
19. The compound ()-12-(3-diethylamino-2-methoxy-1-propyl)-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
20. The compound ()-13-(3-diethylamino-2-methoxy-1-propyl)-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
21. The compound ()-12-(3-dimethylamino-2-methoxy-1-propyl)-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
22. The compound ()-13-(3-dimethylamino-2-methoxy-1-propyl)-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
23. The compound ()-12-[3-(N-benzyl-N-methylamino)-2-methoxy-1-propyl]-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
24. The compound ()-13-[3-(N-benzyl-N-methylamino)-2-methoxy-1-propyl]-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
25. The compound 6,7,12,13-tetrahydro-5-oxo-12-(3-piperidinopropyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
26. The compound 6,7,12,13-tetrahydro-5-oxo-13-(3-piperidinopropyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
27. The compound 6,7,12,13-tetrahydro-12-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
28. The compound 6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
29. The compound 6,7,12,13-tetrahydro-12,13-dimethyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologi-cally acceptable salt thereof.
30. The compound 6,7,12,13-tetrahydro-7-hydroxy-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
31. The compound 7-ethoxy-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
32. The compound 6,7,12,13-tetrahydro-12-methoxycarbonyl-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharm-acologically acceptable salt thereof.
33. The compound 6,7,12,13-tetrahydro-13-methoxycarbonyl-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharm-acologically acceptable salt thereof.
34. The compound ()-6,7,12,13-tetrahydro-12,13-(2-hydroxypropano)-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
35. The compound ()-12-(3-diethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole or a pharmacologically acceptable salt thereof.
36. The compound ()-13-(3-diethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole or a pharmacoloqically acceptable salt thereof.
37. The compound ()-12-(3-piperidino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazole or a pharmacologically acceptable salt thereof.
38. The compound ()-13-(3-piperidino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazole or a pharmacologically acceptable salt thereof.
39. The compound ()-6,7,12,13-tetrahydro-12-(3-N-methyl-amino-2-methoxy-1-propyl)-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazole or a pharmacologically acceptable salt thereof.
40. The compound ()-6,7,12,13-tetrahydro-13-(3-N-methyl-amino-2-methoxy-1-propyl)-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazole or a pharmacologically acceptable salt thereof.
41. Process for the preparation of compounds according to claim 1, wherein A) when X and Y are hydrogen atoms and R1 and R2 are the same but are not hydrogen atoms or one of the symbols R1 and R2 is a hydrogen atom, an indolocarbazole of the formula II:
(II) is alkylated or acylated on one or both indole nitrogen atoms with one or two equivalents of a compound of the general formula III:
R5 - 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 carbon atoms; a haloalkyl or alkoxyalkyl radical with, 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 is a leaving group, or in which R5 -T is a 1,1-disubstituted 3-hydroxyazetidinium halide, in which the substituents at the 1,1-positions are 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, in the presence of one or two equivalents of a base, or a radical R5 which has already been introduced is converted by hydrolysis, ether cleavage, amide formation or reduction into a radical R1 or R2, or B) when X and Y both signify hydrogen atoms and R1 and R2 are different and neither of them is a hydrogen atom, compounds of general formula (I) are prepared by reacting a compound of general formula (I), which has been prepared according to process A) in which either R1 or R2 has one of the meanings given for R5 and the other is a hydrogen atom, with a compound of general formula (III), in which R5 has one of the other meanings given for R5, in the presence of a base in a manner analogous to that described for process A) and, if required, one or both of the radicals with the meaning of R5 is modified, as described in process A), to give one of the radicals R1 or R2;
or C) when, in general formula (I), X or Y is a hydroxyl group and the other is a hydrogen atom, an imide of the formula IV:
(IV) is reduced, and the compound of general formula (I) obtained by process variants A), B) or C) is, if required, converted with an acid into a pharmacologically acceptable salt.
(II) is alkylated or acylated on one or both indole nitrogen atoms with one or two equivalents of a compound of the general formula III:
R5 - 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 carbon atoms; a haloalkyl or alkoxyalkyl radical with, 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 is a leaving group, or in which R5 -T is a 1,1-disubstituted 3-hydroxyazetidinium halide, in which the substituents at the 1,1-positions are 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, in the presence of one or two equivalents of a base, or a radical R5 which has already been introduced is converted by hydrolysis, ether cleavage, amide formation or reduction into a radical R1 or R2, or B) when X and Y both signify hydrogen atoms and R1 and R2 are different and neither of them is a hydrogen atom, compounds of general formula (I) are prepared by reacting a compound of general formula (I), which has been prepared according to process A) in which either R1 or R2 has one of the meanings given for R5 and the other is a hydrogen atom, with a compound of general formula (III), in which R5 has one of the other meanings given for R5, in the presence of a base in a manner analogous to that described for process A) and, if required, one or both of the radicals with the meaning of R5 is modified, as described in process A), to give one of the radicals R1 or R2;
or C) when, in general formula (I), X or Y is a hydroxyl group and the other is a hydrogen atom, an imide of the formula IV:
(IV) is reduced, and the compound of general formula (I) obtained by process variants A), B) or C) is, if required, converted with an acid into a pharmacologically acceptable salt.
42. Pharmaceutical compositions containing, as active material, a compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt thereof and a suitable adjuvant or carrier material.
43. A process for the manufacture of a pharmaceutical composition for the treatment of heart and blood vessel diseases, thromboses, arteriosclerosis, hypertension, inflammatory processes, allergies, cancers and certain degenerative damage of the central nervous system, which process comprises admixing a compound of general formula I according to any one of claims 1 to 40 or a pharmacologically acceptable salt thereof, with a suitable adjuvant or carrier material.
44. Use of a compound of general formula I according to any one of claims 1 to 40 for the treatment of heart and blood vessel diseases, thromboses, arteriosclerosis, hypertension, inflammatory processes, allergies, cancers and certain degenerative damage of the central nervous system.
45. A compound of the general formula I according to any one of claims 1 to 40 or a pharmacologically acceptable salt thereof, for use in the treatment of heart and blood vessel diseases, thromboses, arteriosclerosis, hypertension, inflammatory processes, allergies, cancers and certain degenerative damage of the central nervous system.
46. A commercial package containing, as active material, a compound of general formula I according to any one of claims 1 to 40 or a pharmacologically acceptable salt thereof, together with instructions for its use for the treatment of heart and blood vessel diseases, thromboses, arteriosclerosis, hypertension, inflammatory processes, allergies, cancers and certain degenerative damage of the central nervous system.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3803620A DE3803620A1 (en) | 1988-02-06 | 1988-02-06 | INDOLOCARBAZOL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME |
| DEP3803620.7 | 1988-02-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1337767C true CA1337767C (en) | 1995-12-19 |
Family
ID=6346797
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000590001A Expired - Fee Related CA1337767C (en) | 1988-02-06 | 1989-02-03 | Indolocarbazole derivatives, processes for the preparation thereof and pharmaceutical compositions containing them |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0328000B1 (en) |
| JP (1) | JP2866096B2 (en) |
| KR (1) | KR890013035A (en) |
| CN (1) | CN1035667A (en) |
| AT (1) | ATE117304T1 (en) |
| AU (1) | AU616468B2 (en) |
| CA (1) | CA1337767C (en) |
| DD (1) | DD283394A5 (en) |
| DE (2) | DE3803620A1 (en) |
| DK (1) | DK51489A (en) |
| ES (1) | ES2066798T3 (en) |
| GR (1) | GR3015194T3 (en) |
| HU (1) | HU203758B (en) |
| IE (1) | IE65256B1 (en) |
| PT (1) | PT89623B (en) |
| ZA (1) | ZA89861B (en) |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3010675B2 (en) * | 1989-03-23 | 2000-02-21 | 萬有製薬株式会社 | Antitumor substance BE-13793C |
| WO1991009034A1 (en) * | 1989-12-14 | 1991-06-27 | Schering Corporation | Indolocarbazoles from saccharothrix aerocolonigenes subsp. copiosa subsp. nov. scc 1951 atcc 53856 |
| US5618809A (en) * | 1989-12-14 | 1997-04-08 | Schering Corporation | Indolocarbazoles from saccharothrix aerocolonigenes copiosa subsp. nov SCC 1951 ATCC 53856 |
| DE3942296A1 (en) * | 1989-12-21 | 1991-06-27 | Goedecke Ag | INDOLOCARBAZOL DERIVATIVES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| US5591842A (en) * | 1991-11-29 | 1997-01-07 | Banyu Pharmaceutical Co., Ltd. | Indolopyrrolocarbazole derivatives |
| US5668271A (en) * | 1991-11-29 | 1997-09-16 | Banyu Pharmaceutical Co., Ltd. | Indolopyrrolocarbazole derivatives |
| EP0630242B1 (en) * | 1992-03-20 | 1999-01-20 | The Wellcome Foundation Limited | Further indole derivatives with antiviral activity |
| DE4243321A1 (en) * | 1992-12-21 | 1994-06-23 | Goedecke Ag | Amino acid derivatives of heterocycles as PKC inhibitors |
| AU678435B2 (en) * | 1993-05-10 | 1997-05-29 | F. Hoffmann-La Roche Ag | Substituted pyrroles |
| US5721230A (en) * | 1993-05-10 | 1998-02-24 | Hoffmann-La Roche Inc. | Substituted pyrroles |
| KR100201343B1 (en) * | 1993-05-28 | 1999-06-15 | 바바라 에스 쉴버그 | Pharmaceutical composition for the treatment of pathological conditions of prostate containing indolocarbazole derivatives |
| US5468872A (en) * | 1993-09-16 | 1995-11-21 | Cephalon, Inc. | K-252a functional derivatives potentiate neurotrophin-3 for the treatment of neurological disorders |
| JPH07238044A (en) * | 1993-12-07 | 1995-09-12 | Eli Lilly & Co | Improved method of synthesizing bisindolyl- maleimide |
| YU49200B (en) * | 1993-12-07 | 2004-09-03 | Eli Lilly And Company | Protein kinase c inhibitors |
| US5541347A (en) * | 1993-12-07 | 1996-07-30 | Eli Lilly And Company | Synthesis of bisindolylmaleimides |
| US5723456A (en) * | 1993-12-07 | 1998-03-03 | Eli Lilly & Company | Therapeutic treatment for cardiovascular diseases |
| US5843935A (en) * | 1993-12-07 | 1998-12-01 | Eli Lilly And Company | Protein kinase C inhibitors |
| US5624949A (en) * | 1993-12-07 | 1997-04-29 | Eli Lilly And Company | Protein kinase C inhibitors |
| PT817627E (en) * | 1993-12-23 | 2005-07-29 | Lilly Co Eli | PROTEIN INHIBITORS CINASE C |
| US5922860A (en) * | 1994-05-09 | 1999-07-13 | Banyu Pharmaceutical Co., Ltd. | Antitumor indolopyrrolocarbazole derivatives |
| US5804564A (en) * | 1994-05-09 | 1998-09-08 | Banyu Pharmaceutical Co., Ltd. | Antitumor indolopyrrolocarbazole derivatives |
| US5481003A (en) * | 1994-06-22 | 1996-01-02 | Eli Lilly And Company | Protein kinase C inhibitors |
| US5491242A (en) * | 1994-06-22 | 1996-02-13 | Eli Lilly And Company | Protein kinase C inhibitors |
| DE69911935T3 (en) * | 1998-03-13 | 2008-02-07 | The University Of British Columbia, Vancouver | GRANULATIMIDE DERIVATIVES FOR THE TREATMENT OF CANCER |
| CA2245029A1 (en) | 1998-03-13 | 1999-09-13 | University Of British Columbia | Granulatimide compounds as g2 checkpoint inhibitors |
| US6653290B2 (en) | 2000-10-06 | 2003-11-25 | Bristol-Myers Squibb Company | Tumor proliferation inhibitors |
| BR0208322A (en) | 2001-03-22 | 2004-10-13 | Bristol Myers Squibb Co | Indolopyrrolocarbazole topoisomerase i selective cytotoxic sugar derivatives |
| CA2393720C (en) | 2002-07-12 | 2010-09-14 | Eli Lilly And Company | Crystalline 2,5-dione-3-(1-methyl-1h-indol-3-yl)-4-[1-(pyridin-2-ylmethyl)piperidin-4-yl]-1h-indol-3-yl]-1h-pyrrole mono-hydrochloride |
| CN117486782A (en) * | 2023-12-29 | 2024-02-02 | 中国医学科学院药用植物研究所 | N-substituted carbazole derivative and preparation method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62155284A (en) * | 1985-12-27 | 1987-07-10 | Kyowa Hakko Kogyo Co Ltd | Physiologically active substance k-252 derivative |
| US4737496A (en) * | 1986-10-01 | 1988-04-12 | Ciba-Geigy Corporation | 1,3,4,16b-tetrahydro-2H,10H-indolo[2,1-c]pyrazino-[1,2-a][1,4]benzodiazepines useful as serotonin-2 receptor antagonists |
-
1988
- 1988-02-06 DE DE3803620A patent/DE3803620A1/en not_active Withdrawn
-
1989
- 1989-02-03 PT PT89623A patent/PT89623B/en not_active IP Right Cessation
- 1989-02-03 DE DE58908892T patent/DE58908892D1/en not_active Expired - Fee Related
- 1989-02-03 DK DK051489A patent/DK51489A/en not_active Application Discontinuation
- 1989-02-03 EP EP89101940A patent/EP0328000B1/en not_active Expired - Lifetime
- 1989-02-03 CA CA000590001A patent/CA1337767C/en not_active Expired - Fee Related
- 1989-02-03 ZA ZA89861A patent/ZA89861B/en unknown
- 1989-02-03 AT AT89101940T patent/ATE117304T1/en not_active IP Right Cessation
- 1989-02-03 IE IE35989A patent/IE65256B1/en not_active IP Right Cessation
- 1989-02-03 AU AU29607/89A patent/AU616468B2/en not_active Ceased
- 1989-02-03 HU HU89548A patent/HU203758B/en not_active IP Right Cessation
- 1989-02-03 DD DD89325511A patent/DD283394A5/en not_active IP Right Cessation
- 1989-02-03 ES ES89101940T patent/ES2066798T3/en not_active Expired - Lifetime
- 1989-02-04 CN CN89100641A patent/CN1035667A/en active Pending
- 1989-02-04 KR KR1019890001349A patent/KR890013035A/en not_active Application Discontinuation
- 1989-02-06 JP JP1027350A patent/JP2866096B2/en not_active Expired - Fee Related
-
1995
- 1995-02-27 GR GR950400404T patent/GR3015194T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK51489D0 (en) | 1989-02-03 |
| KR890013035A (en) | 1989-09-21 |
| IE890359L (en) | 1989-08-06 |
| DE3803620A1 (en) | 1989-08-17 |
| CN1035667A (en) | 1989-09-20 |
| HU203758B (en) | 1991-09-30 |
| ATE117304T1 (en) | 1995-02-15 |
| ZA89861B (en) | 1989-11-29 |
| EP0328000A3 (en) | 1991-04-03 |
| EP0328000B1 (en) | 1995-01-18 |
| IE65256B1 (en) | 1995-10-18 |
| PT89623A (en) | 1989-10-04 |
| DD283394A5 (en) | 1990-10-10 |
| GR3015194T3 (en) | 1995-05-31 |
| AU2960789A (en) | 1989-08-10 |
| JP2866096B2 (en) | 1999-03-08 |
| DE58908892D1 (en) | 1995-03-02 |
| ES2066798T3 (en) | 1995-03-16 |
| JPH02149520A (en) | 1990-06-08 |
| EP0328000A2 (en) | 1989-08-16 |
| DK51489A (en) | 1989-08-07 |
| PT89623B (en) | 1994-02-28 |
| AU616468B2 (en) | 1991-10-31 |
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