DD283394A5 - METHOD FOR THE PRODUCTION OF INDILOCARBAZOL DERIVATIVES - Google Patents

Abstract

Novel indolocarbazole derivatives of the general formula I <IMAGE> in which R<1> and R<2> are identical or different and denote hydrogen, a straight-chain or branched alkyl group having 1 to 6 C atoms, a benzyl group, an unsubstituted or substituted aminoalkyl group having up to 12 C atoms, an alkoxycarbonylalkyl radical having up to 6 C atoms, a radical -CH2-CO-NR<3>R<4> in which R<3> and R<4> are identical or different and represent hydrogen, an alkyl group having 1 to 4 C atoms or a benzyl group, or R<1> and/or R<2> denote a haloalkyl, hydroxyalkyl or alkoxyalkyl radical each having up to 6 C atoms, a benzoyloxyalkoxyalkyl, acetyloxyalkoxyalkyl or hydroxyalkoxyalkyl radical each having up to 11 C atoms, or an acyl group having 1 to 4 C atoms or R<1> and R<2> together denote an alkylene group having 2 to 4 C atoms, optionally substituted by hydroxyl, C1-4-alkoxy or amino, X and Y are either identical and in each case both denote hydrogen, or X and Y are different, one of the radicals X or Y representing hydrogen and the other of the two radicals denoting a hydroxyl or an alkoxy group having up to 4 C atoms, with the proviso that not all radicals R<1>, R<2>, X and Y simultaneously denote hydrogen, and their pharmacologically acceptable salts, process for the preparation of the compounds I or of regioisomer mixtures of two of these compounds I and medicines containing at least one of the compounds I.

Description

Process for the preparation of indolocarbazole derivatives Field of application of the invention

The invention relates to processes for the preparation of novel indolocarbazole derivatives which are used in the pharmaceutical industry for the preparation of medicaments and are used in medicine for the treatment of cardiovascular diseases, inflammatory processes, allergies, cancer and certain degenerative damage of the central nervous system.

Characteristic of the known state of the art

In J. Antibiet. 1977, 30, 275 and Biocheiu. Biophys. Res. Commun. 1986, 135, 397 describe indolocarbazoles as inhibitors of protein kinase C. These are mainly indolocarbazole-N, N-glycoside microbial or senosynthetic origin ·

Object of the invention

The invention provides processes for the preparation of novel indolocarbazole derivatives. The compounds prepared according to the invention are potent inhibitors of protein kinases such as protein kinase O and are used in medicaments for the treatment of cardiovascular diseases, inflammatory processes, allergies, cancer and certain degenerative damage of the central nervous system.

of the "essence of the invention

The present invention has for its object to develop processes for the preparation of novel indolocarbazole derivatives which are suitable as inhibitors of protein kinase C.

-2-

According to the invention, novel indolocarbazole derivatives of the general formula I are prepared.

(D

1 2

in which R and R are identical or different and are hydrogen, a straight-chain or branched alkyl group having 1 to 6 C atoms, a benzyl group, an unsubstituted or substituted aminoalkyl group having up to 12 C atoms, an alkoxycarboijylalkyl radical having up to 6, preferably with up to 4 C atoms, a radical -OH ₂ -CO-NR- ^ r in which R ^ and R ^ are identical or different and represent hydrogen, an alkyl group having 1 to 4 C atoms or a benzyl group, or R and / or

2 R is a haloalkyl, hydroxyalkyl or alkoxyalkyl radical having in each case up to 6 C atoms, a benzoyloxyalkoxyalkyl, acetyloxyalkoxyalkyl or hydroxyalkoxyalkyl radical having in each case up to 11

1 2 carbon atoms, an acyl group having 1 to 4 carbon atoms or R and R together represent an alkylene group having 2 to 4 carbon atoms, optionally substituted by hydroxy, C, alkoxy or amino, X and Y are either the same and each of them is hydrogen, or X and Y are different, one of X or Y being hydrogen and the other of the two being hydroxy or alkoxy of up to 4 carbon atoms, with the proviso that not all radicals R ¹ , R ² , X and Y are simultaneously hydrogen, and their pharmacologically acceptable salts, or Regioisomerengemisohe of two of these compounds I and drugs containing at least one of the compounds I.

2 θ 3 3 9 Φ-

Depending on the substitution, the compounds I are prepared by one of the processes described below:

A) In the event that X and Y are hydrogen and R ¹ and R ^{2 are the} same, but not hydrogen, or one of R ¹ or R ^{2 is} hydrogen, compounds of general formula I are obtained by reacting Indolocarbazole of the formula II

.N, 0:

(II)

• N-H

with one or two equivalents of a compound of general formula III

R ⁵ -X III

in the R ^{5 is} a straight-chain or branched alkyl group having 1 to 6 C atoms, an unsubstituted or substituted aminoalkyl group having up to 12 C atoms, an alkoxycarbonylalkyl radical having up to 6, preferably having up to 4 C atoms, a haloalkyl or alkoxyalkyl radical having in each case up to 6 C atoms, a benzoyloxyalkoxyalkyl or acetyloxyalkoxyalkyl radical each having up to 11 C atoms or an acyl group having 1 to 4 C atoms and X is preferably halogen, in particular iodine, bromine and chlorine,

in the presence of one or two equivalents of bases such as hydrides, carbonates, hydroxides, oxides or alkoxides of the alkali or alkaline earth metals, or of organolithium compounds, alkylated or acylated in a conventional manner at one or both indole nitrogen atoms, or by introducing already introduced radicals R ⁵ by conventional methods of preparative organic chemistry (eg Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart 1966)

modified to one of the radicals R ¹ or R ² , for example by hydrolysis, ether cleavage, amide formation or reduction.

Thus, compounds of general formula I ,, in which R ¹ and / or R ^{2 is} a radical -CH ₂ -CO-NR ³ R ⁴ standing, preferably by reacting compounds of general formula I, wherein R ¹ and / or R ^{2 is an} alkoxycarbonylmethyl radical, produced by reaction with amines of the formula HNR ³ R ⁴ , in which R ³ and R ^{4 have} the meanings given above.

Compounds of the general formula I in which R ¹ and / or R ^{2 represent} a hydroxyalkyl radical are preferably obtained by hydrolysis of compounds of the general formula I in which R and / or R ^{z are} a haloalkyl radical, in particular a bromoalkyl or chloroalkyl radical , or by ether cleavage of compounds of the general formula I in which R ¹ and / or R ^{2 is} an alkoxyalkyl radical.

Compounds of the general formula I in which R ¹ and / or R ^{2 represent} a hydroxyalkoxyalkyl radical are prepared by known methods from compounds of the general formula I in which R ¹ and / or R ^{2 represent} a benzoyloxyalkoxyalkyl or acetyloxyalkoxyalkyl radical , manufactured. Particularly preferred hydroxyalkoxyalkyl radicals are 2-hydroxyethoxymethyl and 3-hydroxypropoxymethyl radicals.

Compounds of the general formula I in which R ¹ and / or R ^{2 represent} an N, N-disubstituted 3-amino-2-hydroxypropyl radical are preferably prepared by alkylation of the indolocarbazole of the formula II with 1,1-disubstituted 3-hydroxyazetidinium halides ( J. Org. Chem. 1968, 523).

Compounds of general formula I in which R ¹ and R ² together represent an alkylene radical - (CH ₂ Jn- with η = 2 to 4, are prepared by reacting the indolocarbazole of the formula II with two equivalents of one of the abovementioned bases and a

283324

Equivalent of a dihaloalkane, preferably a dibromoalkane.

Compounds of the general formula I ₁ in which R ¹ and R ² together form a propylene? st the general formula V

-CH ₅ -CH-CH, -

² I ² (V)

in which R is hydroxy, C _1-4 -alkoxy or amino sttht be obtained by reacting the indolocarbazole of formula II with two equivalents of one of the abovementioned bases and epichlorohydrin or epibromohydrin, wherein the initially formed hydroxy-substituted propylene radical by known methods in C ^ ₄ alkoxy- or amino-substituted propylene radicals can be converted.

Compounds of the general formula I in which R ¹ and / or R ^{2 are} a methyl or ethyl radical can also be prepared by alkylation with dimethyl or diethyl sulfate in a known manner.

The described process of alkylating or acylating the indolocarbazole of the formula II in the presence of bases with alkylating or acylating agents is surprising since it was not foreseeable that the introduction of one or two R ⁵ radicals would be selective on the indole nitrogen atoms and not on the Nitrogen atom of the lactam ring takes place.

B) In the case where X and Y are hydrogen, R ¹ and R ^{2 are} different and neither R ¹ nor R ^{2 is} hydrogen, compounds of the general formula I are obtained by reacting compounds of the general formula I which are obtained by process A) were prepared in which either R ¹ or R ^{2 has} one of the meanings given for R ⁵ and the other of the two radicals R ¹ or R ^{2 is} hydrogen, with compounds III, wherein R has another of the meanings given for R ⁵ , prepared in the presence of bases in an analogous manner as in method A) and optionally one or both of the radicals having the meaning

of R ⁵ , as described in method A), to one of the radicals R ¹ or R ² modified.

C) Compounds of the general formula I in which X or Y is a hydroxyl group and the other group is hydrogen are obtained by reduction of the imide of the formula IV

manufactured. As preferred reducing agents, zinc amalgam / hydrogen chloride gas in C1-C4 alcohols or zinc amalgam in glacial acetic acid are used.

Compounds of the general formula I in which X or Y is a C 1 -C 4 -alkoxy group and the other of the two radicals are hydrogen, either by reduction of the imide of formula IV in C 1 -C 4 -alcohols, preferably zinc amalgam / hydrogen chloride gas, or by acid-catalyzed Reaction of compounds of the general formula I in which X or Y represents a hydroxy group and the other represents hydrogen radicals, with C1-C4-alcohols in anhydrous Mn-1.

If the reduction with zinc amalgam / hydrogen chloride gas in C 1 -C 4 -alcohols produces mixtures of compounds of the general formula I in which X or Y is either a cyano or a C 1 -C 4 -alkoxy group and the other of the two radicals is hydrogen, these can be separated by conventional methods such as crystallization or Chromatejraphie.

The compounds of the general formula I thus obtained in which X or Y is a hydroxy or a C ¹ -C ⁴ -alkoxy group and R ¹ and R ^{2 are} hydrogen may then, if appropriate according to process A) or B), be compounds of the formula

general formula I in which X or Y is a hydroxy or a C ¹ -C ⁴ alkoxy group and the other of the two radicals hydrogen and R ¹ and R ^{2 is} one of the definitions given above, but not both simultaneously hydrogen, alkylated or acylated ,

Unsubstituted or substituted aminoalkyl groups having up to 12 C atoms and particularly suitable for R ¹ and / or R ² are unsubstituted aminoalkyl groups, such as a 2-aminoethyl, a 3-aminopropyl or an 1-amino-2-propyl radical, N, N Dialkylaminoalkyl- or N, N-alkylbenzylaminoalkyl groups. Cl-04-alkyl substituents on the nitrogen atoms and 1-4 C-atoms in the alkyl chain, wherein the alkyl chains by further Cl-C4-alkyl radicals, Cl-C4-alkoxy groups or a Hydroxy, in particular a 2-dimethylaminoethyl, a 3-dimethylamino-1-propyl, a 3-dimethylamino-2-propyl, a 2-diethylaminoethyl, a 2- [N-benzyl-N-methylamino] ethyl -, a 3- [N-benzyl-N-methylamino] propyl or a 3-dimethylamino-2-hydroxy-lpropylrest, a 3-diethylamino-2-hydroxy-1-propyl, a 3-piperidino-2-hydroxy -l-propyl, a 3-dimethylamino-2-methoxy-1-propyl, a 3-diethylamino-2-methoxy-1-propyl, a 3-piperidino-2-methoxy-1-propyl, a 3- (N-benzyl-N-methylamino) -2-methoxy-lp ropyl, a 3- (N-benzyl-N-methylamino) -2-hydroxy-1-propyl, a 3- (N-methylamino) -2-methoxy-1-propyl, a 3- (N-Mei hylamino) -2-hydroxy-1-propyl, a 4-dimethylamino-3-methoxy-2-butyl radical or a 2-piperidinoethyl, a 3-piperidinopropyl, a 2-pyrrolidinoethyl, a 3-pyrrolidinopropyl, a 2-morpholinoethyl, a 3-morpholinopropyl, a pyrrolidin-2-ylmethyl, an N-methyl-pyrrolidin-2-ylmethyl, a piperidin-2-ylmethyl, an N-methyl-piperidin-2-ylmethyl group or an unsubstituted or substituted on the nitrogen atom by C _1-4 alkyl piperazinoalkyl group having 1 to 4 carbon atoms in the alkyl chain.

Other particularly suitable radicals for R ¹ and / or R ² are straight-chain or branched alkyl groups having 1 to 4 C atoms, in particular methyl, ethyl, n-propyl, isopropyl and

IS S $ 9 4

η-butyl, Methoxycarbonylmethylgruppen, benzyl groups, 2-methoxyethyl groups, acetyl groups or an alkylene group having 2 to 4 carbon atoms, in particular a butylene group or a

1 2 hydroxy-substituted propylene group, which R and R together form.

Compounds of general formula I according to process A), B)

1 2 or G), in which R and R are different, can be used as regioisomer mixtures. By known separation methods such as crystallization or chromatography, the

be separated two regioisomers.

Compounds of the general formula I which have a chiral center can be used as stereoisomer mixtures or in the form of the enantiomers. The enantiomers can be obtained by the conventional methods used for optical separations of stereoisomers.

Basic compounds of the general formula I which have a

1 2 center of R or R, are preferably converted into crystalline, pharmacologically acceptable salts for the purpose of purification and for galenic reasons. The salts are obtained in the usual way by neutralization of the bases with corresponding inorganic or organic acids.

As acids come z. Hydrochloric, sulfuric, phosphoric, hydrobromic, acetic, tartaric, lactic, citric, malic, salicylic, ascorbic, malonic or succinic acids.

The preparation of the starting material Indolocarbazole of the formulas II and IV is described in the literature or can be carried out in an analogous manner (Heterocycles 1983 »20, 469, Tetrahedron Letters 1983, 1441).

The compounds according to the invention are jJ tente inhibitors of protein kinases such as protein kinase C, So z. For example, the compound of Example 1a in the Enzyra assay of the phosphatidylserine and diacylglycerol-activated protein kinase C exhibited a 50 # inhibition at a concentration of 66 nanomoles / liter. The experiment was carried out according to EP-0S-0 255 126 (inhibition of protein kinase C). Although indolocarbazoles have already been described as inhibitors of protein kinase C (J. Antibiot., 1977, 30, 275; Biochem., Biophys., Res., Co'mmun., 1986, 135, 397). However, these are mainly indolocarbazole-N, N-glycoside microbial or semisynthetic origin.

Protein kinase C plays an important role in intracellular signal transduction and is closely linked to the regulation of contractile, secretory and proliferative processes. Because of these properties, the compounds according to the invention can be used for the treatment of cardiovascular diseases such as thrombosis, arteriosclerosis, hypertension, inflammatory processes, allergies, cancer and certain degenerative damage of the central nervous system. The compounds may be administered in the appropriate formulation enterally or parenterally at doses of 1 to 50 mg / kg.

EXAMPLES Example 1

6,7,12,13-Tetrahydro-5-oxo-12,13-dipropyl-5H-indolo / ~ 2,3-a_7-pyrrolo / ~ * 3> 4- c__7carbazole

20 mg (0.67 mbar) of sodium hydride (80% in mineral oil) are suspended in 10 ml of dry dimethylformamide and 100 mg (0.32 mmol)

6,7,12,13-Te trahydro-5-oxo-5H-indolo / ~ 2,3-a_7pyrrolo / "3, A- carbazole was added in portions at room temperature 120 mg (0.71 mmol) of n-propyl iodide are added and the mixture is stirred at room temperature for 16 hours The solvent is removed in vacuo and the residue is chromatographed on silica gel with toluene / ethyl acetate 1: 1. The fraction of Rf 0.4 is isolated Stirred with diisopropyl ether.The crystals formed are filtered off.

This gives 6.7 »12.13-tetrahydro-5-oxo-12,13-dipropyl-5H-indolo /" 2,3-a 7pyrrolo / "" 3,4-c 7carbazole in the form of beige crystals of Schrnpi 180-185 ⁰ G (dec.), Yield 43%.

In an analogous manner one obtains

12:13-diethyl-6.7.12. ^ -Tetrahydro-S-oxo-SH-indolo / * ^. 3-a 7- p.vrrolo - / "'3" 4-c 7carbazole (La)

Mp.> 225 ⁰ C (dec.) From diisopropyl ether, yield 32%.

With two equivalents of sodium hydride and one equivalent of 1,4-dibromobutane is obtained in an analogous manner:

13.12-Butano-6.7.12. n-tetrahydro-S-oxo-SH-indolo / ^^ - a 7pvrrolo- / "3.4- c 7carbazole (1.b)

Mp.> 300 ⁰ C from diisopropyl ether, yield 53% »

In an analogous manner one obtains

11

12.13-dibenzyl-6.7.12.lS-tetrahvdro-S-oxo-SH-indolof2.3-ai pvrrolo-f3.4-c ") carbazole (lc) mp> 250 * C (dec.) From diisopropyl ether, yield 33%;

12.13-Dioctadecyl-e.7.12.13-tetrahydro-5-oxo-5H-indolor 2.3-ay- pvrrolo-f3.4-clcarbazole fl.d.b. mp. 101-103 * C from diisopropyl ether / ethyl acetate, Yield

12

2 0 3 3 $ 4

Example 2

6.7.12. 13-Tetrahydrobro-5-oxo-12-propyl-5H-indolo [2.3-a "'- pyrrolo [3,4-C) carbazole and

6.7.12.13-tetrahydro-5-oxo-13-proDyl-5H-indolof2.3-a ~ | - pyrroloΓ 3,4-ci-carbazole

After reacting 100 mg (0/32 mmol) of 6,7,12,13-tetrahydro-5-oxo-5H-indolo [2,3-a] pyrrolo [3,4-c] carbazole with 10 mg (0 , 33 mmol) of sodium hydride (80% in mineral oil) and 60 mg (0.35 mmol) of n-propyl iodide analogously to Example 1 crude product is separated by chromatography on silica gel with toluene / ethyl acetate 1: 1. The fraction with Rf 0.3 is isolated, stirred with diisopropyl ether. The formed beige crystals are filtered off.

An approximately 3: 1 mixture of regioisomers of 6.7.12.13-tetrahydro-5-oxo-12-propyl-5H-indolof2.3-aipyrrolof3.4-cicarbazole and 6.7.12.13-tetrahydro-5-oxo-13-propyl is obtained -5H ~ indolor2.3-aiPYrrolo [3.4-c] - * carbazole of the mp ca. 300 * C (dec.), Yield 44%.

In an analogous manner one obtains:

6.7.12.13-Tetrahydro-12- (2-methoxvethvli-5-amino-5Η-1α-α-α-carbonyl) -carboxylate and 6.7.12.13-tetrahydro-13- (2 -methoxy-ethyl ) -δ-oo-oo -δΗ-ίηαοΙο f 2.3-a] pyrrolo f 3.4-c ") - carbazole (2.a) _f mp> 250 * C (dec.) from diisopropyl ether, 5: 1 regioisomer mixture, yield 26%;

with one equivalent of sodium hydride and one equivalent of acetic anhydride after chromatographic separation of the regioisomers:

13-Acetyl-6.7.12.13-tetrahydro-5-oxo-5H-indolor2.3-a] -pyrrolo3.4-c1-carbazole (2.b) . Mp> 315 * C (dec.) From diisopropyl ether, yield 14%;

2 8 3 3 9

6.7.12. lS-tetrahydro - ^ - octadecyl-S-oxo-SH-indolof 2.3-a] -pyrrolor3.4-C | carbazole and 6.7 _f 12. ^ - Tetrahvdro-1S-octadecyl-S-oxo-5H-indolof2.3-a1-pyrrolof3.4-c1> -carbazole (2.c) , mp 170-185 * C from diisopropyl ether / Ethyl acetate, yield 40%, 2: 1 regioisomer mixture.

1 S 3 3 9 4

Example 3

12-Ethl-6,7,12,13-tetrahydro-5-oxo-5H-indolor2.3-aTPvrrolo - [3,4-cicarbazole

The reaction of 200 mg (0 _# 64 mmol) of 6,7,12,13-tetrahydro-5-oxo-5H-indolo [2,3-a] pyrrolo [3,4-c] carbazole with 20 mg (0.66 mmol) of sodium hydride (80% in mineral oil) and 110 mg (0.71 mmol) of ethyl iodide analogously to Example 1 crude product is separated by chromatography on silica gel with toluene / ethyl acetate 1: 1. The fraction of Rf 0.25 is isolated, stirred with toluene / ethanol 9: 1 and the crystals formed are filtered off. The resulting ca. 3: 1 regioisomer mixture of 12-ethyl-6,7,12,13-tetrahydro-5-oxo-5H-indolo [2,3-a] pyrrolo [3,4-c] carbazole and 13 Ethyl-6,7,12,13-tetrahydro-S-oxo-SH-indolo [2,3-a] pyrrolo [3,4-c] carbazole is boiled with acetone and the crystals are filtered off after cooling.

This gives 12-ethyl-6.7.12.13-tetrahydro-5-oxo-5H-indolor 2.3-a "h pvrrolof3.4-c] carbazole in the form of beige crystals of mp> 290 * C (dec.), Yield 27%. ,

Example 4

12- (3-dimethylaminopropyl) -6.7.12 , 13-tetrahydro-5-oxo-5H-indolo [2.3-aiPyrrolof3,4-ci-carbazole and 13- ( 3-dimethylaminopropyl) -6.7.12.13-tetrahydro-5- oxo-5H · indolof2.3-a1pyrrolo [3,4-carbcarbazole

This, after reacting 150 mg (0.48 mmol) of 6,7,12,13-tetrahydro-5-oxo-5H-indolo [2 _/ 3-a] pyrrolo [3,4-c] carbazole with 18 mg (0 , 60 mmol) of sodium hydride (80% in mineral oil) and 73 mg (0.60 mmol) of 3-dimethylaminopropyl chloride analogous to Example 1 crude product is separated by chromatography on silica gel with 'ethyl acetate / acetone 1: 1. The fraction with Rf 0.1 is isolated, stirred with diisopropyl ether. The crystals formed are filtered off.

An approximately 6: 1 regioisomer mixture of 12- (3-dimethylaminopropyl) -6.7.12 is obtained. lS-tetrahydro-S-oxo-SH-indolof2.3-a "| - pyrrolof 3.4-c ~ | ~ carbazole and 13- (3-dimethylaminopropyl-6,7,12,13-tetrahydro-5-oxo-5H-indolor2.3- a] pvrrolor3.4-cicarbazole in the form of beige crystals of mp. 265 * C (dec.), yield 48%.

In an analogous way one obtains:

6.7 f 12.13-Tetrahydro-12- (2-morpholinoethyl) -S-oxo-SH-indolo-Γ2.3-a 1 -pyrrolof3.4-c "~ -carbazole and 6.7.12.13-tetrahydro-13-f- 2- morpholinoethvl) -5-oxo-5H-indolo [2.3-aTpyrrolor3.4-c1-carbazole U.a), mp> 230 * C (dec.) from diisopropyl ether, 3: 1 regioisomer mixture, yield 30%;

6.7.12.13-Tetrahvdro-5-oxo-12- ( 2-pyrrolidinoethyl) -SH-indolo- \ 2. 3-alpyrrolof3.4-c1-carbazole and 6.7.12.13-tetr?, Hydro-5-oxo-13- (2-pyrrolidinoethyl) -5H-indolo-f2.3-a1pyrrolof3,4-c ') -carbazole f4. b) . Mp 239-243 ° C from diisopropyl ether / ethyl acetate, yield 28%;

ie Z 9 3 3 9 4

() -12- (3-diethylamino-2-methoxy-1-propyl) -6.7 _f 12.13 ** tetrahydro-5-oxo-5H-indolof2.3-a! Pyrrolof3,4-C] -carbazole and diethylamino-2 -methoxy-1-propyl) -6.7.12.lS-tetrahydro-S-oxo-SH-indolo-f2.3-aipyrrolof3.4-c ') - carbazole (4.c) _f mp 240-260 ° C (Dec.) From diisopropyl ether / ethyl acetate, yield '54%, 3: 1 regioisomer mixture;

(±) -12- ( 3-Dimethylamino-2-methoxy-1-propyl) -6.7.12.13-tetrahydro-5-oxo-5H-indolof2 , 3-α1-pyrrolo3,4-c1-carbazole and (±) -13- (3-Dimethylamino-2-methoxy-1-propyl) -6.7.12.13-tetrahydro-5-oxo-5H-indolo-2,3-a-pyrrolo3,4-c-carbazole (Ad) . Mp> 190 ° C. (dec.) From diisopropyl ether / ethyl acetate, 7: 3 regioisomer mixture, yield 21%;

() -i2-c3- (N -benzyl-N-methylamino) -2-aethoxy-1-propyli-6,7,12,13-tetrahydro-5-oxo-5H-indolor2.3-aiPvrrolor3.4-cicarbazole and (±) -13-f3-iN-benzyl-N-methyl-amino) -2-methoxy-1-propyl-6,7,12,13-tetrahydro-5-oxo-5H-indolor2 , 3-a1-pyrrolof3,4-c ") -carbazole (4.e ...) mp> 150 * C (dec) from diisopropyl ether / ethyl acetate, 5: 3 mixture of regioisomers, 32% yield;

6.7.12. 1S-Tetrahydro-S-oxo-3- (3-piperidinopropoxy) -SH-indolo f 2.3-a-t-pyrrolof3.4-ci-carbazole and 6.7.12.lS-tetrahydro-S-oxo-13-f3-piperidinopropyl) -5H -indolo-f 2.3-a ") pyrrolor3.4-c") - carbazole (4.f) f mp> 230 * C (dec.) from diisopropyl ether, 7: 4 regioisomer mixture, yield 17%.

Example 5

6.7.3.2.13-Tetrahydro-12-ethyl-5-oxo-5H-indolor 2.3-a] -pyrrolof 3.4-c ") 7carbazole and

6.7.12. lS-Tetrahvdro-1S-methyl-S-oxo-SH-indolor2.3-a "| - pyrrolof 3.4-c") carbazole

29 mg (0.97 mmol) of sodium hydride (80% in mineral oil) are suspended in 20 ml of dry dimethylformamide and 200 mg (0.64 mmol) of 6,7,12, 1S-tetrahydro-6-oxo-SH-indolo [ 2,3-a] pyrrolo [3,4-c] carbazole added portionwise at room temperature. After the gas evolution subsided, 0.09 ml (0.95 mmol) of dimethyl sulfate was added and stirred at room temperature for 72 hours. The solvent is distilled off in vacuo and the residue is treated with 20 ml of potassium carbonate solution. It is extracted twice with 20 ml of ethyl acetate. The ethyl acetate solutions are dried over sodium sulfate and then evaporated in vacuo. The residue is chromatographed on silica gel with dichloromethane / methanol 95: 5. The fraction of Rf 0.4 is isolated, triturated with diisopropyl ether / acetone 9: 1. The crystals formed are filtered off.

An approximately 7: 1 regioisomer mixture of 6.7.12. 13-Tetrahydro-12-methyl-5-oxo-5H-indolo f 2.3-a ) pyrrolo f 3.4-c] -carbazole and 6 _f 7.12.10 -Tetrahvdro-lS-methyl-S-oxo-SH-indolo Γ 2.3-a T pyrrolo Γ 3.4-el - »carbazole in the form of beige crystals of mp> 300 * C (dec.), Yield 38%.

With two equivalents of sodium hydride and dimethyl sulfate is obtained in an analogous manner:

6.7.12.13-tetrahydro-12.13-dimethvl-5-c: fo-5H-indolc. 2.3-ai pvrroloC3.4-c ~ | carbazole (5.a)

Mp 248-251'C from diisopropyl ether, yield 56%

Example 6

6.7.12.13-Tetrahvdro-7-hydroxy-5-oxo-5H-indolor2.3-aipyrrolof3.4-c1carbazole (6.a) and

7-ethoxy-6.7.12.13-tetrahydro-5-oxo-5H-indolor2.3-aipyrrolo - Γ3.4-c! Carbazole (6.b)

To a stirred suspension of 10 g (15 μmol) of zinc stmib and Ig (3.7 mmol) of mercury (IT) chloride in 10 ml of water is added 0.5 ml of conc. Hydrochloric acid added. After about 5 minutes decanting. Then the zinc amalgam is washed first with water and then several times with ethanol. After the addition of 30 ml of dry ethanol, it is cooled with an ice-bath and 330 mg (1.01 mmol) of 6,7,12,13-tetra-hydro-5,7-dioxo-5H-indolo [2,3-a] -pyrrolo [3,4-c] carbazole added. Then, with further cooling for one hour, dry hydrogen chloride gas is slowly introduced. It is filtered, evaporated and the residue chromatographed on silica gel with toluene / ethyl acetate 1: 1. The fraction of Rf 0.3 is isolated and crystallized from ethyl acetate.

Blaßbaige obtained crystals of 7-Ethoxv-6.7.12.13-tetrahydro-5-oxo-5H-indolo Γ 2.3-a] pvrrolo f 3.4-c] carbazole (6.b) mp.> 300 * C, yield 22% , '

The fraction of Rf 0.2 is isolated and stirred with diisopropyl ether. Beige crystals of 6.7.12.13-tetrahydro-7-hydroxy-5-oxo-5H-indolor2.3-aipyrrolof 3.4-C ^- JCa ^ aZoI (6.ai of the mp.> 300 'C, yield 23%.

2 * 339 4

Example 7

6.7.12.13-Tetrahydro-12-methoxycarbonyl-1-yl-Yl-5-oxo-5H-ina-ol-2,3-a-pyrrolo-3,4-c1carbazole and 6,7,12,1-s-tetrahydro-1-methoxycarbonylmethyl-S-oxo-SH-indolo Γ 2.3-a T pyrrolo-f 3.4-c ] carbazole

The after reaction of 150 mg (0.48 mmol) of 6,7,12,13-tetrahydro-5-oxo-5H-indolo [, <i, 3-a] pyrrolo [3,4-c] carbazole with 18 mg The crude product obtained (0.60 mmol of sodium hydride (80% in mineral oil) and 115 mg (0.75 mmol) of methyl bromoacetate analogously to Example 1 is separated by chromatography on silica gel with 95: 5 dichloromethane / methanol The fraction of Rf 0.35 is isolated, stirred with diisopropyl ether and the crystals formed are filtered off.

An approximately 3: 1 mixture of regioisomers of 6.7.12, 13-tetrahydro-12-methoxycarbonylmethyl-5-oxo-5H-indolor2.3-aT pirro-f3.4-c] cirrbazole and 6.7.12.13-tetrahydro- 13-methoxycarbonylmethyl-So ^^ - SH-indolo [2 _f 3-a1pyrrolo-C 3.4-c] carbazole in the form of beige crystals of mp> 300 * C, yield 51%.

Example 8

(±) -6.7.12.13-tetrahydro-i2.13- ( 2-hydroxypropano) -5-oxo-5H-indolof2.3-a] pyrrolo [3,4-c "| carbazol

After reaction of 300 mg (0.96 mmol) of 6,7,12,13-tetrahydro-5-oxo-5H-indolo [2,3-a] pyrrolo [3,4-c] carbazole with 33 mg ( : 1, 1 mmol) of sodium hydride (80% in mineral oil) and 0.1 ml (1.2 mmol) of epibromohydrin in 30 ml of dry dimethylformamide analogous to Example 1 crude product (reaction time 72 h at room temperature) is chromatographed on silica gel with cyclohexane / Tetrahydrofuran 1: 1 separated. The fraction of R _f 0.15 in toluene / ethyl acetate 1: 1 is isolated, stirred with diisopropyl ether / methanol and the crystals formed are filtered off. 6,7,12,13-Tetrahydro-12,13- (2-hydroxypropano) -5-oxo-5H-indolo [2,3-a] pyrrolo [3,4-c] carbazole is obtained in the form of beige crystals that decompose>JOO'C, yield 19%.

Example 9

(±) -12- (3-diethylamino-2-hydroxy-l-propvH-6,7.12.13-tetrahydro-5-oxo-5H-indoloΓ2.3 _{a1pyrrolof3-f} 4-c] carbazole and f ±) -13 - (3- diethvlamino-2-hydroxy-1-propyl-6.7.12.13-tetrahydro-5-oxo-5H-

After reacting 500 mg (1.61 mmol) of 6,7,12,13-tetrahydro-5-oxo-5H-indolo [2,3-a] pyrrolo [3,4-c] carbazole with 58 mg (1 , 92 mmol) of sodium hydride (80% in mineral oil) and 447 mg (2.70 mmol) of ljl-diethyl-S-hydroxyazetidiniumchlorid in 50 ml of dry dimethylformamide analogous to Example 1 (reaction time 48 h at room temperature) obtained crude product is between 200 ml of ethyl acetate and 50 ml of water. The organic phase is separated, dried (sodium sulfate) and evaporated. The residue is chromatographed on silica gel with dichloromethane / methanol 95: 5 separated by chromatography. The fraction of R _f = 0.1 is isolated, stirred with diisopropyl ether / ethyl acetate and the crystals formed are filtered off.

There are obtained (±) -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- (S-diethylamino-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 as a 1: i regioisomer mixture of mp> 195 * C (dec.), Yield 44%.

In an analogous manner one obtains;

f ±) -12- ( 3-piperidino-2-hydroxy-1-propyl) -6.7.12.13-tetrahydro-5 -oxo-5H-indolo [2,3-aipyrrolof3,4-clcarbazole and pi- peridino-2-hydroxy 1-propyl) -6 , 1.Yl. 1S-tetrahydro-S-oxo-SH-indolor2,3-a] pyrrolo [3.4-clcarbazole (9.a) , mp> 205 * C (dec.) from diisopropyl ether, yield 28%.

²² 2 6 3394

Example 10

(±) -6.7.12.13-Tetrahydro-12- (3-N-methylamino-2-methoxy-1-propyl ) -S-oxo-SH-indolo-2,3-a! Pyrrolo-f3,4-c! Carbazole, and ( ±) - 6 f 7 _P J.2, 13-tetrahydro-13- (3 ~ N-methylamino - 2-methoxy-l "propyl) -5-oxo-5H-indolof2.3-a1pyrrolo-r3.4- clcarbazol

100 mg (0.2 mmol) of (±) -12- [3- (N-benzyl-N-methylamino) -2-methoxy-1-propyl] -6,7,12,1-tetrahydro-S-oxo SH-indolo [2,3-a] pyrrolo [3,4-C] Ca ^ aZoI and (±) -13- [3- (N-benzyl-N-methylamino) -2-methoxy-1-propyl] -3- 6,7,12,13-tetrahydro-5-oxo-5H-indolo [2,3-a] pyrrolo [3,4-c] carbazole (example 4.e) in 30 ml of glacial acetic acid _t with 100 mg of palladium on activated carbon (10% Pd / 50% water) for 5 h at 55-60'C hydrogenated. The catalyst is filtered off and the solution is evaporated in vacuo. The residue is partitioned between sodium bicarbonate solution (50 ml) and ethyl acetate (100 ml). The organic phase is separated, dried (sodium sulfate) and evaporated. The residue is stirred with diisopropyl ether / ethyl acetate (4: 1), the crystals are filtered off and dried.

(±) -6,7,12,13-Tetrahydro-12- (3-N-methylamino-2-n-ethoxy-1-propyl) -5-oxo-5H-indolo [2,3-a] pyrrolo [ 3,4-c] carbazole and (±) -6,7,12,1-tetrahydro-IS- (SN-methylamino-methoxy-1-propyl) -5-oxo-5H-indolo [2,3-a] pyrrolo [3,4-c] carbazole in the form of pale beige crystals of mp> 170 ⁰ C (dec.), Yield 62%, as a 3: 1 Regioisomerengemisch.

Claims (1)

2 6 3394 claims 1r Process for the preparation of indolocarbazole derivatives
the general formula I (D, 1 2
in which R and R are the same or different and Hydrogen, a straight-chain or branched alkyl group having 1 to 6 C atoms, a benzyl group, an unsubstituted or substituted aminoalkyl group having up to 12 C atoms, an alkoxycarbonylalkyl group having up to 6 C atoms, a residue -CH ₂ -CO-NR ³ R ⁴ in which R ³ and R ^{4 are} identical or different and for hydrogen, an alkyl group having 1 to
4 C atoms or a benzyl group, or R and / or R is a haloalkyl, hydroxyalkyl or Alkoxyalkylreat each having up to 6 C atoms, a Benzoyloxyalkoxyalkyl-, Acetyloxyalkoxyalkyl- or Hydroxyalkoxyalkylrest each having up to 11 C-atoms, a Acyl group with 1 to 4 C 1 2
Atoms or R and R together form an alkylene group with 2 to 4 carbon atoms, which by hydroxy, C ..- alkoxy
or amino may be substituted, X and Y are either the same and both are each hydrogen, or X and Y are different, wherein one of X or Y is hydrogen and the other of the two radicals is a hydroxy or an alkoxy group with bis to 4 carbon atoms means with the proviso that not all radicals R ¹ , R ² , X and Y are hydrogen at the same time, and their pharmacologically acceptable salts, characterized in that A) In the event that X and Y are hydrogen and R ρ
, and R are the same but are not hydrogen, or 2 6339 e-.ner of the radicals R ¹ or R ^{2 is} hydrogen is an indolocarbazole of the formula II H
.N. 0: (II) with one or two equivalents of a compound of general formula III R ⁵ -X. III in the R ^{5 is} a straight-chain or branched alkyl group having 1 to 6 carbon atoms, an unsubstituted or substituted aminoalkyl group having up to 12 carbon atoms, an alkoxycarbonylalkyl having up to 6 carbon atoms, a haloalkyl or alkoxyalkyl each with up to 6 C atoms, a Benzoyloxyalkoxyalkyl- or Acetyloxyalkoxyalkylrest each having up to 11 carbon atoms or an acyl group having 1 to 4 carbon atoms and X is preferably halogen, in particular iodine, bromine and chlorine, or in the R ⁵ -X for a 1,1-disubstituted 3-hydroxyazetidinium halide, alkylated or acylated in the presence of one or two equivalents of a * r base in a conventional manner at one or both indole nitrogen atoms, or by previously introduced radicals R ⁵ by hydrolysis, ether cleavage, amide formation or Reduction into the radicals R ¹ or R ² transferred, or B) that in the event that X and Y are hydrogen, R ¹ and R ^{2 are} different and neither R ¹ nor R ^{2 is} hydrogen, compounds of general formula I by reacting compounds of general formula I, which are obtained by process A. ) were prepared in which either R ¹ or R ^{2 has} one of the meanings given for R ^ and the other of the two radicals R ¹ or R ^{2 is} hydrogen, with compounds III, at 1 ** 39 5 5 in which Ir has another of the meanings given for Ir, in the presence of bases in an analogous manner as in process A), and optionally one or both of the radicals with the meaning of R, as in process A) 1 ? modified, to one of the radicals R or R is modified or C) that in the event that in the general formula I X or Y is a hydroxy group or a C 1-4 -alkoxy group and the other of the two radicals is hydrogen, an imide of the formula IV reduced, and the compounds I thus obtained according to the variants A, B or O, if desired, are converted with acid into their pharmacologically acceptable salts. 2, Process according to claim 1, characterized in that compounds of general formula I are prepared in which R and / or R is a 2-aminoethyl, a 3-aminopropyl or a 1-amino-2-propyl radical, a 2- Dimethylaminoethyl, a 3-dimethylamino-1-propyl, a 3-dimethylamino-2-propyl, a 2-diethylaminoethyl, a 2- _i -O-benzyl-N-methylamino__7- ethyl, a 3- / ~ N -benzyl-N-methylaraino_7propyl or a 3-dimethylamino-2-hydroxy-i-propyl, a 3-diethylamino-2-hydroxy-1-propyl, a 3-piperidino-2 -hydroxy-1-propyl, a 3-dimethylaminopheno-2-methoxy-1-propyl, a 3-dimethylethyl-2-methoxy-1-propyl, a 3-piperidino-2-methoxy-1-propyl , a 3- (N-benzyl-N-methylamino) -2-methoxy-1-propyl, a 3- (N-benzyl-N-methylamino) -2-h. -hydroxy-1-propyl, a 3- (N -methylamino) -2-methoxy-1-propyl, a 3- (N -methylamino) -2-hydroxy-1-propyl, a 4-dimethylamino-3-methoxy-2-butyl or 2-piperidinoethyl a 3-piperidinoproyl, a 2-pyrrolidinoethyl, a 3-pyrrolidinopropyl, a 2-morpholinoethyl, a 3-morpholinopropyl, a pyrrolidin-2-ylmethyl or an N-methylpyrrolidine-2 ylmethyl, a piperidin-2-ylmethyl, an N-methyl-piperidin-2-ylmethylgruppe or an unsubstituted or on the nitrogen atom by C ₁ ,.-Alkyl siabstituierte piperiazinoalkylgruppe having 1 to 4 C-atoms in the alkyl chain, methyl , Ethyl, n-pro pyl, isopropyl, n-butyl, methoxycarbonylmethyl groups, benzyl groups, 2-methoxyethyl groups, acetyl groups or a butylene group or an unsubstituted or hydroxy-substituted propylene group which 1 2
R and R together form mean. , Use of compounds of general formula 1 according to claim 1, characterized in that they are used for the preparation of medicaments for the treatment of cardiovascular diseases such as thrombosis, arteriosclerosis, hypertension, inflammatory processes, allergies, cancer and certain degenerative damage of the central nervous system.