SK85590A3 - Indolylsubstituted pyrroles, their use as therapeutically effective agent - Google Patents

Abstract

The pyrrole derivatives of the formula <IMAGE> in which R<1> to R<8>, R, X, Y and m have the meaning given in the description, are therapeutically active substances, in particular for use as substances having antiinflammatory, immunological, oncological, bronchopulmonary and cardiovascular activity or as active substances in the treatment of asthma or AIDS. They are prepared from corresponding furandione derivatives in which X and Y stand for =N-R or O.

Description

Field: techniques

The invention relates to indolyl-substituted pyrroles per se and for use as therapeutically active agents, methods and intermediates for their preparation and pharmaceutical compositions based thereon.

BACKGROUND OF THE INVENTION

Protein kinase C (PKC), a class of closely related serine / threonine protein kinases, plays an important role in signal transduction processes (Nishizuka, Y [1984] Nature 308: 693-698). PKC can be activated physiologically by diacylglycerol, which is the primary product of extracellular signal interaction leading to activation of functions and proliferation. Forbol esters such as 12-O-tetadadananlforbol-13-acetate (TPA) can also stimulate PKC activity in vitro and in vivo, and their tumor activity correlates with their ability to activate this enzyme (Castagna et al. [1982] J. Biol Chem. 257: 7847-7851. Although little information is known about the physiological substrates of this enzyme, PKC activation has been associated with processes in T cells leading to the expression and proliferation of the IL-2 receptor (Kumagai et al. [1987] J. Immunol. 139: 1393-). 1399). For these reasons, inappropriate PKC activation may be the cause of various disease states, and its inhibitors may be useful in a variety of therapeutic areas, such as the treatment of inflammatory and cancer diseases.

Only a relatively small number of inhibitors of this enzyme are known. These inhibitors include the natural products staurosporine (Tamaoki et al. [1986] Biochem. Biophys. Res. Commun. 135: 397-402) and K252a, as well as derivatives thereof (JP 93001795). Other disclosed inhibitors are forboid compounds (WO 8707599) and 2-acyloxypropilamin derivatives (EP 255 126). Staurosporine is competitive with respect to ATP and because of binding. the ATP domain is well conserved for serine / threonine and tyrosine specific kinases, which may be the cause of its activity against various kinases. The potent cytotoxic activity of this compound may be due to a lack of selectivity thereof (Tamaoki et al [1986] Biochem. Biophys. Res. Commun. 135: 397-402). Despite its non-selectivity, staurosporine has become a starting point for the development of novel and selective PKC inhibitors, namely bis (indolyl) maleimides (EP 328026). The invention builds on these earlier compounds and results in PKC inhibitors with improved efficacy and retained selectivity with respect to closely related serine / threonine and tyrosine specific kinases.

SUMMARY OF THE INVENTION

The present invention provides indolyl-substituted pyrroles of formula (I)

(I) where

R is hydrogen or hydroxy;

R ¹ and R ² together represent - (CH ₂ ) _n - a

R ⁷ represents a hydrogen atom, or

R ¹ and R ⁷ together represent - (CH ₂ ) _n -a

R ² is H;

R ³ is aryl or heteroaryl;

R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl or alkylsulfonyl;

R ⁸ is - (CH ₂ ) p R ⁹ or - (CH ₂ ) q R ¹⁰ ;

R ⁹ represents a hydrogen atom, an alkylcarbonyl group, an aminoalkylcarbonyl group, a cyano group, an amidino group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylsulfonyl group, an aminocarbonyl group or an aminothiocarbonyl group;

³ · R ⁰ is hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, tri, azido, acylamino, alkylsulfonylamino, aryl sulfonylamino group, an alkylthio, alkoxycarbonylamino, aminoacylaminoskupinu, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulfonyloxy or arylsulfonyloxy, a 5- or 6- a membered saturated nitrogen-containing heterocyclic group which is bonded via a nitrogen atom or represents a group of the formula -UC (V) -W;

U is sulfur or NH;

V is NH, NNO ₂ , NCN or CHNO ₂ ;

W is amino, monoalkylamino or dialkylamino;

one of X and Y is O and the other is O or two hydrogen atoms;

Z is CH or N;

m, p and q are each a number from 0 to 5 and n is a number from 1 to 5, wherein the radicals generally characterized independently or in compounds in the above and the definitions given below have the following meanings:

aryl is phenyl or naphthyl which is optionally substituted with 1 to 3 substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkyl 4 thio, alkylsulfinyl and alkylsulfonyl;

heteroaryl is a 5- or 6-membered heterocyclic aromatic group which optionally contains a fused benzene ring and which is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitroalkyl, amino, alkylsulfonyl, acylamino, acylamino;

alkyl represents a straight or branched alkyl group of up to 7 carbon atoms; and acyl represents a radical derived from an alkanecarboxylic acid having up to 7 carbon atoms or an aromatic carboxylic acid;

provided that when Z is a nitrogen atom, then m and q are each 2 to 5;

as well as pharmaceutically usable salts of the acidic compounds of the formula I with bases and the basic compounds of the formula I with acids.

The invention relates to the above-defined compounds as such, as well as therapeutically active substances, to a process for their preparation as well as to novel intermediates; the invention further relates to pharmaceutical compositions comprising these compounds. The indolyl-substituted pyrrols according to the invention for the treatment or prevention of diseases, in particular inflammatory, immunological, oncological, bronchopulmonary and cardiovascular diseases, as well as for the treatment of asthma or AIDS.

Within the scope of the present invention, an alkyl or alkyl group, alone or in combination, denotes a straight or branched alkyl group having up to 7 carbon atoms, preferably up to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl , butyl, sec-butyl, tert-butyl, and pentyl. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy. The haloalkyl group may contain one or more halogen atoms. Examples of such a group include chloromethyl and trifluoromethyl.

Acyl denotes a group derived from an alkanecarboxylic acid having up to 7 carbon atoms, preferably up to 4 carbon atoms, such as a formyl, acetyl, propionyl or butyryl group, or an aromatic carboxylic acid, for example benzoic acid.

Aryl alone or in combination refers to a monocyclic or polycyclic, preferably a monocyclic or bicyclic group, i. phenyl or naphthyl which may be substituted by one or more, preferably 1 to 3, substituents selected from the group consisting of halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl or alkylsulfinyl. Examples of aryl groups include phenyl, 2-, 3- or 4-chlorophenyl, 3-bromophenyl, 2- or 3-methylphenyl, 2,5-dimethylphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3-methylphenyl, 3-bromophenyl, 3-bromophenyl, 2-trifluoromethylphenyl, -trifluoromethylphenyl, 2-, 3- or 4-nitrophenyl, 3-aminophenyl, 4-aminophenyl, 4-methylthiophenyl, 4-methylsulfinylphenyl, 4-methylsulfonylphenyl and 1- or 2-naphthyl.

Heteroaryl refers to 5- or 6-membered heterocyclic aromatic groups which optionally contain a fused benzene ring and which may be optionally substituted by one or more, preferably 1 to 3, substituents selected from the group consisting of halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl. Examples of such heteroaryl groups include 2- or 3-thienyl, 3-benzothienyl, 3-benzofuranyl, 2-pyrrolyl and 3-indolyl, which may be further substituted as described above. A 5-membered or 6-membered saturated nitrogen-containing heterocyclic group which is bonded via a nitrogen atom may contain an additional nitrogen atom, an oxygen atom or a sulfur atom. Examples of such heterocycles include pyrrolidino, piperidino, piperazino, morpholino and thiomorpholino.

Halogen refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The compounds of formula I, wherein Z is CH and R ⁸ is - (CH 2) p R ⁹ wherein p is between 1 to 5, or is - (CH9) -R ^10, contain an asymmetric carbon atom, and may be present in racemic or optically active form. The invention includes both racemic compounds and optically active isomers.

In preferred compounds of formula I, the symbols R ¹ and R ² together are -CH 2 and R ⁷ is H, m is 1 or 2 and Z is CH; or R ¹ and R ² together are - (CH 2) ₂ - and R ⁷ is H, m is 1 and Z is CH; or R ¹ and R ² together represent CH 2 and R ⁷ is H, m is 2 and Z is CH; or R ¹ and R ⁷ together represent -CH 2 - and R ² represents a hydrogen atom, m represents 1 and Z represents CH; or R ¹ and R ⁷ together represent - (CH ₂ ) ₂ - and R ² represents a hydrogen atom, m represents 0 and Z represents CH; R ³ is preferably phenyl, naphthyl, 3benzotienylovú, 3-benzofuranyl or 3-indolyl, which may optionally be further sub The substituted, in particular, l-methyl-3-indolyl. R @ ⁴ , R @ ⁵ and R @ ⁶ are preferably hydrogen. R 0 is preferably - (CH ₂ ) g R ¹⁰ . q is preferably 1 or 2. R ¹⁰ is preferably hydroxy, amino, mono-, di-, or trialkylamino, azido, acylamino, alkylcarbonyloxy or alkylsulfonyloxy or -UC (V) -W. U is preferably a sulfur atom; V is preferably NH and W is preferably amino.

Particularly preferred are compounds:

3- [8- (Aminomethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5- Dion,

3- [7- (amidinothiomethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2, 5-dione a

3- [6,7,8,9-tetrahydro-8 - [(dimethylamino) methyl] pyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H- pyrrole-2,5-dione, as well as pharmaceutically acceptable acid addition salts thereof.

The compounds of formula I as defined above and their salts can be prepared by the process of the invention

a) reacting a compound of formula II to produce a compound of formula I in which X and Y are oxygen atoms

(II)

in which

R ^1, R ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ R ^8, Z and m are as defined above, with ammonia under pressure or with hexamethyldisilazane and methanol to give a compound of formula I wherein R is a hydrogen atom or a hydroxylamine to form a compound of formula I wherein R is hydroxy, or

(b) to produce a compound of formula I in which one of X and Y is oxygen and the other in two hydrogen atoms, reduces the compound of formula I in which X and Y are oxygen by treatment with lithium aluminum hydride, and

c) optionally reacting the reactive group contained in the compound of formula I obtained; and

d) optionally converting the acidic compound of formula I into a pharmaceutically acceptable salt by treatment with a base, or converting the basic compound of formula I into a pharmaceutically useful salt by treatment with an acid.

The reaction of the compound of formula II with ammonia under pressure according to variant a) of the process according to the invention can conveniently be carried out by treatment with aqueous ammonia, preferably 33% aqueous ammonia and in the presence of an inert water-miscible organic solvent such as dimethylformamide. The reaction is preferably carried out at an elevated temperature, for example at a temperature between about 100 to 150 ° C.

The reaction of the compound of formula II with hexamethyldisilazane and methanol may conveniently be carried out in an inert organic solvent such as a halogenated hydrocarbon such as chloroform, carbon tetrachloride or chlorobenzene or an aromatic hydrocarbon such as benzene, toluene or xylene at elevated temperature, e.g. to 110 ° C.

The reaction of the compound of formula II with hydroxylamine can conveniently be carried out in an inert organic solvent such as dimethylformamide and at room temperature or elevated temperature, preferably at about 100 ° C. The hydroxylamine is preferably used in the form of a salt, such as the hydrochloride, and the reaction is carried out in the presence of a base such as an alkali metal carbonate such as sodium carbonate or potassium carbonate.

The reaction of a compound of formula I in which X and Y are oxygen atoms with lithium aluminum hydride (LiAlH ₄ ) according to variant b) of the process according to the invention can conveniently be carried out in an inert organic solvent such as an aliphatic or cyclic ether (e.g. dimethyl ether) or tetrahydrofuran , at a temperature between about 0 ° C and the reflux temperature of the reaction mixture.

According to variant c) of the process according to the invention, the reactive group contained in the compound of the formula I can be varied in a manner known per se. When R ⁸ is - (CH ₉ ) -R ⁹ in which

Q P

R ⁹ is an alkoxycarbonyl group and p is zero, then it can be converted by treatment with an acid to the corresponding group in which R is a hydrogen atom. The group - (CH 2) q R ¹⁰ in which R ¹⁰ is alkylcarbonyl can be converted to the corresponding group in which R ¹⁰ is hydroxy by treatment with a base. The group - (CH 2) -R ¹⁰ , where R is hydroxy, can be converted to the corresponding group in which R ¹⁰ is amino,

- a monoalkylamino group, a dialkylamino group or a trialkylamino group or a 5- or 6-membered saturated nitrogen-containing heterocyclic group which is bonded via a nitrogen atom first by treatment with trifluoromethanesulphonic anhydride and then by treatment with ammonia, monoalkylamine, dialkylamine or trialkylamine, heterocyclic compounds. A group - _(CH2) gR ^10, wherein R ¹⁰ is hydroxy may be further converted, by reaction of the corresponding alkanesulfonic group in which R ¹⁰ represents an alkylsulfonyloxy group. A group - _(CH2) gR ^10, wherein R ¹⁰ represents an alkylsulfonyloxy group, may be converted by reaction with ammonia

Ί Λ in dimethylformamide to the corresponding group, wherein R is formamido, or it can be treatment with an alkali metal azide into a corresponding group in which R ¹⁰ represents azido, or may be by treatment with thiourea into a corresponding group in which R ¹⁰ is a group -UC (V) -W, wherein U is sulfur, V is NH, and W is amino. Further, the group - (CH 2) q R ¹⁰ wherein R ¹⁰ represents azido, converted by catalytic hydrogenation into a corresponding group in which R ¹⁰ is amino. The group - (CH 2) _and -R ¹⁰ , 10 in which R is alkoxycarbonylamino can be converted to the corresponding group in which R ¹⁰ is amino by treatment with an acid. The group - (CH ₂ ) q R ¹⁰ in which R ¹⁰ is an amino group can be converted to the corresponding group in which R is acylamino by acylation or by treatment with 3,5-dimethyl-N ² -nitro-1-pyrazole-1 -carboxamide to the corresponding group wherein R ¹⁰ is -UC (V) -W, U and V are NH and W is NO ₂ . Furthermore, the - (CH ₂ ) n -R ¹⁰ in which R ¹⁰ is amino can be converted to the corresponding group in which R is isothiocyanato by treatment with 1,1-thiocarbonyldiimidazole. The - (CH ₂ ) g R group in which R is cyano can be converted by treatment with hydrogen chloride and then with ammonia to the corresponding group in which R ⁹ is an amidino group.

A compound of formula I, wherein Z is N, R ⁸ is - (CH _{2) p} R ^9, p is 0 and R ⁹ is hydrogen, can be converted to the corresponding compound wherein R ⁹ is an alkanoyl group, alkoxycarbonyl or aralkoxycarbonyl, by suitable acylation; to the corresponding compound wherein R ⁹ is an alkylsulfonyl group by reaction with an alkanesulfonyl chloride; to the corresponding compound wherein R ⁹ is aminoalkylcarbonyl by reaction with trifluoroacetamidoalkanoyl chloride and then with ammonia; to the corresponding compound, a compound in which R is an aminocarbonyl group, by reaction with 1,1-carbonyldiimidazole and then ammonia; or to the corresponding compound wherein R ⁹ is aminothiocarbonyl by reaction with 1,1-thiocarbonyldiimidazole and then ammonia.

Conversion of an acidic compound of formula I into a pharmaceutically acceptable salt according to variant e) of the process according to the invention can be carried out by treatment with a suitable base in a known manner. Suitable salts are those derived from an organic base such as sodium salts, potassium salts or calcium salts, or salts derived from an organic base such as ethylenediamine or monoethanolamine or diethanolamine. Conversion of a basic compound of formula I into a pharmaceutically acceptable salt can be accomplished by treatment with a suitable acid in a known manner. Suitable salts are those derived from an inorganic acid such as hydrochlorides, hydrobromides, phosphates or sulfates, or from an organic acid such as acetates, citrates, fumarates, tartrates, maleates, methanesulfonates or p-toluenesulfonates.

The starting compounds of formula (II) to be used in process variant (a) according to the invention are novel and, as such, are also an object of the present invention. These compounds can be produced by reacting a compound of formula III

in which

R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ R ⁸ , Z and m are as defined above, with a compound of formula IV

HOOC - CH ₂ - R ³ '(IV) and optionally a functional modification of the reactive group.

The reaction of a compound of formula III with a compound of formula IV is preferably carried out in the presence of an acid binding agent, for example a tertiary amine such as a trialkylamine such as triethylamine or diisopropylethylamine, in an inert organic solvent such as halogenated aliphatic hydrocarbon such as dichloromethane at room temperature.

The optional functional variation of the reactive group in the compound of Formula II can be performed in the same manner as the functional variation of such a group in the compound of Formula I.

Compounds of formula III can be prepared by reacting a compound of formula V

in which

R ^{@ 1} , R ^{@ 2} , R ^{@ 4} , R @ ⁵ , R @ ⁶ , R @ ^7, R @ ⁸ and Z are as defined above, with oxalyl chloride, suitably in an inert organic solvent, such as a halogenated aliphatic hydrocarbon. refluxing the solvent. The resulting compound of formula III may be reacted in situ with a compound of formula IV, or it may be isolated and purified prior to reaction with a compound of formula IV, for example by concentration and subsequent crystallization.

The compounds of formula (V) are known or analogues of known compounds and can be prepared in a similar manner to known compounds.

The compounds of formula I and their pharmaceutically acceptable salts are protein kinase inhibitors; they inhibit cellular processes, for example cell proliferation, and can be used in the treatment or prophylaxis of diseases such as inflammatory diseases such as arthritis, immunological disorders or organ transplantation, as well as oncology. These compounds inhibit HIV infection of cells and are therefore useful in the treatment of AIDS. These compounds also inhibit smooth muscle contraction and can therefore be used against cardiovascular and bronchopulmonary diseases. Furthermore, the compounds are used in the treatment of asthma.

The efficacy of the present compounds in inhibiting protein kinase C can be demonstrated, for example assays as described in BBRC 19 (1979) 1218. The _IC50 values presented in the table below are the concentration of compound that reduced by 50% incorporation of ³² P from ^[gamma-32 P1 ATP to histone induced by protein kinase.

table

Pr.

no.

Compound. IC _5o (nM)

2 3- [8- (Aminomethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5- dione 8 10 3- [7- (amidinothiomethyl) 6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione methanesulfonate 15 31 3- [2- (aminoacetyl) -6,7,8,9tetrahydropyrazinof1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione hydrochloride 50 70 3- [7- (2-aminoethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2 hydrochloride, 5-dione 20 55 3- [6,7,8,9-tetrahydro-8 - [(1-piperidino) methyl] pyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -lH- pyrrole-2,5-dione 30 61 trifluoromethanesulfonate 3- [2,3-dihydro- 2- (dimethylaminomethyl) -1H-pyrrolo [1,2-a] indol-9-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione 20 63 3- [8-amidino-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione hydrochloride 60

11 3- [7- (amidinothiomethyl) 6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione methanesulfonate 10 4 3- [6,7,8,9-tetrahydro-8-] hydrochloride (diethylaminomethyl) pyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione 10 5 3- [6,7,8,9-tetrahydro-8- (dimethylaminoroethyl) pyrido [1,2-a] indol-10-yl] 4- (1-methyl-3-indolyl) -1H-pyrrole-2 hydrochloride , 5-dione 40 7 3- [8-formamidomethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione 75 12 3- [6,7,8,9-tetrahydropyrido [1,2-a] indole- 10-yl] -4- (l-raetyl-3-indolyl) -lH-pyrrole-2,5- T dion 160 17 3- [8- (2-Aminoethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3indolyl) -1H-pyrrole-2, 5-dione 50 28 3- [2-aminomethyl-2,3-dihydro-lH-pyrrolo [1,2-a] indol-9-yl] -4- (1-methyl-3-indolyl) 1H-pyrrole-2,5-dione 8 42 3- [8-Aminomethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl] -1-hydroxy-4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione hydrochloride 110

19

45 3- [8-Aminomethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl] -4- (3-benzo [b] thienyl) -1H-pyrrole-2,5-dione hydrochloride 21 56 3- [6,7,8,9-tetrahydro-8 (diisopropylaminomethyl) pyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5 hydrochloride dione 300 59 3- [8-Aminomethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl] -4- (3-benzofuranyl) -1H-pyrrole-2,5-dione hydrochloride 36 60 3- (3-benzo [b] thienyl) -4- [6,7,8,9-tetrahydro-8-dimetylaminometylpyrido [1,2-a] indol-10-yl] -lH-pyrrole-2,5- dion 98 66 3- [8-Aminomethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl] -4- (5-methoxy-1-methyl-3-indolyl) -1H-pyrrole 2,5- dione 115 72 3- [8-Aminomethyl-6,7,8,9-tetrahydro-2-methoxy-pyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione hydrochloride 210

Efficacy in inhibiting protein kinase C shows a correlation with the ability to treat the above diseases. By inhibiting protein kinase C, efficacy in cellular and tissue assays can be predicted (P. Fitzharris et al., Clin. Exp. Immunol. 46, 185-195 [1981]; HD Soule et al., J. Nat. Cancer Inst. 51, 1409 [1973]; SJ Collins et al., Nature 270, 347 [1977]; C. Sundstrom et al., Int. J. Cancer

19b

17, 565 [1976]; D. Kinchington et al., AIDS 3, 101 [1989];

B. Twomey et al., Biochem. Biophys. Res. Commun. 171, 1087 [1990] and J. C. Gay et al., Inflammation 8, 209 [1984]). Based on the latter assays, therapeutical efficacy in vivo against the respective diseases can then be predicted by analogy with known standard drugs (J. Woo et al., Scand. J. Immunol. 31, 297 [1990]; T. Meyer et al. , Int. J. Cancer 43, 851 [1989] and JA Martin et al., J. Med. Chem. 33, 2137 [1990]).

By way of illustration, the results obtained in the above tests with the compound of Example 2 are given.

Example compound 2

A) Reaction with a mixture of lymphocytes (P. Fitzharris et al., Clin. Exp. Immunol.

46, 185-195 (1981)

Immune disorders, arthritis, organ transplantation;

The standard immunosuppressive drug that is effective in this assay is cyclosporin A (J. Woo et al., Scand. J. Immunol. 31, 297 [1990])

B) Inhibition of cancer cell line growth - oncology of ³ H thymidine incorporation

1. MCF-7 cells [human breast adinocarcinoma (H. D. Soule et al., J. Nat. Cancer Inst. 51 1409 (1973)]

IC ₅₀ 0.53 μΜ

IC ₅₀ 2 μΜ

- 19c -

2. HL 60 cells [human peripheral blood promvelocytic leukemia cells (S.J. Collins et al., Nature 270, 347 (1977)]

3. U937 cells [human histocytic lymphoma (C. Sundstrom et al., Int. J. Cancer 17, 565 (1976))

The standard anti-cancer drug that is effective in this assay is adriamycin. Also, a selective protein kinase C inhibitor exhibits antitumor activity in vivo (T. Meyer et al., Int. J. Cancer 43, 851 [1989])

C) Infectivity of HIV-AIDS (D. Kinchington et al., AIDS 3, 101 [1989]

The standard drug for the treatment of AIDS is AZT, which is effective in this assay (J.A. Martin et al., J. Med. Chem. 33, 2137 [1990])

D) Inhibition of oxidative bursting of neutrophils (B. Twomey et al., Biochem. Biophys. Res. Commun. 171, 1087 [1990]) Inflammation and asthma FMLP and zymosam response is inhibited by indomethacin, a standard anti-inflammatory drug (JC Gay et al., Inflammation 8, 209 [1984]).

IC ₅₀ 5 μΜ

IC ₅₀ 4 μΜ

IC ₅₀ 10 μΜ

IC _5Q versus FLMP 0.6 μΜ zymosam 2.84 μΜ

The above results indicate the validity, assuming the efficacy of the compounds of the invention in vivo.

The pyrroles of the formula I and their salts can be used as medicaments, for example in the form of pharmaceutical preparations which can be administered orally, for example in the form of tablets, dragees, hard or soft gelatine capsules, solutions, emulsions or suspensions. They can also be administered rectally, for example in the form of suppositories, or parenterally in the form of injectable solutions.

For the manufacture of pharmaceutical compositions, these compounds may be formulated with therapeutically inert inorganic and organic carriers. Examples of such carriers for tablets, dragees and hard gelatine capsules include lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof. Suitable carriers for soft gelatin capsules are vegetable oils, waxes, fats, and semi-solid or liquid polyols. Depending on the nature of the active substance, however, it is also possible to dispense with the addition of carriers in the case of soft gelatine capsules. Suitable carriers for making solutions and syrups are water, polyols, sucrose, invert sugar and glucose. Suitable carriers for injectable solutions are water, alcohols, polyols, glycerol and vegetable oils. Suitable carriers for suppositories are vegetable or hardened oils, waxes, fats and semi-liquid polyols.

The pharmaceutical preparations may also contain preservatives, solvents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavor enhancers, salts for varying the osmotic pressure, buffers, coating agents and antioxidants, and optionally other therapeutically active agents.

As mentioned above, the pyrroles of the formula I and their salts can be used in the treatment or prevention of diseases, in particular inflammatory, immunological, bronchopulmonary and cardiovascular diseases, or in the treatment of asthma or AIDS. The dosage may vary within wide limits, but generally ranges from about 5 to 500 mg / day for oral administration to adults, although the value may be increased if necessary. The daily dose can be administered in a single dose or in multiple doses.

The following examples illustrate the invention in more detail, but do not limit the scope thereof in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

A solution of 2.90 g of 3- [8- (acetoxymethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan-

The 2,5-dione in 30 ml of dimethylformamide and 23 ml of 33% aqueous ammonia was heated at 140 ° C for 7 hours. The mixture was then extracted with ethyl acetate, the combined organic extracts were washed with water, dried and evaporated. Crystallization of the residue from ethyl acetate gave 1.87 g of 3- [6,7,8,9-tetrahydro-8- (hydroxymethyl) pyrido [1,2-a] indol-10-yl] -4- (1-methyl- 3-indolyl-1H-pyrrole-2,5-dione, m.p. 262-263 ° C.

(a) A solution of 25 g of ethyl indole-2-carboxylate in 400 ml of dimethylformamide is added dropwise with stirring to a solution of 5.5 g of a 60% dispersion of sodium hydride in mineral oil in 40 ml of dimethylformamide under a nitrogen atmosphere. Then 30.9 g of ethyl bromobutyrate are added dropwise at 0 ° C and the resulting mixture is stirred at room temperature for 18 hours. The reaction was quenched by the addition of 100 mL of water and 30 mL of 2N hydrochloric acid solution and extracted with dichloromethane. The combined organic extracts were washed with water, dried and evaporated. 49 g of an oil are obtained, which is dissolved in ethyl acetate. The solution obtained is washed with water, dried and evaporated. 39 g of an oil are obtained. This oil was added dropwise to a suspension of 20.5 g of potassium tert-butoxide in 750 ml of tetrahydrofuran under a nitrogen atmosphere with stirring. After 1 hour, 200 mL of water was added followed by 92 mL of 2N hydrochloric acid. The mixture was concentrated and the resulting precipitate was filtered off and dried. 25.3 g of ethyl 6,7-dihydro-9-hydroxypyrido [1,2-a] indole-8-carboxylate are obtained, m.p. 101 DEG-103 DEG C. (crystallized from methanol).

(b) A suspension of 19.4 g of the carboxylate of (a) and 16 portions of a spoonful of Raney-nickel in 480 mL of ethanol and 240 mL of water was heated at reflux for 3.5 hours. Next, 4 additional portions of Raney-nickel are added at the tip of a spoon and the mixture is heated under reflux for 1.5 hours. The upper layer was separated by decantation and the catalyst was washed with ethyl acetate. The combined organic phases are concentrated and the precipitate is filtered off and dried. 16.3 g of ethyl 6,7,8,9-tetrahydropyrido [1,2-a] indole-8-carboxylate, m.p. 70 DEG-72 DEG C. (after crystallization from methanol), is obtained.

(c) 16.2 g of the carboxylate of (b) in 200 ml of tetrahydrofuran at 0 ° C are added under a nitrogen atmosphere to a suspension of 2.00 g of lithium aluminum hydride in 600 ml of tetrahydrofuran. After 0.5 h, the reaction was quenched by addition of ethyl acetate, water and 2N hydrochloric acid solution and extracted with diethyl ether. The combined organic extracts were dried and concentrated. Crystallization of the residue from a mixture of diethyl ether and n-hexane gave 11.5 g of 6,7,8,9-tetrahydro-8- (hydroxymethyl) pyrido [1,2-a] indole, m.p. 110-111 ° C.

d) 11.4 g of acetic anhydride was added to a solution of 11.0 g of the product of c) in 100 ml of pyridine, and the resulting solution was stirred under a nitrogen atmosphere for 18 hours. The maximum portion of the pyridine was evaporated and the residue acidified with 2N hydrochloric acid solution. The mixture was extracted with diethyl ether and the combined extracts were washed with sodium bicarbonate solution and water. The extracts are dried and concentrated. 11.25 g of 8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indole is obtained, m.p. 63-64 ° C.

e) 4.13 g of oxalyl chloride are added dropwise to a solution of 8.2 g of tetrahydropyridoindole from d) in 160 ml of diethyl ether with stirring under a nitrogen atmosphere. After 10 minutes, the solvent was removed under reduced pressure and the residue was dissolved in 330 mL of dichloromethane. Then, 6.34 g of 1-methyl-3-indoleacetic acid and 9.20 ml of triethylamine are added to the solution, and the mixture is stirred overnight. An additional 4.60 ml of triethylamine is then added. After 48 hours, the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using ethyl acetate / petroleum ether (1: 2) as eluent. Crystallization from ethyl acetate gave 4.02 g of 3- [8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -furan-2,5-dione, m.p. 174-178 ° C.

Example 2

To 2.50 g of trifluoromethanesulfonic anhydride in 330 ml of dichloromethane was added at 0 ° C under a nitrogen atmosphere a suspension of 1.87 g of the pyroldione of Example 1 and 0.94 g of collidine in 280 ml of dichloromethane. After 2.5 hours the mixture was allowed to warm to 10 ° C. Then 37 ml of 3% aqueous ammonia are added and the mixture is allowed to warm to room temperature. The mixture was washed with water, dried and evaporated. The residue was chromatographed on silica gel eluting with dichloromethane: methanol: acetic acid: water (90: 18: 3: 2). The fractions containing the desired product were combined, washed with 2M hydrochloric acid solution and evaporated. 930 mg of 3- [8-aminomethyl--6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrol-2 is obtained. 5-dione hydrochloride, m.p. 310-313 ° C.

Example 3

To 265 mg of trifluoromethanesulfonic anhydride in 40 ml of dichloromethane at 0 ° C was added under a nitrogen atmosphere a suspension of 200 mg of the product of Example 1 and 100 mg of collidine in 30 ml of dichloromethane. After 5 hours, 0.5 ml of a 33% solution of trimethylamine in ethanol is added and the mixture is stirred for 18 hours. The resulting precipitate was filtered off and dried. 237 mg of 3- [8-aminomethyl-6,7,8,9-tetrahydro-8- (tri- 25-methylammoniummethyl) pyrido [1,2-a] indol-10-yl] -4- (1-methyl) was obtained. -3-indolyl) -1H-pyrrole-2,5-dione trifluoromethanesulfonate, m.p. 320 DEG-324 DEG.

Example 4

To 265 mg of trifluoromethanesulfonic anhydride in 40 ml of dichloromethane at 0 ° C was added under a nitrogen atmosphere a suspension of 200 mg of pyroldione of Example 1 and 100 mg of collidine in 30 ml of dichloromethane. After 5 hours, 0.75 ml of a 33% solution of methylamine in methanol is added and the mixture is stirred for 18 hours. An additional 0.5 ml of the above methylamine solution is then added. After 4 hours, the solvent was evaporated and the precipitate was filtered off and purified by chromatography on silica gel using dichloromethane: methanol: acetic acid: water (90: 18: 3: 2). The product was then stirred for 2 hours with ethyl acetate saturated with hydrogen chloride. The solid obtained is filtered off and dried. 55 mg of 3- [8-aminomethyl-6,7,8,9-tetrahydro-8- (methylaminomethyl) pyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-) is obtained. indolyl) -1H-pyrrole-2,5-dione hydrochloride, m.p. 337-340 ° C.

Example 5

To 185 mg of trifluoromethanesulfonic anhydride in 30 ml of dichloromethane at 0 [deg.] C. was added under a nitrogen atmosphere a suspension of 140 mg of the pyroldione derivative obtained from Example 1 and 70 mg of collidine in 25 ml of dichloromethane. After 1.5 hours, 0.8 ml of a 33% solution of dimethylamine in ethanol is added and the mixture is stirred for 2.5 hours. The solvent was removed under reduced pressure and methanol was added to the residue. A solid is obtained which is then stirred with ethyl acetate saturated with hydrogen chloride. The solid was filtered off and dried. 70 mg of 3- [6,7,8,9-tetrahydro-8- (dimethylaminominethyl) pyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) are obtained. 1 H-pyrrole-2,5-dione hydrochloride, m.p. 335 DEG-336 DEG.

Example 6

To a solution of 170 mg of the pyroldione derivative of Example 1 in 55 mL of dichloromethane was added 87 mg of methanesulfonic anhydride in 1 mL of pyridine. The resulting solution was stirred under nitrogen for 1 hour. An additional 30 mg of methanesulfonic anhydride was then added. After 1 hour the mixture was washed with water, dried and evaporated. Crystallization of the residue from ethyl acetate-n-hexane gave 150 mg of 3- [6,7,8,9-tetrahydro-8 (methylsulfonyloxymethyl) pyrido [1,2-a] indol-10-yl] -4- ( 1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, m.p. 259-261 ° C.

Example 7

A solution of 120 mg of the pyroldione derivative of Example 6 in ml of dimethylformamide and 6 ml of 33% aqueous ammonia was heated at 140 ° C for 6 hours. The cooled mixture was poured into water and the precipitate was filtered off. The product was purified by silica gel chromatography eluting with dichloromethane: acetic acid: methanol: water (60: 18: 2: 3). Mixing with ethyl acetate gave 50 mg of 3- [8-formamidomethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole -2,5-dione, m.p. 332 DEG-334 DEG.

Example 8

A solution of 100 mg of the pyroldione derivative of Example 6 and mg of thiourea in 5 ml of DMF was heated at 80 ° C for 18 hours under a nitrogen atmosphere. The solvent is evaporated and the residue is purified by chromatography on silica gel, eluting with dichloromethane: methanol: acetic acid: water (90: 18: 3: 2). The residue was mixed with ethyl acetate. 80 mg of 3- [8-amidinothiomethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole is obtained. 2,5-dione Methanesulfonate, m.p. 200-205 ° C.

Example 9

In an analogous manner to that described in the example

1, paragraph 1, from 3- [7- (acetoxymethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) of furan-2,5-dione: 3- [6,7,8,9-tetrahydro-7-hydroxymethylpyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H- pyrrole-2,5-dione, m.p. 239-242 ° C.

The furandione, which is used as a starting material, is prepared as follows:

a) 6.6 ml of a 1.6 M solution of butyllithium in n-hexane is added with stirring to a solution of 1.11 g of diisopropylamine in 150 ml of tetrahydrofuran under nitrogen at -78 ° C. The mixture was then allowed to warm to -20 ° C over 5 minutes and then recooled to -78 ° C. Subsequently, 1.85 g of z is added dropwise to the mixture

6,7,8,9-tetrahydropyrido [1,2- a] indol-6-one in 10 ml of tetrahydrofuran. After stirring at -78 ° C for 30 minutes, 1.19 g of ethyl chloroformate is added and the mixture is allowed to warm to room temperature. The solvent was evaporated and the residue was partitioned between diethyl ether and 2M hydrochloric acid solution. The ethereal extracts were washed with saturated sodium bicarbonate solution, dried and evaporated. An oil is obtained which is purified by chromatography on silica gel using dichloromethane as eluent. Crystallization of the product from methanol gave 1.35 g of ethyl 6,7,8,9-tetrahydro-6-oxopyrido [1,2-a] indole-7-carboxylate, m.p. 82-84 ° C.

(b) 30 ml of a borane in tetrahydrofuran solution are added with stirring to a solution of 1.25 g of the carboxylate of (a) and the resulting solution is then heated under reflux for 2 hours under a nitrogen atmosphere. Then, 6 scoops per tip of silica gel are added to the cooled solution and the solvent is evaporated. The evaporation residue is chromatographed on silica gel with ethyl acetate / n-hexane (1: 1). An oil is obtained which is dissolved in 60 ml of dichloromethane containing 1 ml of pyridine and 2 ml of acetic anhydride. After 18 hours, the solution was washed with 16 ml of 2M hydrochloric acid solution and 20 ml of saturated sodium bicarbonate solution, dried and evaporated. To the solution of the oil thus obtained in 60 ml of diethyl ether was added 630 mg of oxalyl chloride under a nitrogen atmosphere. The solvent was then removed under reduced pressure and the residue was dissolved in 100 ml of dichloromethane. 920 mg of 1-methyl-3-indolylacetic acid and 975 mg of triethylamine are added to the obtained solution. After 72 hours the solvent was evaporated and the residue was purified by silica gel chromatography using ethyl acetate / n-hexane (1: 1) as eluent. Crystallization from ethyl acetate gave 390 mg

3- [7- (acetoxymethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan-2,5-dione mp 190-193 ° C.

Example 10

200 mg of trifluoromethanesulfonic anhydride in 50 ml of dichloromethane are added under a nitrogen atmosphere at 0 ° C to a suspension of 150 mg of the pyroldione derivative of Example 9 and 75 mg of collidine in 50 ml of dichloromethane. After 2 hours, 4 mL of a 33% ammonia solution was added and the mixture was allowed to warm to room temperature. The mixture was washed with water, dried and evaporated. The residue was purified by silica gel chromatography using dichloromethane: methanol: acetone: water 90: 18: 3: 2. Crystallization from dichloromethane / n-hexane gave 85 mg of 3- [7-amino-

6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, m.p. 160-165 ° C .

Example 11

A solution of 120 mg of the pyroldione derivative of Example 9 in 80 ml of dichloromethane was treated with 2 ml of pyridine and 100 mg of methanesulfonic anhydride under a nitrogen atmosphere. After stirring for 18 hours, the mixture was washed with 2M hydrochloric acid solution and saturated sodium bicarbonate solution, dried and evaporated. A solution of the obtained product in 40 ml of ethanol containing 200 mg of thiourea was heated under reflux for 72 hours. Then the solvent

The residue is purified by chromatography on silica gel using dichloromethane / methanol / acetone / water = 90/18/3/2. Crystallization from methanol / dichloromethane gives 30 mg of 3- [7-amidinothiomethyl-6,7]. 8,9-Tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) 1H-pyrrole-2,5-dione methanesulfonate, m.p. 195-198 ° C.

Example 12

A solution of 72 mg of 3- (6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan-2,5-dione in 5 mL dimethylformamide and 5 ml of 33% aqueous ammonia were heated at 140 ° C for 4 hours, and the resulting crystals were filtered and dried to give 50 mg of 3- (6,7,8,9-tetrahydropyridol-1,2-a) indole. -10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-

2,5-dione, m.p. 286-289 ° C.

The furandione derivative used as the starting material is prepared as follows:

(a) A solution of 1.03 g of ethyl 6,7-dihydro-9-hydroxypyrido [1,2-a] indole-8-carboxylate in 20 ml of ethanol, 10 ml of water and 10 ml of concentrated hydrochloric acid is heated at room temperature for 3 hours. 80 ° C. Then the solvent is evaporated. 740 mg are obtained

7,8-dihydropyrido [1,2-a] indol-9 (6H) -one, m.p. 138-140 ° C.

(b) A solution of 740 mg of the product obtained under (a)

600 mg of hydrazine hydrate and 440 mg of potassium hydroxide in 2 ml of ethanol and 4 ml of diethylene glycol are heated at 100 ° C for 1.5 hours and then at 180 ° C for 2 hours. 50 ml of dichloromethane are then added to the reaction mixture, and the organic phase is washed with 2M hydrochloric acid solution and water. The solvent was evaporated. 405 mg of 6,7,8,9-tetrahydropyrido [1,2-a] indole are obtained.

(c) 350 mg of oxalyl chloride are added dropwise to a solution of 450 mg of the product of (b) in 13 ml of dichloromethane at 0 ° C. After stirring for two hours, the solvent was evaporated and the residue was dissolved in dichloromethane. To this solution was then added 497 mg of 1-methyl-3-indolylacetic acid and 0.73 ml of triethylamine and the mixture was stirred for 60 hours. The solvent was evaporated and the residue was purified by silica gel chromatography using dichloromethane as eluent. Mixing the product with ethyl acetate gave 100 mg of 3- (6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan-2,5-dione mp 276-278 °.

Example 13

In an analogous manner to that described in Example 1, paragraph 1, from 3- [8- (2-acetoxyethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] - Of 4- (1-methyl-3-indolyl) furan-2,5-dione yields 3- [6,7,8,9-tetrahydro-8- (2-hydroxyethylpyrido [1,2-a] indol-10-yl) -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, m.p. 261 DEG-263 DEG.

FROM

The starting furanedione is prepared as follows:

(a) A solution of 6,52 g of 8- (2-acetoxyethyl) -6,7,8,9-tetrahydro-9-oxopyrido [1,2-a] indole in 48 ml of dichloromethane is treated with 2,5 ml of ethanedithiol and 3, 13 ml of titanium tetrachloride. The resulting solution was then heated under reflux for 18 hours under a nitrogen atmosphere. A further 4 ml of ethanedithiol and 9 ml of titanium tetrachloride were added to the reaction mixture and heating was continued for 4.5 hours. The mixture was then washed with water, dried and evaporated. The evaporation residue is purified by chromatography on silica gel using a 1: 3 mixture of ethyl acetate and petroleum ether. 7.7 g of 8 '- (2-acetoxyethyl) -7', 8'-dihydrospiro- [1,3-dithiolane-2 ', 9' (6H ') -pyrido [1,2-a] indole is obtained.

(b) A solution of 5 g of the product of (a) in 200 ml of ethanol is shaken for 3.5 hours together with 8 portions of Raney-nickel on a spatula tip. The mixture was then filtered and the filter cake was washed with ethanol. The combined filtrates were evaporated and the residue was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (1: 2). 620 mg of 8- (2-acetoxyethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indole are obtained.

(c) 1,19 g of oxalyl chloride are added dropwise at 0 ° C to a solution of 2,29 g of the product of (b) in 50 ml of diethyl ether. After 2.5 hours, the solvent was evaporated and the residue was dissolved in dichloromethane. 1.68 g of 1-methyl-3-indolylacetic acid and 2.45 ml of triethylamine were added to the obtained solution, and the mixture was heated under reflux for 18 hours under a nitrogen atmosphere. The solvent was evaporated and the residue was purified by chromatography on silica gel using ethyl acetate / petroleum ether (1: 2). Crystallization from ethyl acetate gave 625 mg of 3- [8- (2-acetoxyethyl) -

6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan-2,5-dione, m.p. 159-161 ° C.

Example 14

A solution of 115 mg of the product of Example 13 c) in 1 ml of dimethylformamide and 2 ml of 33% aqueous ammonia was heated at 140 ° C for 4 hours. The cooled mixture was evaporated and the residue was purified by silica gel chromatography using 1: 2 ethyl acetate / petroleum ether as eluent. Crystallization from ethyl acetate / petroleum ether gave 13 mg of 3- [8- (2-acetoxyethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl) -3-indolyl) -1H-pyrrole-2,5-dione, m.p.

Example 15

A solution of 500 mg of the pyroldione product of Example 13 in 50 ml of dichloromethane was treated with 218 mg of methanesulfonic anhydride and 1 ml of pyridine. The resulting solution was stirred under nitrogen for 1 hour. An additional 20 mg of methanesulfonic anhydride was then added and stirring was continued for 0.5 hours. The reaction mixture was washed with water, dried and evaporated. Crystallization of the residue from ethyl acetate / petroleum ether yielded 540 mg of 3- [6,7,8,9-tetrahydro-8- (2-methylsulfonyloxyethyl) pyrido [1,2-a] indol-10-yl] -4- (1-methyl-3). (indolyl) -1H-pyrrole-2,5-diene, m.p.

245 ° C.

Example 16

A solution of 500 mg of the pyroldione derivative of Example 15 and 250 mg of sodium azide in 10 ml of dimethylformamide was heated at 70 ° C for 3 hours. The solvent was evaporated and the solid residue was partitioned between ethyl acetate and water. The insoluble matter is filtered off and dried. 425 mg of 3- [8- (2-azidoethyl) - are obtained.

6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3indolyl) -1H-pyrrole-2,5-dione, m.p. 262-264 ° C .

Example 17

200 mg of the pyroldione derivative of Example 16 in 70 ml of methanol containing 40 mg of 10% palladium on carbon are shaken for 48 hours under an atmosphere of hydrogen at 50 psi. The upper layer was separated by decantation and evaporated. The evaporation residue is mixed with 50 ml of ethyl acetate saturated with hydrochloric acid and chromatographed for purification on silica gel with dichloromethane / methanol / acetic acid / water 60/18: 2: 3. Crystallization from ethyl acetate gave 20 mg of 3- [8- (2-aminoethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -lH-pyrrole-2,5-diol ^/ nu, mp 160-165 ° C.

Example 18

In an analogous manner to that described in the example

12, paragraph 1, from 3- [2,3-1H-pyrrolo [1,2-a] indol-9-yl] -4- (1-methyl-3-indolyl) furan-2,5-dione yields 3 -2,3-dihydro-1H-pyrrolo [1,2-a] indol-9-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-

2,5-diene having a melting point of 260 to 270 ° C.

The furandione derivative used as a starting material is prepared as follows:

175 mg of oxalyl chloride was added dropwise to a solution of 200 mg

2,3-dihydro-1H-pyrrolo [1,2-a] indole in 7 mL of diethyl ether at 0 ° C under nitrogen. After 1 hour the solvent was removed by evaporation under reduced pressure and the residue was dissolved in 14 ml of dichloromethane. 245 mg of 1-methyl-3-indolylacetic acid and 265 mg of triethylamine were added to the obtained solution, and they were stirred vigorously for 72 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using petroleum ether ethyl acetate (1: 2). Crystallization from ethyl acetate yielded 70 mg of 3 - [(2,3-dihydro-1H-pyrrolo [1,2-a] indol-9-yl] -4- (1-methyl-3-indolyl) furan-2, 5-dione, m.p. 125-130 ° C.

Example 19

In an analogous manner to that described in the example

1, paragraph 1, from 3- [2-acetoxymethyl-2,3-dihydro-1H-pyrrolo [1,2-a] indol-9-yl] -4- (1-methyl-3-indolyl) furan- 2,5-dione yields 3- [2,3-dihydro-2-hydroxymethyl-1H-pyrrolo [1,2-a] indol-9-yl] -4 (1-methyl-3-indolyl) -1H-pyrrole -2,5-dione, m.p. 238-240 ° C.

The furandione derivative used as a starting material is prepared as follows:

a) To a solution of 5.0 g of ethyl 2,3-dihydro-1-oxo-1H-pyrrolo [1,2-a] indole-2-carboxylate in 180 ml of ethanol and 90 ml of water is added Raney nickel in an amount of 6 doses on the tip of a spatula. The mixture was heated at reflux for 10 hours and then a further 3 portions of Raney-nickel were added at the tip of a spatula. Heating was continued for 5.5 hours, then the reaction mixture was cooled and filtered. The filter cake was washed with ethyl acetate and dichloromethane. The combined filtrates were evaporated and the residue was purified by silica gel chromatography using 1: 2 petroleum ether ethyl acetate as eluent. Crystallization from methanol gave 635 mg of ethyl 2,3-dihydro-1H-pyrrolo [1,2-a] indole-2-carboxylate, m.p. 55-57 ° C.

(b) 4 ml of a solution of lithium aluminum hydride in tetrahydrofuran are added to a solution of 750 mg of the product obtained in (a) in 30 ml of tetrahydrofuran. After one hour, 30 ml of saturated ammonium chloride solution are added and the mixture is evaporated. The residue is extracted with dichloromethane and the organic extract is dried and evaporated by crystallization of the residue from a mixture of diethyl ether and petroleum ether to give 355 mg of 2,3-dihydro-2-hydroxymethyl-1H-pyrrolo [1,2-a] indole, m.p. C.

c) A solution of 355 mg of the product of b) in 20 ml of dichloromethane containing 2 ml of acetic anhydride and 2 ml of pyridine is stirred for 2 hours. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic phase is dried and evaporated. 420 mg of 2-acetoxymethyl-

2,3-dihydro-pyrrolo [1,2-a] indole.

(d) 290 mg of oxalyl chloride are added dropwise to a solution of 420 mg of the product of (c) in 40 ml of diethyl ether under a nitrogen atmosphere. After 1 hour, the solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. 420 mg of 1-methyl-3-indolylacetic acid and 485 mg of triethylamine were added to the obtained solution, and the mixture was stirred for 7 hours. The solvent was evaporated and the residue was purified by chromatography on silica gel using ethyl acetate / petroleum ether (1: 1). Crystallization from ethyl acetate gave 90 mg of 3- [2-acetoxymethyl-2,3-dihydrol-1H-pyrrolo [1,2-a] indol-9-yl] -4- (1-methyl-3-indolyl) furan-2, M.p. 208 DEG-211 DEG.

Example 20

Solution 150 mg of 3- [2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-pyrazino [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan-2,5- of dione in 4 ml of dimethylformamide and 8 ml of a 33% aqueous ammonia solution was heated at 140 ° C for 4 hours. The mixture is then extracted with ethyl acetate and the organic phase is washed with water, dried and evaporated. The resulting product was purified by chromatography on silica gel using dichloromethane / methanol / acetic acid / water as eluent. The resulting imide was dissolved in 30 ml of ethanol and 5 ml of a 2M hydrochloric acid solution, and the resulting solution was heated under reflux for 2 hours. Evaporation of the solvent and mixing of the residue with ethyl acetate gave 35 mg of 3- [1,2,3,4-tetrahydropyrazino [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) 1H-pyrrole- 2,5-dione hydrochloride, m.p. 268-270 ° C.

/

The furandione, which is used as a starting material, is prepared as follows:

a) A solution of 450 mg of 1,2,3,4-tetrahydropyrazino [1,2-a] indole in 30 ml of dichloromethane is reacted at 0 ° C under a nitrogen atmosphere with 303 mg of triethylamine and 615 mg of di (tert-butyl) dicarbonate here. The mixture was stirred at 0 ° C for 4 hours and then washed with saturated sodium bicarbonate solution, dried and evaporated. Crystallization of the oil obtained from methanol afforded 580 mg of tert-butyl 1,2,3,4-tetrahydropyrazino [1,2-a] indole-2-carboxylate, m.p. 103-105 ° C.

(b) 230 mg of oxalyl chloride are added dropwise with stirring to a solution of 450 mg of the product of (a) in 30 ml of diethyl ether at 0 ° C. After stirring the solution, the solvent was evaporated and the residue was dissolved in 50 ml of dichloromethane. 360 mg of 1-methyl-3-indolylacetic acid and 350 mg of triethylamine were added to the obtained solution, and the mixture was stirred for 90 hours. The solvent was evaporated and the residue was chromatographed on silica gel for purification. A 2: 3 mixture of ethyl acetate and petroleum ether is used as eluent. 180 mg of 3- [2-tert-butoxycarbonyl-1,2,3,4-tetrahydropyrazino [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furanate are obtained. 125 DEG -127 DEG C. (after crystallization from ethyl acetate / n-hexane).

Example 21

In an analogous manner to that described in Example 12, paragraph 1, from 3- [5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-1-yl] -4- (1-meyl) -3-indolyl) furan-2,5-dione yields 3- (5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-1-yl] -4- (1-methyl-3-indolyl) 1 H-pyrrole-2,5-dione, m.p. 285-288 ° C.

The furandione derivative used as a starting material can be prepared as follows:

1.22 g of oxalyl chloride are added dropwise to a solution of 1.5 g

5,6-dihydro-4H-pyrrolo [3,2,1] -quinoline in 60 ml of dichloromethane under a nitrogen atmosphere. After one hour, the solvent was removed under reduced pressure and the residue was dissolved in 120 mL of dichloromethane. 1.9 g of 1-methyl-3-indolylacetic acid and 2.02 g of triethylamine were added to the obtained solution, and they were stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (1: 2) to give 690 mg of 3 [5,6-dihydro-4H-pyrrolo [3,2, 1-ij] quinolin-1-yl] -4- (1-methyl-3-indolyl) furan-2,5-dione, m.p. 217-219 ° C.

Example 22

In an analogous manner to that described in Example 12, paragraph 1, from 3- [5-acetoxymethyl-5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-1-yl] -4- of (1-methyl-3-indolyl) furan-2,5-dione gives 3- (5,6-dihydro-5-hydroxymethyl-4H-pyrrolo [3,2,1-ij] quinolin-1-yl] -4 - (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, m.p. 223-225 ° C.

F

The furandione derivative used as a starting material is prepared as follows:

(a) 33.4 ml of a 1.6 M solution of n-butyllithium in hexane are added at -78 ° C under a nitrogen atmosphere to a solution of 8.13 di40 of isopropylamine in 420 ml of tetrahydrofuran. After 0.5 h, 4.6 g of 1,2,5,6-tetrahydro-4-oxo-4H-pyrrolo [3,2,1-ij] - was added. of quinoline and the mixture was stirred at -78'C for 0.5 hour. Ethyl chloroformate (2.77 ml) was then added and stirring was continued for 1 hour. The reaction was quenched by the addition of water and evaporated. The evaporation residue is purified by chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1: 2). Crystallization from diethyl ether gave 2.8 g of ethyl 1,2,5,6-tetrahydro-4-oxo-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxylate, m.p. 88-90 ° C.

(b) 15 ml of a 1M solution of borane in tetrahydrofuran are added to a solution of 2.8 g of the product of (a) in 100 ml of tetrahydrofuran, and the resulting solution is heated under reflux for 2 hours. A further 55 ml of borane is then added and heating is continued for 12 hours. The solvent was removed under reduced pressure. Then water and 2M hydrochloric acid solution were added and the mixture was extracted with dichloromethane. The solvent was evaporated and the residue was dissolved in diethyl ether. The solution is then treated with 12 ml of 1M lithium-c solution

of aluminum hydride in diethyl ether and the mixture was stirred under a nitrogen atmosphere for 18 hours. Water was then added and the mixture was extracted with dichloromethane. Removal of the solvent under reduced pressure gave 1,4 2,5,6-tetrahydro-4H-pyrrolo [3,2,1-ij] quinoline-5-one.

c) A solution of 1.4 g of the product of b) in 50 ml of dichloromethane was treated with 4 ml of acetic anhydride and 2 ml of pyridine. After 4 hours, an additional 4 mL of acetic anhydride was added and the mixture was stirred for 18 hours, the solvent was removed under reduced pressure and the residue partitioned between water and dichloromethane. The organic phase is evaporated and the residue is dissolved in toluene. The toluene solution was refluxed for 18 hours in the presence of 250 mg of 10% palladium on carbon. An additional 250 mg of 10% palladium on carbon was then added and heating was continued for 20 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (1: 2). 350 mg of 5-acetoxymethyl-5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinoline is obtained.

d) 315 mg of oxalyl chloride was added dropwise to a solution of 570 mg of the product of c) in 15 ml of dichloromethane under a nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. 472 mg of 1-methyl-

Of 3-indolylacetic acid and 505 mg of triethylamine and the mixture is stirred for 72 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using dichloromethane as eluent. Crystallization from ethyl acetate-n-hexane gave 140 mg of 3- [5-acetoxymethyl-5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-1-yl] -4- (1-methyl-3). - r

indolyl) furan-2,5-dione, m.p. 198-200 ° C.

Example 23

In an analogous manner to that described in Example 11, 3- [5-amidinothiomethyl-5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-1-yl] was obtained from the pyroldione derivative of Example 22. -

4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione methanesulfonate, m.p. 190-195 ° C.

Example 24

In an analogous manner to that described in Example 2, 3- [5-aminomethyl-5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-1-yl] was obtained from the pyroldione derivative of Example 22. -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione / hydrochloride, m.p. 248-250 ° C.

Example 25

In an analogous manner to that described in Example 1, from 3- [8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4-phenylfuran-2,5 of the dione (obtained as described in the last paragraph of Example 1 but using phenylacetic acid instead of 1-methyl-3-indolylacetic acid) affords 3- [6,7,8,9-tetrahydro-8-hydroxymethylpyrido [1,2-a] Indol-10-yl] -4-phenyl-1H-pyrrole-2,5-dione, m.p. 276-278 ° C.

Example 26

In an analogous manner to that described in Example 1 (1), from 4- [8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl) -3- (benzo) [b] thienyl) furan-2,5-dione (obtained as described in the last paragraph of Example 1, but using 3-benzo [b] thienylacetic acid instead of 1-methyl-3-indolylacetic acid) affords 3- ( benzo [b] thienyl) 4- [6,7,8,9-tetrahydro-8-hydroxymethylpyrido [1,2-a] indol-10-yl] -1H-pyrrole-2,5-dione, m.p. 226-227 ° C.

Example 27

In an analogous manner to that described in the example

1, paragraph 1) from 3- [8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-naphthyl) furan-2,5- of dione (obtained as described in the last paragraph of Example 1, but using 1-naphthylacetic acid instead of 1-methyl-3-indolylacetic acid), 3- [6,7,8,9-tetrahydro-8-hydroxymethylpyrido [1,2- a] indol-10-yl] -4- (1-naphthyl) -1H-pyrrole-2,5dio], m.p. 221-222 ° C.

Example 28

In an analogous manner to that described in the example, 3- [2-aminomethyl-2,3-dihydro-1H-pyrrolo [1,2-a] indol-9-yl] -4- is obtained from the product obtained in Example 19. (1-methyl-3-indole) -1H-pyrrole-2,5-dione, m.p. 208-211 ° C.

Example 29

In an analogous manner to that described in the Example, the pyroldione derivative obtained in Example 25 is obtained from:

3- [8-Aminomethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl] -

4-phenyl-1H-pyrrole-2,5-dione, m.p. 249-250 ° C.

Example 30

A suspension of 100 mg of the pyroldione derivative of Example 20 in 10 ml of dichloromethane was treated with 0.08 ml of triethylamine and 86 mg of phenyl chloroformate under a du44 atmosphere. The mixture was stirred for 2 hours and then the solvent was evaporated. Chromatography of the residue on silica gel (ethyl acetate / n-hexane 1: 1) gave a gum which was dissolved in a mixture of 5 ml of isopropanol and 10 ml of 33% aqueous ammonia. The mixture was diluted with water and extracted with dichloromethane. The combined dichloromethane extracts were dried and evaporated. Crystallization of the residue from ethyl acetate-n-hexane gave 45 mg of 3- [1,2,3,4-tetrahydro-2-phenoxycarbonylpyrazino [1,2-a] indol-10-yl] -4- (1-methyl-3- indolyl) -1H-pyrrole-2,5-dione, m.p. 160-165 ° C.

Example 31

(a) A solution of 80 mg of the pyroldione derivative of Example 20 in ml of dichloromethane is treated with 10 ml of a 5% aqueous solution of sodium bicarbonate. The mixture was then treated with a solution of 125 mg of trifluoroacetamidoacetyl chloride in 5 ml of dichloromethane at reflux. After 10 hours, the phases were separated and the organic phase was dried and evaporated. Chromatography of the residue on silica gel using ethyl acetate / n-hexane (2: 1) as the eluent and crystallization from ethyl acetate-n-hexane gives 70 mg of 3- [2-trifluoroacetamidoacetyl-1,2,3,4-tetrahydropyrazino [ 1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, m.p. 170-172 ° C.

(b) A solution of 65 mg of the product of (a) in 10 ml of methanol was treated with 5 ml of a 33% aqueous ammonia solution. After 4 hours, the solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic phase is washed with water and dried. Chromatography of the residue on silica gel using a 60: 18: 2: 3 mixture of chloroform, methanol, acetic acid and water afforded a gum which was dissolved in glacial acetic acid and 20 ml of 1M hydrochloric acid was added. Evaporation of the solvent and treatment of the residue with diethyl ether gave 35 mg of 3- [2-aminoacetyl-1,2,3,4-tetrahydropyrazino [1,2-a] indol-10-yl] -4- (1-methyl-3- indolyl) -1H-pyrrole-2,5-dione, m.p. 170-172 ° C.

Example 32

a) A solution of 100 mg of the pyroldione derivative of Example 20 in 40 ml of dichloromethane was treated with 125 mg of 1,1-carbonyldiimidazole under a nitrogen atmosphere and the mixture was stirred for 24 hours. The solution obtained is washed with water, dried and evaporated. Mixing the residue with ethyl acetate gave 84 mg of 3 [1,2,3,4-tetrahydro-2,1- (imidazolylcarbonyl) pyrazino [1,2-a] indol-10-yl] -4- (1-methyl-3) (indolyl) -1H-pyrrole-2,5-dione, m.p. 295 DEG C. (decomposition).

(b) Dissolve 80 mg of the product of (a) in a mixture of 20 ml of dimethylformamide and 20 ml of 33% aqueous ammonia. The mixture was stirred for 17 hours and the solvent was evaporated. Chromatography of the residue on silica gel (methanol / ethyl acetate 1: 9) gave 45 mg of 3- [2-carbamoyl-

1,2,3,4-Tetrahydropyrazino [1,2-a] indol-10-yl] -4- (1-methyl- [eta] &lt; 1 &gt;

3-indolyl) -1H-pyrrole-2,5-dione, m.p. 295 DEG C. (decomposition) after crystallization from methanol.

46 Example 33

A solution of 505 mg of the pyroldione derivative of Example 2 in 20 ml of dimethylformamide was treated with a solution of 222 mg

1,1-thiocarbonyldiimidazole in 5 ml tetrahydrofuran. After 17 hours the solvent was evaporated and the residue was purified by silica gel chromatography eluting with methanol / dichloromethane (1:99). Mixing the product with n-hexane gave 297 mg of 3- [6,7,8,9-tetrahydro-8-isothiocyanatopyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) - 1 H-pyrrole-2,5-dione, m.p. 285-287 ° C.

Example 34

250 mg of the pyroldione derivative of Example 2 are added with stirring to a mixture of 25 ml of dichloromethane and 15 ml of a 5% aqueous sodium bicarbonate solution. The mixture was treated with 1 ml of benzoyl chloride and stirred for 10 hours. The phases were separated and the organic phase was dried and evaporated. Chromatography of the residue on silica gel using methanol / dichloromethane (7: 93) as eluent followed by n-hexane gave 220 mg of 3- [8-benzamidomethyl-6,7,8,9-tetrahydropyrazino [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, m.p. 297-303 ° C.

Example 35

A solution of 150 mg of 3- [7-acetoxy-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan-2,5-dione in 6 ml of dimethylformamide and 6 ml of 33% aqueous ammonia are added

Heat 47 to 150 ° C for 6 hours. The mixture was then extracted with ethyl acetate and the organic extracts were washed with water, dried and evaporated. Crystallization of the residue from ethyl acetate gave 120 mg of 3- [6,7,8,9-tetrahydro-7-hydroxypyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) - 1 H-pyrrole-2,5-dione, m.p. 252-255 ° C.

The furandione derivative used as starting material is prepared as follows:

a)

A solution of 14.0 g of indole-2-methanol in 500 ml of dichloromethane is stirred with 76.4 g of activated manganese dioxide. After one hour, the solid was filtered off and washed with dichloromethane. The combined filtrates are concentrated and 33 g of ethoxycarbonylmethylene triphenylphosphorane are added to the residue. The resulting solution was heated to reflux under a nitrogen atmosphere. The solvent was evaporated. The oil obtained is purified by chromatography on silica gel, eluting with ethyl acetate / n-hexane (1: 3). The product obtained is a 20: 1 mixture of E / Z isomers. Crystallization from methanol affords 11.3 g of ethyl (E) -2-indolyl-2-propenoate, m.p. 120-122 ° C.

b) A solution of 7.2 g of the product of a) in 120 ml of dimethylformamide was treated with 1.47 g of a 60% dispersion of sodium hydride in mineral oil. The resulting solution was cooled to 0 ° C and tert-butyl bromoacetate (7.17 g) was added under nitrogen. After 2 hours, the mixture was poured into 100 mL of 2M hydrochloric acid solution and extracted with ethyl acetate. The combined organic extracts were washed with water, dried and evaporated. The oil obtained is purified by chromatography

48 chromatography on silica gel using diethyl ether / etrol ether 1: 3 as the eluent. Crystallization from diethyl ether / n-hexane gave 8.1 g of ethyl (E) - [tert-butoxycarbonylmethyl-2-indolyl] -2-propenoate, m.p. 66-68 ° C.

(c) A solution of 8.0 g of the product of (b) in 300 ml of ethanol is shaken under a hydrogen atmosphere with 800 mg of 10% palladium on carbon. The catalyst was filtered off and washed with ethyl acetate. The combined filtrates were evaporated. An oil is obtained which is dissolved in tetrahydrofuran. The resulting solution was added to a solution of 2.8 g of potassium tert -butoxide in tetrahydrofuran under a nitrogen atmosphere. The mixture was then stirred for 1 hour and the solvent was evaporated. The residue was partitioned between ethyl acetate and 2M hydrochloric acid solution. The organic phase is washed with water, dried and evaporated. The residue was purified by silica gel chromatography eluting with diethyl ether: n-hexane (1: 4). 4.55 g of tert-butyl-6,7,8,9-tetrahydro-

7-oxo-pyrido [1,2-a] indole-carboxylate.

d) A solution of 4.5 g of the product of c) in 200 ml of toluene is mixed with 4 portions of silica gel at the tip of a spatula and the mixture is heated under reflux for 3 hours under a nitrogen atmosphere. The solid was filtered off and washed with toluene. The combined filtrates were evaporated. 2.5 g of 8,9-dihydropyrido [1,2-a] indole-7 (6H) - are obtained.

m.p. 126 DEG -128 DEG C. (crystallized from diethyl ether / n-hexane).

(e) 190 mg of sodium borohydride are added with stirring to a solution of 650 mg of the product of (d) in 50 ml of methanol under a nitrogen atmosphere. The mixture was stirred and then poured into 100 ml of saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate and the combined extracts were dried and evaporated. After crystallization of the product from a mixture of diethyl ether and n-hexane, 500 mg of 6,7,8,9- [tetrahydro-7-hydroxypyrido [1,2-a] indole is obtained, m.p.

f) A solution of 500 mg of the product of e) in 5 ml of pyridine and 2 ml of acetic anhydride is stirred for 8 hours. The mixture was then poured into 50 ml of 2M hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with 5% sodium bicarbonate solution and water, dried and evaporated. 25 mg of 7-acetoxy-6,7,8,9 [tetrahydropyrido [1,2-a] indole, m.p. 90 DEG-95 DEG C. (crystallized from diethyl ether / n-hexane), is obtained.

g) 320 mg of oxalyl chloride are added to a solution of 500 mg of the product of f) in 50 ml of diethyl ether under a nitrogen atmosphere. The solvent was then removed under reduced pressure and the residue was dissolved in 50 ml of dichloromethane. To the obtained solution were added 378 mg of 1-methyl-3-indolylacetic acid and 505 mg of triethylamine and the mixture was stirred for 72 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with ethyl acetate: n-hexane (1: 1). Crystallization from ethyl acetate gave 160 mg of 3- [7-acetoxy-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan -2,5dio not ^from mp 272-275 ° C.

Example 36

A solution of 85 mg of 3- [7-tert-butoxyformamido-6,7,8,9-tetrahydropyrido [1,2-a] indol-107-yl] -4- (1-methyl-3-indolyl) furan-2,5-dione in 5 ml of dimethylformamide and 5 ml of a 33% aqueous ammonia solution were heated at 100 ° C for 1 hour. The cooled mixture was partitioned between ethyl acetate and water. The organic phase is washed with water, dried and evaporated. Crystallization from ethyl acetate-n-hexane gave 70 mg of 3- [7-tert-butoxyformamido-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3- indolyl) -1H-pyrrole-2,5-dione, m.p. 159-163 ° C.

The furandione derivative used as starting material is prepared as follows:

a) A suspension of 555 mg of 8,9-dihydropyrido [1,2-a] indol-7 (6H) -one and 4.62 g of ammonium acetate in 15 ml of methanol is treated with 250 mg of sodium cyanoborohydride. The mixture was stirred and then partitioned between ethyl acetate and water. The organic phase is dried and the solvent is removed under reduced pressure. The residual oil is chromatographed on silica gel using 10% methanol in dichloromethane as the eluent. The obtained indole was dissolved in toluene and 50 mg of 10% palladium on carbon was added to the obtained solution, and the mixture was heated to reflux. The catalyst was filtered off and washed with toluene. The combined filtrates were evaporated. 170 mg of 7-amino-6,7,8,9-tetrahydropyrido [1,2-a] indole are obtained.

(b) 225 mg of di-tert-butyl dicarbonate are added with stirring to a solution of 175 mg of the product of (a) and 112 mg of triethylamine in 20 ml of dichloromethane at 0 ° C under a nitrogen atmosphere. After 18 hours, the solution was washed with saturated sodium bicarbonate solution, dried and evaporated. Crystallization from diethyl ether gives 240 mg of 3- [7-tert-butoxyformamido-

6,7,8,9-tetrahydropyrido [1,2-a] indole, m.p. 137-130 ° C.

(c) 127 mg of oxalyl chloride are added to a solution of 240 mg of the product of (b) in 30 ml of diethyl ether under a nitrogen atmosphere. After 10 minutes, the solvent was removed under reduced pressure and the residue was dissolved in 30 mL of dichloromethane. 170 mg of 1-methyl-3-indolylacetic acid and 200 mg of triethylamine are added and the mixture is stirred for 72 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with ethyl acetate / n-hexane (1: 2). Crystallization from ethyl acetate / n-hexane gave 100 mg of 3- [7-tert-butoxyformamido-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) of furan-2,5-dione, m.p. 141-145 ° C.

Example 37

A saturated solution of hydrogen chloride in 30 ml of ethyl acetate was added with stirring to a suspension of 60 mg of the pyroldione derivative of Example 36 in 50 ml of ethyl acetate, and the mixture was stirred for 18 hours. The solvent was removed under reduced pressure and the residue was mixed with ethyl acetate. 35 mg of 3- [7-amino-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5 are obtained. m.p. 260 DEG-265 DEG.

Example 38

A solution of 80 mg of 3- [8-tert-butoxyformamido-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -furan-2,5 of dione in 2 ml of dimethylformamide and 2 ml of 33% aqueous ammonia was heated at 100 ° C for 1 hour. The resulting solution was cooled to give 60 mg of 3- [8-tert-butoxyformamido-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) 1 H-pyrrole-2, 5-dione, m.p. 153-155 ° C.

The furandione derivative used as a starting material is prepared as follows:

a) A solution of 300 mg of sodium hydroxide in 5 ml of water was added with stirring to a solution of 1.35 g of the carboxylate of Example 1b) in 25 ml of ethanol, and the mixture was heated under reflux for 15 minutes. Then 2 ml of 2M hydrochloric acid solution and 10 ml of water are added to the mixture and the precipitate is filtered off and dried. 1.14 g of 6,7,8,9-tetrahydropyrido [1,2-a] indole-8-carboxylic acid of melting point 244 DEG-246 DEG C. is obtained.

b) A suspension of 900 mg of the product of a) in 1 ml of water and 20 ml of acetone was cooled to 0 ° C, followed by 490 mg of triethylamine followed by 576 mg of ethyl chloroformate. After 0.5 h, 345 mg of sodium azide in 1 mL of water was added and the mixture was stirred at 0 ° C for 1 h. The solvent was removed under reduced pressure and the residue was extracted with dichloromethane. The extracts were evaporated and the residue was purified by silica gel chromatography using dichloromethane as eluent.

The solid obtained was dissolved in 10 ml of toluene and the toluene solution was heated at 100 ° C under nitrogen for 4 hours. Then the solvent is evaporated. 700 mg of 6,7,8,9-tetrahydropyrido [1,2-a] indole-8-isocyanate are obtained, m.p. 87 and 89 ° C.

(c) 4 ml of sodium hydroxide solution are added to a solution of 700 mg of the product of (b) in 50 ml of tetrahydrofuran and the solution is stirred overnight. The solvent was removed under reduced pressure and the residue was extracted with dichloromethane. The dichloromethane extract was evaporated to give the amine, which was dissolved in dichloromethane. 645 mg of di-tert. of butyl carbonate and 300 ml of triethylamine at 0 ° C and the mixture was allowed to warm to room temperature with stirring over 22 hours. The resulting mixture is washed with sodium bicarbonate solution and the organic phase is dried. The solvent was removed under reduced pressure and the residue was extracted with diethyl ether. The ethereal extracts were evaporated and the solid was mixed with petroleum ether. 550 mg of 8-tert-butoxyformamido-

6,7,8,9-tetrahydropyrido [1,2-a] indole, m.p. 155-157 ° C.

d) 256 mg of oxalyl chloride was added dropwise to a solution of 550 mg of the product of c) in 10 ml of diethyl ether at 0 ° C under a nitrogen atmosphere. After 1 hour the solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. To the obtained solution was added 363 mg of 1-methyl-3-indolylacetic acid and 390 mg of triethylamine and the mixture was stirred for 40 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using ethyl acetate / petroleum ether (1: 2) as eluent. After crystallization from a mixture of diethyl ether and petroleum ether, it is obtained

220 mg of 3- [8-tert-butoxyformamido-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan-2, 5-dione, m.p. 155-160 ° C.

Example 39

In an analogous manner to that described in Example 37, 3- [8-amino-

6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3indolyl) -1H-pyrrole-2,5-dione, m.p. 310-315 ° C .

Example 40

A solution of 320 mg of 3- [4- (2-acetoxyethyl) -5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-1-yl] -4- (1-methyl-3-indolyl) furan-

Of 2,5-dione in 2 ml of dimethylformamide and 2 ml of 33% aqueous ammonia was heated at 140 ° C for 12 hours. Water was added to the cooled reaction mixture. Filtration gave 3- [4- (2-hydroxyethyl-5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-1-yl] 4- (1-methyl-3-indolyl) - 1 H-pyrrole-2,5-dione, m.p. 214-215 ° C (crystallized from ethyl acetate).

/

The furandione used as the starting material is prepared as follows:

(a) 25 ml of a 1.6 M solution of n-butyllithium in n-hexane is added to a solution of 4.04 g of diisopropylamine in 20 ml of tetrahydrofuran at 0 ° C under a nitrogen atmosphere. After 10 minutes, the solution was cooled to -78 ° C with stirring and a solution of 9.28 g of tert-butyl acetate in 20 ml of tetrahydrofuran was added. After 10 minutes, 3.46 g of 1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1-ij] quinolin-4-one in 20 ml of tetrahydrofuran was added, followed by 8 ml of boron trifluoride diethyl etherate. The mixture is stirred at -78 ° C and then 20 ml of pyrrolidine are added. The mixture was partitioned between ethyl acetate and water, and the organic extracts were washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography using ethyl acetate / petroleum ether (1: 3) as eluent. 4.1 g of tert-butyl (E) - (1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1-ij] quinolin-4-ylidene) acetate are obtained, m.p. 105-107 ° C. .

(b) A solution of 4 g of the product of (a) in 400 ml of methanol is shaken with 280 mg of 10% palladium on carbon under a nitrogen atmosphere. The catalyst was filtered off and the filtrate was evaporated. 1.99 g of the resulting oil in 100 ml of diethyl ether is then treated with 5 ml of a 1M solution of lithium aluminum hydride in diethyl ether, with stirring for 2 hours. Water was then added to the mixture and the product was extracted with ethyl acetate. The ethyl acetate extracts were dried and concentrated under reduced pressure. 1.44 g of (1,2,6,6-tetrahydro-4H-pyrrolo [3,2,1-ij] quinolin-4 = ethanol) is obtained.

c) 1.44 g of the product of b) in 40 ml of dichloromethane is treated with 10 ml of acetic anhydride and 5 ml of pyridine. The solution was stirred and then evaporated. The residue is dissolved in dichloromethane, the solution is washed with water and the organic phase is separated, dried and concentrated. 1.65 g of 4- (2-acetoxyethyl) -1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1-ij] quinoline are obtained.

d) A solution of 1.6 g of the product of c) in 50 ml of xylene and 100 mg of 10% palladium on carbon was heated at reflux for 12 hours. The catalyst was filtered off and the filtrate was evaporated. 1.7 g of 4- (2-acetoxyethyl) -5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinoline are obtained.

(e) 935 mg of oxalyl chloride are added under stirring under a nitrogen atmosphere to a solution of 1.7 g of the product of (d) in 45 ml of dichloromethane. After 1 hour, the solvent was removed under reduced pressure and the residue was dissolved in 90 ml of dichloromethane.

1.38 g of 1-methyl-3-indolylacetic acid and 1.48 g of triethylamine were added to the obtained solution, and the mixture was stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (1: 2). Crystallization from methanol / water gave 280 mg of 3- [4- (2-acetoxyethyl) -5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-1-yl] -4 (1- methyl 3-indolyl) furan-2,5-dione, m.p. 143-146 ° C.

Example 41

Solution 400 mg 3- [8- (tert-butoxyformamidomethyl) -

6,7,8,9-tetrahydropyrido [1,2- a] indol-10-yl] -4- (1-methyl-)

3-indolyl) furan-2,5-dione in 50 ml of dimethylformamide and 50 ml of water are treated with 2.5 g of hydroxylamine hydrochloride and

2.5 g of potassium carbonate while heating the solution to 100 ° C. Then the solvent was evaporated and the residue was dissolved in dichloromethane. The dichloromethane solution was washed with water and dried. The solvent was removed under reduced pressure and the residue was crystallized from ethyl acetate / petroleum ether. 190 mg of 3- [8- (tert-butoxyformamidomethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -1-hydroxy-4- (1-methyl-3) are obtained. m.p. 238-240 ° C.

The starting derivative can be produced as follows:

(a) 2,4 g of methanesulphonic anhydride and 2 ml of triethylamine are added with stirring to a solution of 2,01 g of 6,7,8,9-tetrahydropyrido [1,2-a] indole-8-methanol in 40 ml of dichloromethane under a nitrogen atmosphere . After 18 hours, the mixture was washed with saturated sodium bicarbonate solution, dried and evaporated. 1.8 g of the obtained oil are dissolved in 10 ml of isopropyl alcohol and 5 ml of 33% aqueous ammonia and the mixture is heated at 80 ° C for 10 hours. The solvent was then removed under reduced pressure and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase is dried and evaporated. 1.3 g of 8-aminomethyl-6,7,8,9-tetrahydropyrido [1,2- a] indole are obtained, m.p. 85-90 ° C.

b) 1.09 g of di-tert-butyl dicarbonate is added with stirring to a solution of 890 mg of 8-aminomethyl-6,7,8,9-tetrahydropyrido [1,2- a] indole and 920 mg of triethylamine in 60 ml of dichloromethane at 0 ° C under a nitrogen atmosphere. After 72 hours, the organic phase is washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was crystallized from petroleum ether. 1.03 g of 8- (tert-butoxyformamidomethyl) -6,7,8,9-tetrahydropyrido [1,2- a] indole is obtained, m.p. 80-85 ° C.

(c) 445 mg of oxalyl chloride are added dropwise to a solution of 1 g of the product of (b) in 20 ml of diethyl ether under nitrogen at 0 ° C. After one hour, the solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. 630 mg of 1-methyl-3-indolylacetic acid and 920 μg of triethylamine are added to the dichloromethane solution and the mixture is stirred for 72 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (1: 2). The resulting solid was crystallized from diethyl ether. 315 mg of 3- [8- (tert-butoxyformamidomethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan-2 are obtained. 5-dione, m.p. 124-126 ° C.

Example 42

In an analogous manner to that described in Example 37, 3- [8-aminomethyl-

6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -1-hydroxy-4- (1-methyl-3-indolyl) pyrrole-2,5-dione / hydrochloride, m.p. 280 m.p. to 282 ° C.

Example 43

In an analogous manner to that described in Example 11, 3- [4- (2-amidinothioethyl-) - was obtained from the product of Example 40.

5,6-Dihydro-4H-pyrrolo [3,2,1-ij] quinolin-1-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione-methanesulfonate, m.p. 185 to 190 ° C.

Example 44

In an analogous manner to that described in Example 2, 3- [4- (2-aminoethyl-

5,6-Dihydro-4H-pyrrolo [3,2,1-ij] quinolin-1-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dionphydrochloride, m.p. 193-195 C.

Example 45

In an analogous manner to that described in the example

2, 3- [8-Aminomethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl] -4- (3-benzo [b] thienyl) -1H-pyrrole is obtained from the product of Example 26 -2, S-dione hydrochloride, m.p. 285 DEG-287 ^DEG C.

Example 46

In an analogous manner to that described in the example

1, from 3- [8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (2-naphthyl) furan-2,5-dione (obtained by the method described in the last paragraph of Example 1, but using 2-naphthylacetic acid instead of 1-methyl-3-indolylacetic acid) gives 3- [6,7,8,9-tetrahydro-8-hydroxymethylpyrido [1,2-a] indole -10-yl] -4- (2-naphthyl) -1H-pyrrole-2,5-dione, m.p. 260-263 ° C.

Example 47

In an analogous manner to that described in the example

2, 3- [8-aminomethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (2-naphthyl) -1H-pyrrole was obtained from the product of Example 46 -

2,5-dione hydrochloride, m.p. &gt; 300 ° C.

Example 48

In an analogous manner to that described in the example

10, 3- [8-Aminomethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-1-yl] -4- (1-naphthyl) -1H-pyrrole- is obtained from the product of Example 47.

2.5-dione, m.p. 167-169 ° C.

Example 49

In an analogous manner to that described in the example

1, paragraph 1) from 1,3 g of 3- [9-acetoxymethyl-7,8,9,10-tetrahydro-6H-azepino [1,2-a] indol-11-yl] -4- (1-methyl- Of 3-indolyl) furan-2,5-dione gives 520 mg of 3- [7,8,9,10-tetrahydro-9-hydroxymethyl-6Hazepino [1,2-a] indol-11-yl] -4- (1-indolyl) furan-2,5-dione. methyl-3-indolyl) -lH-pyrrolo

M.p. 268 DEG-270 DEG.

/

The furandione derivative used as a starting material is prepared as follows:

a) A solution of 18.9 g of ethyl indole-2-carboxylate in 100 ml of dimethylformamide is added to a suspension of 2.64 g of sodium hydride in 50 ml of dimethylformamide. After 1 hour, the solution was added dropwise

20.9 g of ethyl 5-bromovalerate in 100 ml of dimethylformamide. After 48 hours, the mixture is poured into water, extracted with dichloromethane and the combined dichloromethane extracts are washed with water, dried and concentrated. 26.2 g of ethyl 1- (4-ethoxycarbonylbutyl) indole-2-carboxylate are obtained.

b) A solution of the product of a) in 50 ml of tetrahydrofuran was added with stirring to a suspension of 11.2 g of potassium tert-butoxide in 150 ml of tetrahydrofuran. After 36 hours, the mixture was concentrated and the residue was poured into a mixture of water and diethyl ether. The organic phase is dried and concentrated. Chromatography of the residue on silica gel using dichloromethane / methanol (9: 1) as eluent gave a solid which was recrystallized from ethyl acetate-n-hexane. 6.1 g of ethyl 7,8-dihydro-10-hydroxy-6H-azepino [1,2-a] indole-9-carboxylate are obtained, m.p. 74-81 ° C.

c) To a solution of 5.5 g of the product of b) in 200 ml of ethanol was added Raney nickel in 11 portions at the tip of a spatula and 400 ml of water. The mixture was heated at reflux for 4 hours. The cooled mixture was filtered and the filter residue was washed with ethyl acetate. The filtrate was extracted with ethyl acetate ... The combined extracts were dried and evaporated. An oil is obtained which is purified by chromatography on silica gel using dichloromethane as eluent. 2.5 g of 7,8,9,10-tetrahydro-6H-azepino [1,2-a] indole-9-carboxylate are obtained, m.p. 69-70 ° C.

d) A solution of c) in 50 ml of tetrahydrofuran was added dropwise to a mixture of 0.45 g of lithium aluminum hydride in 20 ml of tetrahydrofuran. The mixture was stirred for 2 hours and extracted with diethyl ether after addition of water. The combined extracts were dried and evaporated. Chromatography of the residue on silica gel using dichloromethane as eluent gave 1.90 g

7,8,9,10-tetrahydro-9-hydroxymethyl-6H-azepino [1,2-a] indole, m.p. 109-111 ° C.

(e) To a solution of 1,8 g of (d) in 100 ml of diethyl ether, at 0 ° C, add 1,70 g of acetic anhydride and 0,66 g of pyridine. After 8 hours, an additional 5 g of pyridine was added and the mixture was stirred for 76 hours. The solvent was then removed by evaporation under reduced pressure and the residue was chromatographed on silica gel using dichloromethane as eluent. 1.98 g of 9-acetoxymethyl-7,8,9,10-tetrahydro-6H-azepino [1,2-a] indole is obtained, m.p. 65 ° C.

(f) A solution of 1.90 g of the product of (e) in 50 ml of dichloromethane was cooled to 0 ° C and 1.03 g of oxalyl chloride was added to the obtained solution. After 2 hours the solvent was evaporated, the residue was dissolved in dichloromethane and a solution of 1.5 g of 1-methylindole-3-acetic acid and 1.86 g of triethylamine in dichloromethane was added dropwise. The mixture is evaporated and the residue is chromatographed on silica gel using dichloromethane containing 5% methanol by volume. The solid obtained is crystallized from a mixture of ethyl acetate and n-hexane. 1.55 g of 3- [9-acetoxymethyl-7,8,9,10-tetrahydro-6H-azepino [1,2-a] indol-11-yl] -4- (1-methyl-3-indolyl) are obtained. m.p. of furan-2,5-dione, m.p. 164-166 ° C.

Example 50

In an analogous manner to that described in the example

12, from 0.50 g of 3- [7,8,9,10-tetrahydro-6H-azepino [1,2-a] indol-11-yl] -3- (1-methyl-3-indolyl) furan -2,5-dione is obtained

0.43 g of 3- [7,8,9,10-tetrahydro-6H-azepino [1,2-a] indol-llyl] -3- (1-methyl-3-indolyl) -1H-pyrrole-2, 5-dione having a melting point greater than 300 ° C.

The furandione derivative used as a starting material is prepared as follows:

1.5 g of oxalyl chloride are added dropwise to an ice-cooled solution of 2.0 g of 7,8,9,10-tetrahydro-6H-azepino [1,2-a] indole (cf. J. Org. Chem. 33, 1968, 4286) in 50 ml of dichloromethane. The mixture was stirred for 2 hours. The solvent was then removed under reduced pressure and the residue was dissolved in dichloromethane. A solution of 2.2 g of 1-methyl-3-indolylacetic acid and 2.73 g of triethylamine in 50 ml of dichloromethane is added to the obtained solution. The mixture was stirred and then evaporated. The residue was chromatographed on silica gel using dichloromethane as eluent. 1.0 g of 3- [7,8,9,10-tetrahydro-6H-azepino [1,2-a] indol-11-yl] -3- (1-methyl-3-indolyl) furan-

2,5-dione, m.p. 257-259 ° C.

Example 51

To a solution of 150 mg of the product of Example 49 and 146 mg

2,6-Lutidine in 50 ml of dichloromethane is added dropwise a solution of 290 mg of trifluoromethanesulfonic anhydride at 0 ° C. After 3 hours, 25 ml of 33% aqueous ammonia are added, the mixture is stirred for 16 hours, then extracted with dichloromethane and the combined extracts are dried and evaporated. Chromatography of the residue on silica gel using dichloromethane / methanol / acetic acid / water 90: 18: 3: 2 gives 50 mg of 3- [9-aminomethyl-7,8,9,10-tetrahydro-6H-azepino [1]. , 2-a] indol-l-yl] -3- (l-methyl-3-indolyl) -lH-pyrrole-2,5-diol ^from n ^ acetate, mp 215 DEG C. (dec).

"''IN

Example 52

A mixture of 40 mg of the product of Example 51, 20 ml of sodium bicarbonate and 25 mg of 3,5-dimethyl-N ² -nitro-1-pyrazole-1-carboxamide in 10 ml of ethanol was heated at reflux for 16 hours. The residue is chromatographed on silica gel, eluting with dichloromethane / methanol (9: 1). 15 mg of 3- (1-methyl-3-indolyl) -4- [7,8,9,10-tetrahydro-9 (2-nitroguanidinomethyl) -6H-azepino [1,2-a] indol-11- is obtained. yl] -1Hr of pyrrole-2,5-dione, m.p. 177-178 ° C.

Example 53

In an analogous manner to that described in Example 1 (1), from 0.20 g of 3- [8-acetoxymethyl-7,8,9,10-tetrahydro-6H-azepino [1,2-a] indol-11-yl] ] -4- (1-methyl-3-indolyl) furan-2,5-dione yields 60 mg of 3- [7,8,9,10-tetrahydro-8-hydroxymethyl-6Hazepino [1,2-a] indol-11- yl] -4- (l-methyl-3-indolyl) pyrolZ

2,5-dione, m.p. 109-111 ° C.

The furandione derivative used as a starting material is prepared as follows:

(a) A solution of 5 g of 6,7-dihydro-9-hydroxypyrido [1,2-a] indole-

The 8-carboxylate (prepared as described in Example 1) in 200 ml of dimethylformamide was treated with 550 mg of sodium hydride. The mixture was stirred under a nitrogen atmosphere and then a solution of 3.6 g of ethyl bromoacetate in 50 ml of dimethylformamide was added. After 16 hours, the mixture was poured into water and extracted with diethyl ether. The combined extracts were washed with water, dried and evaporated. 4.4 g of ethyl 8-ethoxycarbonyl-6,7,8,9-tetrahydro-9-oxopyrido [1,2-a] indole-8-acetate are obtained.

b) A solution of 5.0 g of the product of a) in 200 ml of tetrahydrofuran was added dropwise with stirring to a solution of 2.0 g of potassium tert -butoxide in 50 ml of tetrahydrofuran. The mixture was stirred and then 1 ml of glacial acetic acid was added. The reaction mixture was poured into water and extracted with dichloromethane. The combined extracts were dried and evaporated. The residue is chromatographed on silica gel, eluting with dichloromethane / methanol (95: 5). 3.0 g of diethyl 7,8-dihydro-10-hydroxy-6H-azepino [1,2-a] indole-8,9-dicarboxylate are obtained.

c) A mixture of 2.8 g of the product of b) and 0.5 g of boric acid is heated first to 150 ° C and then to 170 ° C. Ice water was added to the cooled mixture and the mixture was extracted with dichloromethane. The combined dichloromethane extracts were dried and evaporated. The residue is chromatographed on silica gel, eluting with dichloromethane / methanol (95: 5). 2.1 g of ethyl-

7,8,9,10-tetrahydro-10-oxo-6H-azepino [1,2-a] indole-8-carboxylate.

d) 2.1 g of the product of c) are dissolved in 80 ml of ethanol and Raney-nickel is added in 4 portions at the tip of a spatula and 50 ml of water. The mixture was then heated at reflux for 4 hours, cooled and filtered. The filter residue was washed with ethyl acetate, the filtrates were extracted with ethyl acetate, and the combined extracts were dried and evaporated. Chromatography of the residue on silica gel using dichloromethane as eluent gave 0.89 g of 7,8,9,10-tetrahydro-6H-azepino [1,2-a] indole-8-carboxylate.

(e) 0.85 g of the product of (d) is dissolved in 50 ml of tetrahydrofuran and the solution obtained is added dropwise with stirring to a suspension of 140 mg of lithium aluminum hydride in 50 ml of tetrahydrofuran. After addition of water, the mixture is extracted with diethyl ether. The combined extracts were dried and evaporated. Chromatography of the residue on silica gel with dichloromethane / methanol (95: 5) yields 0.70 g of 7,8,9,10-tetrahydro-8-hydroxymethyl-6H-azepino [1,2-a] indole, m.p. 90-91. C.

f) 0.70 g of the product of e) is reacted with 0.66 g of acetic anhydride and 0.39 g of pyridine in 50 ml of diethyl ether. 1 g of pyridine and 1 g of acetic acid are then added and the mixture is stirred for 16 hours, then evaporated and the residue is chromatographed on silica gel, eluting with dichloromethane. 0.60 g of 8-acetoxymethyl-7,8,9,10-tetrahydro-6Hazepino [1,2-a] indole is obtained, m.p. 77-79 ° C.

g) To a solution of 0.60 g of the product of f) in 50 ml of dichloromethane was added dropwise 0.33 g of oxalyl chloride. After 2 hours at 10 ° C the solution is evaporated and the residue is dissolved in dichloromethane and this solution is evaporated and the residue is dissolved in dichloromethane and this solution is added to a solution of 0.49 g of 1-methylindole-3-acetic acid and 0, 59 g triethylamine in dichloromethane. After 16 hours, the mixture is evaporated and the residue is chromatographed on silica gel with dichloromethane / methanol (95: 5). 0.51 g of 3- [8-acetoxy-67-methyl-7,8,9,10-tetrahydro- 6H-azepino [1,2-a] indol-11-yl] 4- (1-methyl-3-indolyl) furan-2,5-diene, m.p. 70 ° C.

Example 54

To a solution of 60 mg of the product of Example 53 and 60 mg

Of 2,6-lutidine in 25 ml of dichloromethane is added dropwise at 0 ° C a solution of 116 mg of trifluoromethanesulfonic anhydride in 25 ml of dichloromethane. After 3 hours, 25 ml of aqueous ammonia are added. The organic phase is dried and then concentrated. Chromatography of the residue on silica gel gives mg of 3- [8-aminomethyl-7,8,9,10-tetrahydro-6H-azepino [1,2-a] indol-11-yl] -4- (1-methyl-3- indolyl) -1H-pyrrole-2,5-dione acetate, m.p. 162-163 ° C.

Example 55

To a solution of 0.64 g of the product of Example 1 and 0.4 ml

2.4.6-Collidine in 20 ml of dichloromethane is added dropwise a solution of 0.75 g of trifluoromethanesulfonic anhydride in 10 ml of dichloromethane at 0 ° C. After 2.5 hours, the mixture was mixed with 3 ml piperidine and stirred for 16 hours. Evaporation and chromatography of the residue on silica gel using dichloromethane / methanol (98: 2 to 50:50) as eluent gave 340 mg of 3- [6,7,8,9, -tetrahydro8- (1-piperidinomethyl) pyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -lHpyrol-2,5-dione. Reaction of this product with a saturated solution of hydrogen chloride in ethyl acetate gave the hydrochloride, m.p. 294 ° C (dec.).

Example 56

To a solution of 0.8 g of the product of Example 1 and 0.44 g

2,4,6-Collidine in 30 ml of dichloromethane is added dropwise at 0 ° C a solution of 0.9 g of trifluoromethanesulfonic anhydride in 10 ml of dichloromethane. After 1.5 hours, the mixture was treated with 3.64 g of diisopropylamine, stirred for 16 hours, and then washed with water and saturated aqueous sodium bicarbonate, dried and evaporated. The solid was dissolved in ethyl acetate and a saturated solution of hydrogen chloride in ethyl acetate was added to the ethyl acetate solution. Removal of the solvent under reduced pressure gave 260 mg of 3- [6,7,8,9, -tetrahydro-8- (diisopropylaminomethyl) pyrido [1,2-a] indol-10-yl] 4- (1-methyl-3). (indolyl) -1H-pyrrole-2,5-dione, hydrochloride, m.p. 187 DEG C. (decomposition).

Example 57

To a solution of 1.0 g of 3- [8-acetoxymethyl-6,7,8,9, -tetrahydropyrido [1,2-a] indol-10-yl] - (3-benzofuranyl) furan-2,5-dione ^of nu Chloroform (100 ml) was added hexamethyldisilazane (13.8 ml) and methanol (2.73 ml) and the mixture was heated to 50C with stirring under nitrogen. Then add more

13.8 ml of hexamethyldisilazane and 2.73 ml of methanol and heating is continued for 16 hours. Then equal amounts of hexamethyldisilizane and methanol were added twice and the mixture was kept at 50 ° C for 24 hours. 20 ml of methanol are then added and the mixture is heated under reflux for 15 minutes, then cooled and evaporated, the precipitate is filtered off and successively mixed with ethyl acetate and methanol.

630 mg of 3- [8-acetoxymethyl-6,7,8,9, -tetrahydropyrido [1,2-a] indol-10-yl] - (3-benzofuranyl) -1H-pyrrole-2,5-dione are obtained. mp 234-237 ° C.

/

The furandione derivative used as a starting material is prepared as follows:

1.7 g of oxalyl chloride are added dropwise under a nitrogen atmosphere to a solution of 3.3 g of 8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indole in 200 ml of diethyl ether. After 15 minutes, the solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. To this solution was added 2.4 g of 3-benzofuranyl acetic acid and 5.6 ml of triethylamine and the mixture was stirred overnight. The solvent was then removed under reduced pressure and the residue was chromatographed on silica gel using ethyl acetate / petroleum ether (1: 2). Crystallization of the residue from ethyl acetate / petroleum ether gave 1.62 g of 3- [8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] - (3-benzofuranyl) furan- M.p. 214-215 ° C.

Example 58

To a solution of 300 mg of the product of Example 57 in 40 mL of methanol was added 5 mL of 2M sodium hydroxide solution. After 10 minutes, the mixture was acidified with 5 ml of a 2M hydrochloric acid solution and the methanol was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase is washed with sodium bicarbonate solution and then dried, the solution is evaporated and the precipitate is filtered off. 190 mg of 3- (370 benzofuranyl) -4- [6,7,8,9-tetrahydro-8-hydroxymethylpyrido [1,2-a] indol-10-yl] -1H-pyrrole-2,5-dione are obtained. mp 246-248 ° C.

Example 59

In an analogous manner to that described in Example 2, 3- [8-aminomethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl] -4- (3) was obtained from the product of Example 58. (benzofuranyl) -1H-pyrrole-2,5-dione hydrochloride, m.p. 210-212 ° C.

Example 60

To 118 mg of trifluoromethanesulfonic anhydride in 20 ml of dichloromethane at 0 ° C under a nitrogen atmosphere was added a suspension of 90 mg of the product of Example 26 and 45 mg of collidine in 20 ml of dichloromethane. After 45 minutes, 0.41 ml of a 40% dimethylamine solution in water is added, the mixture is stirred for 1.5 hours, the solution is washed with water and sodium bicarbonate solution and then dried and evaporated. The resulting crystals are filtered off and dried. 60 mg of 3- (3-benzo [b] thienyl) -4- [6,7,8,9-tetrahydro-8-dimethylaminomethylpyrido [1,2-a] indol-10-yl] -1H-pyrrole is obtained. 2,5-dione, m.p. 285-286 ° C.

Example 61

To 546 mg of trifluoromethanesulfonic anhydride in 80 ml of dichloromethane at 0 ° C under a nitrogen atmosphere was added a suspension of 400 mg of the product of Example 19 and 208 mg of collidine in 120 ml of dichloromethane. After 1 hour, add

1.9 ml of 50% aqueous dimethylamine and the mixture was stirred for 3 hours, the solvent was removed and the residue was purified by silica gel chromatography using dichloromethane: methanol: acetone (88: 10: 2) as eluent. Mixing with ethyl acetate followed by recrystallization from methanol gave 295 mg of 3- [2,3-dihydro-2-dimethylamino-methyl-1H-pyrrolo [1,2-a] indol-9-yl] -4- (1- methyl 3-indolyl) 1H-pyrrole-2,5-dione trifluoromethanesulfonate, m.p. 323 DEG-325 DEG.

Example 62

A solution of 400 mg of 3- [8-cyano-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan-2,5- of dione in 12 ml of dimethylformamide and 12 ml of 33% aqueous ammonia was heated at 140 ° C for 3 hours. The mixture was then cooled and the resulting solid was filtered off and dried. 275 mg of 3- [8-cyano-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] 4- (1-methyl-3-indolyl) -1H-pyrrole-2 are obtained. 5-dione, m.p. 312-313 ° C.

/

The furandione derivative used as the starting material is prepared as follows:

a) A suspension of 4.0 g of the product of Example 38a) in 4.4 ml of water and 84 ml of acetone was cooled to 0 ° C and 2.18 g of triethylamine was added, followed by 2.56 g of ethyl chloroformate. The resulting solution was stirred under a nitrogen atmosphere. 0.9 ml of 33% aqueous ammonia is then added and the mixture is allowed to warm

Ί2 to room temperature. An additional 0.5 ml of 33% aqueous ammonia is then added and stirring is continued. The solvent is evaporated, the residue is extracted with dichloromethane and the organic phase is washed with water, dried and evaporated. 2.8 g of 6,7,8,9-tetrahydropyrido [1,2-a] indole-8-carboxamide of melting point 179 DEG-181 DEG C. are obtained.

(b) 991 mg of trifluoroacetic anhydride are added dropwise at 10 ° C to a suspension of 1.0 g of the product of (a) in 15 ml of dioxane. The mixture is then partitioned between dichloromethane and water, the organic phase is dried and the solvent is removed under reduced pressure. The oil obtained is chromatographed on silica gel using ethyl acetate / petroleum ether (1: 1). 740 mg of 6,7,8,9-tetrahydropyrido [1,2-a] indole-8-carbonitrile are obtained, m.p. 116-118 ° C.

(c) 518 mg of oxalyl chloride are added to a solution of 800 mg of the product of Example 62 (b) in 100 ml of diethyl ether under a nitrogen atmosphere. The solvent was evaporated and the residue was dissolved in dichloromethane. 771 mg of 1-methyl-3-indolylacetic acid and 1.24 g of triethylamine are added to the obtained solution, the mixture is stirred overnight, the solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel using 10% methanol in dichloromethane as eluent. agents. The fractions containing the desired product were evaporated and the crystals were filtered off and dried. 3- [8-Cyano-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furanine is obtained, m.p. C.

Example 63

A solution of 200 mg of the product of Example 62 in 250 mL of methanol was charged with hydrogen chloride gas at 0 ° C. The solvent was then removed under reduced pressure and the residue was dissolved in 50 ml of dichloromethane and 250 ml of ethanol. Ammonia gas is then introduced into the solution and the solvent is evaporated. The residue was purified by silica gel chromatography, eluting with dichloromethane: methanol: acetic acid: water (90: 18: 3: 2). Mixing with ethyl acetate gave 75 mg of 3- [8-amidino-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole M.p. 237-239 ° C.

Example 64

A solution of 50 mg of 3- [8-carbamoyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan-2,5 of dione in 4 ml of dimethylformamide and 4 ml of 33% aqueous ammonia was heated to 140 ° C. The mixture is extracted with ethyl acetate and the organic phase is washed with water and then dried. The maximum amount of solvent was evaporated and the resulting precipitate was filtered off and dried to give 20 mg of 3- [8-carbamoyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1- methyl-3-indolyl) -1H-pyrrole-2,5-dione, m.p. 315-316 ° C.

The furandione derivative used as a starting material is prepared as follows:

178 mg of oxalyl chloride are added to a solution of 300 ml of the product of Example 62a) in 40 ml of dichloromethane under a nitrogen atmosphere. The solvent was then removed under reduced pressure and the evaporation residue was dissolved in dichloromethane. 265 mg of 1-methyl-3-indolylacetic acid and 424 mg of triethylamine were added to the obtained solution, and they were stirred for 60 hours. Then the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using 10% methanol in dichloromethane as eluent. Crystallization from ethyl acetate gave 70 mg of 3- [8-carbamoyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan -2,5-dione, m.p. 307 DEG-309 DEG.

Example 65

In an analogous manner to that described in Example 1 (1), 3- [8-acetoxymethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl] -4- (5 -methoxy-1-methyl-3-indolyl) furan-2,5-dione yields 3- [6,7,8,9-tetrahydro-8-hydroxymethylpyrido [1,2-a] indol-10-yl] -4- ( 5-methoxy-1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, m.p. 300 DEG-303 DEG.

/

The furandione derivative used as a starting material is obtained as follows:

0.4 ml of oxalyl chloride was added dropwise to a solution of 906 mg of 8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indole in 35 ml of diethyl ether under a nitrogen atmosphere. The solvent was then removed under reduced pressure and the residue was dissolved in dichloromethane. 940 mg of 5-methoxy-1-methyl-3-indolylacetic acid and 1.16 ml of triethylamine are added to the obtained solution, and the mixture is stirred for 40 hours. The solvent was then removed under reduced pressure and the residue was purified by silica gel chromatography at rt

75 using a 1: 2 mixture of ethyl acetate and n-hexane as eluent. Crystallization from ethyl acetate / petroleum ether gave 250 mg of 3- [8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (5-methoxy-1-methyl) M.p. 259-261 ° C.

Example 66

In an analogous manner to that described in the example

2, 3- [8-aminomethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl] -4- (5-methoxy-1-methyl-3-indolyl) was obtained from the product of Example 65 1 H-pyrrole-2,5-diorole hydrochloride, m.p. 268-270 ° C.

Example 67

In an analogous manner to that described in Example 1 (1), 3- [8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (5 bromo-1-methyl-3-indolyl) furan-2,5-dione yields 3- [6,7,8,9-tetrahydro-8-hydroxymethylpyrido [1,2-a] indol-10-yl] -4- ( 5-bromo-1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, m.p. 316 DEG-318 DEG.

/

The furandione derivative used as a starting material is obtained as follows:

(a) 500 mg of sodium hydride dispersion in mineral oil is added to a solution of 1 g of 5-bromoindole-3-acetic acid in 50 ml of tetrahydrofuran and the mixture is stirred under nitrogen for 1 hour. Methyl iodide (820 mg) was then added and the mixture was stirred overnight

76 was stirred under nitrogen for 24 hours. 5 ml of water are then added and the solvent is removed under reduced pressure, a 2M hydrochloric acid solution is added to the residue, and the resulting precipitate is filtered off, washed with n-hexane and dried. The resulting solid was recrystallized from diethyl ether. 5-Bromo-1-methyl-indolylacetic acid of melting point 192 DEG-194 DEG C. is obtained.

(b) 500 mg of oxalyl chloride are added to a solution of 900 mg of the product of (a) in 100 ml of diethyl ether under a nitrogen atmosphere. Then the solvent was evaporated and the residue was dissolved in dichloromethane. 800 mg of the product from a) and 810 mg of triethylamine are added to the obtained solution, and the mixture is stirred for 48 hours, the solvent is removed under reduced pressure and the residue is purified by silica gel chromatography using ethyl acetate / n-hexane 1: 1 as eluent. Crystallization of the obtained solid from ethyl acetate gave 400 mg of 3- [8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10yl] -4- (5-bromo-1-methyl-3). m.p. 215-220 ° C; indolyl) furan-2,5-dione;

Example 68 In an analogous manner to that described in the example

2, 3- [8-aminomethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl] -4- (5-bromo-1-methyl-3-indolyl) was obtained from the product of Example 67 -1H-pyrrole-2,5-dione hydrochloride, m.p. &gt; 310 ° C.

Example 69

A solution of 200 mg of 3- [7- (2-acetoxyethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan-

The 2,5-dione in 2 ml of dimethylformamide and 1 ml of 33% aqueous ammonia was heated to 140 ° C, then 1 ml of 2M sodium hydroxide solution was added to the obtained cooled solution, and the mixture was stirred for 2 hours. The reaction mixture was then acidified with 2M hydrochloric acid solution and evaporated. The residue was partitioned between ethyl acetate and water and the organic phase was dried, the solvent was evaporated and the resulting solid was mixed with ethyl acetate. 115 mg of 3- [6,7,8,9-tetrahydro-7 (2-hydroxyethyl) pyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-) are obtained.

From indolyl) -1H-pyrrole-2,5-dione, m.p. 236-238 ° C.

The furandione derivative used as a starting material is obtained as follows:

(a) 400 mg of a 60% dispersion of sodium hydride in mineral oil is added to a solution of 2.24 g of triethylphosphonoacetate in 40 ml of dimethoxyethane under a nitrogen atmosphere. The solution was then cooled to 0 ° C and 1.85 g of the product of Example 35d) in 10 ml of dimethoxyethane was added to the cooled solution. The mixture was stirred overnight and then evaporated, the residue was dissolved in dichloromethane and then the dichloromethane solution was washed with water, dried and evaporated. The residue was purified by silica gel chromatography eluting with diethyl ether / petroleum ether (1: 3). 1.55 g of a mixture of ethyl- (E- and (Z) - (6,7,8,9-tetrahydropyrido [1,2-a] indole) are obtained.

7-ylidene) acetate. A solution of 1.4 g of this product from ethanol was shaken with 280 mg of 10% palladium on carbon under a hydrogen atmosphere, then the catalyst was filtered off and the filtrate was evaporated. 1.2 g of ethyl 6,7,8,9-tetrahydropyrido [1,2-a] indole-7-acetate are obtained, m.p. 66-68 ° C after crystallization from a mixture of diethyl ether and petroleum ether.

(b) To a solution of 1.2 g of the product of (a) in 100 ml of diethyl ether, 3.5 ml of a 1M solution of lithium aluminum hydride in diethyl ether is added and, after stirring for one hour, 50 ml of aqueous ammonium chloride are added. The mixture is extracted with diethyl ether and the organic phase is dried and evaporated. 1.01 g are obtained

6,7,8,9-tetrahydro-7- (2-hydroxyethyl) pyrido [1,2-a] indole, m.p. 70-72 ° C after crystallization from diethyl ether / petroleum ether.

c) To a solution of 1.04 g of the product of b) in 30 ml of dichloromethane was added 6 ml of acetic anhydride in 3 ml of pyridine and the solution was stirred under nitrogen, then the mixture was evaporated to dryness and the residue dissolved in dichloromethane. The organic phase was washed with 2M hydrochloric acid solution and water, dried and evaporated. The residue was purified by silica gel chromatography using a 1: 4 mixture of diethyl ether and petroleum ether. 550 mg of 7- (2-acetoxyethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indole is obtained.

(d) 250 μg of oxalyl chloride are added to a solution of 670 mg of the product of (c) in 12 ml of dichloromethane under a nitrogen atmosphere. The solvent was then removed under reduced pressure and the residue was dissolved in dichloromethane. 493 mg of 1-methyl-3-indolylacetic acid and 527 mg of triethylamine were added to the obtained solution, and the mixture was stirred, then the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using ethyl acetate / petroleum ether 1: 2. eluent. 350 mg of 3- [7 (2-acetoxyethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan-2 are obtained, 182 DEG-184 DEG C. after crystallization from ethyl acetate.

Example 70

In an analogous manner to that described in Example 2, 3- [7- (2-aminoethyl-

6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl] -4- (l-methyl-3-indolyl) -lH-pyrrole-2,5-diónŕhyd _Vol hiorid mp 240-242 ° C

Example 71

In an analogous manner to that described in Example 1 (1), 3- [8-acetoxymethyl-6,7,8,9-tetrahydro-2-methoxy-pyrido [1,2-a] indol-10-yl] -4- (l-methyl-3-indolyl) furan

2,5-dione: 3- [6,7,8,9-tetrahydro-8-hydroxymethyl-2-methoxy-pyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) - 1 H -pyrrole-2,5-dione, m.p. 195-197 ° C.

The furandione derivative used as a starting material is obtained as follows:

(a) 2 g of 60% sodium hydride in mineral oil are washed with n-hexane and, after decantation, suspended in 100 ml of dimethylformamide under a nitrogen atmosphere. A solution of 10 g of ethyl 5-methoxyindole-2-carboxylate in 100 ml of dimethylformamide is then added to the suspension obtained, and the mixture is stirred. 9.8 g of ethyl 4-bromobutyrate are then added and the mixture is stirred for 2 hours. After cooling, 50 ml of 1M hydrochloric acid solution and 400 ml of water are added. The mixture was extracted with diethyl ether and the combined extracts were washed with brine. The organic phase is dried and evaporated. A solution of the obtained oil in tetrahydrofuran was added to a mixture of 5.2 g of potassium tert-butoxide in 200 ml of tetrahydrofuran under a nitrogen atmosphere. The mixture was then cooled and neutralized with 1M hydrochloric acid solution. Water was added to the mixture and extraction was performed with diethyl ether. The combined extracts were washed with water and brine and then dried. Evaporation of the solvent and crystallization of the residue from ethyl acetate yielded 6.7 g of ethyl

6,7-dihydro-9-hydroxy-2-methoxypyrido [1,2-a] indole-8-carboxylate, m.p. 157-160 ° C.

(b) 5 g of the product of (a) in 200 ml of ethanol are treated with Raney-nickel under a nitrogen atmosphere for 10 portions on a spatula tip and 100 ml of water. The suspension is heated to reflux, then cooled and filtered. The solid was washed with ethyl acetate and the volatiles from the combined filtrates were removed under reduced pressure. The aqueous suspension is extracted with ethyl acetate, the combined extracts are washed with brine and dried. Evaporation of the solvent and crystallization of the residue from methanol yields

2.41 g of ethyl 6,7,8,9-tetrahydro-2-methoxypyrido [1,2-a] indole-8-carboxylate, m.p. 104-105 ° C.

c) To a solution of 2.3 g of the product of b) in 25 ml of tetrahydrofuran was added a suspension of 260 mg of lithium aluminum hydride in 20 ml of tetrahydrofuran under a nitrogen atmosphere. Then 10 ml of ethyl acetate and 20 ml of water are added to the mixture, the mixture is acidified by addition of 1M hydrochloric acid solution to pH 3 and extracted with diethyl ether. The combined extracts were washed with water and dried. Evaporation of the solvent gave 1.85 g of 6,7,8,9-tetrahydro-2-methoxypyrido [1,2-a] indole-8-methanol, m.p. 95-96 ° C (crystallized from ethyl acetate-n-hexane). .

d) 1 g of the product of c) in 10 ml of pyridine was treated with 1.5 g of acetic anhydride. The solvent was evaporated, the residue was partitioned between diethyl ether and 5% aqueous ammonium chloride, the organic phase was washed with brine, dried and evaporated. Crystallization of the residue from a mixture of diethyl ether and n-hexane gave 0.84 g of 8-acetoxymethyl-6,7,8,9-tetrahydro-2-methoxypyrido [1,2-a] indole, m.p. 98-100 ° C.

(e) A suspension of 800 mg of the product of (d) in 25 ml of diethyl ether is added with the addition of 0.27 ml of oxalyl chloride under nitrogen, then the solvent is evaporated, the residue is dissolved in 20 ml of dichloromethane and 555 mg of N-methylindole- 3-acetic acid and 0.8 ml triethylamine. The mixture was stirred for 65 hours and then the solvent was evaporated under reduced pressure. Chromatography of the residue on silica gel, eluting with ethyl acetate / n-hexane (1: 1), afforded 380 mg of 3- [8-acetoxymethyl-

6,7,8,9-tetrahydro-2-methoxy-pyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) furan-2,5-dione, m.p. 131-133 ° C (decomposition) after crystallization from a mixture of toluene and n-hexane.

Example 72

In an analogous manner to that described in the example

2, 3- [8-aminomethyl-

6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3indolyl) -1H-pyrrole-2,5-dione hydrochloride, m.p. 235-238 ° C (dec.).

Example 73

a) To a solution of 150 mg of the product of Example 20 in dichloromethane under a nitrogen atmosphere was added 135 mg of 1,1'-thiocarbonyldiimidazole and after 17 hours the mixture was washed with water and dried. The solvent was evaporated and the residue was crystallized from ethyl acetate. 150 mg of 3- [1,2,3,4-tetrahydro-2- (1-imidazolylthiocarbonyl) pyrazino [1,2-a] indol-10-yl] 4- (1-methyl-3-indolyl) - are obtained. 1 H-pyrrole-2,5-dione, m.p. 244-247 ° C (dec.).

b) To a solution of 140 mg of a) in 10 ml of DMF was added 20 ml of 33% aqueous ammonia. After 17 hours, the suspension is filtered and the solid is washed with water and then dried. 95 mg of 3- [1,2,3,4-tetrahydro-2-thiocarbamoylpyrazino [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole is obtained.

2,5-dione, m.p. 278 DEG C. (decomposition).

Example 74

To a solution of 150 mg of the product of Example 20 in 50 ml of dichloromethane was added 3 ml of acetic anhydride and 3 ml of triethyl83 amine, and after 17 hours the mixture was washed with water. The organic phase is dried and evaporated. The evaporation residue is dissolved in dichloromethane and 0.08 ml of diethylamine is added to the obtained solution. After 17 hours the solution was evaporated. Crystallization of the residue from a mixture of dichloromethane and n-hexane gave 80 mg

3- [2-Acetyl-1,2,3,4-tetrahydropyrazino [1,2-a] indol-10-yl] -

4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, m.p. 308-310 ° C.

Example 75

In an analogous manner to that described in Example 74, 3- [8-acetamidomethyl-

6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3indolyl) -1H-pyrrole-2,5-dione, m.p. 270-273 ° C .

Example 76

To a solution of 150 mg of the product of Example 20 in 40 mL of dichloromethane was added 40 mg of triethylamine and 44 mL of methanesulfonyl chloride. After 17 hours, the mixture is washed with water, the organic phase is dried and evaporated. Chromatography of the residue on silica gel using a 2: 1 mixture of ethyl acetate and n-hexane as well as ethyl acetate alone gives 95 mg of 3- [1,2,3,4-tetrahydro-2-methanesulfonyl-pyrazino [1,2] -α] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-diene, m.p. 298-301 ° C (dec.).

Example 77

To a solution of 3.0 g of the product of Example 1 in 100 ml of tetrahydrofuran was added a suspension of 1.8 g of lithium aluminum hydride in 50 ml of tetrahydrofuran at 0 ° C. The mixture was then heated under reflux for 16 hours, cooled, 10 ml of water added and extracted with dichloromethane. The combined dichloromethane extracts were washed with aqueous sodium bicarbonate solution, dried and evaporated. Chromatography of the solid obtained on silica gel using dichloromethane / methanol (95: 5) as eluent gave

(a) 400 mg of 1,5-dihydro-3- [6,7,8,9-tetrahydro-8-hydroxymethylpyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -2H-pyrrol-2-one, m.p. 205-207 ° C;

b) 160 mg of 1,5-dihydro-4- [6,7,8,9-tetrahydro-8-hydroxymethyl-pyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -2H-pyrrol-2-one, m.p. 201-203C.

Example 78

In an analogous manner to that described in Example 1 (1), from 0.5 g of 3- [8-acetoxymethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl is obtained. ] -4- (3-trifluoromethylphenyl) furan

2.5-dione yields 110 mg of 3- [6,7,8,9-tetrahydro-8-hydroxymethylpyrido [1,2-a] indol-10-yl] -4- (3-trifluoromethylphenyl) -1H-pyrrole-

2.5-dione with a melting point of 77-79 ° C.

The furandione derivative used as the starting material is prepared as follows:

To a solution of 3.0 g of 8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indole in 50 ml of dichloromethane cooled to 0-4 ° C was added dropwise 1.7 g of oxalyl chloride. After two hours, the solvent was evaporated and the residue was dissolved in dichloromethane. The resulting solution was added to a solution of 2.7 g of (α, α, α-trifluoro-m-tolyl) acetic acid and 3.2 g of triethylamine in 70 ml of dichloromethane. The mixture was stirred for 16 hours and then evaporated. The residue is chromatographed on silica gel, eluting with dichloromethane / methanol (95: 5). 700 mg of 3- [8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (3-trifluoromethylphenyl) furan-2,5-dione are obtained, m.p. 176 to 177 ° C.

Example 79

In an analogous manner to that described in Example 1 (1), from 1.0 g of 3- [8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] Of 4- (4-methoxyphenyl) furan-2,5-dione gives 150 mg of 3- [6,7,8,9-tetrahydro-8-hydroxymethylpyrido [1,2-a] indol-10-yl] -4- (4-methoxyphenyl) -1H-pyrrole-2,5-dione, m.p. 77-79 ° C.

I

The furandione derivative used as the starting material is prepared as follows:

To a solution of 3.0 g of 8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indole in 50 ml of dichloromethane cooled to 0-4 ° C was added dropwise 1.7 g of oxalyl chloride. After two hours, the solvent was evaporated and the residue was dissolved in dichloromethane. The resulting solution was added to a solution of 2.24 g of p-methoxyphenylacetic acid and 3.2 g of triethylamine in 70 ml of dichloromethane. The mixture was stirred for 16 hours and then evaporated. Chromatography of the residue on silica gel using dichloromethane / methanol (95: 5) as eluent gave 2 g of 3- [8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (4-methoxyphenyl) furan-2,5-dione, m.p. 79-82 ° C.

Example 80

In an analogous manner to that described in the example

1, paragraph 1), from 0.8 g of 3- [8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (2-chlorophenyl) furan -2,5-dione gives 120 mg of 3- (2-chlorophenyl) -4- [6,7,8,9-tetrahydro-8-hydroxymethylpyrido [1,2-a] indol-10-yl] -1H-pyrrole -2,5-dione, m.p. 232-233 ° C.

/ /

The furandione derivative used as a starting material is obtained as follows:

To an ice-cooled solution of 4.0 g of 8-acetoxymethyl-

6,7,8,9-tetrahydropyrido [1,2-a] indole in 50 ml dichloromethane was added dropwise with 2.2 g oxalyl chloride. After two hours, the solvent was evaporated and the residue was dissolved in dichloromethane. The solution thus obtained was added to a solution of 3.0 g of 2-chlorophenylacetic acid and 4.0 g of triethylamine in dichloromethane. The mixture was stirred for 16 hours and then evaporated. Chromatography of the residue on silica gel using dichloromethane / methanol (95: 5) as eluent gave

0.9 g of 3- [8-acetoxymethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (2-chlorophenyl) furan-2,5-dione, m.p.

Mp 168-171 ° C.

Example 81

In an analogous manner to that described in Example 51, 30 mg of 3- [8-aminomethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] are obtained from 80 mg of the product of Example 78. -4- (3-trifluoromethylphenyl) -1H-pyrrole-2,5-dione, m.p. 202-204 ° C.

Example 82

In an analogous manner to that described in Example 51, 88 mg of 3- [8-aminomethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] are obtained from 80 mg of the product of Example 79. -4- (4-methoxyphenyl) -1H-pyrrole-2,5-dione, m.p. 195-196 ° C.

Example 83

In an analogous manner to that described in Example 53, 57 mg of 3- [8-aminomethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] are obtained from 80 mg of the product of Example 80. -4- (2-chlorophenyl) -1H-pyrrole-2,5-dicin, m.p. 206 DEG-208 DEG C. (dec.).

The following galenic preparations are produced in a known manner:

Example A

ingredients for 1 tablet compound of formula I 5.0 mg lactose 125.0 mg maize starch 75.0 mg talc 4.0 mg magnesium stearic acid salt 1.0 mg tablet weight 210.0 mg

Example

Ingredients per 1 capsule

compound of formula I 10,0 mg lactose 165.0 mg corn starch 20.0 mg talc 5.0 mg

capsule fill weight 200.0 mg

Claims (20)

PATENT CLAIMS An indolyl-substituted pyrrol of formula I (I) wherein R is hydrogen or hydroxy; R ¹ and R ² together represent the group "( ^CH ₂ ) _n -a" R ⁷ represents a hydrogen atom, or R ¹ and R ⁷ together represent a group "( ^c H ₂ ) _n -a R ² is H; R ³ is aryl or heteroaryl; R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl or alkylsulfonyl; R ⁸ is - (CH ₂ ) p R ⁹ or - (CH ₂ ) g R ¹⁰ ; R ⁹ represents a hydrogen atom, an alkylcarbonyl group, an aminoalkylcarbonyl group, a cyano group, an amidino group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylsulfonyl group, an aminocarbonyl group or an aminothiocarbonyl group; R ¹⁰ is hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, tri, azido, acylamino, alkylsulfonylamino, arylsulfonylamino, alkylthio, alkoxycarbonylamino, aminoacylaminoskupinu, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulfonyloxy or arylsulfonyloxy, a 5- or 6-membered saturated heterocyclic a nitrogen-containing group which is bonded via a nitrogen atom or represents a group of the formula -UC (V) -W; U is sulfur or NH; V is NH, NO ₂ , NCN or CHNO ₂ ; W is amino, monoalkylamino or dialkylamino; one of X and Y is O and the other is O or two hydrogen atoms; Z is CH or N; m, p and q are each from 0 to 5 and n is from 1 to 5, wherein the radicals generally described independently occurring or in the compounds in the above definitions have the following meanings: aryl is phenyl or naphthyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl; heteroaryl is a 5- or 6-membered heterocyclic aromatic group optionally containing a fused benzene ring and optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, alkylsulfonyl, amino, sulfonyl, acylamino, acylamino, acylamino, acylamino, acylamino, acylamino, acylamino; ; alkyl represents a straight or branched alkyl group of up to 7 carbon atoms; and * acyl represents a radical derived from an alkanecarboxylic acid having up to 7 carbon atoms or an aromatic t-carboxylic acid; wherein when Z is a nitrogen atom, then m and q are each 2 to 5; as well as pharmaceutically usable salts of the acidic compounds of the formula I with bases and the basic compounds of the formula I with acids. 2. Indolylsubstituované pyrroles according to claim 1, of formula I, wherein R is H, R ⁹ is hydrogen, alkylcarbonyl, cyano, amidino, alkoxycarbonyl, alkylsulfonyl, aminocarbonyl or aminothiocarbonyl group, and R ¹⁰ is OH, C , halogen, amino, monoalkylamino, dialkylamino '= group, tri, azido, acylamino, alkylsulfonylamino, arylsulfonylamino, alkylthio, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulphonyloxy or arylsulphonyloxy or a group -uc (V) -W and R ^1, R ² R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ U, V, W, X, Y, Z, m, n, p, and q are as defined in claim 1 as well as pharmaceutically usable acid salts compounds of the formula I with bases and basic compounds of the formula I with acids. 3. Indolylsubstituované pyrroles according to claim 1, of formula I, wherein R ¹ and R ² together are -CH ₂ - and R is H, m is 1 or% 2 and Z are CH, and the other symbols are as defined in claim 1 or 2, as well as the pharmaceutically usable salts of the acidic compounds of the formula I with bases and the basic compounds of the formula I with acids. 4. A compound according to claim 1, wherein the pyrrolyl is substituted by a pyrrole. Ί 9 of formula I, wherein R ^x and R together are - (CH ₂ ) ₂ - ^and R is hydrogen, m is 1 and Z is CH and the other symbols are as defined in claim 1 or 2, such as also the pharmaceutically usable salts of the acidic compounds of the formula I with bases and the basic compounds of the formula I with acids. 5. Indolylsubstituované pyrroles according to claim 1, of formula I, wherein R ^x and R together are -CH ₂ - and R ⁷ is H, m is 2 and Z is N ·, and the other symbols are as defined in of claim 1 or 2, as well as the pharmaceutically usable salts of the ⁴ acidic compounds of the formula I with bases and the basic compounds of the formula I with acids. 6. The indolyl-substituted pyrrol of claim 1, wherein: Ί 7 of the general formula I, in which R and R together represent skun> x> -CH ₂ - and R is hydrogen, m is 1, Z is CH and the other symbols are as defined in claim 1 or 2, as well as pharmaceutically usable salts of the acidic compounds of the formula I with bases and the basic compounds of the formula I with acids. 7. A compound according to claim 1, wherein R ^{@ 1} and R @ ⁷ together represent a group. - (CH ₂ ) ₂ ^{- and R} is hydrogen, m is 0, Z is CH and the other symbols are as defined in claim 1 or 2, as well as pharmaceutically usable salts of the acidic compounds of formula I with bases and basic compounds of the formula I with acids. The indolyl-substituted pyrrol of claim 1, Q of formula I wherein R is phenyl, naphthyl, 3-benzofuranyl, 3-benzothienyl or 3-indolyl, optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl , hydroxy, alkoxy, haloalkyl, nitro, acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl and the other symbols are as defined in any one of claims 1 to 6, wherein alkyl and acyl are as defined in claim 1 as well as pharmaceutically usable salts acidic compounds of the formula I with bases and basic compounds of the formula I with acids. 9. Indolylsubstituované pyrroles according to claim 8 of formula I, wherein R ³ is L-methyl-3-indolyl group and the other symbols are as defined in Claim 8, as well as the pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of the formula I with acids. A compound according to any one of claims 1 to 9, wherein R ⁴ , R ⁵ and R ⁶ are each hydrogen and the other symbols are as defined in any one of claims 1 to 9, as well as pharmaceutically usable acid salts. compounds of the formula I with bases and basic compounds of the formula I with acids. A compound according to any one of claims 1 to 10, wherein R 0 is - (CH ₂ ) g R ¹⁰ and the other symbols are as defined in any one of claims 1 to 10, as well as pharmaceutically usable acid salts. compounds of the formula I with bases and basic compounds of the formula I with acids. 12. A compound according to claim 11, wherein q is 1 or 2 and the other symbols are as defined in claim 11, as well as pharmaceutically acceptable salts of the acidic compounds of the formula I with bases and the basic compounds of the formula I with acids. . 13. Indolylsubstituované pyrroles according to claim 1, of formula I, wherein R ^xu is hydroxy, amino, monoalkylamino, dialkylamino, tri, azido, acylamino, alkylcarbonyloxy or alkylsulphonyloxy or a group -uc (V) -W, wherein the terms alkyl and acyl are as defined in claim 1 and other symbols are as defined in claim 11 or 12, as well as pharmaceutically usable salts of the acidic compounds of the formula I with bases and the basic compounds of the formula I with acids. 14. A compound according to claim 13, wherein U is S, V is NH and W is amino, and the other symbols are as defined in claim 13, as well as the pharmaceutically acceptable salts of the acidic compounds of formula I with bases and bases. compounds of formula I with acids. Indolyl-substituted pyrroles according to any one of claims 1 to 14, in which X and Y are in each case oxygen and the other symbols have the meaning given in any one of claims 1 to 14, as well as pharmaceutically usable salts of acidic compounds of the formula I with bases and basic compounds of the formula I with acids. The indolyl-substituted pyrrol of claim 1 or 2 selected from the group consisting of 3- [8- (aminomethyl) -6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl] -4- (l-methyl-3-indolyl) -lH-pyrrole-2,5- dione, 3- [7- (amidinothiomethyl) -6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole -2,5-dione and "c 3- [6,7,8,9-tetrahydro-8 - [(dimethylamino) methyl] pyrido [1,2-a] indol-10-yl] -4- (1-methyl-3-indolyl) -1H-pyrrole- 2,5-dione, as well as their pharmaceutically usable salts of these compounds. \ 97 \ Intermediates (i) for the preparation of indolyl-substituted pyrrole of general formula I according to claim 1 (general formula II) Λ Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^7, R ⁸ , Z and m are as defined in claim 1. Indolyl-substituted pyrroles according to any one of claims 1 to 16 for use as therapeutically active substances, in particular for use as anti-inflammatory, immunological, oncological, bronchopulmonary and cardiovascular active substances and as active substances for the treatment of asthma and AIDS. Process for the preparation of indolsubstituted pyrroles, as well as their pharmaceutically usable salts with bases, in the case of acidic compounds, and with acids, in the case of basic compounds, according to any one of claims 1 to 16, characterized in that: a) reacting a compound of formula II to produce a compound of formula I in which X and Y are oxygen atoms Ktorom Λ in which R ^1, R ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ R ^8, Z and m are as defined above, with ammonia under pressure or with hexamethyldisilazane and methanol to give a compound of formula I wherein R is a hydrogen atom or a hydroxylamine to form a compound of formula I wherein R is hydroxy, or (b) to produce a compound of formula I in which one of X and Y is oxygen and the other in two hydrogen atoms, reduces the compound of formula I in which X and Y are oxygen by treatment with lithium aluminum hydride, and c) optionally reacting the reactive group contained in the compound of formula I obtained; and d) optionally, converting the acidic compound of formula I into a pharmaceutically acceptable salt by treatment with a base, or converting the basic compound of formula I into a pharmaceutically acceptable salt by treatment with an acid. Pharmaceutical compositions, in particular anti-inflammatory, immunological, oncological, bronchopulmonary or cardiovascular agents or compositions for the treatment of asthma or AIDS, characterized in that they comprise an indolyl-substituted pyrrole according to any one of claims 1 to 16 and an inert carrier.