IE64184B1 - Substituted pyrroles - 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

The present invention relates to substituted pyrroles, especially to those of the general formula t wherein R is hydrogen or hydroxy, R1 and R2 together are a group of the formula -(CH2)n- and R7 is hydrogen or R1 and R7 together are a group of the formula -(CH2)n- and R2 is hydrogen; R3 is aryl or heteroaryl; R4, R5 and R6 are hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulphinyl or alkylsulphonyl; R8 is a group of the formula -(CH2)P-R9 or -(CH2)q-R10; R9 is hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkyIsuIphonyI, aminocarbonyl or aminothiocarbonyl; R10 is hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylsulphonylamino, arylsulphonylamino, alkylthio, alkoxycarbonylamino, aminoacylamino, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulphonyloxy or arylsulphonyloxy, a 5- or 6-membered saturated nitrogen-containing heterocycle attached via the N atom or a group of the formula -U-C(V)-W; U is a S atom or NH; V is the group NH, NNO2, NCN or CHNO2; W is amino, mono- or dialkylamino; one of X and Y is an 0 atom and the other is 0 or (H,H); Z is the group CH or a N atom; m, p and q are a number from 0 to 5 and n is a number from 1 to 5, with the proviso that m and q are a number from 2 to 5 when Z is a N atom; as well as pharmaceutically usable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids.

The invention is concerned with the compounds defined above per se and as therapeutically active substances, a process for their manufacture and novel intermediates; medicaments io which contain these compounds and the manufacture of these medicaments as well as the use of said compounds in the treatment or prophylaxis of illnesses, especially of inflammatory, immunological, oncological, bronchopulmonary and cardiovascular disorders and in the treatment of asthma or AIDS, or for is the manufacture of such medicaments.

In the scope of the invention alkyl, alone or in combination, means a straight-chain or branched alkyl group with up to 7, preferably up to 4, C atoms such as methyl, ethyl, propyl, 2u isopropyl, butyl, s-butyl, t-butyl and pentyl. Examples of alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy and tbutoxy. A haloalkyl can contain one or more halogen atoms. Examples of such groups are chloromethyl and trifluoromethyl. Acyl means a group which is derived from an alkanecarboxylic acid with up to 7, preferably up to 4, C atoms, e.g. formyl, acetyl, propionyl or butyryl, or from an aromatic carboxylic acid, e.g. benzoyl. Aryl, alone or in combination, means a monocyclic or polycyclic group, preferably a monocyclic or bicyclic group, i.e. phenyl or naphthyl, which may be substituted by one or more substituents, preferably 1-3 substituents, from the following group: halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulphinyl or alkylsulphonyl. Examples of aryl .groups are phenyl, 2-, 3- or 4-chlorophenyl, 3-bromophenyl, 2- or 3-methylphenyl, 2,5-dimethylphenyl, 4-methoxy35 phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-, 3or 4-nitrophenyl, 3-aminophenyl, 4-aminophenyl, 4-methylthiophenyl, 4-methylsulphinylphenyl, 4-methylsulphonylphenyl and 1or 2-naphthyl. Heteroaryl means a 5- or 6-membered hetero cyclic aromatic group which can optionally contain a fused benzene ring and which may be substituted by one or more, preferably 1-3, substituents from the following group: halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulphinyl and alkylsulphonyl. Examples of such heteroaryl groups are 2- or 3-thienyl, 3-benzothienyl, 3benzofuranyl, 2-pyrrolyl and 3-indolyl which may be substituted as described above. The 5- or 6-membered saturated nitrogencontaining heterocycle attached via a N atom can contain a io further nitrogen, oxygen or sulphur atom. Examples of such heterocycles are pyrrolidino, piperidino, piperazino, morpholino and thiamorpholino. Halogen means fluorine, chlorine, bromine or iodine. is The compounds of formula I in which Z is the group CH and R8 is a group -(CH2)P-R9 in which p is a number between 1 and 5 or -(CH2)q-R10 contain an asymmetric C atom and can therefore exist in racemic or optically active form. The invention includes not only the racemic compounds, but also the optically active 2o isomers.

In the preferred compounds of formula I, R1 and R2 together are -CH2- and R7 is hydrogen, m is the number 1 or 2 and Z is CH; or R1 and R2 together are -(CH2)2- and is hydrogen, m is the number 1 and Z is the group CH; or R1 and R2 together are -CH2and R7 is hydrogen, m is the number 2 and Z is a N atom; or R1 and R7 together are -CH2- and R2 is hydrogen, m is the number 1 and Z is the group CH; or R1 and R7 together are -(CH2)2- and R2 is hydrogen, m is 0 and Z is the group CH. R3 is preferably phenyl, naphthyl, 3-benzothienyl, 3-benzofuranyl or 3-indolyl which may be optionally substituted as defined above, especially 1-methyl3-indolyl. Preferably, R4, R5 and R6 are hydrogen. R8 is preferably -(CH2)q-R10. Preferably, q is 1 or 2. R10 is preferably hydroxy, amino, mono-, di- or trialkylamino, azido, acylamino, alkylcarbonyloxy or alkylsulphonyloxy or a group -U-C(V)-W. U is preferably S; V is preferably NH and W is preferably amino.

Especially· preferred compounds are: 3-[8-( Aminomethy 1)-6,7,8,9-tet rahydropyrido[ 1,2-a]indol1 0-y I]-4-( 1 -methyl-3-indoly 1)-1 H-pyrrole-1,5-dione, 3-[7-(amidinothiomethyl)-6,7,8,9-tetrahydropyrido[l ,2ajindol-1 0-yl]-4-(1 -methyl-3-indolyl)-l H-pyrrole-2,5-dione and 3-[6,7,8,9-tetrahydro-8-[(dimethylamino)methyl]pyrido[1,2-a]indol-l 0-y I]-4-(1 - methyl-3-indoly 1)-1 H-pyrrole-2,5dione and pharmaceutically acceptable acid addition salts thereof.

The above-defined compounds of formula I and salts thereof can be manufactured by a) for the manufacture of a compound of formula I in which X and Y are oxygen, reacting a compound of the general formula wherein R1, R2, R3, R4, R5, R6, R7, R8, Z and m have the significance given in claim 1, with ammonia under pressure or with hexamethyldisilazane and methanol to give a compound of formula I in which R is hydrogen or with hydroxylamine to give a compound of formula I in which R is hydroxy, or b) for the manufacture of a compound of formula I in which one of X and Y is oxygen and the other is (H,H), reducing a compound of formula I in which X and Y are oxygen with lithium aluminium hydride, or c) if desired, functionally modifying a reactive group present in a compound of formula I obtained, and d) if desired, converting an acidic compound of formula I into a pharmaceutically usable salt with a base or converting a basic compound of formula I into a pharmaceutically usable salt with an acid.

The reaction of a compound of formula II with ammonia under pressure according to variant a) is conveniently carried out using aqueous ammonia, preferably 33% aqueous ammonia, and in the presence of a water-miscible inert organic solvent such as dimethylformamide (DMF). The reaction is preferably carried out at an elevated temperature, e.g. a temperature between about 100 is and150°C.

The reaction of a compound of formula II with hexamethyldisilazane and methanol can be conveniently carried out in an inert organic solvent such as a halogenated hydrocarbon, e.g. 2u chloroform, carbon tetrachloride or chlorobenzene, or an aromatic hydrocarbon, e.g. benzene, toluene or xylene, at an elevated temperature, e.g. between about 40 and 110°C.

The reaction of a compound of formula II with hydroxyl25 amine can be conveniently carried out in an inert organic solvent such as DMF and at room temperature or at elevated temperature, preferably at about 100°C. Preferably, the hydroxylamine is 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, e.g. sodium or potassium carbonate.

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

According to variant c), a reactive group present in a compound of formula I can be modified in a manner known per se. When R8 is a group -(CH2)p-R9 in which R9 is alkoxycarbonyl and p is 0, [this group can] be converted into a corresponding group in which R9 is hydrogen by treatment with an acid. A group •(CH2)q-R10 in which R10 is alkylcarbonyloxy can be converted into a corresponding group in which R10 is hydroxy by treatment with a base. A group -(CH2)q-R10 in which R10 is hydroxy can be converted into a corresponding group in which R]0 is amino, io mono-, di- or trialkylamino or a 5- or 6-membered saturated Ncontaining heterocycle attached via the nitrogen atom by treatment firstly with trifluoromethanesulphonic anhydride and subsequently with ammonia, a mono-, di- or trialkylamine or an appropriate heterocycle. A group of the formula -(CH2)q-R10 in is which R10 is hydroxy can be converted using an alkanesulphonic anhydride into the corresponding group in which R10 is alkylsulphonyloxy, A group of the formula -(CH2)q-R10 in which R10 is alkylsulphonyloxy can be converted into the corresponding group in which R10 is formamido by reaction with ammonia in DMF or into the corresponding group in which R10 is azido by reaction with an alkali metal azide or into the corresponding group in which R10 is a group -U-C(V)-W, U is a S atom, V is a NH group and W is amino by reaction with thiourea. Further, a group -(CH2)q-R10 in which R10 is azido can be converted by catalytic hydrogenation into a corresponding group in which R10 is amino.

A group -(CH2)q-R10 in which R10 is alkoxycarbonylamino can be converted into a corresponding group in which R10 is amino by treatment with an acid. A group -(CH2)q-R10 in which R10 is amino can be acylated to the corresponding group in which R10 is acylamino or can be reacted with 3,5-dimethyl-N2-nitro-l pyrazole-1-carboxamide to the corresponding group in which R10 is a group -U-(C(V)-W, U and V are the group NH and W is the group NNO2. Further, a group -(CH2)q-R10 in which R10 is amino can be converted into the corresponding group in which R10 is isothiocyanato by treatment with 1,1-thiocarbonyldiimidazole. A group -(CH2)P-R9 in which R9 is cyano can be converted by treatment with hydrogen chloride and then with ammonia into the corresponding group in which R9 is amidino.

A compound of formula I in which Z is a N atom, R8 is a group -(CH2)P-R9, p is 0 and R9 is hydrogen can be converted into the corresponding compound in which R9 is alkanoyl, alkoxycarbonyl or aralkoxycarbonyl by appropriate acylation; into the corresponding compound in which R9 is alkylsulphonyl by reaction with an alkanesulphonyl chloride; into the corresponding compound in which R9 is aminoalkcarbonyl by treatment with trifluoroacetamidoalkanoyl chloride and then with ammonia; into a corresponding compound in which R9 is aminocarbonyl by io treatment with 1,1-carbonyldiimidazole and then with ammonia; or into the corresponding compound in which R9 is aminothiocarbonyl by treatment with 1,1-thiocarbonyldiimidazole and then with ammonia. is The conversion of an acidic compound of formula I into a pharmaceutically usable salt according to variant e) can be carried out by treatment with a suitable base in a manner known per se. Suitable salts are those derived from an inorganic base, e.g. sodium, potassium or calcium salts, or from an organic base such as ethylenediamine or mono- or diethanolamine. The conversion of a basic compound of formula I into a pharmaceutically usable salt can be carried out by treatment with a suitable acid in a manner known per se. Suitable salts are those derived from an inorganic acid such as hydrochlorides, hydrobro25 mides, phosphates or sulphates or from an organic acid, e.g. acetates, citrates, fumarates, tartrates, maleates, methanesulphonates or p-toluenesulphates.

The starting compounds of formula II in variant a) are novel and as such are an object of the invention. They can be prepared by reacting a compound of the formula wherein R1, r2, R4, R5, R6, R7, R8, Z and m have the above significance, with a compound of the formula HOOC-CH2-R3 IV wherein R3 has the above significance, and, if desired, by functionally modifying a reactive group.

The reaction of a compound of formula III with one of 10 formula IV is preferably carried out in the presence of an acidbinding agent, e.g. a tertiary amine such as a trialkylamine, e.g. triethylamine or diisopropylethylamine, and in an inert organic solvent such as a halogenated aliphatic hydrocarbon such as dichloromethane at room temperature.

The optional functional modification of a reactive group in a compound of formula II can be carried out in the same manner as the functional modification of such a group in a compound of formula I.

The compounds of formula III can be prepared by reacting a compound of the formula z R1 ^R8 wherein R1, R2, R4, R5, R6, R7, r8, z and m have the above significance, with oxalyl chloride, conveniently in an inert organic solvent such as a halogenated aliphatic hydrocarbon at a temperature between about 0°C and the reflux temperature of the solvent. The resulting compound of formula III can be reacted in situ with the compound of formula IV or can be isolated and purified, e.g. by concentration followed by crystallization, prior to the reaction with a compound of formula IV.

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

The compounds of formula I and their pharmaceutically acceptable salts are protein kinase inhibitors; they inhibit cellular processes, e.g. cell proliferation, and can be used in the treatment or prophylaxis of illnesses, e.g. of inflammatory disorders such as arthritis, of immune diseases or in organ transplants as well as in oncology. They inhibit infection of cells by human immunodeficiency virus and are thus useful in the treatment of AIDS. They also inhibit smooth muscle contraction and can therefore be used against cardiovascular and bronchopulmonary disorders. Further, they are useful in asthma therapy.

The activity of the present compounds in inhibiting protein kinase C can be demonstrated e.g. on the basis of the assay system described in BBRC 19 (1979) 1218. The IC50 values in the following Table are those concentrations of test substance which reduce by 50% the protein kinase-induced incorporation of 32P from [γ-32ρ]ΑΤΡ into histone.

Table Compound IC50 3-[8-(Aminomethyl)-6,7,8,9-tetrahydropyridolu [1,2-a]indol-1 0-yl]-4-(l -methyl-3-indolyl)-1 Hpyrrole-2,5-dione hydrochloride 8 nM 3-[7-( Amidinothiomethy 1)-6,7,8,9-tetrahydro.. py rido [ 1,2-a]indol-l 0-yl]-4-(1 -me thy I-3-indolyl )15 1 H-pyrrole-2,5-dione methanesulphonate 1 5 nM 3-[2-(Aminoacetyl)-l ,2,3,4-tetrahydropyrazino[1,2 - a ]'i ndo I-1 0-yl]-4-( 1 -methyl-3-indolyl)-1 Hpyrrole-2,5-dione hydrochloride 50 nM 3-[ 7-(2-Aminoe thy 1)-6,7,8,9-tetrahydropyrido[1,2-a]indol-1 0-yl]-4-(1 -me thy I-3-indolyl )-1 Hpyrrole-2,5-dione hydrochloride 20 nM 3-[6,7,8,9-Tetrahydro-8-[(1-piperidino)methyl]pyrido[1,2-a]indol-10-yl]-4-(1 -methyl-3-indoly 1)1 H-pyrrole-2,5-dione nM 30 3-[2,3-Dihydro-2-(dimethylaminomethyl)-1 Hpyrrolo[l ,2-a]indol-9-yl]-4-( 1 -methyl-3-indolyl)1 H-pyrrole-2,5-dione trifluoromethanesulphonate 20 nM 3-[8-Amidino-6,7,8,9-tetrahydro[1,2-a]indol-1 035 y I]-4-( 1 - me thy I-3-indoly I )-1 H-pyrrole-2,5-dione hydrochloride 60 nM 3-[7-(Amidinothiomethyl)-6,7,8,9-tetrahydropyrido[1,2-ajindol-l 0-yl]-4-( 1 -methyl-3-indolyl)1 H-pyrrole-2,5-dione methanesulphonate lOnM The pyrroles of formula I and their salts can be used as medicaments, e.g. in the form of pharmaceutical preparations which can be administered orally, e.g. in the form of tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. They can also be administered rectally, e.g. in the io form of suppositories, or parenterally, e.g. in the form of injection solutions.

For the manufacture of pharmaceutical preparations these compounds can be processed with therapeutically inert, inorganic is or organic carriers. Lactose, maize starch or derivatives thereof, talc, stearic acid or its salts are examples of such carriers for tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are vegetable oils, waxes, fats and semisolid or liquid polyols. Depending on the nature of the active 2o substance no carriers are, however, generally required in the case of soft gelatine capsules. Suitable carriers for the manufacture of solutions and syrups are water, polyols, saccharose, invert sugar and glucose. Suitable carriers for injection solutions are water, alcohols, polyols, glycerine and vegetable oils and the like.

Suitable carriers for suppositories are vegetable or hardened oils, waxes, fats and semi-liquid polyols.

The pharmaceutical preparations can also contain preserving agents, solubilizing agents, stabilizing agents, so wetting agents, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants as well as, if desired, other therapeutically valuable substances.

As mentioned above, the pyrroles of formula I and their salts can be used in the treatment or prophylaxis of illnesses, especially of inflammatory, immunological, bronchopulmonary and cardiovascular disorders or in the treatment of asthma or of AIDS. The dosage can vary within wide limits, but generally, in the case of oral administration to adults, lies in the range of about 5 to 500 mg/day, although the upper value may be exceeded when required. The daily dosage can be administered as a single dose or in divided doses.

Example 1 A solution of 2.90 g of 3-[8-(acetoxymethyl)-6,7,8,9io tetrahydropyrido[1,2-a]indol-1 0-yl]-4-(1 -methyl-3indolyl)furan-2,5-dione in 30 ml of DMF and 23 ml of 33% aqueous ammonia is heated to 140°C for 7 hours. The mixture is extracted with ethyl acetate and the combined organic extracts are washed with water, dried and evaporated. Crystallization of is the residue from ethyl acetate gives 1.87 g of 3-[6,7,8,9tetrahydro-8-(hydroxymethyl)-pyrido[1,2-a]indol-1 0-y l]-4-( 1 methyl-3-indolyl)-1 H-pyrrole-2,5-dione, m.p. 262-263°C. a) A solution of 25 g of ethyl indole-2-carboxylate in 400 ml of DMF is added while stirring to a solution of 5.5 g of a 60% dispersion of sodium hydride in mineral oil in 40 ml of DMF under a nitrogen atmosphere. 30.9 g of ethyl bromobutyrate are added dropwise to the mixture at 0°C and the resulting mixture is stirred at room temperature for 18 hours. The reaction is terminated by adding 100 ml of water and 30 ml of 2N hydrochloric acid and the mixture is extracted with dichloromethane. The combined organic extracts are washed with water, dried and evaporated. There are obtained 49 g of an oil which is dissolved in ethyl acetate. The solution is washed with water, dried and evaporated. 39 g of an oil are obtained. This is added dropwise while stirring to a suspension of 20.5 g of potassium t-butoxide in 750 ml of THF under a nitrogen atmosphere. After 1 hour 200 ml of water and then 92 ml of 2N hydrochloric acid are added. The mixture is concentrated and the resulting precipitate is filtered off and dried. There are obtained 25.3 g of ethyl 6,7dihydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate, m.p. 101103°C after crystallization from methanol. b) A suspension of 19.4 g of the carboxylate from a) and 16 spoon spatulas of Raney-nickel in 480 ml of ethanol and 240 ml of water is heated under reflux for 3.5 hours. A further 4 spoon spatulas of Raney-nickel are then added and the mixture is heated under reflux for 1.5 hours. The supernatant is decanted off and the catalyst is washed with ethyl acetate. The combined organic phases are concentrated and the precipitate is filtered off and dried. There are obtained 16.3 g of ethyl 6,7,8,9-tetrahydropyrido[l ,2-a]indole-8-carboxylate, m.p. 70-72°C-after crystalliiu zation from methanol. c) 1 6.2 g of the carboxylate from b) in 200 ml of THF are added to a suspension of 2.00 g of L1AIH4 in 600 ml of THF at 0°C under a nitrogen atmosphere. After 0.5 hour the reaction is terminated is by the addition of ethyl acetate, water and 2N hydrochloric acid and the mixture is extracted with diethyl ether. The combined organic extracts are dried and evaporated. Crystallization of the residue from diethyl ether/n-hexane gives 11.5 g of 6,7,8,9tetrahydro-8-(hydroxymethyl)pyrido[l ,2-a]indole, m.p. 11020 Π1 °C. d) 11.4 g of acetic anhydride are added to a solution of 11.0 g of the product from c) in 1 00 ml of pyridine and the resulting solution is stirred under nitrogen for 18 hours. The majority of the pyridine is evaporated and the residue is acidified with 2N hydrochloric acid. The mixture is extracted with diethyl ether and the combined extracts are washed with sodium bicarbonate solution and with water. The extracts are dried and evaporated. There are obtained 11.25 g of 8-acetoxymethyl-6,7,8,9-tetra30 hydropyrido[l ,2-a]indole, m.p. 63-64°C. e) 4.13 g of oxalyl chloride are added dropwise to a solution of 8.2 g of the. tetrahydropyridoindole from d) in 160 ml of diethyl ether under a nitrogen atmosphere. After 10 minutes the solvent is removed under reduced pressure and the residue is dissolved in 330 ml of dichloromethane. 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. A further 4.60 ml of triethyl14 amine are added. After 48 hours the solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel with ethyl acetate/petroleum ether (1:2). Crystallization from ethyl acetate gives 4.02 g of 3-[8-acetoxymethyl5 6,7,8,9-tetrahydropyrido[1,2-a]indol-1 -y I]-4-(1 -methyl-3indolyl)furan-2,5-dione, m.p. 174-178°C.

Example 2 io 2.50 g of trifluoromethanesulphonic anhydride in 330 ml of dichloromethane are treated at 0°C under a nitrogen atmosphere with a suspension of 1.87 g of the pyrroledione from Example 1 and 0.94 g of collidine in 280 ml of dichloromethane. After 2.5 hours the mixture is allowed to warm to 10°C. 37 ml of 33% is aqueous ammonia are then added and the mixture is allowed to warm to room temperature. The mixture is washed with water, dried and evaporated. The residue is chromatographed on silica gel with dichloromethane/methanol/acetic acid/water (90:18:3:2). The combined product-containing fractions are 2u treated with 2M hydrochloric acid and evaporated. There are obtained 930 mg of 3-[8-aminomethyl-6,7,8,9-tetrahydropyrido[l ,2-a]indol-1 0-y I]-4-(1 - methy 1-3-indoly I )-1 H-pyr role2,5-dione hydrochloride, m.p. 310-313°C.

Example 3 265 mg of trifluoromethanesulphonic anhydride in 40 ml of dichloromethane are treated at 0°C under a nitrogen atmosphere with a suspension of 200 mg of the product from Example 1 and 1 00 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 is filtered off and dried. There are obtained 237 mg of 3[6,7,8,9-tetrahydro-8-(trimethylammoniomethyl)pyrido[1,235 a]indol-10-yl]-methanesulphonate, m.p. 320-324°C.

Example 4 265 mg of trifluoromethanesulphonic anhydride in 40 ml of dichloromethane are treated at 0°C under a nitrogen atmosphere with a suspension of 200 mg of the pyrroledione from 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. A further 0.5 ml of the above methylamine solution is added. After 4 hours, the solvent is evaporated and the precipitate is filtered off and purified by chromatography over silica gel with dichloromethane/methanol/acetic acid/water (90:18:3:2). The product is stirred with ethyl acetate saturated with hydrogen chloride for 2 hours. The resulting solid is filtered off and dried. There are obtained 55 mg of 3-(6,7,8,9-tetrahydro-8-(methylaminomethyl)pyrido[l ,2-a]indol-l 0-yI]4-( 1 - methyl-3-indoly 1)-1 Hpyrrole-2,5-dione hydrochloride, m.p. 337-340°C.

Example 5 185 mg of trifluoromethanesulphonic anhydride in 30 ml of dichloromethane are treated at 0°C under a nitrogen atmosphere with a suspension of 1 40 mg of the pyrroledione product from Example 1 and 70 mg of collidine in 25 ml of dichloromethane. After 1.5 hour 0.8 ml of a 33% solution of dimethylamine in ethanol is added and the mixture is stirred for 2.5 hours. The solvent is removed under reduced pressure and the residue is mixed with methanol. There is obtained a solid which is stirred with ethyl acetate saturated with hydrogen chloride. The solid is filtered off and dried. There are obtained 70 mg of 3-(6,7,8,9tetrahydro-8-(dimethylaminomethyl)pyrido[l ,2-a]indol-l 0-y I]-4(1-methyl-3-indolyl)-l H-pyrrole-2,5-dione hydrochloride, m.p. 335-336°C.

Example 6 A solution of 1 70 mg of the pyrroledione product from Example 1 in 55 ml of dichloromethane is treated with 87 mg of methanesulphonic anhydride in 1 ml of pyridine. The resulting solution is stirred under nitrogen for 1 hour. A further 30 mg of methanesulphonic anhydride are then added. After 1 hour the mixture is washed with water, dried and evaporated. Crystalliza5 tion of the residue from ethyl acetate/n-hexane gives 1 50 mg of 3-[6,7,8,9-tetrahydro-8-(methylsulphonyloxymethyl)pyrido[1,2a ] indol-1 0-y I]-4-( 1 -methy 1-3-indoly 1)-1 H-pyrrole-2,5-dione, m.p. 259-261 °C. ιυ Example 7 A solution of 120 mg of the pyrroledione product from Example 6 in 6 ml of DMF and 6 ml of 33% aqueous ammonia is heated to 1 40°C for 6 hours. The cooled mixture is poured into is water and the precipitate is filtered off. The product is purified by chromatography over silica gel with dichloromethane/acetic acid/methanol/water (60:18:2:3). Trituration with ethyl acetate gives 50 mg of 3-[8-formamidomethyl-6,7,8,9-tetrahydropyrido [ 1,2-a ] indol-1 0-y I]-4-(1 -methyl-3-indolyl)-1 H-pyrrole20 2,5-dione, m.p. 332-334°C.

Example 8 A solution of 100 mg of the pyrroledione product from Example 6 and 75 mg of thiourea in 5 ml of DMF is heated at 80°C under a nitrogen atmosphere for 18 hours. The solvent is evaporated and the residue is purified by chromatography over silica gel with dichloromethane/methanol/acetic acid/water (90:18:3:2). The residue is triturated with ethyl acetate. There are obtained 80 mg of 3-[8-[amidinothiomethyl-6,7,8,9tetrahydropyrido[1,2-a]-indol-1 0-y I]-4-( 1 -methyl-3-indolyl)1 H-pyrrole-2,5-dione methanesulphonate, m.p. 2OO-2O5°C.

Example 9 Analogously to Example 1, 1st paragraph, from 3-[7acetoxymethyl-6,7,8,9-tetrahydropyrido[1,2-a] indol-1 0-yl]-4(1-methyl-3-indolyl)furan-2,5-dione there is obtained 317 [6,7,8,9-tetrahydro-7-hydroxymethylpyrido[1,2-a]indol-1 0-yl]-4(1 -methyl-3-indolyl)-1 H-pyrrole-2,5-dione, m.p. 239-242°C.

The starting furandione is prepared as follows: a) 6.6 ml of a 1.6M solution of n-butyllithium in n-hexane are added while stirring to a solution of 1.11 g of diisopropylamine in 150 ml of THF at -78°C under nitrogen. The mixture is allowed to warm to -20°C for 5 minutes and is then cooled to -78°C. 1.85 g of 6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one in 1 0 ml of THF are then added dropwise. After stirring at -78°C for 0.5 hour 1.19 g of ethyl chloroformate are added and the mixture is allowed to warm to room temperature. The solvent is evaporated and the residue is partitioned between diethyl ether and 2M hydrochloric acid. The ethereal extracts are washed with saturated sodium bicarbonate solution, dried and concentrated. An oil is obtained. This is purified by chromatography over silica gel with dichloromethane. Crystallization of the product from methanol gives 1.35 g of ethyl 6,7,8,9-tetrahydro-6-oxo-pyrido[1,2-a]-indole-7carboxylate, m.p. 82-84°C. b) 30 ml of a IM solution of borane in THF are added while stirring to a solution of 1.25 g of the carboxylate from a) and the resulting solution is heated under reflux for 2 hours under a nitrogen atmosphere. 6 spoon spatulas of silica gel are added to the cooled solution and the solvent is evaporated. The residue is purified by chromatography over silica gel with ethyl acetate/nhexane (1:1). There is obtained an oil which is dissolved in 60 ml of dichloromethane containing 1 ml of pyridine and 2 ml of acetic anhydride. After 18 hours the solution is washed with 16 ml of 2M hydrochloric acid and 20 ml of saturated sodium bicarbonate solution, dried and evaporated. A solution of the resulting oil in 60 ml of diethyl ether is treated with 630 mg oxalyl chloride under a nitrogen atmosphere. Then, the solvent is removed under reduced pressure and the residue is dissolved in 100 ml of dichloromethane. 920 mg of 1-methyl-3-indolylacetic acid and 975 mg of triethylamine are added to this solution. After 72 hours the solvent is evaporated and the residue is purified by chromatography over silica gel with ethyl acetate/n-hexane (1:1). Crystallization from- ethyl acetate gives 390 mg of 3-[7acetoxymethyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-1 0-yl]-4(1 -methyl-3-indolyl)furan-2,5-dione, m.p. 190-193°C.

Example 10 200 mg of trifluoromethanesulphonic anhydride in 50 ml of dichloromethane are treated at 0°C under a nitrogen atmosphere iu with a suspension of 1 50 mg of the pyrroledione product from Example 9 and 75 mg of collidine in 50 ml of dichloromethane. After 2 hours 4 ml of a 33% aqueous ammonia solution are added and the mixture is left to warm to room temperature. The mixture is washed with water, dried and evaporated. The residue is is purified by chromatography over silica gel with dichloromethane/methanol/acetone/water (90:18:3:2). Crystallization from dichloromethane/n-hexane gives 85 mg of 3-[7aminomethyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-l 0-y 1)-4(1 methyl-3-indolyl)-l H-pyrrole-2,5-dione, m.p. 160-165°C.

Example 11 A solution of 120 mg of the pyrroledione product from Example 9 in 80 ml of dichloromethane is treated with 2 ml of pyridine and 100 mg of methanesulphonic anhydride under a nitrogen atmosphere. After stirring for 18 hours the mixture is washed with 2M hydrochloric acid and saturated sodium bicarbonate solution, dried and evaporated. A solution of the resulting product in 40 ml of ethanol containing 200 mg of thiourea is heated under reflux for 72 hours. The solvent is evaporated and the residue is purified by chromatography over silica gel with dichloromethane/methanol/acetone/water (90:18:3:2). Crystallization from methanol/dichloromethane gives 30 mg of 3-[7-amidinothiomethyl-6,7,8,9-tetrahydro35 pyrido[ 1,2-a]indol-1 0-yl]-4-( 1 -methyl-3-indolyl)-1 H-pyrrole2,5-dione methanesulphonate, m.p. 195-198°C.

Example 12 A solution of 72 mg of 3-(6,7,8,9-tetrahydropyrido[1,2a]indol-l 0-yl)-4-(1-methyl-3-indolyl)furan-2,5-dione in 5 ml of DMF and 5 ml of 33% aqueous ammonia is heated to 140°C for 4 hours. The resulting crystals are filtered off and dried. There are obtained 50 mg of 3-(6,7,8,9-tetrahydropyrido[l ,2-a]indol1 0-yl)-4-(1 -methyl-3-indolyl)-1 H-pyrrole-2,5-dione, m.p. 286289°C.

The starting furandione is prepared as follows: io 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, 1 0 ml of water and 10 ml of concentrated hydrochloric acid is heated to 80°C for 3 hours. The solvents are evaporated. There are obtained 740 mg is of 7,8-dihydropyrido[l ,2-a]indol-9(6H)-one, m.p. 138-140°C. b) A solution of 740 mg of the product from a), 600 mg of hydrazine hydrate and 440 mg of potassium hydroxide in 2 ml of ethanol and 4 ml of diethylene glycol is heated to 100°C under 2o reflux for 1.5 hours and then to 1 80°C for 2 hours. 50 ml of dichloromethane are added and the organic phase is washed with 2M hydrochloric acid and water. The solvent is evaporated. There are obtained 405 mg of 6,7,8,9-tetrahydropyrido[l ,2-a]indole. c) 350 mg of oxalyl chloride are added dropwise to a solution of 450 mg of the product from b) in 131 ml of dichloromethane at 0°C. After stirring for 2 hours the solvent is evaporated and the residue is dissolved in dichloromethane. 497 mg of l-methyl-3indolylacetic acid and 0.73 ml of triethylamine are added to this solution and the mixture is stirred for 60 hours. The solvent is evaporated and the residue is purified by chromatography over silica gel with dichloromethane. Trituration of the product with ethyl acetate gives 100 mg of 3-(6,7,8,9-tetrahydropyrido[1,2a]indol-l 0-yl)-4-(1 -methyl-3-indolyl)furan-2,5-dione, m.p. 27635 2 7 8°C.

Example 1 3 Analogously to Example 1,1st paragraph, from 3-[8-(2acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-1 0-y I]-4-( 1 methyl-3-indolyl)furan-2,5-dione there is obtained 3-[6,7,8,9tetrahydro-8-(2-hydroxyethyl)pyrido[1,2-a]indol-1 0-y I]-4-( 1 methyl-3-indolyl)-1 H-pyrrole-2,5-dione, m.p. 261-263°C.

The starting furandione is prepared as follows: a) A solution of 6.52 g of 8-(2-acetoxyethyl)-6,7,8,9tetrahydro-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 is heated under reflux under nitrogen for 1 8 hours. A further 4 ml of ethanedithiol and 9 ml of titanium tetrachloride are added and the heating is continued for 4.5 hours. The mixture is washed with water, dried and evaporated. The residue is purified by chromatography over silica gel with ethyl acetate/petroleum ether (1:3). There are obtained 7.7 g of 8'-(2-acetoxyethyl)-7',8'-dihydrospiro[1,3-dithiolane2',9'(6'H)-pyrido[l, 2-a]indole]. b) A solution of 5 g of the product from a) in 200 ml of ethanol is shaken with 8 spoon spatulas of Raney-nickel for 3.5 hours.

The mixture is filtered and the filter cake is washed with ethanol. The combined filtrates are evaporated and the residue is purified by chromatography over silica gel with ethyl acetate/ petroleum ether (1:2). There are obtained 620 mg of 8-(2acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-a] indole. c) 1.19 g of oxalyl chloride are added dropwise to a solution of 2.29 g of the product from b) in 50 ml of diethyl ether at 0°C.

After 2.5 hours the solvent is evaporated and the residue is dissolved in dichloromethane. 1.68 g of 1-methyl-3-indolylacetic acid and 2.45 ml of triethylamine are added to this solution and the mixture is heated under reflux under nitrogen for 18 hours.

The solvent is evaporated and the residue is purified by chromatography over silica gel with ethyl acetate/petroleum ether (1:2). Crystallization from ethyl acetate gives 625 mg of 3-(8(2-acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-a] indol-1 0-y I )-4(1-methyl-3-indolyl)-furan-2,5-dione, m.p. 159-1 61 °C.

Example 14 A solution of 11 5 mg of the product of Example 1 3c) in 1 ml of DMF and 2 ml of 33% aqueous ammonia is heated to 140°C for 4 hours. The cooled mixture is evaporated and the residue is 10 purified by chromatography over silica gel with ethyl acetate/ petroleum ether (2:1). Crystallization from ethyl acetate/ petroleum ether gives 13 mg of 3-[8-(2-acetoxyethyl)-6,7,8,9tetrahydropyridofl,2-a]indol-1 0-yl]-4-( 1 -methyl-3-indolyl)-l Hpyrrole-2,5-dione, m.p. 272-274°C.

Example 1 5 A solution of 500 mg of the pyrroledione product from Example 1 3 in 50 ml of dichloromethane is treated with 218 mg 2u of methanesulphonic anhydride and 1 ml of pyridine. The resulting solution is stirred under a nitrogen atmosphere for 1 hour. A further 20 mg of methanesulphonic anhydride are added and the stirring is continued for 0.5 hour. The mixture is washed with water, dried and evaporated. Crystallization of the residue 25 from ethyl acetate/petroleum ether gives 540 mg of 3-(6,7,8,9tetrahydro-8-(2-methylsulphonyloxyethyl)pyrido[1,2-a] indol-1 0yl]-4-(1 -methyl-3-indolyl)-l H-pyrrole-2,5-dione, m.p. 224245°C.

Example 16 A solution of 500 mg of the pyrroledione product from Example 1 5 and 250 mg of sodium azide in 10 ml of DMF is heated at 70°C for 3 hours. The solvent is evaporated and the solid is partitioned between ethyl acetate and water. Insoluble material is filtered off and dried. There are obtained 425 mg of 3-(8-(2azidoethyl)-6,7,8,9-tetrahydropyrido[l,2-a]indol-10-yl]-4-( 1 methyl-3-indolyl)-lH-pyrrole-2,5-dione, m.p. 262-264°C.

Example 17 200 mg of the pyrroledione product from Example 16 in 70 ml of methanol containing 40 mg of 10% Pd/C are shaken under a hydrogen atmosphere under a pressure of 3 atmospheres for 48 hours. The supernatant is decanted off and evaporated. The residue is treated with 50 ml of a saturated solution of hydrogen chloride in ethyl acetate and purified by chromatography over silica gel with dichloromethane/methanol/acetic acid/water (60:18:2:3). Crystallization from ethyl acetate gives 20 mg of 3[8-(2-aminoethyl)-6,7,8,9-tetrahydropyrido[1,2-a]-indol-1 O-yljlo 4-(1 -methyl-3-indolyl)-1 H-pyrrole-2,5-dione, m.p. 160-1 65°C.

Example 1 8 Analogously to Example 12, 1st paragraph, from 3-[2,3dihydro-1 H-pyrrolo[ 1,2-a ] i nd ol-9-y I ]-4-(1 -methyl-3-indolyl) 15 furan-2,5-dione there is obtained 3-[2,3-dihydro-1 H-pyrrolo[1,2· a]indol-9-yl]-4-( 1 -methy 1-3-indoly 1)-1 H-pyrrole-2,5-dione, m.p. 260°C-270°C.

The starting furandione is prepared as follows: 175 mg of oxalyl chloride are added dropwise to a solution of 200 mg of 2,3-dihydro-1 H-pyrrolo[1,2-a]indole in 7 ml of diethyl ether at 0°C under a nitrogen atmosphere. After 1 hour the solvent is removed under reduced pressure and the residue is dissolved in 1 4 ml of dichloromethane. 245 mg of l-methyl-3indolylacetic acid and 265 mg of triethylamine are added to this solution and the mixture is stirred for 72 hours. The solvent is removed under reduced pressure and the residue is purified by chromatography over silica gel with ethyl acetate/petroleum ether (1:2). Crystallization from ethyl acetate gives 70 mg of 3[2,3-dihydro-1 H-pyrrolo[1,2-a ] indol-9-yl]-4-( 1 -methyl-3indolyl)furan-2,5-dione, m.p. 125-130°C.

Example 1 9 Analogously to Example 1, 1st paragraph, from 3-[2acetoxymethyl-2,3-dihydro-1 H-pyrrolo[l ,2-a]indol-9-yl]-4-( 1 methyl-3-indolyl)furan-2,5-dione there is obtained 3-[2,3dihydro-2-hydroxymethyl-1 H-pyrrolo[l,2-a]indol-9-yI]-4-(1 methyl-3-indolyl)-1 H-pyrrole-2,5-dione, m.p. 238-240°C.

The starting furandione is prepared as follows: a) 6 spoon spatulas of Raney-nickel are added to a solution of 5.08 g of ethyl 2,3-dihydro-l-oxo-1 H-pyrrolo[l ,2-a]indole-2carboxylate in 1 80 ml of ethanol and 90 ml of water. The mixture is heated under reflux for 10 hours and then a further 3 spoon spatulas of Raney-nickel are added. The heating is continued for .5 hours, whereupon the mixture is cooled and filtered. The filter cake is washed with ethyl acetate and dichloromethane.

The combined filtrates are evaporated and the residue is purified by chromatography over silica gel with diethyl ether/petroleum ether (1:2). Crystallization from methanol gives 635 mg of ethyl 2,3-dihydro-1 H-pyrrolo[l ,2-a]indole-2-carboxylate, m.p. 55-57°C. b) 4 ml of a IM solution of L1AIH4 in THF are added to a solution of 750 mg of the product from a) in 30 ml of THF. After 1 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. Crystallization of the residue from diethyl ether/petroleum ether gives 355 mg of 2,3-dihydro-2-hydroxymethyl-l H-pyrrolo[l ,2-a]indole, m.p. 76-78°C. c) A solution of 355 mg of the product from b) in 20 ml of dichloromethane containing 2 ml of acetic anhydride and 2 ml of pyridine is stirred for 2 hours. The solvents are evaporated and the residue is partitioned between dichloromethane and water.

The organic phase is dried and evaporated. These are obtained 420 mg of 2-acetoxymethyl-2,3-dihydro-l H-pyrrolo[l ,2-a]indole. d) 290 mg of oxalyl chloride are added dropwise to a solution of 420 mg of the product from c) in 40 ml of diethyl ether under a nitrogen atmosphere. After 1 hour the solvent is removed under reduced pressure and the residue is dissolved in dichloromethane. 420 mg of 1-methyl-3-indolylacetic acid and 485 mg of triethylamine are added to this solution and the mixture is stirred for 72 hours. The solvent is evaporated and the residue is purified by chromatography over silica gel with ethyl acetate/petroleum ether (1:1). Crystallization from ethyl acetate gives 90 mg of 3[2-acetoxymethyl-2,3-dihydro-l H-pyrrolo[1,2-a)indol-9-yl)-4(1-methyl-3-indolyl)furan-2,5-dione m.p 208-21 1°C.

Example 20 A solution of 150 mg of 3-[2-t-butoxycarbonyl-l ,2,3,4tetrahydropyrazino[l,2-a]indol-1 0-y 1)-4-( 1 -methyl-3-indolyl) furan-2,5-dione in 4 ml of DMF and 8 ml of a 33% aqueous ammonia solution is heated to 1 40°C for 4 hours. The mixture is extracted with ethyl acetate and the organic extract is washed with water, dried and evaporated. The resulting product is purified by chromatography over silica gel with dichloromethane/methanol/acetic acid/water. The resulting imide is dissolved in 30 ml of ethanol and 5 ml of 2M hydrochloric acid and the resulting solution is heated under reflux for 2 hours. Evaporation of the solvent and trituration of the residue with ethyl acetate gives 35 mg of 3-[l ,2,3,4-tetrahydropyrazino[1,2a) indol-1 0-y I )-4-(1 - methyl-3-indolyl)-1 H-pyrrole-2,5-dione hydrochloride, m.p. 268-270°C The starting furandione is prepared as follows: a) A solution of 450 mg of 1,2,3,4-tetrahydropyrazino[l ,2a)indole in 30 ml of dichloromethane is treated at 0°C under a nitrogen atmosphere with 303 mg of triethylamine and 615 mg of di(t-butyl) dicarbonate. The mixture is stirred at 0°C for 4 hours and then washed with saturated sodium bicarbonate solution, dried and evaporated. Crystallization of the resulting oil from methanol gives 580 mg of 5-butyl 1,2,3,4-tetrahydropyazino[1,2a] indole-2-carboxylate, m.p. 1O3-1O5°C. b) 230 mg of oxalyl chloride are added dropwise while stirring to a solution of 450 mg of the product from a) in 30 ml of diethyl ether at 0°C. After stirring the solution is evaporated and the residue is dissolved in 50 ml of dichloromethane. 360 mg of 1methyl-3-indolylacetic acid and 350 mg of triethylamine are added and the mixture is stirred for 90 hours. The solvent is ιυ evaporated and the residue is purified by chromatography over silica gel with ethyl acetate/petroleum ether (2:3). There are obtained 180 mg of 3-[2-t-butoxycarbonyl-1,2,3,4-tetrahydropyrazino[l ,2-a]indol-l 0-y I]-4-( 1 -methyl-3-indolyl)furan-2,5dione, m.p. 125-127°C after crystallization from ethyl acetate/n15 hexane.

Example 21 Analogously to Example 12, 1st paragraph, from 3-(5,6dihydro-4H-pyrrolo[3,2,1 -ij]quinolin-1 -y I )-4-( 1 -methyl-3indolyl)furan-2,5-dione there is obtained 3-(5,6-dihydro-4Hpyrrolo[3,2,1 -ij]quinolin-1 -y I )-4-(1 - me thy I-3-indolyl )-1 Hpyrroloe-2,5-dione, m.p. 285-288°C. 2s The starting furandione is prepared as follows: 1.22 g of oxalyl chloride are added dropwise to a solution of 1.5 g of 5,6-dihydro-4H-pyrrolo[3,2,1 -ij]-quino!ine in 60 ml of dichloromethane under a nitrogen atmosphere. After 1 hour the 3Q solvent is removed under reduced pressure and the residue is dissolved in 120 ml of dichloromethane. 1.9 g of 1-methyl-3indolylacetic acid and 2.02 g of triethylamine are added to this solution and the mixture is stirred for 18 hours. The solvent is removed under reduced pressure and the residue is purified by 35 chromatography over silica gel with ethyl acetate/petroleum ether (1:2). Further purification by chromatography using dichloromethane and crystallization from ethyl acetate gives 690 mg of 3-(5,6-dihydro-4H-pyrrolo[3,2,1 -ij]quinolin-1-yl)-4-( 1methyl-3-indolyl)furan-2,5-dione, m.p. 217-219°C.

Example 22 Analogously to Example 1, 1st paragraph, from 3-[5acetoxymethyl-5,6-dihydro-4H-pyrrolo[3,2,1 -ij]quinolin-l-yl]-4(1 -methyl-3-indolyl)furan-2,5-dione there is prepared 3-[5,6dihydro-5-hydroxymethyl-4H-pyrrolo[3,2,1 -ij]quinolin-l -y I]-45 (1 -methyl-3-indolyl)-l H-pyrrole-2,5-dione, m.p. 223-225°C.

The starting furandione is prepared as follows: a) 33.4 ml of a 1.6M solution of n-butyllithium in hexane are io added to a solution of 8.13 ml of diisopropylamine in 420 ml of THF at -78°C under a nitrogen atmosphere. After 0.5 hour 4.6 g of 1,2,5,6-tetrahydro-4-oxo-4H-pyrrolo[3,2,1-ijjquinoline are added and the mixture is stirred at -78°C for 0.5 hour. 2.77 ml of ethyl chloroformate are added and the stirring is continued for 1 hour. is The reaction is interrupted by adding water and the mixture is evaporated. The residue is purified by chromatography over silica gel with ethyl acetate/petroleum ether (1:2). Crystallization from diethyl ether gives 2.8 g of ethyl 1,2,5,6-tetrahydro-4-oxo4H-pyrrolo[3,2,l -ij]quinoline-5-carboxylate, m.p. 88-90°C. b) 1 5 ml of a 1 M solution of borane in THF are added to a solution of 2.8 g of the product from a) in 100 ml of THF and the resulting solution is heated under reflux for 2 hours. A further 55 ml of borane are added and the heating is continued for 12 hours. The solvent is removed under reduced pressure. Water and 2M hydrochloric acid are added and the mixture is extracted with dichloromethane. The solvent is evaporated and the residue is dissolved in diethyl ether. The solution is treated with 12 ml of a 1 M solution of L1AIH4 in diethyl ether and the mixture is stirred under a nitrogen atmosphere for 1 8 hours. Water is added and the mixture is extracted with dichloromethane. Removal of the solvent under reduced pressure gives 1.4 g of 1,2,5,6-tetrahydro4 H-pyrro Io [3,2,1 -ij]quinoline-5-me thanol.

Example 22 Analogously to Example 1, 1st paragraph, from 3-[5acetoxymethyl-5,6-dihydro-4H-pyrrolo[3,2,1 -ij]quinolin-1 -yl]-4(1-methyl-3-indo(yl)furan-2,5-dione there is prepared 3-[5,6dihydro-5-hydroxymethyl-4H-pyrrolo[3,2,1 -ijjquinolin-1 -ylJ-45 (1-methyl-3-indolyl)-1 H-pyrrole-2,5-dione, m.p. 223-225°C.

The starting furandione is prepared as follows: a) 33.4 ml of a 1.6M solution of n-butyllithium in hexane are io added to a solution of 8.13 ml of diisopropylamine in 420 ml of THF at -78°C under a nitrogen atmosphere. After 0.5 hour 4.6 g of 1,2,5,6-tetrahydro-4-oxo-4H-pyrrolo[3,2,1 -ij]quinoline are added and the mixture is stirred at -78°C for 0.5 hour. 2.77 ml of ethyl chloroformate are added and the stirring is continued for 1 hour. is The reaction is interrupted by adding water and the mixture is evaporated. The residue is purified by chromatography over silica gel with ethyl acetate/petroleum ether (1:2). Crystallization from diethyl ether gives 2.8 g of ethyl 1,2,5,6-tetrahydro-4-oxo4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate, m.p. 88-90°C. b) 1 5 ml of a 1 M solution of borane in THF are added to a solution of 2.8 g of the product from a) in 100 ml of THF and the resulting solution is heated under reflux for 2 hours. A further 55 ml of borane are added and the heating is continued for 12 hours. The solvent is removed under reduced pressure. Water and 2M hydrochloric acid are added and the mixture is extracted with dichloromethane. The solvent is evaporated and the residue is dissolved in diethyl ether. The solution is treated with 12 ml of a 1M solution of UAIH4 in diethyl ether and the mixture is stirred 30 under a nitrogen atmosphere for 18 hours. Water is added and the mixture is extracted with dichloromethane. Removal of the solvent under reduced pressure gives 1.4 g of 1,2,5,6-tetrahydro4H-pyrrolo[3,2,1 -ij] quinoline-5-methanol. c) A solution of 1.4 g of the product from b) in 50 ml of dichloromethane is treated with 4 ml of acetic anhydride and 2 ml of pyridine. After 4 hours a further 4 ml of acetic anhydride are added and the mixture stirred for 18 hours, the solvent is removed under reduced pressure and the residue is partitioned between water and dichlormethane. The organic phase is evaporated and the residue is dissolved in toluene and heated under reflux in toluene in the presence of 250 mg of 10% Pd/C. A further 250 mg of 10% Pd/C are added and the heating is continued for 20 hours. The mixture is filtered and the filtrate is evaporated. The residue is purified by chromatography over silica gel with ethyl acetate/petroleum ether (1:2). There are obtained 350 mg of 5-acetoxymethyl-5,6-dihydro-4H-pyrrolo[3,2,l ij ]q u inoline. d) 315 mg of oxalyl chloride are added dropwise to a solution of 570 mg of the product from c) in 1 5 ml of dichloromethane under a nitrogen atmosphere. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane. 472 mg of 1 -methyl-3-indolylacetic acid and 505 mg of triethylamine are added and the mixture is stirred for 72 hours. The solvent is removed under reduced pressure and the residue is purified by chromatography over silica gel with dichloromethane. Crystallization from ethyl acetate/n-hexane gives 140 mg'of 3[5-acetoxymethyl-5,6-dihydro-4H-pyrrolo[3,2,1 -ij]quinoline-1 yl]-4-(l-methyl-3-indolyl)furan-2,5-dione, m.p. 198-200°C.

Example 23 Analogously to Example 11, from the pyrroledione product of Example 22 there is obtained 3-[5-amidinothiomethyl-5,6dihydro-4H-pyrrolo[3,2,1 -ij]quinolin-l -yI]-4-( 1 -methy 1-3indolyl)-! H-pyrrole-2,5-dione methanesulphonate, m.p. 190195°C.

Example 24 Analogously to Example 2, from the pyrroledione product of Example 22 there is obtained 3-[5-aminomethyl-5,6-dihydro-4H28 pyrrolo[3.2.1 - ij]quinolin-l -yl]-4-( 1 -methyl-3-indolyl)-l Hpyrrole-2,5-dione hydrochloride, m.p. 248-250°C.

Example 25 Analogously to Example 1, 1st paragraph, from 3-[8acetoxymethyl-6,7,8,9-tetrahydropyrido[1,2-a] indol-1 0-yl]-4phenylfuran-2,5-dione (obtained as described in the last paragraph of Example 1, but using phenylacetic acid in place of 1 io methyl-3-indolylacetic acid) there is obtained 3-(6,7,8,9tetrahydro-8-hydroxymethylpyrido(l,2-a]indol-1 0-yl]-4-phenyl1 H-pyrrole-2,5-dione, m.p. 276-278°C.

Example 26 Analogously to Example 1, 1st paragraph, from 4-(8acetoxymethyl-6,7,8,9-tetrahydropyrido(1,2-a] indol-1 0-y l]-3(3-benzo[b]thienyl)-furan-2,5-dione (obtained as described in the last paragraph of Example 1, but using 3-benzo(b]thienylacetic 2υ acid in place of 1 -methyl-3-indolylacetic acid) there is obtained 3-3(benzo[b]thienyl)-4-[6,7,8,9-tetrahydro-8-hydroxymethylpyrido(1,2-a]indol-l 0-yl]-l H-pyrrole-2,5-dione, m.p. 226-227°C.

Example 27 Analogously to Example 1, 1st paragraph, from 3-(8acetoxymethyl-6,7,8,9-tetrahydropyrido(l ,2-a]indol-l 0-yl]-4(1-naphthyl)furan-2,5-dione (obtained as described in the last paragraph of Example 1, but using 1-naphthylacetic acid in place of 1-methyl-3-indolylacetic acid) there is obtained 3-(6,7,8,9tetrahydro-8-hydroxymethylpyrido[l,2-a]indol-1 0-y l]-4-( 1 naphthyl)-l H-pyrrole-2,5-dione, m.p. 221-222°C.

Example 28 35 Analogously to Example 10, from the product of Example 19 there is obtained 3-[2-aminomethyl-2,3-dihydro-1 H-pyrrolo[l ,229 a ] - i nd ο I - 9-y I ] - 4 - (1 -methy l-3-indolyl)-1 H-pyrrole-2,5-dione, m.p. 208-21 1 °C.

Example 29 Analogeusly to Example 10, from the pyrroledione product of Example 25 there is obtained 3-[8-aminomethyl-6,7,8,9-tetra· hydropyrido[1,2-a] indol-1 0-y I]-4-phenyl-1 H-pyrrole-2,5-dione, m.p. 249-250°C.

Example 30 A suspension of 100 mg of the pyrroledione product of Example 20 in 10 ml of dichloromethane is treated under nitrogen with 0.08 ml of triethylamine and 86 mg of phenyl chloroformate. The mixture is stirred for 2 hours and then the solvent is evaporated. Chromatography of the residue over silica gel with ethyl acetate/n-hexane (1:1) gives a gum-like product which is dissolved in a mixture of 5 ml of isopropanol and 10 ml of 33% aqueous ammonia. The mixture is diluted with water and extracted with dichloromethane. The combined dichloromethane extracts are dried and evaporated. Crystallization of the residue from ethyl acetate/n-hexane gives 45 mg of 3-[1,2,3,4-tetrahydro-2-phenoxycarbonylpyrazino[1,2-a] indol-1 0-yl]-4-( 1 methyl-3-indolyl)-1 H-pyrrole-2,5-dione, m.p. 160-165°C.

Example 31 a) A solution of 80 mg of the pyrroledione product of Example 20 in 20 ml of dichloromethane is treated with 10 ml of a 5% aqueous sodium bicarbonate. The mixture is treated under reflux with a solution of 125 mg of trifluoroacetamidoacetyl chloride in 5 ml of dichloromethane. After 10 hours the phases are separated and the organic phase is dried and evaporated. Chromatography of the residue over silica gel with ethyl acetate/n-hexane (2:1) and crystallization from ethyl acetate/n-hexane gives 70 mg of 3-[2[trifluoroacetamidoacetylj-l ,2,3,4-tetrahydropyrazino [1,230 a) indol-1 0-y I)-4-(1 - methyl-3-indoly 1)-1 H-pyrrole-2,5-dione, m.p. 1 70-1 72°C. b) A solution of 65 mg of the product from a) in 10 ml of 5 methanol was treated with 5 ml of a 33% aqueous ammonia solution. After 4 hours the solvent is evaporated and the residue is partitioned between dichloromethane and water. The organic phase is washed with water, dried and evaporated. Chromatography of the residue over silica gel with chloroform/methanol/ io acetic acid/water (60:18:2:3) gives a gum-like product which is dissolved in glacial acetic acid and treated with 20 ml of IM hydrochloric acid. Evaporation of the solvent and trituration of the residue with diethyl ether gives 35 mg of 3-[2-aminoacetyl1,2,3,4-tetrahydropyrazino[1,2-a) indol-1 0-y 1)-4-( 1 -methyl-315 indolyl)-l H-pyrrole-2,5-dione hydrochloride, m.p. 235°C (decomposition).

Example 32 2u a) A solution of 100 mg of the pyrroledione product of Example 20 in 40 ml of dichloromethane is treated under a nitrogen atmosphere with 125 mg of 1,1 -carbonyldiimidazole and the mixture is stirred for 24 hours. The solution is washed with water, dried and evaporated. Trituration of the residue with ethyl acetate gives 84 mg of 3-[l ,2,3,4-tetrahydro-2-(l imidazolylcarbonyl)pyrazino[1,2-a) indol-1 0-y I)-4-(1 - me thy 1-3indoly))-! H-pyrrole-2,5-dione, m.p. 295°C (decompostion). b) 80 mg of the product from a) are dissolved in a mixture of ml of DMF and 20 ml of 33% aqueous ammonia. The mixture is stirred for 1 7 hours and the solvent is evaporated. Chromatography of the residue over silica gel with methanol/ethyl acetate (1:9) gives 45 mg of 3-[2-carbamoyl-l ,2,3,4-tetrahydropyrazino[ 1,2-a] indol-1 0-y I]-4-( 1 -methyl-3-indoly I )-1 H-pyrrole-2,535 dione, m.p. 295°C (decompostion) after crystallization from methanol.

Example 33 A solution of 505 mg of the pyrroledione product of Example 2 in 20 ml of DMF is treated with a solution of 222 mg of 1,1thiocarbonyldiimidazole in 5 ml of THF. After 1 7 hours the solvent is evaporated and the residue is purified by chromato5 graphy over silica gel with methanol/dichloromethane (1:99).

Trituration with n-hexane gives 297 mg of 3-[6,7,8,9-tetrahydro8-isothiocyanatopyrido[1,2-a]indol-l 0-y I]-4-( 1 -methy 1-3indolyl)-l H-pyrrole-2,5-dione, m.p. 285-287°C. io Example 34 250 mg of the pyrroledione product of Example 2 are added while stirring to a mixture of 25 ml of dichloromethane and 15 ml of 5% aqueous sodium bicarbonate. The mixture is treated is with 1 ml of benzoyl chloride and stirred for 10 hours. The phases are separated and the organic phase is dried and evaporated. Chromatography of the residue over silica gel with methanol/dichloromethane (7:93) followed by trituration with n-hexane gives 220 mg of 3-[8-benzamidomethyl-6,7,8,9-tetrahydro2u pyrido[1,2-a ] indol-1 0-y I]-4-( 1 -methyl-3-indolyl)-1 H-pyrrole2,5-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-2,5dione in 6 ml of DMF and 6 ml of 33% aqueous ammonia is heated to 1 50°C for 6 hours. The mixture is extracted with ethyl acetate and the organic extracts are washed with water, dried and evaporated. Crystallization of the residue from ethyl acetate gives 120 mg of 3-[6,7,8,9-tetrahydro-7-hydroxypyrido[1,2a] indol-1 -y 1-4-(1 - methy 1-3-indoly 1)-1 H-pyrrole-2,5-dione, m.p. 252-255°C.

The starting furandione 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-IV oxide. After 1 hour the solid is filtered off and washed with dichloromethane. The combined filtrates are concentrated and 33 g of carbethoxymethylenetriphenylphosphorane are added. The resulting solution is heated under reflux under a nitrogen atmosphere. The solvent is evaporated. The oil obtained is purified by chromatography over silica gel with ethyl acetate/nhexane (1:3). The product is a 20:1 mixture of the E/Z isomers. iu Crystallization from methanol gives 11.3 g of ethyl (E)-2indolyl-2-propenoate, m.p. 120-122°C. b) A solution of 7.2 g of the product from a) in 1 20 ml of DMF is treated with 1.47 g of a 60% dispersion of sodium hydride in is mineral oil. The resulting solution is cooled to 0°C and 7.17 g of t-butyl bromoacetate are added under a nitrogen atmosphere.

After 2 hours the mixture is poured into 1 00 ml of 2M hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are washed with water, dried and evaporated.

The oil obtained is purified by chromatography over silica gel with diethyl ether/petroleum ether (1:3). Crystallization from diethyl ether/n-hexane gives 8.1 g of ethyl (E)-3-l-t-butoxycarbonylmethyl-2-indolyl]-2-propenoate, m.p. 66-68°C. c) A solution of 8.0 g of the product from b) in 300 ml of ethanol is shaken with 800 mg of 10% Pd/C under a hydrogen atmosphere. The catalyst is filtered off and washed with ethyl acetate. The combined filtrates are evaporated. There is obtained an oil which is dissolved in THF. The solution is added to a solution of 2.8 g of potassium t-butoxide in THF under a nitrogen atmosphere. Then, the mixture is stirred for 1 hour and the solvent is evaporated. The residue is partitioned between ethyl acetate and 2M hydrochloric acid. The organic phase is washed with water, dried and evaporated. The residue is purified by chromatography over silica gel with diethyl ether/n-hexane (1:4). There are obtained 4.55 g of t-butyl 6,7,8,9-tetrahydro-7oxopyrido[l ,2-a]indole-6-carboxylate. d) A solution of 4.5 g of the product from c) in 200 ml of toluene is treated with four spoon spatulas of silica gel and the mixture is heated under reflux for 3 hours under a nitrogen atmosphere. The solid is filtered off and washed with toluene.

The combined filtrates are evaporated. There are obtained 2.5 g of 8,9-dihydropyrido[l ,2-a]indol-7(6H)-one, m.p. 1 26-1 28°C after crystallization from diethyl ether/n-hexane. e) 190 mg of sodium borohydride are added while stirring to a iu solution of 650 mg of the product from d) in 50 ml of methanol under a nitrogen atmosphere. The mixture is stirred and then poured into 100 ml of saturated ammonium chloride solution. The mixture is extracted with ethyl acetate and the combined extracts are dried and evaporated. After crystallization of the is product from diethyl ether/n-hexane there are obtained 500 mg of 6,7,8,9-tetrahydro-7-hydroxypyrido[l ,2-a]indole, m.p. 99-1 00°C. f) A solution of 500 mg of the product from e) in 5 ml of pyridine and 2 ml of acetic anhydride is stirred for 8 hours. The mixture is poured in to 50 ml of 2M hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are washed with 5% sodium bicarbonate solution and water, dried and evaporated. There are obtained 25 mg of 7-acetoxy-6,7,8,9tetrahydropyrido[1,2-a]indole, m.p. 90-95°C after crystallization from diethyl ether/n-hexane. g) 320 mg of oxalyl chloride are added to a solution of 500 mg of the product from f) in 50 ml of diethyl ether under a nitrogen atmosphere. Then, the solvent is removed under reduced pressure and the residue is dissolved in 50 ml of dichloromethane. 378 mg of 1-methyl-3-indolylacetic acid and 505 mg of triethylamine are added to this solution and the mixture is stirred for 72 hours. The solvent is removed under reduced pressure and the residue is purified by chromatography over silica gel with ethyl acetate/n35 hexane (1:1). After crystallization from ethyl acetate there are obtained 160 mg of 3-[7-acetoxy-6,7,8,9-tetrahydropyrido[l ,2a]indol-l 0-yl]-4-( 1-methyl-3-indolyl)furan-2,5-dione, m.p. 272275°C.

Example 36 A solution of 85 mg of 3-[7-t-butoxyformamido-6,7,8,9tetrahydropyridop , 2-a] indol-1 0-y I]-4-(1 -methy 1-3-indoly 1)furan-2,5-dione in 5 ml of DMF and 5 ml of a 33% aqueous ammonia solution is heated to 100°C for 1 hour. The cooled mixture is partitioned between ethyl acetate and water. The organic phase is washed with water, dried and evaporated. After crystallization from ethyl acetate/n-hexane there are obtained 70 mg of 3-[7-t-butoxyformamido-6,7,8,9-tetrahydro-pyrido[1,2-a ] indol-1 0-yl]-4( 1 -methyl-3-indolyl)-1 H-pyrrole-2,5-dione, io m.p. 1 59-1 63°C.

The starting furandione is prepared as follows: a) A suspension of 555 mg of 8,9-dihydropyrido[1,2-a]-indol15 7(6H)-one and 4.62 g of ammonium acetate in 1 5 ml of methanol is treated with 250 mg of sodium cyanoborohydride. The mixture is 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 over silica gel with 10% methanol in dichloromethane. The indoline obtained is dissolved in toluene and heated under reflux with 50 mg of 10% Pd/C. The catalyst is filtered off and washed with toluene. The combined filtrates are evaporated. There are obtained 170 mg of 7-amino-6,7,8,9-tetrahydropyrido[1,2-a] indole. b) 225 mg of di-t-butyl dicarbonate are added while stirring to a solution of 1 75 mg of the product from a) and 112 mg of triethylamine in 20 ml of dichloromethane at 0°C under a nitrogen atmosphere. After 18 hours the solution is washed with saturated sodium bicarbonate solution, dried and evaporated.

After crystallization from diethyl ether there are obtained 240 mg of 7-t-butoxyformamido-6,7,8,9-tetrahydropyrido[1,2a]indole, m.p. 137-139°C. c) 127 mg of oxalyl chloride are added to a solution of 240 mg of the product from b) in 30 ml of diethyl ether under a nitrogen atmosphere. After 10 minutes the solvent is removed under reduced pressure and the residue is 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 is removed under reduced pressure and the residue is purified by chromatography over silica gel with ethyl acetate/n-hexane (1:2). Crystallization from ethyl acetate/nhexane gives 100 mg of 3-[7-t-butoxyformamido-6,7,8,9-tetrahydropyrido[l,2-a]indol-1 0-yl]-4-( 1 -methyl-3-indolyl)furan-2,5dione, m.p. 141 -145°C.

Example 37 A saturated solution of hydrogen chloride in 30 ml of ethyl acetate is added while stirring to a suspension of 60 mg of the pyrroledione product of Example 36 in 50 ml of ethyl acetate and the mixture is stirred for 1 8 hours. The solvent is removed under reduced pressure and the residue is triturated with ethyl acetate. There are obtained 35 mg of 3-[7-amino-6,7,8,9-tetrahydropyrido[ 1,2-a]indol-1 0-yl]-4-( 1 -methyl-3-indolyl)-l H-pyrrole2,5-dione hydrochloride, m.p. 260-265°C.

Example 38 A solution of 80 mg of 3-[8-t-butoxyformamido-6,7,8,9tetrahydropyridofl,2-a]indol-1 0-yl]-4-( 1 -methyl-3-indolyl)furan-2,5-dione in 2 ml of DMF and 2 ml of 33% aqueous ammonia is heated to 100°C for 1 hour. The solution is cooled and there are obtained 60 mg of 3-[8-t-butoxyformamido-6,7,8,9-tetrahydropyrido[1,2-a]indol-1 0-ylj-4-( 1 -methyl-3-indolyl)-l Hpyrrole-2,5-dione, m.p. 1 53-1 55°C.

The starting furandione is prepared as follows: a) A solution of 300 mg of sodium hydroxide in 5 ml of water is added while stirring to a solution of 1.35 g of the carboxylate product from Example lb) in 25 ml of ethanol and the mixture is heated under reflux for 1 5 minutes. 2 ml of 2M hydrochloric acid and 10 ml of water are added and the precipitate is filtered off and dried. There are obtained 1.14 g of 6,7,8,9-tetrahydropyrido[l ,2-a]indole-8-carboxylic acid, m.p. 244-246°C. b) A suspension of 900 mg of the product from a) in 1 ml of water and 20 ml of acetone is cooled to 0°C and treated with 490 mg of triethylamine followed by 576 mg of ethyl chloroformate. After 0.5 hour 345 mg of sodium azide in 1 ml of water are added and the mixture is stirred at 0°C for 1 hour. The solvent is removed under reduced pressure and the residue is extracted with dichloromethane. The extracts are evaporated and the residue is purified by chromatography over silica gel with dichloromethane. The solid obtained is dissolved in 1 0 ml of toluene and heated to 100°C for 4 hours under a nitrogen atmosphere. The solvent is evaporated. There are obtained 700 mg of 6,7,8,9-tetrahydropyrido[l ,2-a]indole-8-isocyanate, m.p. 87-89°C. c) 4 ml of a 2M sodium hydroxide solution are added to a solution of 700 mg of the product from b) in 50 ml of THF and the solution is stirred overnight. The solvent is removed under reduced pressure and the residue is extracted with dichloromethane. The dichloromethane extract is evaporated and there is obtained an amine which is dissolved in dichloromethane. 645 mg of di-t-butyl dicarbonate and 300 ml of triethylamine are added at 0°C and the mixture is left to warm to room temperature while stirring for 22 hours. The mixture is washed with sodium bicarbonate solution and the organic phase is dried. The solvent is removed under reduced pressure and the residue is extracted with diethyl ether. The ethereal extracts are evaporated and the solid is triturated with petroleum ether. There are obtained 550 mg of 8-t-butoxyformamido-6,7,8,9-tetrahydropyrido[l ,2a]indole, m.p. 1 55-157°C. d) 256 mg of oxalyl chloride are added dropwise to a solution of 550 mg of the product from c) in 10 ml of diethyl ether at 0°C under a nitrogen atmosphere. After 1 hour the solvent is removed under reduced pressure and the residue is dissolved in dichloromethane. 363 mg of 1-methyl-3-indolylacetic acid and 390 mg of triethylamine are added and the mixture is stirred for 40 hours.

The solvent is removed under reduced pressure and the residue is purified by chromatography over silica gel with ethyl acetate/ petroleum ether (1:2). After crystallization from diethyl ether/ petroleum ether there are obtained 200 mg of 3-[8-t-butoxyformamido-6,7,8,9-tetrahydropyrido[l,2-a]indol-1 0-yl]-4-( 1 -methyli° 3-indolyl)furan-2,5-dione, m.p. 1 55-160°C.

Example 39 Analogously to Example 37, from the pyrroledione product is of Example 38 there is obtained 3-[8-amino-6,7,8,9-tetrahydropy rido [ 1,2-a] indol-1 0-y I]-4-( 1 -me thy I-3-indoly I )-1 H-pyrrole2,5-dione hydrochloride, m.p. 310-31 5°C.

Example 40 A solution of 320 mg of 3-[4-(2-acetoxyethyl)-5,6-dihydro4H-pyrrolo[3,2,l-ij]quinolin-l-yl]-4-(l -methyl-3-indolyl)furan2,5-dione in 2 ml of DMF and 2 ml of 33% aqueous ammonia is heated to 140°C for 12 hours. Water is added to the cooled 25 mixture. After filtration there are obtained 210 mg of 3-[4-(2hydroxyethyl)-5,6-dihydro-4H-pyrrolo[3,2,1 -ij]quinolin-l-yl)-4(1-methyl-3-indolyl)-l H-pyrrole-2,5-dione, m.p. 214-21 5°C after crystallization from ethyl acetate.

The starting furandione is prepared as follows: a) 25 ml of 1.6M solution of n-butyllithium in n-hexane are added to a solution of 4.04 g of diisopropylamine in 20 ml of THF at 0°C under nitrogen. After 10 minutes the solution is cooled to 35 - 78°C and a solution of 9.28 g of t-butyl acetate in 20 ml of THF is added. After 10 minutes 3.46 g of 1,2,5,6-tetrahydro-4Hpyrrolo[3,2,l-ij]quinolin-4-one in 20 ml of THF are 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 is partitioned between ethyl acetate and water and the organic extracts are washed with water and sodium chloride solution, dried and evaporated. The residue is purified by chromatography over silica gel with ethyl acetate/petroleum ether (1:3). There are obtained 4.1 g of t-butyl (E)-(l ,2,5,6tetrahydro-4H-pyrrolo[3,2,1 -ij]quinolin-4-ylidene)acetate, m.p. 105-107°C. b) A solution of 4 g of the product from a) in 400 ml of methanol is shaken with 280 mg of 10% Pd/C under a hydrogen atmosphere for 1 8 hours. The catalyst is filtered off and the filtrates are evaporated. 1.99 g of the resulting oil in 100 ml of diethyl ether are treated with 5 ml of a 1 M solution of LiAlH4 in diethyl ether and the mixture is stirred for 2 hours. Water is added and the product is extracted with ethyl acetate. The ethyl acetate extracts are dried and concentrated under reduced pressure. There are obtained 1.44 g of 1,2,5,6-tetrahydro-4Hpyrrolo[3,2,1 -ij]quinoline-4-ethanol. c) 1.44 g of the product from b) in 40 ml of dichloromethane are treated with 10 ml of acetic anhydride and 5 ml of pyridine. The solution is, 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. There are obtained 1.65 g of 4-(2-acetoxyethyl)-1 ^.S^-tetrahydro-AHpyrrolofS^, 1-ij]quinoline. d) A solution of 1.6 g of the product from c) in 50 ml of xylene and 100 mg of 10% Pd/C is heated under reflux for 12 hours. The catalyst is filtered off and filtrate is evaporated. There are obtained 1.7 g of 4-(2-acetoxyethyl)-5,6-dihydro-4H-pyrrolo[3,2,1 -ijjquinoline. e) 935 mg of oxalyl chloride are added while stirring to a solution of 1.7 g of the product from c) in 45 ml of dichloromethane under a nitrogen atmosphere. After 1 hour the solvent is removed under reduced pressure and the residue is dissolved in 90 ml of dichloromethane. 1.38 g of 1 -methyl-3-indolylacetic acid and 1.48 g of triethylamine are added to the solution and the mixture is stirred for 1 8 hours. The solvent is removed under reduced pressure and the residue is purified by chromatography s over silica gel with ethyl acetate/petroleum ether (1:2).

Crystallization from methanol/water gives 280 mg of 3-[4-(2acetoxyethyl)-5,6-dihydro-4H-pyrrolo[3,2,1 -ij]-qui noli n-1 -yl]4-(1-methyl-3-indolyl)furan-2,5-dione, m.p. 143-146°C. io Example 41 A solution of 400 mg of 3-[t-butoxyformamido)methyl]6,7,8,9-tetrahydropyrido[1,2-a] indol-1 0-yl]-4-( 1 -methyl-3indolyl)furan-2,5-dione in 50 ml of DMF and 50 ml of water is is treated with 2.5 g of hydroxylamine hydrochloride and 2.5 g of potassium carbonate and the solution is heated to 1 00°C. The solvents are evaporated and the residue is dissolved in dichloromethane, washed with water and dried. The solvent is removed under reduced pressure and the residue is crystallized from ethyl 2u acetate/petroleum ether. There are obtained 190 mg of 3-[8-(tbutoxyformamidomethyl)-6,7,8,9-tetrahydropyrido[l ,2-a]indol1 0-y I]-1 -hydroxy-4-( 1 -methyl-3-indoly I) pyrrole-2,5-dione, m.p. 238-240°C.

The starting furandione is prepared as follows: a) 2.4 g of methanesulphonic anhydride and 2 ml of triethylamine are added while stirring to a solution of 2.01 g of 6,7,8,9tetrahydropyrido[l ,2-a]indole-8-methanol in 40 ml of dichloro30 methane under a nitrogen atmosphere. After 1 8 hours the mixture is washed with saturated sodium bicarbonate solution, dried and evaporated. 1.8 g of the oil obtained are dissolved in 10 ml of isopropanol and 5 ml of 33% aqueous ammonia and the mixture is heated to 80°C for 10 hours. The solvent is removed under 35 reduced pressure and the residue is partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase is dried and evaporated. There are obtained 1.3 g of 8aminomethyl-6,7,8,9-tetrahydropyrido[1,2-a]indole, m.p. 85-90°C. b) 1.09 g of di-t-butyl dicarbonate are added while stirring to a solution of 890 mg of 8-aminomethyl-6,7,8,9-tetrahydropyrido[1,2-ajindole 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 is crystallized from petroleum ether. There are obtained 1.03 g of 8-(t-butoxyformamidomethyl)-6,7,8,9-tetrahydropyrido[1,2ajindole, m.p. 80-85°C. c) 445 mg of oxalyl chloride are added dropwise to a solution of 1 g of the product from b) in 20 ml of diethyl ether under a nitrogen atmosphere at 0°C. After 1 hour the solvent is removed under reduced pressure and the residue is dissolved in dichloro15 methane. 630 mg of 1-methyl-3-indolyacetic acid and 920 μΙ of triethylamine are added to this solution and the mixture is stirred for 72 hours. The solvent is removed under reduced pressure and the residue is purified by chromatography over silica gel with ethyl acetate/petroleum ether (1:2). The resulting solid is crystallized from diethyl ether. There are obtained 315 mg of 3-[8-(t-butoxyformamidomethyl)-6,7,8,9-tetrahydropy rido [ 1,2-a ] indol-1 0-y l]-4-( 1 -methyl-3-indolyl)furan-2,5dione, m.p. 124-126°C.

Example 42 Analogously to Example 37, from the product of Example 41 there is obtained 3-[8-aminomethyl-6,7,8,9-tetrahydropyrido[1,2-a] indol-1 0-y I ] -1 -hydroxy-4-( 1 -me thy I-3-indoly I) pyrrole30 2,5-dione hydrochloride, m.p. 280-282°C.

Example 43 Analogously to Example 11, from the product of Example 40 35 there is obtained 3-[4-(amidinothioethyl)-5,6-dihydro-4Hpyrrolo[3,2,1 - ijjquinolin-1 -y I]-4-(1 - methyl-3-indoly 1)-1 Hpyrrole-2,5-dione methanesulphonate, m.p. 185-190°C.

Example 44 Analogously to Example 2, from the product of Example 40 there is obtained 3-[4-(2-aminoethyl)-5,6-dihydro-4H-pyrrolo[3,2,1 -ij]quinolin-l -y I]-4-( 1 -me thy I-3-indoly I )-1 H-pyrrole-2,5 dione hydrochloride, m.p. 193-195°C.

Example 45 Analogously to Example 2, from the product of Example 26 there is obtained 3-[8-aminomethyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-1 0-yl-4-(3-benzo[b]thienyl)-l H-pyrrole-2,5-dione hydrochloride, m.p. 285-287°C.

Example 46 Analogously to Example 1, 1st paragraph, from 3-(8acetoxymethyl-6,7,8,9-tetrahydropyrido[1,2-a] indol-1 0-yl]-4(2-naphthyl)furan-2,5-dione (obtained as described in the last paragraph of Example 1, but using 2-naphthylacetic acid in place of 1 -methyl-3-indolylacetic acid) there is obtained 3-(6,7,8,9tetrahydro-8-hydroxymethylpyrido[1,2-a] indol-1 0-yl]-4-( 2naphthyl)-! H-pyrrole-2,5-dione, m.p. 260-263°C.

Example 47 Analogously to Example 2, from the product of Example 46 there is obtained 3-[8-aminomethyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-1 0-yl]-4-(2-naphthyl)-1 H-pyrrole-2,5-dione hydrochloride, m.p. >300°C.

Example 48 Analogously to Example 10, from the product of Example 27 there is obtained 3-[8-aminomethyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-1 -yI]-4-( 1 -naphthyl)-1 H-pyrrole-2,5-dione, m.p. 167-169°C.

Example 49 Analogously to Example 1, 1st paragraph, from 1.3 g of 3[9-acetoxymethyl-7,8,9,l 0-tetrahydro-6H-azepino[l ,2-a]indol11 -yl]-4-(l -methyl-3-indolyl)furan-2,5-dione there are obtained 520 mg of 3-[7,8,9,10-tetrahydro-9-hydroxymethyl-6H-azepino5 [1,2-a]indol-l 1 -yI]-4-( 1 -methyl-3-indolyl)-l H-pyrrole-2,5dione, m.p. 268-270°C.

The starting furandione is prepared as follows: io a) A solution of 18.9 g of ethyl indole-2-carboxylate in 100 ml of DMF is added to a suspension of 2.64 g of sodium hydride in 50 ml of DMF. After 1 hour a solution of 20.9 g of ethyl 5bromovalerate in 100 ml of DMF is added dropwise. After 48 hours the mixture is poured into water, extracted with dichloro15 methane and the combined dichloromethane extracts are washed with water, dried and concentrated. There are obtained 26.2 g of ethyl 1 -(4-ethoxycarbonylbutyl)indole-2-carboxylate. b) A solution of the product from a) in 50 ml of THF is added 2o while stirring to a suspension of 11.2 g of potassium t-butoxide in 150 ml of THF. After 36 hours the mixture is concentrated and the residue is poured into a mixture of water and diethyl ether. The organic phase is dried and concentrated. Chromatography of the residue over silica gel with dichloromethane/methanol (9:1) gives a solid which is recrystallized from ethyl acetate/nhexane. There are obtained 6.1 g of ethyl 7,8-dihydro-10hydroxy-6H-azepino[l ,2-9]indole-9-carboxylate, m.p. 74-81 °C. c) A solution of 5.5 g of the product from b) in 200 ml of ethanol is treated with 11 spoon spatulas of Raney-nickel and 400 ml of water. The mixture is heated under reflux for 4 hours. The cooled mixture is filtered and the residue is washed with ethyl acetate. The filtrate is extracted with ethyl acetate. The combined extracts are dried and concentrated. There is obtained an oil which is purified by chromatography over silica gel with dichloromethane. There are obtained 2.5 g of ethyl 7,8,9,10tetrahydro-6H-azepino[l ,2-a]indole-9-carboxylate, m.p. 69-70°C. d) A solution of the product from c) in 50 ml of THF is added dropwise to a mixture of 0.45 g of L1AIH4 in 20 ml of THF. The mixture is stirred for 2 hours and, after the addition of water, extracted with diethyl ether. The combined extracts are dried and concentrated. Chromatography of the residue over silica gel with dichloromethane gives 1.90 g of 7,8,9,1 0-tetrahydro-910 hydroxymethyl-6H-azepino[1,2-a]indole, m.p. 109-111 °C. e) A solution of 1.8 g of the product from d) in 100 ml of diethyl ether is treated at 0°C with 1.70 g of acetic anhydride and 0.66 g of pyridine. After 8 hours a further 5 g of pyridine are is added and the mixture is stirred for 76 hours. The solvents are removed under reduced pressure and the residue is chromatographed over silica gel with dichloromethane. There are obtained 1.98 g of 9-acetoxymethyl-7,8,9,l 0-tetrahydro-6H-azepino[l ,2ajindole, m.p. 65°C. 2U f) A solution of 1.90 g of the product from e) in 50 ml of dichloromethane is cooled to 0°C and treated with 1.03 g of oxalyl chloride. After 2 hours the solvent is evaporated, the residue is dissolved in dichloromethane and added dropwise to a solution of 1-5 g of 1-methylindole-3-acetic acid and 1.86 g of triethylamine in dichloromethane. The mixture is evaporated and the residue is chromatographed over silica gel with dichloromethane containing 5% methanol by volume. The solid obtained is recrystallized from ethyl acetate/n-hexane. There are obtained 1.55 g of 3-[930 acetoxymethyl-7,8,9,1 0-tetrahydro-6H-azepino[l ,2-a]indol-1 1 yl]-4-(l-methyl-3-indolyl)furan-2,5-dione, m.p. 164-166°C.

Example 50 Analogously to Example 12, from 0.50 g of 3-[7,8,9,1 0tetrahydro-6H-azepino[l,2-a]indol-1 1 -yl]-3-(1 -methyl-3indolyl)furan-2,5-dione there is obtained 0.43 g of 3-[7,8,9,l 044 tetrahydro-6H-azepino[1,2-a]indol-11 -yI]-3-(1 -methyl-3indolyl)-!H-pyrrole-2,5-dione, m.p. >300°C.

The starting furandione is prepared as follows: 1.5 g of oxalyl chloride are added dropwise to an ice-cold solution of 2.0 g of 7,8,9,1 0-tetrahydro-6H-azepino[1,2-a]indole (J. Org. Chem. 33, 1968, 4286) in 50 ml of dichloromethane. The mixture is stirred for 2 hours. The solvent is removed in a vacuum and the residue is dissolved in dichloromethane. The solution is added to a solution of 2.2 g of 1 -methyl-3-indolylacetic acid and 2.73 g of triethylamine in 50 ml of dichloromethane. The mixture is stirred and then evaporated. The residue is' chromatographed over silica gel with dichloromethane and there is obtained 1.0 g of 3-[7,8,9,1 0-tetrahydro-6H-azepino[1,2a]indol-11-yl]-3-(1-methyl-3-indolyl)furan-2,5-dione, m.p. 257259°C.

Example 51 A solution of 1 50 mg of the product of Example 49 and 146 mg of 2,6-lutidine in 50 ml of dichloromethane is added dropwise to a solution of 290 mg of trifluoromethanesulphonic anhydride at 0°C. After 3 hours 25 ml of 33% aqueous ammonia are added, the mixture is stirred for 1 6 hours, then extracted with dichloromethane and the combined extracts are dried and evaporated. Chromatography of the residue over silica gel with dichloromethane/methanol/acetic acid/water (90:18:3:2) gives 50 mg of 3-[9-aminomethyl-7,8,9,10-tetrahydro-6H-azepino[1,2a ] indol-1 1 -y 1-4-(1 - me thy I-3-indoly I )-1 H-pyrrole-2,5-dione acetate, m.p. 215°C (decomposition).

Example 52 A mixture of 40 mg of the product of Example 51, 20 mg of sodium bicarbonate and 25 mg of 3,5-dimethyl-N2-nitro-1 pyrazole-1-carboxamide in 10 ml of ethanol is heated under reflux for 16 hours, then evaporated and the residue is chromato45 graphed over silica gel with dichloromethane/methanol (9:1). There are obtained 1 5 mg of 3-( 1-methyl-3-indolyl)-4-[7,8,9,1 0tetra hydro-9-(2-nitroguan idi no methy 1)-6 H-azepino[ 1,2-a]-indol11-yl]-l H-pyrrole-2,5-dione, m.p. 177-178°C.

Example 53 Analogously to Example 1, 1st paragraph, from 0.20 g of 3[8-acetoxymethyl-7,8,9,1 0-tetrahydro-6H-azepino[l , 2-a] indoliu 11-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione there are obtained 60 mg of 3-(7,8,9,10-tetrahydro-8-hydroxymethyl-6H-azepino[1,2-a]indol-l 1 -y I]-4-( 1 -methyl-3-indoly 1)-1 H-pyrrole-2,5dione, m.p. 1 09-111 °C. is The starting furandione is prepared as follows: a) A solution of 5 g of ethyl 6,7-dihydro-9-hydroxypyrido[1,2a] indole-8-carboxylate (prepared as described in Example 1) in 200 ml of DMF is treated with 550 mg of sodium hydride. The mixture is stirred under a nitrogen atmosphere and then a solution of 3.6 g of ethyl bromoacetate in 50 ml of DMF is added. After 16 hours the mixture is poured into water and extracted with diethyl ether. The combined extracts are washed with water, dried and evaporated. There are obtained 4.4 g of ethyl 825 ethoxycarbonyl-6,7,8,9-tetrahydro-9-oxopyrido[1,2-a]indole-8acetate. b) A solution of 5.0 g of the product from a) in 200 ml of THF is added dropwise while stirring to a solution of 2.0 g of 30 potassium t-butoxide in 50 ml of THF. The mixture is stirred and then 1 ml of glacial acetic acid is added. The mixture is poured into water and extracted with dichloromethane. The combined extracts are dried and evaporated. The residue is chromatographed over silica gel with dichloromethane/methanol (95:5).

There are obtained 3.0 g of diethyl 7,8-dihydro-1 0-hydroxy-6Hazepino[l ,2-a]indole-8,9-dicarboxylate. c) A mixture of 2.8 g of the product from b) and 0.5 g of boric acid is heated to 150°C and then to 170°C. Ice-water is added to the cooled mixture and the mixture is extracted with dichloromethane. The combined dichloromethane extracts are dried and evaporated. The residue is chromatographed over silica gel with dichloromethane/methanol (95:5). There are obtained 2.1 g of ethyl 7,8,9,1 0-tetrahydro-10-oxo-6H-azepino[l ,2-a]indole-8carboxylate. iu d) 2.1 g of the product from c) are dissolved in 80 ml of ethanol and treated with 4 spoon spatulas of Raney-nickel and 50 ml of water. The mixture is heated under reflux for 4 hours, then cooled and filtered. The residue is washed with ethyl acetate, the filtrates are extracted with ethyl acetate, the is combined extracts are dried and concentrated. Chromatography of the residue over silica gel with dichloromethane gives 0.89 g of ethyl 7,8,9,1 0-tetrahydro-6H-azepino[1,2-a]indole-8-carboxylate. e) 0.85 g of the product from d) is dissolved in 50 ml of THF and added dropwise while stirring to a suspension of 140 mg of L1AIH4 in 50 ml of THF. After the addition of water the mixture is extracted with diethyl ether. The combined extracts are dried and evaporated. Chromatography of the residue over silica gel with dichloromethane/methanol (95:5) gives 0.70 g of 7,8,9,10tetrahydro-8-hydroxymethyl-6H-azepino[1,2-a]indole, m.p. 9091 °C. f) 0.70 g of the product from e) is treated with 0.66 g of acetic anhydride and 0.39 g of pyridine in 50 ml of diethyl ether. g of pyridine and 1 g of acetic acid are added and the mixture is stirred for 1 6 hours, then evaporated and the residue is chromatographed over silica gel with dichloromethane. There is obtained 0.60 g of 8-acetoxymethyl-7,8,9,10-tetrahydro-6H35 azepino[1,2-a]indole, m.p. 77-79°C. g) A solution of 0.60 g of the product from f) in 50 ml of dichloromethane is treated dropwise with 0.33 g of oxalyl chloride. After 2 hours the solution is evaporated and the residue is dissolved in dichloromethane and this solution is added to one of 0.49 g of 1-methylindole-3-acetic acid and 0.59 g of triethylamine in dichloromethane. After 16 hours the mixture is evaporated and the residue is chromatographed over silica gel with dichloromethane/methanol (95:5). There is obtained 0.51 g of 3-[8-acetoxymethyl-7,8,9,l 0-tetrahydro-6H-azepino[1,2a]indol-11 -yl]-4-(1 -methyl-3-indolyl)furan-2,5-dione, m.p. 70°C.

Example 54 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 to a solution of 11 6 mg of trifluoromethanesulphonic anhydride in 25 ml of dichloromethane at 0°C. After 3 hours 25 ml of aqueous ammonia are added to the solution. The organic phase is dried and concentrated. Chromatography of the residue on silica gel gives 30 mg of 3-[8-aminomethyl-7,8,9,1 0-tetrahydro-6H-azepino[1,2a ]indo 1-1 1 -y I]-4-( 1 - me thy 1-3-indoly I )-1 H-pyrrole-2,5-dione acetate, m.p. 162-163°C.

Example 55 A solution of 0.64 g of the product of Example 1 and 0.4 ml of 2,4,6-collidine in 20 ml of dichloromethane is added dropwise to a solution of 0.75 g of trifluoromethanesulphonic anhydride in 10 ml of dichloromethane at 0°C. After 2.5 hours the mixture is treated with 3 ml of piperidine and stirred for 16 hours. Evaporation and chromatography of the residue over silica gel with dichloromethane/methanol (from 98:2 to 50:50) gives 340 mg of 3-[6,7,8,9-tetrahydro-8-( 1-piperidinomethyl)pyrido[1,2-a] indol-1 0-yl]-4-( 1 - me thy I-3-indoly I)-IH-pyrrole2,5-dione. Treatment of this product with saturated solution of hydrogen chloride in ethyl acetate gives the hydrochloride, m.p. 294°C (decomposition).

Example 56 A solution of 0.8 g of the product of Example 1 and 0.44 g of 2,4,6-collidine in 30 ml of dichloromethane is added to a solution of 0.9 g of trifluoromethanesulphonic anhydride in 10 ml of dichloromethane at 0°C. After 1.5 hours the mixture is treated with 3.64 g of diisopropylamine, stirred for 16 hours and then washed with water and saturated aqueous sodium bicarbonate solution, dried and evaporated. The solid is dissolved in ethyl acetate and treated with a saturated solution of hydrogen chloride in ethyl acetate. Removal of the solvent in a vacuum gives 260 mg of 3-[6,7,8,9-tetrahydro-8-(diisopropylaminomethyl)pyrido[ 1,2-a]-indol-1 0-y I]-4-( 1 -methyl-3-indoly I )-1 Hpyrrole-2,5-dione hydrochloride, m.p. 1 87°C (decomposition).

Example 57 A solution of 1.0 g of 3-[8-acetoxymethyl-6,7,8,9-tetrahydropyrido[l ,2-a]indol-1 0-yl]-4-3-benzofuranyl)furan-2,5-dione in 100 ml of chloroform is treated with 13.8 ml of hexamethyldisilazane and 2.73 ml of methanol and heated to 50°C while stirring under a nitrogen atmosphere for 6 hours. A further 13.8 ml of hexamethyldisilazane and 2.73 ml of methanol are added and the heating is continued for 16 hours. Two further additions of the same quantities of hexamethyldisilazane and methanol are effected and the mixture is held at 50°C for 24 hours. 20 ml of methanol are then added and the mixture is heated under reflux for 1 5 minutes, then cooled and evaporated, the precipitate is filtered off and triturated in succession with ethyl acetate and methanol. There are obtained 630 mg of 3-[8-acetoxymethyl6,7,8,9-tetrahydropyrido[l ,2-a]indol-1 0-yl]-4-(3-benzofuranyl)1 H-pyrrole-2,5-dione, 234-237°C.

The starting furandione is prepared as follows: 1.7 g of oxalyl chloride are added dropwise to a solution of 3.3 g of 8-acetoxymethyl-6,7,8,9-tetrahydropyrido[l ,2-a]indole in 200 ml of diethyl ether under a nitrogen atmosphere. After 1 5 minutes the solvent is removed under reduced pressure and the residue is dissolved in dichloromethane. 2.4 g of 3-benzofuranylacetic acid and 5.6 ml of triethylamine are added to this solution and the mixture is stirred overnight, the solvent is removed under reduced pressure and the residue is chromatographed by chromatography over silica gel with ethyl acetate/petroleum ether (1:2). Crystallization of the residue from ethyl acetate/petroleum ether gives 1.62 g of 3-[8-acetoxymethyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(3-benzofuranyl)furan-2,5-dione, m.p. 21 4lo 215°C.

Example 58 A solution of 300 mg of the product of Example 57 in 40 ml is of methanol is treated with 5 ml of 2M sodium hydroxide. After minutes the mixture is acidified with 5 ml of 2M hydrochloric acid and the methanol is removed under reduced pressure and the residue is 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. There are obtained 190 mg of 3-(3-benzofuranyl)-4[6,7,8,9-tetrahydro-8-hydroxymethylpyrido[1,2-a] indol-1 0-yl]1 H-pyrrole-2,5-dione, m.p. 246-248°C.

Example 59 Analogously to Example 2, from the product of Example 58 there is obtained 3-[8-aminomethyl-6,7,8,9-tetrahydropyrido[1,2-a] indol-1 0-yl]-4-(3-benzofuranyl)-1 H-pyrrole-2,5-dione hydrochloride, m.p. 210-212°C.

Example 60 118 mg of trifluoromethanesulphonic anhydride in 20 ml of 35 dichloromethane are treated at 0°C under a nitrogen atmosphere with 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% solution of dimethylamine in water is added and the mixture is stirred for 1.5 hours, the solution is washed with water and sodium bicarbonate solution and then dried and evaporated and the resulting crystals are filtered off and dried. There are obtained 60 mg of 3-(3-benzo[b]thienyl)-4[6,7,8,9-tetrahydro-8-dimethylaminomethylpyrido[l ,2-a]indol1 0-yl]-1 H-pyrrole-2,5-dione, m.p. 285-286°C.

Example 61 546 mg of trifluoromethanesulphonic anhydride in 80 ml of dichloromethane are treated at 0°C under a nitrogen atmosphere with a suspension of 400 mg of the product of Example 1 9 and 208 mg of collidine in 120 ml of dichloromethane. After 1 hour 1.9 ml of-50% aqueous dimethylamine are added and the mixture is stirred for 3 hours, the solvent is removed and the residue is subjected to chromatography over silica gel with dichloromethane/methanol/acetone (88:10:2). Trituration with ethyl acetate followed by recrystallization from methanol gives 295 mg· of 3-[2,3-dihydro-2-dimethylaminomethyl-l H-pyrrolo[l ,2-a]indol-9-yl]-4-(l-methyl-3-indolyl)-l H-pyrrole-2,5-dione trifluoromethanesulphonate, m.p. 323-325°C.

Example 62 A solution of 400 mg of 3-[8-cyano-6,7,8,9-tetrahydropyrido[l ,2-a]indol-l 0-y l]-4-( 1 -methyl-3-indolyl)furan-2,5-dione in 12 ml of DMF and 12 ml of 33% aqueous ammonia is heated to 1 40°C for 3 hours. The mixture is cooled and the resulting solid is filtered off and dried. There are obtained 275 mg of 3-[8cyano-6,7,8,9-tetrahydropyrido[l ,2-a]indol-l 0-yl]-4-( 1 -methyI3-indolyl)-1 H-pyrrole-2,5-dione, m.p. 312-313°C.

The starting furandione is prepared as follows: a) A suspension of 4.0 g of the product from Example 38a) in 4.4 ml of water and 84 ml of acetone is cooled to 0°C and 2.18 g of triethylamine and then 2.56 g of ethyl chloroformate are added. The resulting solution is stirred under a nitrogen atmosphere. 0.9 ml of 33% aqueous ammonia is added and the mixture is left to warm to room temperature. A further 0.5 ml of 33% aqueous ammonia is added and the stirring is continued. The solvent is evaporated, the residue is extracted with dichloromethane and the organic phase is washed with water, dried and evaporated. There are obtained 2.8 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole8-carboxamide, m.p. 179-1 81 °C. b) 991 mg of trifluoroacetic anhydride are added dropwise to a iu suspension of 1.0 g of the product from a) in 1 5 ml of dioxan at 0°C. The mixture is partitioned between dichloromethane and water, the organic phase is dried and the solvent is removed under reduced pressure. The resulting oil is chromatographed over silica gel with ethyl acetate/petroleum ether (1:1). There is are obtained 740 mg of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8carbonitrile, m.p. 11 6-11 8°C. c) 518 mg of oxalyl chloride are added to a solution of 800 mg of the product from b) in 100 ml of diethyl ether under a nitrogen atmosphere. The solvent is evaporated and the residue is dissolved in dichloromethane. 771 mg of 1-methyl-3-indolylacetic acid and 1.24 g of triethylamine are added to this solution, the mixture is stirred overnight, the solvent is then removed under reduced pressure and the residue is purified by chromato25 graphy over silica gel with 10% methanol in dichloromethane. The fractions containing the desired product are evaporated and the crystals are filtered off and dried. There are obtained 560 mg of 3-[8-cyano-6,7,8,9-tetrahydropyrido[1,2-a]indol-l 0-yl]-4-( 1 methyl-3-indolyl)furan-2,5-dione, m.p. 309-31 1°C.

Example 63 Gaseous hydrogen chloride is bubbled into a solution of 200 mg of the product of Example 62 in 250 ml of methanol at 35 0°C. The solvent is then removed under reduced pressure and the residue is dissolved in 50 ml of dichloromethane and 250 ml of ethanol. Ammonia is bubbled into the solution and the solvent is then evaporated. The residue is purified by chromatography over silica gel with dichloromethane/methanol/acetic acid/water (90:18:3:2). Trituration with ethyl acetate gives 75 mg of 3-[8amidino-6,7,8,9-tetrahydropyrido[l ,2-a] indol-1 0-y I]-4-(1 methyl-3-indolyl)-1 H-pyrrole-2,5-dione hydrochloride, m.p. 237s 239°C.

Example 64 A solution of 50 mg of 3-[8-carbamoyl-6,7,8,9-tetrahydro10 pyrido [1,2-a] indol-1 0-y I]-4-( 1 - me thy 1-3-indolyl) furan-2,5-dione in 4 ml of DMF and 4 ml of 33% aqueous ammonia is heated to 1 40°C. The mixture is extracted with ethyl acetate and the organic phase is washed with water and then dried. The majority of the solvent is evaporated and the precipitate obtained is filtered 15 off and dried. There are obtained 20 mg of 3-[8-carbamoyl6,7,8,9-tetrahydropyrido[l,2-a]indol-1 0-yl]-4-( 1 -methyl-3indolyl)-! H-pyrrole-2,5-dione, m.p. 315-316°C.

The starting furandione is prepared as follows: 2U 178 mg of oxalyl chloride are added to a solution of 300 mg of the product of Example 62a) in 40 ml of dichloromethane under a nitrogen atmosphere. Then, the solvent is removed under reduced pressure and the residue is dissolved in dichloromethane. 265 mg of 1 -methyl-3-indolylacetic acid and 424 mg of triethylamine are added and the mixture is stirred for 60 hours, the solvent is then removed under reduced pressure and the residue is purified by chromatography over silica gel with 10% methanol in dichloromethane. Crystallization from ethyl acetate gives 70 mg 30 of 3-[8-carbamoyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-10-yl]4-(1-methyl-3-indolyl)-furan-2,5-dione, m.p. 307-309°C.

Example 65 35 Analogously to Example 1, 1st paragraph, from 3-[8-acetoxymethyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-10-y l]-4-( 5methoxy-1 -methyl-3-indolyl)furan-2,5-dione there is obtained 3-[6,7,8,9-tetrahydro-8-hydroxymethylpyrido[1,2-a] indol-1 0-y I]53 4-(5-methoxy-1 -methyl-3-indolyl)-1 H-pyrrole-2,5-dione, m.p. 300-303°C.

The starting furandione is prepared as follows: 0.4 ml of oxalyl chloride is 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. Then, the solvent is removed under reduced pressure and the residue is io dissolved in dichloromethane. 940. mg of 5-methoxy-1 -methyl-3indolylacetic acid and 1.16 ml of triethylamine are added and the mixture is stirred for 40 hours, the solvent is then removed under reduced pressure and the residue is purified by chromatography over silica gel with ethyl acetate/n-hexane (1:2). Crystallization is from ethyl acetate/petroleum ether gives 250 mg of 3-[8-acetoxymethyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-1 0-yl]-4-(5methoxy-1 -methyl-3-indolyl)furan-2,5-dione, m.p. 259-261 °C.

Example 66 2U Analogously to Example 2, from the product of Example 65 there is obtained 3-[8-aminomethyl-6,7,8,9-tetrahydropyrido[1,2,a]indol-l 0-yl]-4-(5-methoxy-l - methy I-3-indoly I )-1 H-pyrrole-2,5-dione hydrochloride, m.p. 268-270°C.

Example 67 Analogously to Example 1, 1st paragraph, from 3-[8-acetoxymethyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-1 0-yl]-4-(530 bromo-1 -methyl-3-indolyl)furan-2,5-dione there is obtained 3[6,7,8,9-tetrahydro-8-hydroxymethylpyrido[l,2-a]indol-1 0-yl]-4(5-bromo-l-methyl-3-indolyl)-l H-pyrrole-2,5-dione, m.p. 316318°C.

The starting furandione is prepared as follows: a) 500 mg of a dispersion of sodium hydride in mineral oil are added to solution of 1 g of 5-bromoindole-3-acetic acid in 50 ml of THF and the mixture is stirred under a nitrogen atmosphere for hour. 820 mg of methyl iodide are added and the mixture is stirred under a nitrogen atmosphere for 24 hours. 5 ml of water are added and the solvent is removed under reduced pressure, the residue is treated with 2M hydrochloric acid and the resulting precipitate is filtered off, washed with n-hexane and dried. The resulting solid is recrystallized from diethyl ether. There is obtained 5-bromo-l -methyl-3-indolylacetic acid, m.p. 192194°C. b) 500 mg of oxalyl chloride are added to a solution of 900 mg of the product from a) in 100 ml of diethyl ether under a nitrogen atmosphere. Then, the solvent is evaporated and the residue is dissolved in dichloromethane. 880 mg of the product from a) and 810 mg of triethylamine are added and the mixture is stirred for 48 hours, the solvent is then removed under reduced pressure and the residue is purified by chromatography over silica gel with ethyl acetate/n-hexane (1:1) to give 400 mg of a solid. Crystallization of the product obtained from ethyl acetate gives 3-[8acetoxymethyl-6,7,8,9-tetrahydropyrido[1,2-a] indol-1 0-yl]-4(5-bromo-1 -methyl-3-indolyl)furan-2,5-dione, m.p. 21 5-220°C.

Example 68 Analogously to Example 2, from the product of Example 67 there is obtained 3-[8-aminomethyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-1 0-yl]-4-(5-bromo-1 -me thy 1-3-indoly I)-1 Hpyrrole-2,5-dione hydrochloride, m.p. >310°C.

Example 69 A solution of 200 mg of 3-[7-(2-acetoxyethyl)-6,7,8,9tetrahydropyrido[1,2-a]indol-1 0-y l]-4-( 1 -methyl-3-indolyl)furan-2,5-dione in 2 ml of DMF and 1 ml of 33% aqueous ammonia is heated to 140°C, then 1 ml of a 2M solution of sodium hydroxide is added to the cooled solution and the mixture is stirred for hours, then acidified with 2M hydrochloric acid and evaporated. The residue is partitioned between ethyl acetate and water and the organic phase is dried, the solvent is evaporated and the solid obtained is triturated with ethyl acetate. There are obtained 1 1 5 mg of 3-[6,7,8,9-tetrahydro-7-(2-hydroxyethyl)-pyrido[1,2a] indol-1 0-y I]-4-(1-me thyl-3-indolyl)-1 H-pyrrole-2,5-dione, s m.p. 236-238°C.

The starting furandione is prepared as follows: a) 400 mg of a 60% dispersion of sodium hydride in mineral oil io are added to a solution of 2.24 g of triethyl phosphonoacetate in ml of dimethoxyethane under a nitrogen atmosphere. Then, the solution is cooled to 0°C and 1.85 g of the product from Example 35d) in 1 0 ml of dimethoxyethane are added. The mixture is stirred overnight and then evaporated, the residue is dissolved in is dichloromethane and the solution is then washed with water, dried and evaporated. The residue is purified by chromatography over silica gel with diethyl ether/petroleum ether (1:3). There are obtained 1.55 g of a mixture of ethyl (E)- and (Z)-(6,7,8,9tetrahydropyridop,2-a]-indol-7-ylidene)acetate. A solution of 20 1.4 g of this product in ethanol is shaken with 280 mg of 10% Pd/C under a hydrogen atmosphere, the catalyst is then filtered off and the filtrate is evaporated. There are obtained 1.2 g of ethyl 6,7,8,9-tetrahydropyridop ,2-a]indole-7-acetate, m.p. 6668°C after crystallization from diethyl ether/petroleum ether. b) A solution of 1.2 g of the product from a) in 100 ml of diethyl ether is treated with 3.5 ml of 1 M solution of L1AIH4 in diethyl ether and, after stirring for 1 hour, treated with 50 ml of aqueous ammonium chloride. The mixture is extracted with 30 diethyl ether and the organic phase is dried and evaporated. There are obtained 1.01 g of 6,7,8,9-tetrahydro-7-(2-hydroxyethyl)pyridop ,2-a]indole, m.p. 70-72°C after recrystallization from diethyl ether/petroleum ether. c) A solution of 1.04 g of the product from b) in 30 ml of dichloromethane is treated with 6 ml of acetic anhydride and 3 ml of pyridine and the solution is stirred under a nitrogen atmosphere, the mixture is then evaporated to dryness and the residue is dissolved in dichloromethane. The organic phase is washed with 2M hydrochloric acid and with water, dried and evaporated. The residue is purified by chromatography over silica gel with diethyl ether/petroleum ether (1:4). There are obtained 670 mg of 7-(2-acetoxy-ethyl)-6,7,8,9-tetrahydropyrido[1,2a]indole. d) 250 μΙ of oxalyl chloride are added to a solution of 670 mg of the product from c) in 1 2 ml of dichloromethane under a io nitrogen atmosphere. Then, the solvent is removed under reduced pressure and the residue is dissolved in dichloromethane. 493 mg of 1-methyl-3-indolylacetic acid and 527 mg of triethylamine are added and the mixture is stirred, then the solvent is removed under reduced pressure and the residue is purified by chroma15 tograpy over silica gel with ethyl acetate/petroleum ether (1:2). There are obtained 350 mg of 3-[7-(2-acetoxyethyl)-6,7,8,9tetrahydropyrido[1,2-a] indole-1 0-yl]-4-( 1 -methyl-3-indolyl)furan-2,5-dione, m.p. 182-184°C after crystallization from ethyl acetate.

Example 70 Analogously to Example 2, from the product of Example 69 there is obtained 3-[7-(2-aminoethyl)-6,7,8,9-tetrahydropyrido25 [ i, 2-a] indol-1 0-y I]-4-( 1 -methy 1-3-indoly 1)-1 H-pyrrole-2,5dione hydrochloride, m.p. 240-242°C.

Example 71 30 Analogously to Example 1, 1st paragraph, from 3-[8acetoxymethyl-6,7,8,9-tetrahydro-2-methoxypyrido[1,2-a]indol1 0-yl]-4-( 1-methyl-3-indolyl)furan-2,5-dione there is obtained 3-[6,7,8,9-tetrahydro-8-(hydroxymethyl)-2-methoxypyrido[1,2a] indol-1 0-y I]-4-(1 -me thy 1-3-indoly I )-1 H-pyrrole-2,5-dione, 35 m.p. 1 95-1 97°C.

The starting furandione is prepared as follows: a) 2 g of a 60% sodium hydride dispersion in mineral oil are washed with n-hexane by decantation and suspended in 100 ml of DMF under a nitrogen atmosphere. A solution of 1 0 g of ethyl 5methoxyindole-2-carboxylate in 100 ml of DMF is added and the mixture is stirred. Then, 9.8 g of ethyl 4-bromobutyrate are added and the mixture is stirred for 2 hours, then cooled and treated with 50 ml of IM hydrochloric acid and 400 ml of water. The mixture is extracted with diethyl ether and the combined extracts are washed with sodium chloride solution. The organic phase is dried and evaporated. A solution of the resulting oil in THF is added to a mixture of 5.2 g of potassium t-butoxide in 200 ml of THF under a nitrogen atmosphere. Then, the mixture is cooled and neutralized with IM hydrochloric acid. Water is added and the mixture is extracted with diethyl ether. The combined extracts are washed with water and sodium chloride solution and then dried. Evaporation of the solvent and crystallization of the residue from ethyl acetate gives 6.7 g of ethyl 6,7-dihydro-9hydroxy-2-methoxypyrido[l ,2-a]indole-8-carboxylate, m.p. 1571 60°C. b) 5 g of the product from a) in 200 ml of ethanol are treated under a nitrogen atmosphere with 10 spoon spatulas of Raneynickel and 100 ml of water. The suspension is heated under reflux, then cooled and filtered. The solid is washed with ethyl acetate and the volatile constituents are removed in a vacuum from the combined filtrates. The aqueous suspension is extracted with ethyl acetate, the combined extracts are washed with sodium chloride solution and dried. Evaporation of the solvent and crystallization of the residue from methanol gives 2.41 g of ethyl 6,7,8,9-tetrahydro-2-methoxypyrido[l ,2-a]indole-8carboxylate, m.p. 104-105°C. c) A solution of 2.3 g of the product from b) in 24 ml of THF is added to a suspension of 260 mg of L1AIH4 in 20 ml of THF under a nitrogen atmosphere. Then, the mixture is treated with 10 ml of ethyl acetate followed by 20 ml of water, acidified to pH 3 with IM hydrochloric acid and extracted with diethyl ether. The combined extracts are washed with water and dried. Evaporation of the solvent gives 1.85 g of 6,7,8,9-tetrahydro-2-methoxypyridop,2-a]indole-8-methanol, m.p. 95-96°C after crystallization from ethyl acetate/n-hexane. d) 1 g of the product from c) in 10 ml of pyridine is treated with 1.5 g of acetic anhydride. Then, the solvent is evaporated, the residue is partitioned between diethyl ether and 5% aqueous ammonium chloride, the organic phase is washed with sodium chloride solution, dried and evaporated. Chrystallization of the io residue from diethyl ether/n-hexane gives 0.84 g of 8acetoxymethyl-6,7,8,9-tetrahydro-2-methoxypyrido[l ,2-a]indole, m.p. 98-100°C. e) A suspension of 800 mg of the product from d) in 25 ml of is diethyl ether is treated with 0.27 ml of oxalyl chloride under a nitrogen atmosphere, then the solvent is evaporated, the residue is dissolved in 20 ml of dichloromethane and treated with 555 mg of N-methylindole-3-acetic acid and 0.8 ml of triethylamine. The mixture is stirred for 65 hours and then the solvent is evaporated 2u under reduced pressure. Chromatography of the residue over silica gel with ethyl acetate/n-hexane (1:1) gives 380 mg of 3[8-acetoxymethyl-6,7,8,9-tetrahydro-2-methoxypyrido[1,2ajindol-l 0-yl]-4-(1 -methyl-3-indolyl)furan-2,5-dione m.p. after crystallization from toluene/n-hexane 131-133°C (decomposition).

Example 72 Analogously to Example 2, from the product of Example 71 3θ there is obtained 3-[8-aminomethyl-6,7,8,9-tetrahydro-2methoxypyridop,2-a]indol-1 0-yl]-4-( 1 -methyl-3-indolyl)-l Hpyrrole-2,5-dione hydrochloride, m.p. 235-238°C (decomposition).

Example 73 a) A solution of 1 50 mg of the product from Example 20 in dichloromethane is treated under a nitrogen atmosphere with 135 mg of 1,1 '-thiocarbonyldiimidazole and, after 17 hours, washed with water and dried. The solvent is evaporated and the residue is crystallized from ethyl acetate. There are obtained 150 mg of 3-[l ,2,3,4-tetrahydro-2-(l-imidazolylthiocarbonyl)pyrazino[1,2-a] indol-1 0-y I]-4-( 1 -methyl-3-indoly I )-1 H-pyrrole5 2,5-dione, m.p. 244-247°C. b) A solution of 140 mg of the product from a) in 10 ml of DMF is treated with 20 ml of 33% aqueous ammonia. After 17 hours the suspension is filtered and the solid is washed with water and io then dried. There are obtained 95 mg of 3-[1,2,3,4-tetrahydro-2thiocarbamoylpyrazino[l ,2-a]indol-1 0-yl]-4-( 1 -methy 1-3indolyl)-! H-pyrrole-2,5-dione, m.p. 278°C (decomposition).

Example 74 A solution of 1 50 mg of the product of Example 20 in 50 ml of dichloromethane is treated with 3 ml of acetic anhydride and 3 ml of triethylamine and, after 1 7 hours, washed with water. The organic phase is dried and evaporated, the residue is dis20 solved in dichloromethane and treated with 0.08 ml of diethylamine. After 17 hours the solution is evaporated. Crystallization of the residue from dichloromethane/n-hexane gives 80 mg of 3[2-acetyl-l ,2,3,4-tetrahydropyrazino[1,2-a]indol-10-yl]-4-(l methyl-3-indolyl)-l H-pyrrole-2,5-dione, m.p. 308-31 0°C.

Example 75 Analogously to Example 74, from the product of Example 2 there is obtained 3-[8-acetamidomethyl-6,7,8,9-tetrahydro30 pyrido[l,2-a]indol-l 0-y I]-4-( 1 -me thy 1-3-indoly I )-1 H-pyrrole2,5-dione, m.p. 270-273°C.

Example 76 35 A solution of 150 mg of the product of Example 20 in 40 ml of dichloromethane is treated with 40 mg of triethylamine and 44 mg of methanesulphonyl chloride. After 17 hours the solution is washed with water, the organic phase is dried and evaporated.

Chromatography of the residue over silica gel with ethyl acetate/ n-hexane (2:1) and ethyl acetate gives 95 mg of 3-[1,2,3,4-tetrahydro-2-methanesulphonylpyrazino[ 1,2-a]indol-1 0-yl]-4-( 1 methyl-3-indolyl)-l H-pyrrole-2,5-dione, m.p. 298-301 °C (decomposition).

Example 77 A solution of 3.0 g of the product of Example 1 in 1 00 ml of THF is added to a suspension of 1.8 g of lithium aluminium hydride in 50 ml of THF at 0°C. The mixture is heated to reflux for 16 hours, then cooled, treated with 10 ml of water and extracted with dichloromethane. The combined dichloromethane extracts are washed with aqueous sodium bicarbonate solution, dried and evaporated. Chromatography of the resulting solid over silica gel with dichloromethane/methanol (95:5) gives a) 400 mg of 1,5-dihydro-3-[6,7,8,9-tetrahydro-8-hydroxymethylpyrido[ 1,2-a] indol-1 0-yl]-4-(methyl-3-indolyl)-2H-pyrrole-2-one, m.p. 205-207°C, and b) 160 mg of 1,5-dihydro-4-[6,7,8,9-tetrahydro-8-hydroxymethylpyrido[1,2-a] indol-1 0-yl]-3-( 1 -methyl-3-indolyl)-2Hpyrrole-2-one, m.p. 201-203°C.

Example 78 Analogously to Example 1, 1st paragraph, from 0.5 g of 3[8-acetoxymethyl-6,7,8,9-tetrahydropyrido[1,2-a] indol-1 0-y l]-4(3-trifluoromethylphenyl)furan-2,5-dione there are obtained 110 mg of 3-[6,7,8,9-tetrahydro-8-hydroxymethylpyrido[l ,2a ] indol-1 0-yl]-4-(3-trifluoromethylphenyl)-1 H-pyrrole-2,5dione, m.p. 77-79°C.

The starting furandione is prepared as follows: 1.7 g of oxalyl chloride are added dropwise to a solution, cooled to 0-4°C, of 3.0 g of 8-acetoxymethyl-6,7,8,9-tetrahydro61 pyridop ,2-ajindole in 50 ml of dichloromethane. After 2 hours the solvent is evaporated and the residue is dissolved in dichloromethane. The solution is added to a solution of 2.7 g of (α,α,αtrifluoro-m-tolyl)-acetic acid and 3.2 g of triethylamine in 70 ml of dichloromethane. The mixture is stirred for 16 hours and then evaporated. The residue is chromatographed over silica gel with dichloromethane/methanol (95:5). There are obtained 700 mg of 3- [8-acetoxymethyl-6,7,8,9-tetrahydropyrido[l ,2-a j indol-1 0-yI]4- (3-trifluoromethylphenyl)furan-2,5-dione, m.p. 176-177°C.

Example 79 Analogously to Example 1, 1st paragraph, from 1.0 g of 3[8-acetoxymethyl-6,7,8,9-tetrahydropyrido[l ,2-a]indol-l 0-yl j-4(4-methoxyphenyl)furan-2,5-dione there are obtained 150 mg of 3- [6,7,8,9-tetrahydro-8-hydroxymethylpyrido[l ,2-a j indol-1 0-y lj4- (4-methoxyphenyl)-1 H-pyrrole-2,5-dione, m.p. 228°C (decomposition).

The starting furandione is prepared as follows: 1.7 g of oxalyl chloride are added dropwise to a solution, cooled to 0-4°C, of 3.0 g of 8-acetoxymethyl-6,7,8,9-tetrahydropyridop ,2-ajindole in 50 ml of dichloromethane. After 2 hours the solvent is evaporated and the residue is dissolved in dichloromethane. The solution is 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 is stirred for 16 hours and then evaporated. Chromatography of the residue over silica gel with dichloromethane/methanol (95:5) gives 2 g of 3-[8-acetoxymethyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-1 0-yl]-4-(4methoxyphenyl)-furan-2,5-dione, m.p. 79-82°C.

Example 80 Analogously to Example 1, 1st paragraph, from 0.8 g of 3[8-acetoxymethyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-1 0-yl]-4(2-chlorophenyl)furan-2,5-dione there are obtained 120 mg of 362 (2-chlorophenyl)-4-[6,7,8,9-tetrahydro-8-hydroxymethylpyrido[1,2-a]indol-l 0-yl]-l H-pyrrole-2,5-dione, m.p. 232-233°C.

The starting furandione is prepared as follows: 2.2 g of oxalyl chloride are added dropwise to an ice-cold solution of 4 g of 8-acetoxymethyl-6,7,8,9-tetrahydropyrido[1,2ajindole in 50 ml of dichloromethane. After 2 hours the solvent is evaporated and the residue is dissolved in dichloromethane. This solution is added to a solution of 3.0 g of 2-chlorophenylacetic acid and 4.0 g of triethylamine in dichloromethane. The mixture is stirred for 16 hours and then evaporated. Chromatography of the residue over silica gel with dichloromethane/methanol (95:5) gives 0.9 g of 3-[8-acetoxymethyl-6,7,8,9-tetrahydropyrido[l ,2ajindol-l 0-yl]-4-(2-chlorophenyl)furan-2,5-dione, m.p. 168171 °C.

Example 81 Analogously to Example 51, from 80 mg of the product of Example 78 there are obtained 30 mg of 3-[8-aminomethyl6.7.8.9- tetrahydropyrido[l,2-a]indol-1 0-yl]-4-(3-trifluoromethylphenyl)- 1 H-pyrrole-2,5-dione, m.p. 202-204°C.

Example 82 Analogously to Example 52, from 100 mg of the product of Example 79 there are obtained 88 mg of 3-[8-aminomethyl6.7.8.9- tetrahydropyrido[l ,2-a]indol-1 0-yl]-4-(4-methoxyphenyl)-1 H-pyrrole-2,5-dione, m.p. 1 95-196°C.

Example 83 Analogously to Example 53, from 80 mg of the product of Example 80 there are obtained 57 mg of 3-[8-aminomethyl6,7,8,9-tetrahydropyrido[l ,2-a]indol-1 0-yl]-4-(2-chlorophenyΟΙ H-pyrrole-2,5-dione, m.p. 206-208°C (decomposition).

The following galenical preparations manner known per se: are produced in Example A Inaredient Per tablet Compound of formula 1 5.0 mg Lactose 125.0 mg Maize starch 75.0 mg Talc 4.0 mg Magnesium stearate 1.0 ma Tablet weight 210.0 ma Inaredient Example B Per caosule Compound of formula 1 10.0 mg Lactose 1 65.0 mg Maize starch 20.0 mg Talc 5.0 ma Capsule fill weight 200.0 ma

Claims (27)

1. Compounds of the general formula R wherein R is hydrogen or hydroxy, R 1 and R 2 together are agroup of the formula -(CH2)n- and R 7 is hydrogen or R 1 and R 7 together are a group of the formula -(CH2)n- and R 2 is hydrogen; R 2 is aryl or heteroaryl; R 4 , R 5 and R 5 are hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulphinyl or alkylsulphonyl; R 8 is a group of the formula -(CH2)p-R 9 or -(CH 2 ) q -R 10 ; R 9 is hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkylsulphonyl, aminocarbonyl, or aminothiocarbonyl; R 10 is hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylsulphonylamino, arylsulphonylamino, alkylthio, alkoxycarbonylamino, aminoacylamino, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulphonyloxy or arylsulphonyloxy, a 5- or 6-membered saturated nitrogen-containing heterocycle attached via the N atom or a group of the formula -U-C(V)-W; U is a S atom or NH; V is the group NH, NNO2, NCN or CHNO2; W is amino, mono- or dialkylamino; one of X and Y is an 0 atom and the other is 0 or (H,H); Z is the group CH or a N atom; as well as pharmaceutically usable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids.

2. Compounds according to claim I, wherein R is hydrogen, R 9 is hydrogen, alkylcarbonyl, cyano, amidino, alkoxycarbonyl, alkylsulphonly, aminocarbonyl or aminothiocarbonyl and R 10 is hydroxy, alkoxy, halogen, amino, monalkyl5 amino, dialkyamino, trialkylamino, azido, acylamino, alkylsulphonylamino, arylsulphonylamino, alkylthio, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulphonyloxy or arylsulphonyloxy or a group of the formula -U-C(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 have the io significance given in claim 1.

3. Compounds according to claim 1 or 2, wherein R 1 and R 2 together are -CH2- and R 7 is hydrogen, m is the number 1 or 2 and Z is the group CH.

4. Compounds according to claim 1 or 2, wherein R 1 and R 2 together are -(CH2)2- and R 7 is hydrogen, m is the number 1 and Z is the group CH. 20 5. Compounds according to claim 1 or 2, wherein R 1 and

5.R 2 together are -CH2- and R is hydrogen, m is the number 2 and Z is a N atom.

6. Compounds according to claim 1 or 2, wherein R 1 and 25 R 7 together are -CH2- and R 2 is hydrogen, m is the number 1 and Z is the group CH.

7. Compounds according to claim 1 or 2, wherein R 1 and R 7 together are -(CH2)2- and R 2 is hydrogen, m is 0 and Z is the 3u group CH.

8. Compounds according to any one of claims 1 to 6, wherein R 3 is phenyl, naphthyl, 3-benzothienyl, 3-benzofuranyl or 3-indolyl which is optionally substituted by one or more 35 substituents from the group of halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulphinyI and a I ky Is u I pho nyl.

9. Compounds according to claim 8, wherein R 3 is 1 -methyl-3-indolyl.

10. Compounds according to any one of claims 1-9, 5. Wherein R 4 , R 5 and R 6 are hydrogen.

11. Compounds according to any one of claims 1-10, wherein R 8 is a group of the formula -(CH2)q-R 10 . iu

12. Compounds according to claim 11, wherein q is the number 1 of 2.

13. Compounds according to claim 11 or 12, wherein R 10 is hydroxy, amino, monalkylamino, dialkylamino, trialkylamino, is azido, acylamino, alkylcarbonyloxy or a group of the formula -U-C(V)-W.

14. Compounds according to claim 13, wherein U is a S atom, V is the group NH and W is amino.

15. Compounds according to any one of claims 1-14, wherein X and Y are oxygen.

16. Compounds according to claim 1 or 2 from the 25 following group: 3-[8-(Aminomethyl)- 6. , 7. , 8. , 9. -tetrahydropyrido[1,2-a] indol-1 0y I]-4-( 1 -methy 1-3-indoly 1)-1 H-pyrrole-2,5-dione, 3-[7-amidinothiomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol30 i o-yI]-4-(1 -methy 1-3-indolyI)-1 H-pyrrole-2,5-dione, 3-[6,7,8,9-tetrahydro-8-[(dimethylamino)methyl]pyrido[1,2a] indol-1 0-y I]-4-(1 -methyl-3-indoly 1)-1 H-pyrrole-2,5-dione and pharmaceutically usable salts thereof.

17. Compounds of the general formula wherein R 1 , R 2 · R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, and m have the significance given in claim 1.

18. Compounds according to any one of claims 1-16 for 5 use as therapeutically active substances, especially for use as antiinflammatory, immunological, oncological, bronchopulmonary and cardiovascular active substances or as active substances in the treatment of asthma or AIDS. io 19. A process for the manufacture of the compounds according to any one of claims 1-16, characterized by (a) for the manufacture of a compound of formula I in which X and Y are oxygen, reacting a compound of the general formula wherein R 1 , R 2 · R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, and m have the significance given in claim 1, with ammonia under pressure or with hexamethyldisilazane and methanol to give a compound of formula I in which R is hydrogen or with hydroxylamine to give a compound of formula I in which R is hydroxy, or 5 (b) for the manufacture of a compound of formula I in which one of X and Y is oxygen and the other is (H,H), reducing a compound of formula I in which X and Y are oxygen with lithium aluminium hydride, or

19. (c) if desired, functionally modifying a reactive group present in a compound of formula I obtained, and (d) if desired, converting an acidic compound of formula I into a pharmaceutically usable salt with a base or converting a basic is compound of formula I into a pharmaceutically usable salt with an acid.

20. A pharmaceutical preparation, especially an antiinflammatory, immunological, oncological, bronchopulmonary or 20 cardiovascular preparation or a preparation for the treatment of asthma or of AIDS, containing a compound according to any one of claims 1-16 and an inert carrier material.

21. The use of a compound according to any one of claims 25 i-i6 for the manufacture of a pharmaceutical preparation against inflammatory, immunological, oncological, bronchopulmonary or cardiovascular disorders or against asthma or AIDS.

22. A compound as claimed in claim 1, substantially as hereinbefore described and exemplified.

23. A compound as claimed in claim 17, substantially as hereinbefore described and exemplified.

24. A process for the manufacture of a compound as claimed in claim 1, substantially as hereinbefore described and exemplified.

25. A compound as claimed in claim 1, whenever manufactured by a process as claimed in a preceding claim.

26. A pharmaceutical preparation according to claim 20, substantially as hereinbefore described.

27. Use according to claim 21, substantially as hereinbefore described.