CA2010636C - Substituted pyrroles - Google Patents

Abstract

Compounds of the formula (see formula I) wherein R represents hydrogen or hydroxy, R1 and R2 together represent a group of the formula -(CH2)n- and R7 represents hydrogen or R1 and R7 together represent a group of the formula -(CH2)n- and R2 represents hydrogen: R3 represents an aryl or heteroaryl group; R4, R5 and R6 each independently represent hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulphinyl or alkylsulphonyl: R8 represents a group of the formula -(CH2)p-R9 or -(CH2)q-R10: R9 represents hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkylsulphonyl, aminocarbonyl or aminothiocarbonyl; R10 represents 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 nitrogen atom or a group of the formula -U-C(V)-W:
U represents S or NH; V represents NH, NNO2, NCN, CHNO2: W represents amino, monoalkylamino or dialkylamino: one of X and Y represents O and the other represents O or (H,H); Z represents CH or N: m stands for 0-5, with the proviso that m stands for 2-5 when Z represents N: n stands for 1-5: p stands for 0-5: and q stands for 0-5, with the proviso that q stands for 2-5 when Z stands for N;
as well as pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids, are useful in the control or prevention of inflammatory, immunological, oncological.
bronchopulmonary or cardiovascular disorders or for the treatment of asthma or AIDS. They can be prepared from correspondingly substituted furandiones.

Description

201.0636 The present invention relates to substituted pyrroles.
More particularly, the invention is concerned with compounds of the general formula Y

R
R~ ( iH2)m Rl/ ~R8 I
wherein R represents hydrogen or hydroxy, R1 and RZ together represent a group of the formula -(CHZ)n- and R7 represents hydrogen or Rl and R7 together represent a group of the formula -(CH2)n- and R2 represents hydrogen; R3 represents an aryl or heteroaryl group: R4, R5 and R6 each independently represent hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, vitro, amino, acylamino, alkylthio, alkylsulphinyl or alkyl-sulphonyl; Re represents a group of the formula -(CEI2)p-R9 or -(CHZ)q_R10~ R9 represents ~ hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkyl-sulphonyl, aminocarbonyl or aminothiocarbonyl; R10 represents hydroxy, alkoxy, halogen, amino, monoalkyl-amino, dialkylamino, trialkylamino, azido, acylamino, Me/8.1.90 201.0636 alkylsulphonylamino, arylsulphonylamino, alkylthio.
alkoxycarbonylamino, aminoacylamino, aminocarbonyl-amino, isothiocyanato, alkylcarbonyloxy, alkyl-sulphonyloxy or arylsulphonyloxy, a 5- or 6-membered saturated nitrogen-containing heterocycle attached via the nitrogen atom or a group of the formula -U-C(V)-W;
U represents S or NEI; V represents NEI. NN02, NCN, CHN02; W represents amino, monoalkylamino or dialkylamino: one of X and Y represents O and the 1p other represents O or (II,H): Z represents CH or N: m stands for 0-5, with the proviso that m stands for 2-5 when Z represents N; n stands for 1-5; p stands for 0-5; and q stands for 0-5, with the proviso that q stands for 2-5 when Z stands for N;
as well as pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids.
Objects of the present invention are the compounds of formula I and their aforementioned salts per se and as therapeutically active substances; a process for the manufacture of said compounds and salts and novel inter-mediates useful in said process; medicaments containing said compounds and salts and the manufacture of these medicaments: and the use of said compounds and salts in the control or prevention of illnesses, especially in the control or prevention of inflammatory, immunological.
ontological, bronchopulmonary and cardiovascular disorders or in the treatment of asthma or AIDS, or for the 3p manufacture of a medicament against inflammatory, immuno-logical, ontological, bronchopulmonary and cardiovascular disorders or against asthma or AIDS.
As used herein, the term "alkyl", alone or in 3,5 combination, means a straight-chain or branched-chain alkyl group containing a maximum of 7, preferably a -~ 3 -201,0636 maximum of 4, carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, tert.butyl, pentyl and the like. The term "alkoxy", alone or in combinations, means an alkyl group as defined earlier which is attached via an oxygen atom, examples of alkoxy groups being methoxy.
ethoxy, propoxy, isopropoxy, butoxy, tert.butoxy and the like. A haloalkyl group can carry one or more halogen atoms, with examples of such groups being chloromethyl, trifluoromethyl etc. The term "aryl" means an acyl group derived from an alkanoic acid containing a maximum of 7, preferably a maximum of 4, carbon atoms (e. g. formyl acetyl, propionyl, butyryl etc) or from an aromatic carboxylic acid (e. g. benzoyl etc). The term "aryl", alone or in combination, means a monocyclic or polycyclic group.
preferably a monocyclic or bicyclic group, i.e. phenyl or naphthyl, which can be substituted or unsubstituted, for example with one or more, preferably one to three, substituents, selected from halogen, alkyl, hydroxy.
alkoxy, haloalkyl, vitro, amino. acylamino, alkylthio, pp alkylsulphinyl and alkylsulphonyl. Examples of such aryl groups are phenyl. 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl. 3-bromophenyl, 2-methylphenyl, 3-methyl-phenyl. 2,5-dimethylphenyl. 4-methoxyphenyl, 2-trifluoro-methylphenyl, 3-trifluoromethylphenyl, 2-nitrophenyl, 3-nitrophenyl. 4-nitrophenyl, 3-aminophenyl. 4-amino-phenyl, 4-methylthiophenyl, 4-methylsulphinylphenyl.
4-methylsulphonylphenyl. 1-naphthyl. 2-naphthyl and the like. The term "heteroaryl" means a 5-membered ar 6-membered heterocyclic aromatic group which can optionally carry a fused benzene ring and which can be substituted or unsubstituted, for example with one or more, preferably one to three, substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, vitro, amino, acylamino, alkylthio, alkylsulphinyl and alkylsulphonyl.
3,5 Examples of such heteroaryl groups are 2-thienyl.
3-thienyl. 3-benzothienyl. 3-benzofuranyl, 2-pyrrolyl.

-Q_ 3-indolyl and the like which can be unsubstituted or substituted in the manner indicated. The 5- or 6-~membered saturated nitrogen-containing heterocycle attached via the nitrogen atom can contain a further nitrogen atom or an oxygen or a sulphur atom, examples of such heterocycles being pyrrolidino, piperidino, piperazino, morpholino and thiamorpholino. The term "halogen" means fluorine, chlorine, bromine or iodine.
The compounds of formula I in which Z represents CH
and R8 represents a group of the formula -(CEIZ)p-R9 in which p stands for 1-5 or -(CH2)q-R1~ contain an asymmetric carbon atom and can therefore exist in racemic or optically active form. The present invention includes ~5 within its scope not only the racemic compounds, but also the optically active isomers.
In preferred classes of compounds of formula I, R1 and R2 together represent -CHZ- and R~ represents hydrogen, m stands for 1 or 2 and Z represents CH: or R1 and Rz together represent -(CHZ)Z- and R~
represents hydrogen, m stands for 1 and Z represents CH:
or R1 and R2 together represent -CH2- and R~
represents hydrogen, m stands for 2 and Z represents N: or R1 and R7 together represent -CHZ- and R2 represents hydrogen, m stands for 1 and Z represents CEI:
or R1 and R~ together represent -(CH2)2- and R2 represents hydrogen, m stands for O and Z represents CH.
R3 preferably represents phenyl, naphthyl, 3-benzo-thienyl, 3-benzofuranyl or 3-indolyl which is optionally substituted as defined earlier, especially 1-methyl-3--indolyl. Preferably, R4, R5 and R6 each represent hydrogen. RB preferably represents a group of the formula -(CH2)q-R10. Preferably, q stands for 1 or 2. Rl~ preferably represents hydroxy, amino, monoalkyl-amino, dialkylamino, trialkylamino, azido, acylamino, alkylcarbonyloxy or alkylsulphonyloxy or a group of the formula -U-C(V)-W. Preferably, U represents S. V
represents NFI and W represents amino.
Especially preferred compounds provided by the invention are:
3-[e-(Aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]-indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, 3-[7-(amidinothiomethyl)-6,7.8,9-tetrahydropyrido-[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-lI3-pyrrole--2,5-dione and ~-[6,7,8,9-tetrahydro-8-[(dimethylamino)methyl]pyrido [1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5 ~5 -dione and their pharmaceutically acceptable acid addition salts.
According to the process provided by the present invention, the compounds of formula I as well as 20 pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I
with acids are manufactured by (a) for the manufacture of a compound of formula I in 25 which X and Y both represent O, reacting a compound of the general formula Rd . O
RS
30 ~~ r~' . Ra R- ~ ~Rs ~Rs R~
(~2)m II
35 Rl/Z\kg wherein R1. Rz. R3, R4, R5, R6. R~, R8, Z and m have the significance given earlier.
with ammonia under pressure or with hexamethyldisilazane and methanol to give a compound of formula I in which R
represents hydrogen or with hydroxylamine.to give a compound of formula I in which R represents hydroxy, or (b) for the manufacture of a compound of formula I in which one of X and Y represents O and the other represents (H~fi)~ reducing a compound of formula I in which X and Y
both represent O with lithium aluminium hydride, or (c) if desired, functionally modifying a reactive centre present in a compound of formula I obtained, and (d) also if desired, converting an acidic compound of formula I into a pharmaceutically acceptable salt with a base or converting a basic compound of formula I into a pharmaceutically acceptable salt with an acid.
The reaction of a compound of formula II with ammonia under pressure in accordance with embodiment (a) of the process is conveniently carried out using aqueous ammonia (preferably 33% aqueous ammonia) and in the presence of a water-miscible inert organic solvent such as dimethyl-formamide or the like. The reaction is preferably carried out at an elevated temperature, for example a temperature in the range of about 100°C to about 150°C.
The reaction of a compound of formula.II with hexa-methyldisilazane and methanol, also in accordance with embodiment (a) of the process, is conveniently carried out in an inert organic solvent such as a halogenated hydro-carbon (e. g. chloroform, carbon tetrachloride or chloro-3,5 benzene) or an aromatic hydrocarbon (e. g. benzene, toluene ~osos3s or a xylene) and at an elevated temperature (e.g. a temperature between about 40°C and 110°C.
The reaction of a compound of formula II with hydroxylamine, also in accordance with embodiment (a) of the process, is conveniently carried out in an inert organic solvent such as dimethylformamide or the like and at room temperature or an elevated temperature, preferably at an elevated temperature (e. g. about 100°C).
Expediently, 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 both represent O with lithium aluminium hydride in accordance with embodiment (b) of the process is expediently carried out in an inert organic solvent such as an aliphatic or cyclic ether (e. g. diethyl ether, tetrahydrofuran etc) at a temperature between about 0°C
and the reflux temperature of the reaction mixture.
A reactive centre present in a compound of formula I
can be modified,~if desired, in accordance with embodiment (c) of the process. All of these modifications can be carried out according to methods known per se. For example, when Re represents a group of the formula -(CH2)p-R9 in which R9 represents alkoxycarbonyl and p stands for O, this group can be converted into a corresponding group in which R9 represents hydrogen by treatment with an acid. Aqain, for example, a group of the formula -(CHZ)g-R10 in which R10 represents alkyl-carbonyloxy can be converted into a corresponding group in which R10 represents hydroxy by appropriate base 3,5 treatment. A group of the formula -(CHZ)q-R10 in which R10 represents hydroxy can be converted into a 2osos3s _8_ corresponding group in which R10 represents amino, mono-alkylamino, dialkylamino, trialkylamino or a 5- or 6-membered saturated nitrogen-containing heterocycle attached via the nitrogen atom by treatment firstly with trifluoromethanesulphonic anhydride and subsequently with ammonia, a monoalkylamine, a dialkylamine, a trialkylamine or an appropriate heterocycle, respectively. A group of the formula -(CH2)q-R10 in which R10 represents hydroxy can be reacted with an alkanesulphonic anhydride to give a corresponding group in which R10 represents alkylsulphonyloxy. A group of the formula -(CHZ)q-R10 in which R10 represents alkylsulphonyloxy can be converted into a corresponding group in which R10 represents formamido by reaction with ammonia in dimethyl-formamide or in Which R10 represents azido by reaction with an alkali metal azide or in which R10 represents a group of the formula -U-C(V)-W in which U represents S, V
represents NH and W represents amino by reaction with thiourea. Further, a group of the formula -(CH2)q-R
in which R10 represents azido can be converted by catalytic hydrogenation into a corresponding group in which R10 represents amino. A group of the formula -(GEI2)q-R10 in which R10 represents alkoxy-carbonylamino can be converted into a corresponding group in which R10 represents amino by treatment with an acid.
A group of the formula -(CHZ)q-R10 in which R10 represents amino can be acylated to give a corresponding group in which R10 represents acylamino or can be reacted with 3,5-dimethyl-NZ-vitro-1-pyrazole-1-carbox-amide to give a corresponding group in which R10 represents a group of the formula -U-(C(V)-W wherein U
represents NH, V represents NH and W represents NN02.
Further, a group of the formula -(CH2)q-R10 in which R10 represents amino can be converted into a corresponding group in which R10 represents isothio-cyanato by reaction with 1.1-thiocarbonyldiimidazole. A

group of the formula -(CFi2)p-R9 in which R9 represents cyano can be treated with hydrogen chloride and subsequently with ammonia to give a corresponding group in which R9 represents amidino. Again, for example, a compound of formula I in which Z represents N and Ra represents a group of the formula -(CHZ)p-R9 wherein p stands for O and R9 represents hydrogen can be converted into a corresponding compound in Which R9 represents alkylcarbonyl, alkoxycarbonyl or aralkoxy-1p carbonyl by appropriate acylation, into a corresponding compound in which R9 represents alkylsulphonyl by reaction with an alkanesulphonyl chloride, into a corresponding compound in which R9 represents amino-alkylcarbonyl by treatment with a trifluoroacetamido-alkanoyl chloride and subsequent reaction with ammonia, into a corresponding compound in which. R9 represents aminocarbonyl by treatment with 1,1-carbonyldiimidazole and subsequent reaction with ammonia or into a corresponding compound in which R9 represents aminothio-carbonyl by treatment with 1,1-thiocarbonyldiimidazole and subsequent reaction with ammonia. It will be appreciated that the foregoing modifications are given by way of example only and that other modifications within the purview of a person skilled in the art are also possible.
The conversion of an acidic compound of formula T into a pharmaceutically acceptable salt in accordance with embodiment (d) of the .process can be carried out by treatment with a suitable base in a manner known per se.
Suitable salts are those derived not only from inorganic bases, for example, sodium salts, potassium salts, calcium salts and the like, but also from organic bases such as ethylenediamine, monoethanolamine, diethanolamine and the like. The conversion of a basic compound of formula I into a pharmaceutically acceptable salt, also in accordance with embodiment (d) of the process, can be carried out by - to -treatment with a suitable acid in a manner known per se.
Suitable salts are those derived not only from inorganic acids, for example, hydrochlorides, hydrobromides, , phosphates, sulphates and the like, but also from organic acids, for example acetates, citrates, fumarates, tartrates, maleates, methanesulphonates, p-toluene--sulphonates and the like.
The compounds of formula II which are used as starting materials in embodiment (a) of the process are novel and form a further object of the present invention. They can be prepared by reacting a compound of the general formula -a R' III
Z
R1/ \R8 wherein R, R, R4, R5, R6, R~, Re, Z and m have the significance given earlier, with a compound of the general formula wherein R3 has the significance given earlier, and, Where required, functionally modifying a reactive centre presont in a compound of formula II obtained.

The reaction of a compound of formula III with a compound of formula IV is preferably carried out in the presence of an acid-binding agent, expediently a tertiary amine such as a trialkylamine (e. g. triethylamine, diisopropylethylamine etc), and in an inert organic solvent such as a halogenated aliphatic hydrocarbon (dichloromethane etc) at about room temperature.
The optional functional modification of a reactive substituent present in a compound of formula II can be carried out in the same manner as described earlier in connection with the functional modification of a reactive centre present in a compound of formula I.
The compounds of formula III can be prepared, in turn.
by reacting a compound of the general formula RS
R6 ~ N ~RZ
R7 ' V
(CH2)m Rl/ Z~R8 wherein Rl, R2. R4. R5~ R6, R~. Ra, Z
and m have the significance given earlier.
with oxalyl chloride, conveniently in an inert organic solvent such as a halogenated aliphatic hydrocarbon (e. g.
dichloromethane etc) at a temperature from about 0°C to the reflex temperature of the solvent. The resulting compound of formula III can be reacted in situ with the - 12 - X09"0636 compound of formula IV or can be isolated and purified (e. g. by concentration followed by crystallization) prior to the reaction with the compound of formula IV.
The compounds of formula V hereinbefore are known compounds or analogues of known compounds which can be prepared in a similar manner to the known compounds.
Further, certain of the Examples hereinafter contain detailed information containing the preparation of the 1p respective starting materials.
The compounds of formula I and their pharmaceutically acceptable salts are protein kinase inhibitors; they inhibit cellular processes, for example cell prolifera-15 lion, and can be used in the control or prevention of illnesses, for example in the control or prevention of inflammatory disorders such as arthritis, immune diseases, in conjunction with organ transplants and also in oncology. They inhibit infection of cells with human 20 immunodeficiency virus and are thus useful in the treatment of AIDS. The compounds and salts of the present invention also inhibit smooth muscle contraction and can therefore be used against cardiovascular and broncho-pulmonary disorders. Further, they are also useful in 25 asthma therapy.
The activity of the present compounds in inhibiting protein kinase C can be demonstrated by means of the in vitro assay system described e.g. in BBRC 19 (1979) 1218.
The IC50 figures in the following Table, represent that concentration of test compound which reduces by 50%
the protein kinase-induced incorporation of 32P from [Y-32P]ATP into histone.

Table Compound IC50 3-[8-(Aminomethyl)-6,7,8,9-tetrahydro-pyrido[1,2-a]indol-10-yl)-4-(1-methyl-3--indolyl)-iH-pyrrolet2,5-dione hydro-chloride 8 nM
3-[7-(Amidinothiomethyl)-6.7.8.9-tetra-hydropyrido[1,2-a]indol-10-yl]-4-(1-methyl--3-indolyl)-1H-pyrrole-2,5-dione methane-sulphonate 15 nM
3-[2-(Aminoacetyl)-1,2,3,4-~tetrahydro--pyrazino[1,2-a]indol-10-yl]-4-(1-methyl--3-indolyl)-1H-pycrole-2.5-dione hydro-20 Chloride 50 nM
3-[7-(2-Aminoethyl)-6,7,8,9-tetrahydro-pyrido[1,2-a]-indol-10-yl]-4-(1-methyl--3-indolyl)-1H-pyrrole-2,5-dione hydro-25 chloride ZO nM
3-[6,7.8.9-Tetrahydro-8-[(1-piperidino)--methyl]pyrido[1,2-a]indol-10-yl]-4-(1--methyl-3-indolyl)-1H-pyrrole-2.5-dione 30 nM
3-[2,3-Dihydro-2-(dimethylaminomethyl)--1H-pyrrolo[1,2-a]indol-9-yl]--4-(1-methyl--3-indolyl)-7-H-pyrrole-2,5-dione trifluoro-methanesulphonate ~ 20 nM

- 1 ~ - 20~.0~36 3-[e-Amidino-6,7,8,9-tetrahydropyrido-[1,2-a]indol-10-yl]-4-(1-methyl-3--indolyl)-1H-pyrrole-2,5-dione hydro-chloride 60 nM

3-[7-(Amidinothiomethyl)-6,7,8,9-tetra-hydropyrido[1,2-a]indol-10-yl]-4--(1-methyl-3-indolyl)-1EI-pyrrole-2,5-dione methanesulphonate 10 nM
The compounds of formula I and their aforementioned salts can be used as medicaments, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, they can also be administered rectally (e.g. in the form of suppositories) or parenterally (e.g. in the form of injection solutions) For the manufacture of pharmaceutical preparations the compounds of formula I and their aforementioned salts can be formulated with therapeutically inert, inorganic or organic carriers. Lactose, maize starch or derivatives thereof. talc, stearic acid or its salts and tha like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, generally required in the case of soft gelatine capsules. Suitable carriers for the manufacture of solutions and syrups are, for example.
water, polyols, saccharose, invert sugar, glucose and the like. Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerine, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid polyols and the like.
The pharmaceutical preparations can also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts for 1p varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other thera-peutically valuable substances. Medicaments containing a compound of formula I or a salt thereof as defined above and a therapeutically inert carrier as well as a process for the manufacture of such medicaments are also objects of the present invention. This process comprises bringing a compound of formula I or a salt thereof as defined above into a galenical administration form together with a therapeutically inert carrier material and, if desired, 2p one or more other therapeutically active substances.
As mentioned above, the compounds of formula I and their aforementioned salts can be used in the control or prevention of illnesses, especially in the control or prevention of inflammatory, immunological, broncho--pulmonary and cardiovascular disorders or for the treatment of asthma or of AIDS. The dosage can vary within wide .limits and will. of course, be adjusted to the individual requirements in each particular case. In gp general, in the case of oral administration to adults, a daily dosage of about 5 mg to about 500 mg should be appropriate, although the upper limit may be exceeded when this is found to be expedient. The daily dosage can be administered as a single dose or in divided doses.
The following Examples illustrate the present invention:

- 16 - 20.0636 Example 1 A solution of 2.90 g of 3-[8-(acetoxymethyl)-6,7,8,9--tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3--indolyl)furan-2,5-dione in 30 ml of DMF and 23 ml of 33%
aqueous ammonia was heated to 140°C for 7 hours. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to dryness.
Crystallization of the residue from ethyl acetate gave 1.87 g of 3-[6,7,8,9-tetrahydro-8-(hydroxymethyl)pyrido-[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5--dione in the form of a red solid of melting point 262-263°C.
The furandione starting material was prepared as follows:
a) A solution of 25 g of ethyl indole-2-carboxylate in 400 ml of DMF was added to a stirred 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 were then added dropwise to the mixture at 0°C and the resulting mixture was stirred at room temperature for 18 hours. The reaction was quenched with 100 ml of water and 30 ml of 2M hydrochloric acid and the mixture was extracted with dichloromethane. The combined organic extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to give 49 g of 3p an oil. This oil was dissolved in ethyl acetate and the solution was washed with water, dried over anhydrous sodium sulphate and evaporated to give 39 g of an oil.
This oil was added dropwise to a stirred suspension of 20.5 g of potassium t-butoxide in 750 ml of THF under a nitrogen atmosphere. After 1 hour Z00 ml of water and then 92 ml of 2M hydrochloric acid were added. The mixture was concentrated and the resulting precipitate was filtered off and dried to give 25.3 g of ethyl 6,7-dihydro-9--hydroxypyrido[1,2-a]indole-8-carboxylate. A sample was crystallized from methanol and gave crystals of melting point 101-103°C.
b) A suspension of 19.4 g of the carboxylate of a) and 16 spoon spatula measures of Raney nickel in 480 ml of ethanol and 240 ml of water was heated to reflux for 3.5 hours. A further 4 spoon spatula measures of Raney nickel were then added and the mixture was heated to reflux for a further 1.5 hours. The supernatant was decanted off and the catalyst was washed with ethyl acetate. The combined organic phases were concentrated and the precipitate was~filtered off and dried to give 16.3 g of ethyl 6.7,8,9--tetrahydropyrido[1,2-a]indole-8--carboxylate.. A sample was r_rystallized from methanol to give a solid of melting point 70-72°C.
c) 16.2 g of the carboxylate of b) in 200 ml of THF were added to a suspension of 2.00 g of lithium aluminium hydride in 600 ml of THF at 0°C under a nitrogen atmosphere. After 0.5 hour the reaction was quenched by the successive additions of ethyl acetate, Water and 2M
hydrochloric acid and the mixture was extracted with diethyl ether. The combined organic extracts were dried and evaporated. Crystallization of the residue from diethyl ether/n-hexane gave 11.5 g of 6,7.8,9-tetra-hydro-8-(hydroxymethyl)pyrido[1,2-a]indole of melting point 11.0-111°C.
d) 11.4 g of acetic anhydride were added to a solution of 11.0 g of the pyridoindole from c) in 100 ml of pyridine and the resulting solution was stirred under a nitrogen atmosphere for 18 hours. The majority of the pyridine was 3,5 removed by evaporation and the residue was acidified with 2M hydrochloric acid. The mixture was extracted with diethyl ether and the combined extracts were washed with sodium bicarbonate solution and with water. The extracts were dried and evaporated to dryness to give 11.25 g of 8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido(1,2-a]indole of melting point 63-64°C.
e) 4.13 g of oxalyl chloride were added dropwise to a solution of 8.2 g of the tetrahydropyridoindole of d) in 160 ml of diethyl ether under a nitrogen atmosphere. After minutes the solvent was removed under reduced pressure 10 and the residue was dissolved in 330 ml of dichloro-methane. 6.34 g of 1-methyl-3-indolylacetic acid and 9.20 ml of triethylamine were added to this solution and the mixture was stirred overnight. A further 4.60 ml of triethylamine were added. After 4B hours, the solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (1:2). Crystallization from ethyl acetate gave 4.02 g of 3-[e-(acet.oxymethyl)-6,7,8,9-tetra-hydropyrido[1,2-a]indol-10--yl]-4-(1-methyl-3--indolyl)furan----2.5-dione of melting point 174-178°C.
Example 2 2.50 g of trifluoromethanesulphonic anhydride in 330 ml of dichloromethane were treated at 0°C under a nitrogen atmosphere with a suspension of 1.87 g of pyrroledione product of Example 1 and 0.94 q of collidine in 280 ml of dichloromethane. After 2.5 hours, the mixture was allowed to warm to 10°C. 37 ml of 33% aqueous ammonia were then added and the mixture was allowed to warm to room temperature overnight. The mixture was washed with water, dried and evaporated. The residue was subjected to chromatography on silica gel with dichloromethane/
methanol/acetic acid/water (90:18:3:2). The combined 3,5 product-containing fractions were treated with 2M
hydrochloric acid and evaporated to give 930 mg of 3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-- 19 _ 2010636 -10-yl]-4-(1-methyl-3-indolyl)--1H-pyrrole-2,5-dione hydrochloride of melting point 310-313°C.
Example 3 265 mg of trifluoromethanesulphonic anhydride in 40 ml of dichloromethane were treated at 0°C under a nitrogen atmosphere with a suspension of 200 mg of the pyrroledione product of Example 1 and 100 mg of collidine in 30 ml of dichloromethane. After 5 houcs 0.5 ml of a 33% solution of trimethylamine in ethanol was added and the mixture was stirred for 18 hours. The resulting precipitate was filtered off and dried to give 237 mg of 3-[6,7,8,9-tetra-hydro-8-[(trimethylammonio)methyl]pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione trifluoro-methanesulphonate of melting point 320-324°C.
Example 4 265 mg of trifluoromethanesulphonic anhydride in 40 ml of dichloromethane were treated at 0°C under a nitrogen atmosphere with a suspension of 200 mg of the pyrroledione product of Example 1 and 100 mg of collidine in 30 ml of dichloromethane. After 5 hours 0.75 mI of a 33% solution of methylamine in methylated spirit was added and the mixture was stirred for 18 hours. A further 0,5 ml of the aforementioned methylamine solution was thon added. After 4 hours, the solvent was removed by evaporation and the precipitate was filtered off and purified. by chromato-graphy on silica gel with dichloromethane/methanol/acetic acid/water (90:18:3:2). The solid product was stirred with ethyl acetate saturated with hydrogen chloride for 2 hours. The resulting solid was filtered off and dried to give 55 mg of 3-[6,7,8.9-tetrahydro-8-[(methylamino)--'methyl]pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H--pyrrole-2,5-dione hydrochloride of melting point 337-340°C.

Example 5 185 mg of trifluoromethanesulphonic anhydride in 30 ml of dichloromethane were treated at 0°C under a nitrogen atmosphere with a suspension of 140 mg of the pyrroledione product of 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 was added and the mixture was stirred for 2.5 hours. The solvent was removed under reduced pressure and the residue was triturated with methanol to give a solid which was stirred with ethyl acetate saturated with hydrogen chloride. The solid was filtered off and dried to give 70 mg of 3-[6,7,8,9-tetra-hydro-8-[(dimethylamino)methyl]pyrido[1,2-a]indol-10-yl]--4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of melting point 335-336°C.
Example.6 A solution of 170 mg of the pyrroledione product of Example 1 in 55 ml of dichloromethane was treated with 87 mg of methanesulphonic anhydride and 1 ml of pyridine.
The resulting solution was stirred under nitrogen for 1 hour. A further 30 mg of methanesulphonic anhydride were then added. After 1 hour, the mixture was washed with water, dried and evaporated. Crystallization of the residue from ethyl acetate/n-hexane gave 150 mg of 3-[6,7,8.9-tetrahydro-8-(methylsulphonyloxymethyl)pyrido-[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5--dione of melting point 259-261°C.
Example 7 A solution of 120 mg of the pyrroledione product of 3,5 Example 6 in 6 ml of DMf and 6 ml of 33% aqueous ammonia was heated to 140°C for 6 hours. The cooled mixture was poured into water and the precipitate was filtered off.

- 21 _ 2010F36 The product was purified by chromatography on silica gel with dichloromethane/acetic acid/methanol/water (60:18:2:3). Trituration with ethyl acetate gave 50 mg of 3-[8--(formamidomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-ZO-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5--dione of melting point 332-334°C.
Example 8 A solution of 100 mg of the pyrroledione product of Example 6 and 75 mg of thiourea in 5 ml of DMF was heated to 80°C under a nitrogen atmosphere for 18 hours. The solvent Was removed by evaporation and the residue was purified by chromatography on silica gel with dichloro--methane/methanol/acetic acid/water (90:18:3:2). The residue was triturated with ethyl acetate to give 80 mg of 3-[8-[(amidinothio)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]-indol-10-yl]-4--(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione methanesulphonate of melting point 200-205°C.
Example 9 In a manner analogous to that described in the first paragraph of Example 1, from 3-[7-(acetoxymethyl)-6,7,8,9--tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3--indolyl)furan-2,5-dione there was prepared 3-[6,7,8,9--tetrahydro-7-(hydroxymethyl)pyrido[1,2-a]indol-10-yl]-4--(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 239-242°C.
The furandione starting material was prepared as follows:
a) 6.6 ml of a 1.6M solution of n-butyllithium in 3,5 n-hexane were added to a stirred solution of 1.11 g of diisopropylamine in 150 ml of THF at -78°C undez nitrogen.
The mixture was allowed to warm to -20°C for 5 minutes and was then again cooled to -78°C. 1.85 g of 6,7,8,9-tetra-hydropyrido[1,2-a]indol-6-one in 10 ml of THF were then added dropwise. After stirring at -78°C for 0.5 hour 1.19 g of ethyl chloroformate were added and the mixture was allowed to warm to room temperature. The solvent was removed by evaporation and the residue was partitioned between diethyl ether and 2M hydrochloric acid. The ethereal extracts were washed with saturated sodium bicarbonate solution, dried and concentrated to give an oil. This oil was purified by chromatography on silica gel with dichloromethane. Crystallization of the product from methanol gave 1.35 g of ethyl 6,7,8,9-tetrahydro-6-oxo-pyrido[1,2-a]indole-7-carboxylate of melting point 82-84°C.
b) 30 ml of a 1M solution of borane in TEIF were added to a stirred solution of 1.25 g of the carboxylate of a) and the resulting solution was heated to reflux for 2 hours under a nitrogen atmosphere. 6 spoon spatula measures of silica qel were added to the cooled solution and the solvent was removed by evaporation. The residue was purified by chromatography on silica gel with ethyl acetate/n-hexane (1:1) to give an oil. This oil was dissolved in 60 ml of dichloromethane containing 8 ml of pyridine and 2 ml of acetic anhydride. After 1B hours, the solution was washed with 60 ml of 2M hydrochloric acid and 20 ml of saturated sodium bicarbonate solution, dried and evaporated to give an oil. A solution of this oil in 60 ml of diethyl ether was treated with 630 mg oxalyl chloride under a nitrogen atmosphere. Then the solvent was removed under reduced pressure and the residue was dissolved in 100 ml of dichloromethane. 920 mg of 1-methyl-3-indolyl-acetic acid and 975 mg of triethylamine were added to this solution. After 72 hours, the solvent was removed by evaporation and the residue was purified by chromatography 3,5 on silica gel with ethyl acetate/n-hexane (1:1), Crystal-lization from ethyl acetate gave 390 mg of 3-[7-(acetoxy-methyl)-6,7,8,9-tetrahydropyrido(1,2-a]indol-10-yl]-4-__ 2 3 - iii~~~sa,~s --(1-methyl-3'-~indolyl)furan-2.5-dione of melting point 190-193°C.
Example 10 200 mg of trifluoromethanesulphonic anhydride in 50 ml of dichloromethane were treated at 0°C under a nitrogen atmosphere with a suspension of 150 mg of the pyrroledione product of Example 9 and 75 mg of collidine in 50 ml of 1p dichloromethane. After 2 hours 4 ml of 33% aqueous ammonia were added and the mixture was left to warm to room tempecature overnight. The mixture was washed with water, dried and evaporated to dryness. The residue was purified by chromatography on silica gel with dichloromethanel methanol/acetone/water (90:18:3:2). Crystallization from dichloromethane/n-hexane gave 85 mg of 3-[7-(aminomethyl)--6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl--3-indolyl)-1H-.pyrrole-2,5-dione of melting point 160-165°C.
Example 11 A solution of 120 mg of the pyrroledione product of Example 9 in 80 ml of'dichloromethane was treated with 2 ml of pyridine and 100 mg of methanesulphonic anhydride under a nitrogen atmosphere. After stirring for 18 hours the mixture was washed with 2M hydrochloric acid and saturated sodium bicarbonate solution, dried and evaporated to give 130 mg of a gum. This gum was dissolved in 40 ml of ethanol containing 200 mg of thiourea and tha mixture was heated to reflux for 72 hours. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel with dichloromethane/
methanol/acetone/water (90:18:3:2). Crystallization from methanol/dichloromethane gave 30 mg of 3-(7-(amidinothio-methyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4--(1-methyl-3-indolyl)-1H-pyrrole-2.5-dione methanesul-2 4 - 201.Ofi36 phonate of melting point 195-198°C.
Example 12 A solution of 72 mg of 3-(6,7,8,9-tetrahydropyrido-(1,2-a]indol-10-yl)-4-(1-methyl-3-indolyl)furan-2,5-dione in 5 ml of DMF and 5 ml of 33% aqueous ammonia was heated to 140°C for 4 hours. The resulting crystals were filtered off and dried to give 50 mg of 3-(6,7,8,9-tetrahydro-pYrido[1,2-a]indol-10-yl)-4-(1-methyl-3-indolyl)-lEI-pyrrole-2,5-dione of melting point 286-289°C.
The furandione starting material was prepared as follows:
a) A solution of 1.03 g of ethyl 6,7-dihydro-9--hydroxypyrido[1,2-a]indole-8-carboxylate in 20 ml of . ethanol, 10 ml of water and 10 ml of concentrated hydro-chloric acid was heated at 80°C for 3 hours. The solvents were evaporated to give 740 mg of 7,8-dihydropyrido-[1,2-a]indol-9(6FI)-one of melting point 138-140°C.
b) A solution of 740 mg of the product of a), 600 mg of hydrazine hydrate and 440 mg of potassium hydroxide in 2 ml of ethanol and 4 ml of diethylene glycol was heated at 100°C under reflux for 1.5 hours. Then the mixture was heated at 180°C for 2 hours. 50 ml of dichloromethane were added and the organic phase was washed with 2M hydro-chloric acid and water. The solvent was removed by evaporation to give 405 mg of 6,7,8,9-tetrahydropyrido-[1,2-a]i.ndole.
c) 350 mg of oxalyl chloride were added dropwise to a solution of 450 mg of the product of b) in 13 ml of 3,5 dichloromethane at 0°C. After stirring for'2 hours the solvent was removed by evaporation and the residue was dissolved in dichloromethane. 497 mg of 1-methyl-3-- 2 5 - 2p~,0636 -indolylacetic acid and 0.73 ml of triethylamine were added to this solution and the mixture was stirred at room temperature for 60 hours. The solvent was evaporated and the residue was purified by chromatography on silica gel with dichloromethane. Trituration of the product with ethyl acetate gave 100 mg of 3-(6,7,8,9-tetrahydro-pyrido[1,2-a]indol-10-yl)-4-_(1-methyl-3-indolyl)furan-2,5--dione in the form of a red solid of melting point 276-278°C.
Example 13 In a manner analogous to that described in the first paragraph of Example 1, from 3-[e-(2-acetoxyethyl)--6,7,8,9-tetrahydropyrido[1,2-a]indol-10--yl]-4--(1-methyl---3-indolyl)furan-2,5-dione there was prepared 3-[6,7,8,9--tetrahydro-8-(2-hydcoxyethyl)pyrido[1,2-a]indol-10-yl]-4--(1-methyl-3-indolyl)-lEI-pyrrole-2,5-dione of melting point 261-263°C.
'fhe furandione starting material was prepared as follows:
a) A solution of 6.52 g of 8-(2-acetoxyethyl)-6,7,8,9--tetrahydro-9-oxopyrido[i,2-a]indole in 48 ml of dichloromethane was treated with 2.5 ml of ethanedithiol and 3.13 ml of titanium tetrachloride. The resulting solution was heated at refl:ux under nitrogen for 18 hours.
A further 4 ml of ethanedithiol and 9 ml of titanium tetrachloride were added and heating was continued for 4.5 hours. The mixture was washed with water, dried over and evaporated. The residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (1:3) to give 7.7 g of B'-(2-acetoxyethyl)-7~,8~-dihydrospiro-3~ [1,3-dithiolane-2',9'(6~H)-pyrido[1,2-a]indole].

- 2 6 - 20a.0~36 b) A solution of 5 g of the product of a) in 200 ml of ethanol was shaken with 8 spoon spatula measures of Raney nickel for 3.5 hours. The mixture was filtered and the filter residue was washed with ethanol. The combined filtrate and washings were evaporated to dryness and the residue was purified by chromatography on silica gel with ethyl acetate! petroleum ether (1:2) to give 620 mg of 8-(2-acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole.
c) 1.19 g of oxalyl chloride were added dropwise to a solution of 2.29 g of the product of b) in 50 ml of diethyl ether at 0°C. After 2.5 hours the solvent was removed by evaporation and the residue was dissolved in dichloromethane. 1.68 g of 1-methyl-3-indolylacetic acid and 2.45 ml of triethylamine were added to this solution and the mixture was heated to reflux under nitrogen for 18 hours. The solvent was evaporated and the residue Was purified by chromatography on silica gel with ethyl acetate/petroleum ether (1:2). Crystallization from ethyl acetate gave 625 mg of 3--[8-(2-acetoxyethyl)--6,7,8,9--tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-furan-2,5-dione of melting point 159-161°C.
Examvle 14 A solution of 115 mg of 3-[8-.(2-acetoxyethyl)-6,7,8,9--tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-furan-2,5-dione in 1 ml of DMF arid 2 ml of 33% aqueous ammonia was heated to 140°C for 4 hours. The cooled mixture was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (2:1). CrysCallization from ethyl acetate/petroleum ether gave 13 mg of 3-(8-(2-acetoxyethyl)-6,7,8,9-tetra-hydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H--PYrrole-2,5-dione of melting point 272-274°C.

2o~.os3s Example 15 A solution of 500 mg of the pyrroledione product of Example 13 in 50 ml of dichloromethane was treated with 218 mg of methanesulphonic anhydride and 1 ml of pyridine.
The resulting solution was stirred at room temperature under a nitrogen atmosphere for 1 hour. A further 20 mg of methanesulphonic anhydride were then added and stirring was continued for 0.5 hour. The mixture was washed with water, dried and evaporated. Crystallization of the residue from ethyl acetate/pettoleum ether gave 540 mg of 3-[6,7,8,9-tetrahydto-8-(2-methylsulphonyloxy-ethyl)pyrido-[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-lfl-pyrrole-2,5--dione of melting point 244-245°C.
Example l6 A solution of 500 mg of the pyrroledione product of Example 15 and 250 mg of sodium azide in 10 ml of DMF was heated at 70°C for 3 hours. The solvent was removed by evaporation and the solid was partitioned between ethyl acetate and water. The insoluble material was filtered off and dried to give 425 mg of 3-[B-(2-azidoethyl)-6,7,8,9--tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 262-264°C.
Example 17 200 mg of the pyrroledione product of Example 16 in 7-0 ml of methanol containing 40 mg of l0% Pd/C were shaken under a hydrogen atmosphere at a pressure of 3 atmospheres for 48 hours. The supernatant was decanted off and evaporated. The residue was treated with 50 ml of a saturated solution of hydrogen chloride in ethyl acetate 3,5 and was then purified by chromatography on silica gel with dichloromethane/methanol/acetic acid/water (60:18:2:3).
Crystallization from ethyl acetate gave 20 mg of - 2 s - 20.0636 3-[8-(2-aminoethyl)-6,7,8.9-tetrahydropyrido[1,2-a]-indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 160-165°C.
Example 18 In a manner analogous to that described in the first paragraph of Example 12, from 3-[2.3-dihydro-lEI-pyrrolo-[1.2-a]indol-9-yl]-4-(1-methyl-3--indolyl)furan-2,5-dione there was obtained 3-[2.3-dihyaro-lEI-pyrrolo[1,2-a]indol--9-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2.5-dione of melting point 260-270°C.
The furandione starting material was prepared as follows:
1'75 mg. of oxalyl chloride were added dropwise to a solution of 200 mg of 2,3-dihydro.-lEI-pyrrolo[1,2-a]indole in 7 ml of diethyl ether at 0°C under a~nitrogen atmosphere. After 1 hour the solvent was removed under reduced pressure and the residue was dissolved in 14 ml of dichloromethane. 245 mg of 1-methyl-3-indolylacetic acid and 265 mg of triethylamine were added to this solution and the mixture was stirred at room temperature for 72 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (1:2). Crystalli-zation from ethyl acetate gave 70 mg of 3-[2.3-dihydto--1H-pyrrolo[1,2-a]indol-9-yl]-4-(1-methyl-3-indolyl)furan--2,5-dione of melting point 125-130°C, Example 19 In a manner analogous to that described in the first paragraph of Example 1, from 3-[2-(acetoxymethyl)-2,3--dihydro-1H-pyrrolo[1,2-a]indol-9-yl]-4-(1-methyl-3---indolyl)furan-2,5-dione there was prepared 3-[2.3-201.0636 -dihydro-2-(hydroxymethyl)-lEI-pyrrolo[1,2-a]indol-9-yl]-4--(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 238-240°C.
The furandione starting material was prepared as follows:
a) 6 spoon spatula measures of Raney nickel were added to a solution of 5.08 g of ethyl 2.3~-dihydro-1-oxo-1H--pY~rolo(1,2-a]indole-2-carboxylate in 180 ml of ethanol and 90 ml of water. The mixture was heated to reflux for 10 hours and then a further 3 spoon spatula measures of Raney nickel were added. Heating was continued for 5.5 hours, whereupon the mixture was cooled and filtered.
Z'he filter residue was washed with ethyl acetate and dichloromethane. The combined filtrate and washings were evaporated and the residue was purified by chromatography on silica gel with diethyl etherl.petroleum ether (1:2).
Crystallization from methanol gave 635 ing of ethyl 2,3-dihydro-lEI--pyrrolo[1,2-a]indole-2-carboxylate of melting point 55-57°C.
b) 4 ml of a 1M solution of lithium aluminium hydride in TEIF were added to a solution of 750 mg of ethyl 2,3-dihydro-1EI-~pyrrolo(1,2-a]indole-2-carboxylate in 30 ml of TEIF. After 1 hour 30 ml of saturated ammonium chloride solution were added and the mixture was evaporated. The residue was extracted with dichloromethane and the organic extract was dried and evaporated. Crystallization of tho residue from diethyl ether/petroleum ether gave 355 mg of 2,3-dihydro-2-(hydroxymethyl)-lEI-pyrrolo[1,2-a]indole of melting point 76-78°C.
c) A solution of 355 mg of the product of b) in 20 ml of dichloromethane containing 2 ml of acetic anhydride and 2 ml of pyridine was stirred for 2 hours. The solvents were evaporated and the residue was partitioned between 2osos3s dichloromethane and water. The organic phase was dried and evaporated to give 420 mg of 2-(acetoxymethyl)-2,3--dihydro-lEI-pyrrolo[1,2-a]indole.
d) 290 mg of oxalyl chloride were added dropwise to a solution of 420 mg of the product of c) in 14 ml of-diethyl ether under a nitrogen atmosphere. After 1 hour the solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. 420 mg of 1-methyl-3-indolylacetic acid and 485 mg of triethylamine were added to this solution and the mixture was stirred for 72 hours. The solvent was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (1:1). Crystallization from ethyl acetate gave 90 mg of 3-[2-(acetoxymethyl)--2,3-dihydro--lEI-pyrrolo(1,2-a]indol-9-yl]-4-(1-methyl-3-indolyl)furan---2,5-dione of melting point 208-211°C.
Example 20 A solution of 150 mg of 3-[2-t-butoxycarbonyl-1.2,3.4--tetrahydropyrazino[1,2-a]indol-10--yl]-4-(1-methyl-3--indolyl)furan-2,5-dione in 4 mI of DMF and a ml of 33%
aqueous ammonia was heated to 140°C for 4 hours. The mixture was extracted with ethyl acetate and the organic extract was washed with water, dried and evaporated to give a gum. Purification was effected by chromatography on silica gel with dichloromethane/methanol/acetic acid/
water. The resulting amide was dissolved in 30 ml of ethanol and 5 ml of 2M hydrochloric acid and the resulting solution was heated to reflux for 2 hours. Removal of the solvent by evaporation and trituration of the residue with ethyl acetate gave 35 mg of 3-[1.2,3,4-tetrahydropyrazino-[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole--2.5-dione hydrochloride of melting point 268-270°C.

The furandione starting material was prepared as follows:
a) A solution of 450 mg of 1,2,3,4-tetrahydropyrazino--[1,2-a)indole in 30 ml of dichloromethane was treated at 0°C under a nitrogen atmosphere with 303 mg of triethyl-amine and 615 mg of di(t-butyl) dicarbonate. The mixture was stirred at 0°C for 4 hours and then washed with saturated sodium bicarbonate solution, dried and evaporated to give an oil. Crystallization from methanol gave 580 mg of t-butyl 1,2,3,4-tetrahydropyrazino[1,2-a]-indole-2-carboxylate of melting point 103-105°C.
b) 230 mg of oxalyl chloride were added dropwise to a ~5 stirred solution of 450 mg of the product of a) in 30 ml of diethyl ether at 0°C. After stirring, the solution was evaporated and the residue was dissolved in 50 ml of dichloromethane. 360 mg of 1-methyl-3-indolylacetic acid and 350 mg of triethylamine were added and the mixture was 20 stirred for 90 hours. The solvent was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (2:3)to give 180 mg of a gum. A sample was crystallized from ethyl acetate/n-hexane to give 3-[2-t-butoxycarbonyl-1,2,3,4-tetrahydropyra-25 zino[1,2-a]indol-10-yl)-4-(1-methyl-3-indolyl)furan-2,5--dione of melting point 125-127°C.
Examvle 21 30 In a manner analogous to that described in the first paragraph of Example 12, from 3-(S,6-dihydro-4H-pyrrolo-[3,2,1-ij]quinolin-1-yl)-4-(1-methyl-3-indolyl)furan-2,5--dione there was prepared 3-(5,6-dihydro-4II-pyrcolo-[3,2,1-ij)quinolin-1-yl)-4-(1-methyl-3-indolyl)-1H-pyrrole-3,5 -2,5-dione of melting point 285-288°C.

The furandione starting material was prepared as follows:
1.22 g of oxalyl chloride were added dropwise to a solution of 1.5 g of 5.6-dihydro-4H-pyrrolo[3,2,1-ij]-quinoline in 60 ml of dichloromethane under a nitrogen atmosphere. After 1 hour the solvent was removed under -reduced pressure and the residue was dissolved in 120 ml of dichloromethane. 1.9 g of 1-methyl-3-~indolylacetic acid and 2.02 g of triethylamine were added to this solution and the mixture was stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (1:2). Further purification by chromatography was effected with dichloromethane.
Crystallization from ethyl acetate gave 690 mg of 3-(5,6-dihydro-4H-pyrrolo[3,2.1-ij]quinolin-1-yl)-4--(1-methyl-3-indolyl)furan-2,5-dione of melting point 217-219°C.
Example 22 In a manner analogous to that described in the first paragraph of Example 1, from 3-[5-(acetoxymethyl)-5,6--dihydro-4H-pyrrolo[3.2,1-ij]quinolin-1-yl]-4-(1-methyl-3--indolyl)furan-2,5-dione there Was prepared 3-[5,6--dihydco-5-(hydroxymethyl)-4H-pyrrolo[3.2,1-ij]quinolin-1--yl]-4-(1-methyl-3-indolyl)-lEI-pyrrole-2,5-dione of melting point 223-225°C.
The furandione starting material was prepared as follows:
a) 33.4 ml of a 1.6M solution of n-butyllithium in hexane were added to a solution of 8.13 ml of diisopropylamine in 420 ml of TEIF at -78°C under a nitrogen atmosphere. After 0.5 hour 4.6 g of 1,2.5,6-tetrahydro-4-oxo-~4FI-pyrrolo-3 3 - 2o~.os3s [3,2,1-ij)quinoline were added and the mixture was stirred at -78°C for 0.5 hour. 2.77 ml of ethyl chloroformate were added and stirring was continued for 1 hour. The reaction was quenched with water and the mixture was evaporated.
The residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (1:2). Crystallization from diethyl ether gave 2.8 g of ethyl 1,2,5,6--tetrahydro-4-oxo-4FI-pyrrolo[3,2,1-ij]quinoline-5--carboxylate of melting point 88-90°C.
b) 15 ml of a 1M solution of borane in TEIF were added to a solution of 2.8 g of the product of a) in 100 ml of TEIF
and the resulting solution was heated to reflux for 2 hours. A further 55 mh of borane were added and heating was continued for 12 hours. The solvent was removed under reduced pressure, water and 2M hydrochloric acid were added and the mixture was extracted with dichloromethane.
The solvent was evaporated and the residue was dissolved in diethyl ether. The solution obtained~was treated with 12 ml of a 1M solution of lithium aluminium hydride in diethyl ether and the mixture was stirred under a nitrogen atmosphere for 18 hours. Water was added and the mixture was extracted with dichloromethane. Removal of the solvent under reduced pressure gave 1.4 g of 1,2,5,6-tetrahydro--4H-pYrrolo[3.2.1-ij]quinoline-5-methanol.
c) A solution of 1.4 g of the product of b) in 50 ml of dichloromethane was treated with 9 ml of acetic anhydride and 2 ml of pyridine. After 4 hours a further 4 ml of acetic anhydride were added and the mixture was stirred for 18 hours. Ths solvent was removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic phase was evaporated and the residue was dissolved in toluene and heated to reflux in 3,5 the presence of 250 mg of 10% Pd/C for 18 hours. A further 250 mg of 10% Pd/C were then added and heating was continued for a further 20 hours. The mixture was filtered - 3 4 - '~ro9..~~a,~~
and the filtrate was evaporated. The residue obtained was purified by chromatography on silica gel with ethyl acetate/petroleum ether (1:2) to give 350 mg of 5-(ace-toxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline.
d) 315 mg of oxalyl chloride were added to a solution of 570 mg of the product of c) in 15 ml of dichloromethane under a nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. 472 mg of 1-methyl-3-indolylacetic acid and 505 mg of triethylamine were added and the mixture was stirred for 72 hours. The solvent was removed under reduced pressure and the residue was purified by chromato-graphy on silica gel with dichloromethane. Crystallization y5 from ethyl acetate/n-hexane gave 140. mg of 3-[5-(acetoxy-methyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl]-4--(1-methyl-3-indolyl)furan-2,5-dione solid of melting point 198-200°C.
20 Example 23 In a manner analogous to that described in Example 11, from the pyrroledione product of Example 22 there was prepared 3-[5-(amidinothiomethyl)-5,6-dihydro-4H-pyrrolo-25 (3,2,1-ij]quinolin-1-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole -2,5-dione methanesulphonate of molting point 190-195°C.
Example 24 30 In a manner analogous to that described in Example 2, from the pyrroledione product of Example 22 there was prepared 3-(5-(aminomethyl)-5,6-dihydro-4H-pyrrolo-(3,2,1-ij]quinolin-1-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole--2,5-dione hydrochloride of melting point 248-250°C.

Example 25 20~,0~3f In a manner analogous to that described in the first paragraph of Example 1, from 3-[8-(acetoxymethyl)-6.7.8,9--tetrahydropyrido[1.2-a]indol-10-yl]-4-phenylfuran-2,5--dione (obtained as described in the last paragraph of Example 1 by using phenylacetic acid in place of 1-methyl--3-indolylacetic acid) there was prepared 3-[6.7,8,9--tetcahydro-8-(hydroxymethyl)pyrido[1,2-a]indol-10-yl]-4--phenyl-1H-pyrrole-2.5-dione of melting point 276-278°C.
Examine 26 In a manner analogous to that described in the first Paragraph of Example 1, from 4-[8-(acetoxymethyl)-6,7.8,9--tetrahydropyrido[1,2-a]indol-10-yl]-3-(3-benzo[b]thienyl)-furan-2,5-dione (obtained as described in the last paragraph of Example 1 by using 3-benzo[b]thienylacetic acid in place of 1-methyl-3-indolylacetic acid) there was prepared 3-(3-benzo[b]thienyl)-4-[6.7,8,9-tetrahydro-8---(hydroxymethyl)pyrido[1,2-a]indol-10-yl]-1H-pyrrole-2.5--dione of melting point 226-7.27°C.
Example 27 In a manner analogous to that described in the first paragraph of Example 1, from 3-[8-(acetoxymethyl)-6,7,8,9--tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-naphthyl)furan--2,5-dione (obtained as described in the last paragraph of Example 1 by using 1-naphthylacetic acid in place of 1-methyl-3-indolylacetic acid) there was prepared 3-[6,7,8,9-tetrahydro-e-(hydroxymethyl)pyrido[1,2-a]indol--10-yl]-4-(1-naphthyl)-1H-pyrrole-2.5-dione of melting point 221-222°C.

Example 28 201.0636 In a manner analogous to that described in Example 10, from the pyrroledione product of Example 19. there was prepared 3-[2-(aminomethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]-indol-9-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 208-211°C.
Example 29 In an analogous manner to that described in Example 10, from the pyrroledione product of Example 25, there was prepared 3-(8-(aminomethyl)-6,7,8,9-tetrahydro--pyrido[1,2-a]indol-10-yl]-4-phenyl-1H-pyrrole-2,5-dione of melting point 249-250°C.
Example 30 A suspension of 100 mg of the pyrro2edione product of Example 20 in 10 ml of dichloromethane was treated under nitrogen with 0.08 ml of triethylamine and 86 mg of phenyl chloroformate. The mixture was stirred for 2 hours and then the solvent was evaporated. Chromatography of the residue on silica gel with ethyl acetate/n-hexane (1:1) gave a gum which was dissolved in a mixture of 5 ml of isopropanol and 10 ml of 33~ aqueous ammonia. The mixture was diluted with water and extracted with dichloromethane.
The combined dichloromethane extracts were dried and, evaporated. Crystallization of the residue from ethyl acetate/n-hexane gave 45 mg of 3-[1:2,3,4-tetrahydro-2--(phenoxycarbonyl)pyrazino[1,2-a]indol-10-yl]-4-(1-methyl--3-indolyl)-1H-pyrrole-2,5-dione of melting point 160-165°C.

3 7 20~.0~36 Example 31 a) A solution of 80 mg of the pyrroledione product of Example 20 in 20 ml of dichloromethane was treated with 10 ml of 5% aqueous sodium hydrogen carbonate. The stirred mixture was treated with a solution of 125 mg of trifluoroacetamidoacetyl chloride in 5 ml of dichloro-methane. After 17 hours, the phases were separated and the organic phase was dried and evaporated. Chromatography of the residue on silica gel with ethyl acetate/n-hexane (2:1) and crystallization from ethyl acetate/n-hexane gave 70 mq of 3-[2-[(trifluoroacetamido)acetyl]-1,2,3,4-tetra--hydropyrazino[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)--1H-pyrrole-2,5-dione of melting point 170-172°C.
b) A solution of 65 mg of the product of a) in 10 ml of methanol was treated with 5 ml of 33% aqueous ammonia.
After 4 hours the solvent was cemoved by evaporation and the residue was partitioned between dichloromethane and water. The organic phase was washed with water, dried and evaporated. Chromatography of the residue on silica gel - with chloroform/methanol/acetic acid/water (60:18:2:3) gave a gum which was dissolved in glacial acetic acid and treated with 20 ml of lM hydrochloric acid. Evaporation of the solvent and trituration of the residue with diethyl ether gave 35 mg of 3-[2-(aminoacetyl)-1.2,3,4-tetrahydro-pyrazino[1,2-a]indol-10-yl]-9-(1-methyl-3-indolyl)-1H--pyrrole-2,5-dione hydrochloride of melting point 235°C
(decomposition).
Example 32 a) A solution of 100 mg of the pyrroledione product of Example 20 in 40 ml of dichloromethane was treated under a nitrogen atmosphere with 125 mg of 1,1-carbonyldiimidazole and the mixture was stirred for 24 hours. The solution was washed with water, dried and evaporated. Trituration of 20.0636 the residue with ethyl acetate gave 84 mg of 3-[1,2,3,4--tetrahydro-2-(1-imidazolylcarbonyl)pyrazino[1,2-a)indol-10-yl]-4-(1-methyl-3-indolyl)-lI-I-pyrrole-2,5-dione of melting point 295°C (decomposition).
b) 80 mg of the product of a) were dissolved in a mixture of ZO ml of DMF and 20 ml of 33~ aqueous ammonia. The mixture was stirred for 17 hours and the solvent was evaporated. Chromatography of the residue on silica gel with methanol/ethyl acetate (1:9) gave a solid which was crystallized from methanol. There were obtained 45 mg of 3-[2-carbamoyl--1,2,3,4-tetrahydropyrazino(1.2-a]indol--10-yl]-4-(1-methyl-3-indolyl)-lI-I-pyrrole-2,5-dione of melting point 295°C (decomposition).
Example 33 A solution of 505 mg of the pyrroledione product of Example 2 in 20 ml of DMF was treated with a solution of 222 mg of 1,1-thiocarbonyldiimidazole in 5 ml of THF.
After 17 hours the solvent was evaporated and the residue was purified by chromatography on silica gel with methanol/dichloromethane (1:99). Trituration with n-hexane gave 297 mg of 3-[6,7.8,9-tetrahydro-8-isothiocyanato-pYrido[1.2-a]indol-10-yl]-4-(1-methyl-~3-indolyl)-1PI-pyrrole-2,5-dione in the form of a red solid of melting point 285-287°C.
Examule 34 250 mg of the pyrroledione product of Example 2 were stirred in a mixture of 25 ml of dichloromethane and 15 ml of 5% aqueous sodium hydrogen carbonate. The mixture was treated with 1 ml of benzoyl chloride and stirred foc 17 hours. The phases were separated and the organic phase was dried and evaporated. Chromatography of the residue on silica gel with methanol/dichloromethane (7:93) followed 201.0636 by trituration with n-hexane gave 220 mg of 3-[8-(benz-amidomethyl)-6,7.8.9-tetrahydropyrido[1,2-a]indol-10-yl]--4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 297-303°C.
Example 35 A solution of 150 mg of 3-[7-acetoxy-6.7,8,9-tetra hydropyrido[1.2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan -2.5-dione in 6 ml of DMF and 6 ml of 33% aqueous ammonia was heated to 150°C for 6 hours. The mixture was extracted with ethyl acetate and the organic extracts were washed with water, dried and evaporated. Crystallization of the residue from ethyl acetate gave 120 mg of 3-[6,7,8,9-wtetrahydro-7-hydroxypyrido[1,2-a]indol-10--y1]-4-(1-methyl--3-indolyl)-1H-pyrrole-2.5-dione of melting point 252-255°C.
The furandione starting material was prepared as 2~ follows:
a) A solution of 14.0 g of indole-2-methanol in 500 ml of dichloromethane was stirred with 76.4 g of activated manganese-IV oxide. After 1 hour the solid was filtered off and washed with dichloromethane. The combined washings were concentrated and 33 g of (carbethoxymethylene)-triphenylphosphorane Were added. The resulting solution was heated to reflux under a nitrogen atmosphere. The solvent was evaporated to give an oil which was purified 3p by chromatography on silica gel with ethyl acetate!
n-hexane (1:3). The product was obtained as a 20:1 mixture of E!Z isomers. Crystallization from methanol gave 11.3 g of ethyl (E)-2-indolyl-2-propenoate of melting point 120-122°C.
b) A solution of 7.2 g of ethyl (E)-2-indolyl-2--propenoate in 120 ml of DMF was treated with 1.47 g of a 60% dispersion of sodium hydride in mineral oil. The resulting solution was cooled to 0°C and 7.17 g of t-butyl bromoacetate were added under an atmosphere of nitrogen.
After 2 hours the mixture was poured into 100 ml of 2M
hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with water, dried and evaporated to give an oil. This oil was purified by chromatography on silica gel with diethyl ether/petroleum ether (1:3). Crystallization from diethyl ether/n-hexane gave 8.1 g of ethyl (E)-3-(1-t-butoxycarbonylmethyl) -2-indolyl]-2-propenoate of melting point 66-68°C.
c) A solution of 8.0 g of the product of b) in 300 ml of ethanol was shaken with 800 mg of 10% Pd/C under a hydrogen atmosphere. The catalyst was filtered off and washed with ethyl acetate. The combined filtrate and washings were evaporated to give an oil which was dissolved in TFIF. The solution was added to a solution of 2.8 g of potassium t-butoxide in THF under a nitrogen atmosphere. Then the mixture was left tc stir for 1 hour and the solvent was evaporated. The residue was pactitioned between ethyl acetate and 2M hydrochloric acid. The organic phase was washed with water, dried and evaporated. The residue was purified by chromatography on silica gel with diethyl ether/n-hexane (1:4). There are obtained 4.55 g of t-butyl 6,7,8,9-tetrahydro-7-oxo--pyrido[I,2-a]indole-6-carboxylate.
d) A solution of 4.5 g of the product of c) in 200 ml of toluene was treated with four spoon spatula measures of silica gel and the mixture was heated to reflux for 3 hours under a nitrogen atmosphere. The solid was filtered off and washed with toluene. The combined filtrate and washings were evaporated to give a solid.
Crystallization from diethyl ether/n-hexane gave 2.5 g of 8.9-dihydropyrido[1,2-a]indol-7(6H)-one of melting point 126-128°C.

e) 190 mg of sodium borohydride were added to a stirred solution of 650 mg of 8,9-dihydropyrido[1.2-a]indol---7(6EI)-one in 50 ml of methanol under a nitrogen atmosphere. The mixture was stirred and then poured into 100 ml of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and the combined extracts were dried and evaporated to give a solid. This was crystallized from diethyl ether/n-hexane and gave 500 mg of 6.7,8,9-tetrahydro-7-hydroxypyrido[1,2-a]indole of melting point 99-100°C.
f) A solution of 500 mg of the product of e) in 5 ml of pyridine and 2 ml of acetic anhydride was stirred for 8 hours. The mixture was poured into 50 ml of 2M
hydrochloric acid and extracted with ethyl acetate. The combined orgahic extracts were washed with 5% sodium bicarbonate solution and water, dried and evaporated to ' give 520 mg of an oil. A sample was crystallized from diethyl ether/n-hexane. and there was obtained 7-acetoxy-6.7.8,9-tetrahydropyrido[1,2-a]indole of melting point 90-95°C.
g) 320 mg of oxalyl chloride were added to a solution of 500 mg of the product of f) in 50 ml of diethyl ether under a nitrogen atmosphere. Then the solvent was removed under reduced pressure and the residue was dissolved in 50 ml of dichloromethane. 378 mg of 1-methyl-3-indolyl-acetic acid and 505 mg of triethylamine were added to this solution and the mixture was stirred for 72 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel with ethyl acetate/n-hexane (1:1). Crystallization from ethyl acetate gave 160 mg of 3-[7-acetoxy-6,7,8,9-tetrahydropyrido-[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2.5-dione of melting point 272-275°C.

Example 36 A solution of 85 mg of 3-[7-t-butoxyfocmamido-6,7,8.9--tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3--indolyl)furan-2.5-dione in 5 ml of DMF and 5 ml of 33%
aqueous ammonia was heated to 100°C for 1 hour. The cooled mixture was pactitioned between ethyl acetate and water.
The organic phase was washed with water, dried and evaporated. Crystallization from ethyl acetate/n-hexane gave 70 mg of 3-[7-t-butoxyformamido-6,7,8.9-tetrahydro-pyrido[1.2-a]indol-.10-yl]-4-(1-methyl-3-indolyl)-1FI-pyrrole-2.5-dione of melting point 159-163°C.
The furandione starting material was prepared as 15 follows:
a) A suspension of 555 mg of 8.9-dihydropyrido[1.2-a]-indol-?(6FI)-one and 4.62 g of ammonium acetate in 15 ml of methanol was treated with 250 mg of sodium cyanoboro-20 hydride. The mixture was stirred and then partitioned between ethyl acetate and water. The organic phase was dried and the solvent was removed under reduced pressure.
The residual oil was subjected to chromatography on silica gel with 10% methanol in dichloromethane. The indoline 2b obtained was dissolved in toluene and heated to reflux with 50 mg of 10% Pd/C for 4 hours. The catalyst was filtered off and washed with toluAne. The combined filtrate and washings were evaporated to give 170 mg of 7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indole.
b) 225 mg of di-t-butyl dicarbonate were added to a stirred solution of 175 mg of the product of a) and 112 mg of triethylamine in 20 ml of diehloromethane at 0°C under a nitrogen atmosphere. After 18 hours the solution was 3,5 washed with saturated sodium bicarbonate solution, dried and evaporated to give an oil. Crystallization from diethyl ether gave 240 mg of 7-t-butoxyformamido--6,7.8,9--tetrahydropyrido[1,2-a]indole of melting point 137-139°C.
c) 127 mg of oxalyl chloride were added to a solution of 240 mg of the product of b) in 30 ml of diethyl ether under a nitrogen atmosphere. After 10 minutes the solvent was removed under reduced pressure and the residue was dissolved in 30 ml of dichloromethane. 170 mg of 1-methyl--3-indolylacetic acid and 200 mg of triethylamine were added to the resulting solution and the mixture was stirred for 72 hours. The solvent was removed under reduced pressure and the residue was purified by chromato-graphy on silica gel with ethyl acetate/n-hexane (1:2).
Crystallization from ethyl acetate/n-hexane gave 100 mg of 3-(7-t-butoxyformamido-6,7.8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione of melting point 141-145°C.
Example 37 A saturated solution of hydrogen chloride in 30 ml of ethyl acetate was added to a stirred suspension of 60 mg of the pyrroledione product of Example 36 in 50 ml of ethyl acetate and the mixture was stirred for 18 hours.
The solvent was removed under reduced pressure and the z5 residue was triturated with ethyl acetate to give 35 mg of 3-[7-amino-6,7,8.9-tetrahydropyrido[1.2-a]indol-l0-yl]-4-(1-methyl-3-indolyl)-1H-pycrole-2,5-dione hydrochloride of melting point 260-265°C.
30 Example 38 A solution of 80 mg of 3-(8-t-butoxyformamido-6,7,8,9--tetrahydropyrido[1,2-a]indol-10-yl]-4-tl-methyl-3-indolyl)-fucan-2,5-dione in 2 ml of DMF and 2 ml of 33~ aqueous 35 ammonia was heated to 100°C for 1 hour. The solution was cooled and gave 60 mg of 3-[8-t-butoxyformamido-6,7,8,9--tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 153-155°C.
The furandione starting material was prepared as f o 11 ows a) A solution of 300 mg of sodium hydroxide in 5 ml of water was added to a stirred solution of 1.35 g of the carboxylate product of Example 1b) in 25 ml of ethanol and the mixture was heated to reflux for 15 minutes. 2 ml of 2M hydrochloric acid and 10 ml of water were added and the precipitate obtained was filtered off and dried to give 1.14 g of 6,7,8,9-tetrahydropyrido[1,2-a)indole-8-car-boxylic acid of melting point 244-246°C.
b) A suspension of 900 mg of the product of a) in 1 ml of water and 20 ml of acetone was cooled to 0°C and treated With 490 mg of triethylamine followed by 5?6 mg of ethyl chloroformate. After 0.5 hour 345 mg of sodium azide in 1 ml of water were added and the mixture was stirred at 0°C for 1 hour. The solvent was removed under reduced pressure and the residue was extracted with dichloro-methane. The extracts were evaporated and the residue was purified by chromatography on silica gel with dichloro-methane. The obtained solid was dissolved in 10 ml of toluene and heated to 100°C for 4 hours under a nitrogen atmosphere. The solvent was evaporated to give 700 mg of 6,7,8,9-tetrahydropyrido(1,2-a]indole-e-isocyanate of melting point 87-89°C.
c) 4 ml of a 2M sodium hydroxide solution were added to a solution of 700 mg of the product of b) in 50 ml of THF
and the solution obtained was stirred overnight. The solvent was removed under reduced pressure and the residue was extracted with dichloromethane. The dichloromethane 3,5 extract was evaporated to give an amine which was redissolved in dichloromethane. 645 mg of di-t-butyl dicarbonate and 300 mg of triethylamine were added at 0°C

20.0636 and the mixture was allowed to warm to room temperature while stirring for 72 hours. The mixture Was washed with sodium bicarbonate solution and the organic phase was dried. The solvent was removed under reduced pressure and the residue was extracted with diethyl ether. The ethereal extracts were evaporated and the solid obtained was triturated with petroleum ether to give 550 mg 8-t-butoxy-formamido-6,7,8,9-tetrahydropyrido[1.2-a]indole of melting point 155-157°C.
d) 256 mg of oxalyl chloride were added to a solution of 550 mg of the product of c) in 10 ml of diethyl ether at 0°C under a nitrogen atmosphere. After 1 hour the solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. 363 mg of 1-methyl-3--indolylacetic acid and 390 mg of triethylamine were added and the mixture was stirred for 40 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (1:2). Crystallization from diethyl ether/petroleum ether gave 200 mg of 3-[8-t-butoxyformamido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione of melting point 155-160°C.
Examule 39 In a manner analogous to that described in Example 37.
from the pyrroledione product of Example 38, there was Prepared 3-[8-amino-6,7.8,9-tetrahydropyrido[1.2-a]indol--10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2.5-dione hydro-chloride of melting point 310-315°C.
Example 40 A solution of 320 mg of 3-[4-(Z-acetoxyethyl)-5.6--dihydro-9H-pyrrolo[3.2,1-ij]quinolin-1-yl]-4-(1-methyl-3--. 4 6 _ 2o~.os~s -indolyl)furan-.2,5-dione in 2 ml of DMFand 2 ml of 33%
aqueous ammonia was heated to 140°C for 12 hours. Water was added to the cooled mixture which was filtered to give 210 mg of a solid. A sample was crystallized from ethyl acetate to give 3-[4-(2-hydroxyethyl)-5,6-dihydro--4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1-methyl-3--indolyl)-1H-pyrrole-2,5-dione of melting point 214-215°C.
The furandione starting material was prepared as follows:
a) 25 ml of a 1.6M solution of n-butyllithium in n-hexane were added to a solution of 4.04 g of diisopropylamine in ml of THF at 0°C under nitrogen. After 10 minutes the 15 stirred solution was cooled to -78°C and a solution of 9.28 g of t-butyl acetate in 20 ml of THF was added. After 10 minutes 3.46 g of 1.2,5,6-tetrahydro-4H-pyrrolo-[3,2,1-ij]quinolin-9-one in 20 ml of THF. was added followed by 8 ml of boron trifluoride diethyl etherate.
20 The mixture was stirred at -78°C and then 20 ml of pyrrolidine were added. The mixture was partitioned between ethyl acetate and Water and the organic extracts were washed with water and sodium chloride solution, dried and evaporated. The residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (1:3).
There were obtained 4.1 g of t-butyl (E)-(1,2,5,6-tetra-hydro-4H-pyrrolo[3.2.1-ij]quinolin--4-ylidene)acetate of melting point 105-107°C.
b) A solution of 4 g of the product of a) in 400 ml of methanol was shaken with 280 mg of 10% Pd/C under a hydrogen atmosphere for 18 hours. The catalyst was filtered off and the filtrate was evaporated to an oil.
1.99 g of this oil in 100 ml of diethyl ether were treated with 5 ml of a 1M solution of lithium aluminium hydride in diethyl ether and the mixture was stirred for 2 hours.
Water was added and the product was extracted with ethyl - 47 - zo~.os3s acetate. The ethyl acetate extracts were dried and concentrated under reduced pressure to give 1.44 g of 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-ethanol.
c} 1.44 g of the product of b) in 40 ml of dichloro-methane were treated with 10 ml of acetic anhydride and 5 ml of pyridine. The solution obtained was stirred and then evaporated. The residue was dissolved in dichloro-methane, the solution was washed with water, the organic phase was separated, dried and concentrated to give 1.65 g of 4-(2-acetoxyethyl)-1,2.5,6-tetrahydro-4H-pyrrolo-[3,2,1-ij]quinoline.
d) A solution of 1.6 g of the product of c) in 50 ml of xylene and 100 mg of 10% Pd/C was heated to reflux for 12 hours. The catalyst was filtered off and the filtrate was evaporated to give 1.7 g of 4-(2-acetoxyethyl)-5,6--dihydro-4H-pyrrolo[3,2,1-ij]quinoline.
20 e) 935 mg of oxalyl chloride were added to a stirred solution of 1.7 g of the product of c) in 45 ml of dichloromethane under a nitrogen atmosphere. After 1 hour the solvent was removed under reduced pressure and the residue was dissolved in 90 ml of dichloromethane. 1.38 g 25 of 1-methyl-3-indolylacetic acid and 1.48 g of triethyl-amine were added to this solution and the mixture obtained was stirred for 18 hours. The solvent Was removed under reduced pressure and the residue was purified by chromato-graphy on silica gel with ethyl acetate/petroleum ether 30 (1:2). Crystallization from methanol/water gave 280 mg of 3-[4-(2-acetoxyethyl)-5,6-dihydro-4H-pyrrolo[3.2.1-ij]-quinolin-1-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione of melting point 143-146°C.

Example 41 20.0636 A solution of 400 mg of 3-(8-[(t-butoxyformamido)-methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4--(1-methyl-3-indolyl)furan-2,5-dione in 50 ml of DMF and 50 ml of water was treated with 2.5 g of hydroxylamine hydrochloride and 2.5 g of potassium carbonate and the solution obtained was heated to 100°C. The solvents were evaporated and the residue was dissolved in dichloro-methane, washed with water and dried. The solvent was removed under reduced pressure and the residue was crystallized from ethyl acetate/petroleum ether to give 190 mg of 3-[8-[(t-butoxyformamido)methyl]-6.7,8,9-, -tetrahydropyrido(1,2-a]indol-10-yl]-1-hydroxy-4-(1-methyl--3-indolyl)pyrrole-2,5-dione of melting point 238-240°C.
The furandione starting material was prepared as f o 11 ows a) 2.4 g of methanesulphonic anhydride and 2 ml of triethylamine were added to a stirred solution of 2.01 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-methanol in 40 ml of dichloromethane under a nitrogen atmosphere.
After 18 hours the mixture was washed with saturated sodium bicarbonate solution, dried and evaporated to an oil. 1.8 g of this oil were dissolved in 10 ml of isopropanol and 5 ml of 33% aqueous ammonia and the mixture was heated to 80°C for 10 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase was dried and evaporated to give 1.3 g of 8-aminomethyl-6.7.8.9-tetra-hydropyrido[1,2-a]indole of melting point 85-90°C.
3,,5 b) 1.09 g of di-t-butyl dicarbonate were added to a stirred solution of 890 mg of 8-aminomethyl-6,7,8,9-tetra-. hydropyrido[1,2-a]indole and 920 mg of triethylamine in - 4 9 _ ~0~.0636 60 ml of dichloromethane at 0°C under a nitrogen atmosphere. Aftec 72 hours the organic phase was washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was crystallized from petroleum ether to give 1.03 g of 8-[(t-butoxyformamido)methyl]--6,7,8,9-tetrahydropyrido[1,2-a]indole of melting point 80-85°C.
c) 445 mg of oxalyl chloride were added dropwise to a solution of 1 g of the product of b) in 20 ml of diethyl ether under a nitrogen atmosphere at 0°C. After 1 hour the solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. 630 mg of 1-methyl-3--indolylacetic acid and 920 of of triethylamine were added to this solution and the mixture was stirred for 72 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel With ethyl aaetate/petroleum.ether (1:2). The resulting solid was crystallized from diethyl ether and there were obtained 315 mg of 3-[8-[(t-butoxyformamido)-methyl]-6,7.8.9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1--methyl-3-indolyl)furan-2,5-dione of melting point 124-126°C.
Example 42 In a manner analogous to that described in t;xamplo 37, fcom the product of Example 41 these was prepared 3-[e-(aminomethyl)-6,7.8,9--tetrahydropyrido[1.2-a]indol--10-Y1]-1-hydr,oxy-4-(1-methyl-3-indolyl)pyrrole-2,5-dione hydrochloride of melting point 280-282°C.
Example 43 In a manner analogous to that described in Example 11.
from the product of Example 40 there was prepared 3-[4-[2-(amidinothio)ethyl]-5,6-dihydro-4H-pyrrolo-- 5 0 - 209.0636 [3.2,1-ij]quinolin-1-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole--2,5-dione methanesulphonate of melting point 185-19o°C.
Example 44 In a manner analogous to that described in Example 2, from the product of Example 40 there was prepared 3-[4-(2-aminoethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]-quinolin-1-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of melting point 193-195°C.
Example 45 In a manner analogous to that described in Example 2, from the product of Example 26 there was obtained 3-[8-(aminomethyl)-6.7,8,9-tetrahydropyrido[1,2--a]indol--10-yl]-4-(3-benzo[b]thienyl)-1H-pyrrole-2,5-dione hydro-chloride of melting~point 285-287°C.
Example 46 In a manner analogous to that described in the first paragraph of Example 1, from 3-[e-(acetoxymethyl)--6,7,8.9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(2--naphthyl)furan-2,5-dione (obtained as described in the Last paragraph of Example 1 by using Z-naphthylacetic acid in place of 1-methyl-3-indolylacetic acid) there was prepared 3-[6.7,8,9-tetcahydro-e-(hydroxymethyl)pyrido-[1,2-a]indol-10-yl]-4-(2-naphthyl)-1H-pyrrole-2,5-dione of melting point 260-263°C.
Example 47 In a manner analogous to that described in Example 2, 3,5 from the product of Example 46 there was obtained 3-[8--(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]--4-(2-naphthyl)-1H-pyrrole-2,5-dione hydrochloride of 201.0636 melting point >300°C.
Example 48 5 In an analogous manner to that described in Example 10. from the product of Example 27 there was prepared 3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido--[1,2-a]indol--1-yl]-4-(1-naphthyl)-lEI-pyrrole--2,5-dione of melting point 167-169°C.
Example 49 In a manner analogous to that described in the first paragraph of Example 1, from 1.3 g of 3-[9-(acetoxy-methyl)-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-11-yl]-4 (1-methyl-3-indolyl)furan-2,5-dione there were obtained 520 mg of 3-[7.8,9,10-tetrahydro-9-(hydroxymethyl)-6H--azepino[1.2-a]indol-11-yl]-4-(1-.methyl-3-indolyl)-lI-I--pyrrole-2.5-dione of melting point 268=270°C.
The furandione starting material was prepared as follows:
a) A solution of 18.9 g of ethyl indole-2-carboxylate in 100 ml of DMF Was added to a suspension of 2.64 g of sodium hydride in 50 ml of DMF. After 1 hour a solution of 20.9 q of ethyl 5-bromovalerate in 100 ml of DMF was added dropwise. After 48 hours the mixture was poured into water, extracted with dichloromethane and the combined dichloromethane extracts were washed with water, dried and concentrated to give 26.2 g of ethyl 1-(4-ethoxycarbonyl-butyl)indole-2-carboxylate.
b) This oil was dissolved in 50 ml of THF and the solution was added to a stirred suspension of 11.2 g of potassium t-butoxide in 150 ml of THF. After 36 hours the mixture was concentrated and the residue was poured into a 2o~os3s mixture of water and diethyl ether. The organic phase was dried and concentrated. Chromatography of the residue on silica gel with dichloromethane/methanol (9:1) gave a solid which was recrystallized from ethyl acetate/
n-hexane, there being obtained 6.1 g of ethyl 7,8-dihydro--10-hydroxy-6H-azepino(1,2-a]indole-9-carboxylate of melting point 74-81°C.
c) 5.5 g of this solid were dissolved in 200 ml of ethanol and treated with 11 spoon spatula measures of Raney nickel and 400 ml of water. The mixture was heated at reflux for 4 hours. The cooled mixture was filtered and the residue was washed with ethyl acetate. The filtrate was extracted with ethyl acetate. The combined extracts and washings were dried and concentrated to give an oil which was purified by chromatography on silica gel with dichloromethane. there being obtained 2.5 g of ethyl 7,8.9.10-tetrahydro-6H-azepino[1,.2-a]indole-9-carboxylate of melting point 69-70°C.
d) This solid was dissolved in 50 ml of THF and added dropwise to a mixture of 0.45 g of lithium aluminium hydride in 2o ml of THF. The mixture was stirred for 2 hours and then water was added. The resulting mixture was extracted with diethyl ether and the combined extracts were dried and concentrated. Chromatography of the residue on silica gel with dichloromethane gave 1.9o g of 7,8,9,10-tetrahydro-9-(hydroxymethyl)-6H-azepino(1.2-a]-indole of melting point 109-111°C.
e) 1.8 g of this solid were dissolved in 100 ml of diethyl ether at 0°C and treated with 1.70 g of acetic anhydride and 0.66 g of pyridine. After a hours a further 5 g of pyridine were added and the mixture was stirred foe 76 hours. The solvents were removed under reduced pressure and the residue was chromatographed on silica gel with dichloromethane. there being obtained 1.98 g of _ 5 3 _.
20.0636 9-(acetoxymethyl)-7,8,9,10-tetcahydro-6EI-azepino[1.2-a]-indole of melting point 65°C.
f) 1.90 g of this solid were dissolved in 50 ml of dichloromethane, the solution was cooled to 0°C and treated with 1.03 g of oxalyl chloride. After 2 hours the solvent was removed by evaporation and the residue was 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 was concentrated and the residue was chromatographed on silica gel with dichloromethane containing 5% methanol by volume. The solid obtained was recrystallized from ethyl acetate/n-hexane to give 1.55 g of 3-[9-(acetoxymethyl)--~~8~9~10-tetrahydro-6I-I-azepino[1:2-a]indol-11-yl]-4--(1-methyl-3-indolyl)furan-2.5-dione of melting point 164-166°C.
Example 50 in a manner analogous to that described in Example 12.
from 0.50 g of 3-[7.8.9.10-tetrahydro-6H-azepino[1:2-a]-indol-11-yl]-3-(1-methyl-3-indolyl)furan-2,5-dione there was obtained 0.43 g of 3-[7~8~9,10-tetrahydro-6H-azepino-[1.2-a]indol-11-yl]-3-(1-methyl-3-indolyl)-1H-pyrrole-2,5--dione of melting point >300°C.
The furandione starting matecial was prepared as follows:
1.5 g of oxalyl chloride were added dropwise to an ice-cold solution of 2.0 g of 7.8~9~10-tetrahydro-6H--azepino[1,2-a]indole (J. Org. Chem. 33, 1968, 4286) in 50 ml of dichloromethane. The mixture was stirred for 2 hours. The solvent was removed in a vacuum and the residue was dissolved in dichloromethane. The solution 'obtained was added to a solution of 2.2 g of 1-methyl-3-- 5 4 - ~olos3s -indolylacetic acid and 2.73 g of triethylamine in 50 ml of dichloromethane. The mixture was stirred and then concentrated. The residue was chromatographed on silica gel with dichloromethane and there was obtained 1.0 g of 3-[7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-11-yl]-3-(1-methyl-3-indolyl)furan-2,5-dione of melting point 257-259°C.
Example 51 A solution of 150 mg of the product of Example 49 and 146 mg of 2,6-lutidine in 15 ml of dichloromethane was added to a solution of 290 mg of trifluoromethanesulphonic anhydride at 0°C. After 3 hours 25 ml of 33% aqueous y5 ammonia were added and the mixture was stirred for 16 hours. The mixture was extracted with dichloromethane and the combined extracts were dried and concentrated.
Chromatography of the residue on silica gel with dichloromethane/methanol/acetic acid/water (90:18:3:2) gave 50 mg of 3-[9-(aminomethyl)-7,8,9,10-tetrahydro--6H-azepino[1,2-a]indol-11-yl]-4-(1-methyl--3-indolyl)-1H--pyrrole-2,5-dione acetate of melting point 215°C
(decomposition).
Example 52 A mixture of 40 mg of the product of Example 51, 20 mq of sodium bicarbonate and 25 mg of 3,5-dimethyl--N2--nitro-1-pyrazole-1-ca=boxamide in 10 ml of ethanol was heated at reflux for 16 hours. The mixture was concentrated and the residue was chromatographed on silica gel with dichloromethane/methanol (9:1). There were obtained 15 mg of 3-(1-methyl-3-indolyl)-4-[7,8.9,10---tetrahydro-9-[(2-nitroguanidino)methyl]-6H-azepino[1,2-a]-3,5 indol-11-yl]-1H-pyrrole-Z,5-dione of melting point 177-178°C.

~p~.o636 Example 53 In a manner analogous to that described in the first paragraph of Example 1, from 0.20 g of 3-[8-(acetoxy-5 methyl)-7.8,9,10-tetrahydro-6H-azepino[1,2-a]indol-11-yl]-4 (1-methyl-3-indolyl)furan-2,5-dione there were obtained 60 mg of 3-[7,8,9,10-tetrahydro-8-(hydroxymethyl)-6H--azepino[1,2-a]indol-11-yl]-4-(1-methyl-3-indolyl)-1H--pyrrole-2,5-dione of melting point 109-111°C.
The furandione starting material was prepared as follows:
a) A solution of 5 g of ethyl 6,7-dihydro-9-hydroxy-pYrido[1,2-a]indole-8-carboxylate (prepared as described in Example 1) in 200 ml of DMF was treated with 550 mg of sodium hydride. The mixture was stirred under a nitrogen atmosphere and then a solution of. 3.6 g of ethyl bromoacetate in 50 ml of DMF was added.~After 16 hours the mixture was poured into water and extracted with diethyl ether. The combined extracts were washed with water, dried and concentrated to give 4.4 g of ethyl 8-(ethoxycar-bonyl)-6.7,8,9-tetrahydro-9-oxopyrido[1,2-a]indole-8--acetate. ' b) A solution of 5.0 g of the product of a) in 200 ml of THF was added dropwise to a stirred solution of 2.0 g of potassium t-butoxide in 50 ml of THF. The mixture was stirred and then 1 ml of glacial acetic acid was added.
The mixture was poured into water and extracted with dichloromethane. The combined extracts were dried and concentrated. The residue was chromatographed on silica gel with dichloromethanelmethanol (95:5) to give 3.0 g of diethyl 7,8-dihydro-10-hydroxy-6H-azepino[1.2-a]indole--8,9-dicarboxylate.

2~~.~636 c) A mixture of 2.8 g of the product of b) and 0.5 g of boric acid was heated at 150°C for 1 hour and at 170°C for 3 hours. Ice-water was added to the cooled mixture and the whole was extracted with dichloromethane. The combined dichloromethane extracts were dried and concentrated. The residue was chromatographed on silica gel with dichloro-methanelmethanol (95:5). There were obtained 2.1 g of ethyl 7,8.9.10-~tetrahydro-10-oxo-6H-azepino[1.2-a]-indole-B-carboxylate.
d) 2.1 g of the product of c) were dissolved in 80 m1 of ethanol and treated with 4 spoon spatula measures of Itaney nickel and 50 ml of water. The mixture was heated at reflux for 4 hours, cooled and filtered, and the residue was washed with ethyl acetate. The filtrate was extracted with ethyl acetate. The combined extracts and washings were dried and concentrated. Chromatography of the residue on silica gel with dichloromethane gave 0.89 g of ethyl 7.8,9,10-tetrahydro-6H-azepino[1,2-a]indole-e-carboxylate.
e) 0.85 g of the product of d) Was dissolved in 50 ml of THF and added dropwise to a stirred suspension of 140 mq of lithium aluminium hydride in 50 ml of THF. After the addition of water. the mixture was extracted with diethyl ether. The combined extracts were dried and concentrated.
Chromatography of the residue on silica gel with dichloro-methane/methanol (95:5) gave 0.70 q of 7.8.9,10-tetra-hydro-e-(hydroxymethyl)-6H-azepino[1.2-a]indole of melting point 90-91°C.
f) 0.70 g of the product of e) was treated with 0.66 g of acetic anhydride and 0.39 g of pyridine in 50 ml of diethyl ether. A further 1 g of pyridine and a further 1 g of acetic acid were added and the mixture was stirred for 16 hours. Then, the mixture was concentrated and the .
residue was chromatographed an silica gel with dichloro-methane, there being obtained 0.60 g of 8-(acetoxymethyl)-209.0636 -7,8.9,10-tetrahydro-6H-azepino[1,2-a]indole of melting point 77-79°C.
g) A solution of 0.60 g of the product of f) in 50 ml of dichloromethane was treated dropwise with 0.33 g of oxalyl chloride. After leaving to stand at 10°C for 2 hours the solution was concentrated and the residue was dissolved in dichloromethane. The solution was added to a solution of 0.49 g of 1-methylindole-3-acetic acid and 0.59 g of y0 triethylamine in dichloromethane. After 16 hours the mixture was concentrated and the residue was chromato-graphed on silica gel with dichloromethane/methanol (95:5). There was obtained 0.51 g of 3-[8-(acetoxymethyl)--7,8,9.10-tetrahydro-6H-azepino[1,2-a]indol-11-yl]-4-y5 -(1-methyl--3-indolyl)furan-2.5-dione of melting point 70°C.
Example 54 A solution of 60 mg of the product 'of Example 53 and 20 60 mg of 2,6-lutidine in 25 ml of dichloromethane was added dropwise to a solution.of 116 mg of trifluoro-methanesulphonic anhydride in 25 ml of dichloromethane at 0°C. After 3 hours. 25 ml of aqueous ammonia were added to the solution. The organic phase was dried and concentra-25 ted. Chromatography of the residue on silica gel gave 30 mg of 3-[8-(aminomethyl)-7,8,9,10-tetrahydro-6H--azepino[1,2-a]indol-11-yl]-4-(1-methyl-3-indolyl)-1H--pyrrole-2,5-dione acetate of melting,point 162-163°C.
30 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 was added dropwise to a solution of 0.75 g of trifluoro-methanesulphonic anhydride in 10 ml of dichloromethane at 0°C. After 2.5 hours the mixture was treated with 3 ml of piperidine and stirred for 16 hours. Concentration and a -- 20x.0636 chromatography of the residue on silica gel with dichloro-methane/methanol (gradient from 98:2 to 50:50) gave 340 mg of 3-(6,7,8,9-tetrahydro-8-[(1-piperidino)methyl]pyrido-[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-5 -dione. This was converted into the hydrochloride of melting point 294°C (decomposition), by treatment with a saturated solution of hydrogen chloride in ethyl acetate.
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 was added to a solution of 0.9 g of trifluoromethanesulphonic anhydride in 10 ml of dichloromethane at 0°C. After 1,5 hour the mixture was treated with 3.64 g of diisopropyl-amine and stirred for 16 hours. The mixture was washed with water and then With saturated aqueous sodium bicarbonate solution, dried and concentrated. The solid obtained was dissolved in ethyl acetate~and treated with a saturated solution of hydrogen chloride in ethyl acetate.
Removal of the solvent in vacuo gave 26o mg of 3-[6,7,8,9--tetcahydro-8-((diisopcopylamino)methyl]pytido[1,2-a]-indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of melting point 187°C (decomposition).
Example 57 A solution of 1.0 g of 3-(e-(acetoxymethyl)-6,7,8,9--tetrahydropyrido(1,2-a]indol-10-yl]-4-(3-benzofuranyl)-furan-2,5-dione in 100 ml of chloroform was treated with 13.8 ml of hexamethyldisilazane and 2.73 ml of methanol and the solution obtained was heated to 50°C while stirring under a nitrogen atmosphere for 6 hours. A
fucther 13.8 ml of hexamethyldisilazane and 2.73 ml of methanol were added and the heating was continued for 16 hours. Two fucther additions of the same quantities of hexamethyldisilazane and methanol were effected and the - 5 9 - 20.0636 temperature of the mixture was held at 50°C for a further 24 hours. 20 ml of methanol were added and the mixture was heated to reflux for 15 minutes, cooled and concentrated.
The precipitate was filtered off and triturated in succession with ethyl acetate and methanol. There were obtained 630 mg of 3-[8-(acetoxymethyl)-6,7,8.9-tetra-hydropyrido[1,2-a]indol-10-yl]-4-(3-benzofuranyl)-11I--pyrrole-2,5-dione of melting point 234-237°C.
The furandione starting material was prepared as follows:
1.7 g of oxalyl chloride were added dropwise to a solution of 3.3 g of 8-(acetoxymethyl)-6,7,8,9-tetra-i5 hYdropyrido[1,2-a]indole in 200 ml of diethyl ether under a nitrogen atmosphere. After 15 minutes the solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. 2.4. g of 3-ben2ofuranyl-acetic acid and 5.6 ml of triethylamine~were added to this solution and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue Was pucified by chromatography on silica gel with ethyl acetate/petcoleum ether (1:2). Crystallization of the residue from ethyl acetate/petroleum ether gave 1.62 g of 25 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol--10-yl]-4-(3-benzofuranyl)furan-2,5-dione of melting point 214-215°C.
Examvle 58 A solution of 300 mg of the product of Example 57 in ml of methanol was treated with 5 ml of 2M sodium hydroxide. After 10 minutes the mixture was acidified with 5 ml of 2M hydrochloric acid and the methanol was removed 3,5 under reduced pressure. The residue was partitioned between ethyl acetate and water. The phases were separated and the organic phase was washed with sodium bicarbonate - 6 0 - 201.0636 solution and dried. The solution was concentrated and the precipitate was filtered off to give 190 mg of 3-(3-benzo-furanyl)-4-[6,7,8,9-tetrahydro--8-(hydroxymethyl)pyrido-[1,2-a]indol-10-yl]-1H-pyrrole-2,5-dione of melting point 246-248°C.
Example 59 In a manner analogous to that described in Example 2, from the product of Example 58 there was prepared 3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol--10-yl]-4-(3-benzofuranyl)-1H-pyrrole-2,5-dione hydro-chloride of melting point 210-212°C.
Examule 60 118 mg of trifluoromethanesulphonic anhydride in 20 ml of dichloromethane were 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 dichloro-methane. After 45 minutes 0.41 ml of a 40% solution of dimethylamine in water was added and the mixture was stirred for 1.5 hours. The solution obtained was washed with water and sodium bicarbonate solution, and then dried. The solution was concentrated and the resulting crystals were filtered off and dried to give 60 mg of 3-(3-benzo[b]thienyl)-4-[6,7,8,9-tetrahydro-8-(dimethyl-aminomethyl)pyrido[1,2-a]indol-10-yl]-1H-pyrrole-2,5-dione of melting point 285-286°C.
Examuie 61 546 mg of trifluoromethanesulphonic anhydride in e0 ml of dichloromethane were treated at 0°C under a nitrogen atmosphere with a suspension of 400 mg of the product of Example 19 and 208 mg of collidine in 120 ml of dichloro-methane. After 1 hour 1.9 ml of 40% aqueous dimethylamine 20.0636 were added and the mixture was stirred for 3 hours. The solvent was removed and the residue was subjected to chromatography on silica gel with dichloromethane/
methanol/acetone (88:10:2). Trituration with ethyl acetate followed by recrystallization from methanol gave 295 mg of 3-[2,3-dihydro-2-(dimethylaminomethyl)-1PI-pyrrolo[1,2-a]-indol-9-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5--dione trifluoromethanesulphonate of melting point 323-325°C.
Example 62 A solution of 400 mg of 3-[8-cyano-6.7,8,9-tetra--hydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan--2,5-dione in 12 ml of DMF and 12 ml of 33% aqueous ammonia was heated to 140°C for 3 hours. The mixture was cooled and the resulting solid was filtered off and dried to give 275 mg of 3-[8-cyano-6.7,8,9-tetrahydropyrido-[1-,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5--dione of melting point 312-313°C.
The furandione starting material was prepared as f o 11 ows a) A suspension of 4.0 g of the product of Example 38a) in 4.4 ml of water and 84 ml of acetone was cooled to 0°C
and 2.18 g of triethylamine were added. 2.56 g of ethyl chloroformate were then added and the resulting solution was stirred under a nitrogen atmosphere. 0.9 ml of 33%
aqueous ammonia were added and the mixture was allowed to warm to room temperature. A further 0.5 ml of 33% aqueous ammonia was added and stirring was continued. The solvent was evaporated and the residue was extracted with of dichloromethane. The organic phase was washed with of water, dried and concentrated to give 2.8 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxamide of melting point 179-181°C.

zosos3s b) 991 mg of trifluoroacetic anhydride were added dropwise to a suspension of 1.0 g of 6,7,8,9-tetrahydro-pyrido[1,2-a]indole-8-carboxamide in 15 ml of dioxan at 10°C. The mixture was partitioned between dichloromethane and water and the organic phase was dried. The solvent was removed under reduced pressure to give an oil which was subjected to chromatography on silica gel with ethyl acetate/petroleum ether (l:i). There were obtained 740 mg of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carbonitrile of melting point 116-118°C.
c) 518 mg of oxalyl chloride were added to a solution of 800 mg of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-cacbo-nitrile in 100 ml of diethyl ether under a nitrogen ~5 atmosphere. The solvent was evaporation and the residue was dissolved in of dichloromethane. 771 mg of 1-methyl-3--indolylacetic acid and 1.24 g of triethylamine were added to this solution and the mixture'was stirred overnight.
The solvent was removed under reduced pressure and the 20 residue was purified by chromatography on silica gel with 10% methanol in dichloromethane. The fractions containing the desired product were concentrated and the crystals obtained were filtered off and dried to give 560 mg of 3-[B-cyano-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-25 -(1-methyl-3-indolyl)furan-2,5-dione of melting point 309-31I°C.
Example 63 30 Hydrogen chloride gas was bubbled through a solution of 200 mg of the product of Example 62 in 250 ml of methanol at 0°C. The solvent was then removed under reduced pressure and the residue was dissolved in 50 ml of dichloromethane and 250 ml of ethanol. Ammonia was bubbled 35 through the solution and the solvent was then evaporated.
The residue was purified by chromatography on silica gel with dichloromethane/methanol/acetic acid/water (90:18:3:2). Trituration with ethyl acetate gave 75 mg of 3-[8-amidino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]--4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of melting point 237-239°C.
example 64 A solution of 50 mg of 3-[8-carbamoyl-6,7.8,9-tetra hydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan -2,5-dione in 4 ml of nMF and 4 ml of 33% aqueous ammonia was heated to 140°C. The mixture Was extracted with of ethyl acetate and the organic phase was washed with water and then dried. The majority of the solvent was evaporated and the precipitate obtained was filtered off and dried.
There were obtained 20 mg of 3-[8--carbamoyl-6,7,8.9-tetra-hydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H--pyrrole-2,5-dione of melting point 315-316°C.
The furandione starting material was prepared as Zp follows:
178 mg of oxalyl chloride were 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 was removed under reduced pressure and the residue was dissolved in dichloromethane. 265 mg of 1-methyl-3--indolylacetic acid and 424 mg of triethylamine were added and the mixture was stirred for about 60 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel with 10%
methanol in dichloromethane. Crystallization from ethyl acetate gave 70 mg of 3-(8-carbamoyl-6,7,8,9-tetra-hydropyrido(1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-furan-2,5-dione of melting point 307-309°C.

- 6 4 - 2p9.0636 Example 65 In a manner analogous to that described in the first paragraph of Example 1, from 3-[e-(acetoxymethyl)-6,7,8,9--tetrahydropyrido[1,2-a]indol-10-yl]-4-(5-methoxy-1--methyl-3-indolyl)furan-2,5-dione there was prepared 3-[6.7,8,9-tetrahydro-8-(hydroxymethyl)pyrido[1.2-a]indol--10-yl]-4-(5-methoxy-1-methyl-3-indolyl)-1H-pyrrole-2,5--dione of melting point 300-303°C.
The furandione starting material was prepared as follows:
0.4 ml of oxalyl chloride were added 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 was removed under reduced pressure and the residue was dissolved in of dichloro-methane. 940 mg of 5-methoxy-1-methyl-3=indolylacetic acid and 1.16 ml of triethylamine were added and the mixture was stirred for 40 hours. The solvent was removed under reduced pressure and the residue was purified by chromato-graphy on silica gel with ethyl acetate/n-hexane (1:2).
Crystallization from ethyl acetate/petroleum ether gave 250 mg of 3-[8-(acetoxymethyl)-6.7.8.9-tetrahydropyrido-[1.2-a]indol-10-yl]-4-(5-methoxy-1-methyl-3-indolyl)furan--2.5-dione of melting point 259-261°C.
Examvle 66 In a manner analogous to that described in Example 2, from the product of Example 65 there was prepared 3-[e-(aminomethyl)-6.7.8.9-tetrahydropyrido[1,2-a]indol-l0--yl]-4-(5-methoxy-1-methyl-3-indolyl)-1FT-pyrrole-2,5-dione 3,5 hydrochloride of melting point 268-270°C.

Example 67 In a manner analogous to that described in the first paragraph of Example 1, from 3-[8-(acetoxymethyl)-6,7,8,9--tetrahydropyrido[1,2-a]indol-10-yl]-4-(5-bromo-1-methyl--3-indolyl)furan-2,5-dione there was prepared 3-[6,7,8,9--tetrahydro-8-(hydroxymethyl)pyrido[1.2-a]indol-10-yl]-4--(5-bromo-1-methyl-~3-indolyl)-1H-pyrcole-2,5-dione of melting point 316-31B°C.
The furandione starting material was prepared as f o 11 ows a) 500 mg of a 60% dispersion of sodium hydride in ~5 mineral oil were added to solution of 1 g of 5-bcomo-indole-3-acetic acid in 50 ml of TEIF and the mixture was stirred under a nitrogen atmosphere for 1 hour. 820 mg (5.8 mmol) of methyl iodide were .then added and the mixture was stirred under a nitrogen atmosphere for 24 hours. 5 ml of water were added and the solvent was removed under reduced pressure. The residue was treated with 2M hydrochloric acid and the precipitate formed was filtered off, washed with n-hexane and dried. The obtained solid was recrystallized from diethyl ether to give 5-btomo-1-methyl-3-indolylacetic acid of melting point 192-194°C.
b) 500 mq of oxalyl chloride were added to a solution of 900 mg of the product of a) in 100 ml of diethyl ether g0 under a nitrogen atmosphere. Then the solvent was evaporated and the residue was dissolved in dichloro-methane. 880 mg of 5-bromo-1-methyl-3-indolylacetic acid and 810 mg of triethylamine were added and the mixture was stirred for 48 hours. The solvent was removed under reduced pressure and the residue was purified by chromato-graphy on silica gel with ethyl acetate/n-hexane (1:1) to give 400 mg of a solid. A sample was recrystallized from - 6 6 - I~i~~.~~~6 ethyl acetate to give 3-[8-(acetoxymethyl)-6,7,8,9-tetra--hydropyrido[1,2-a]indol-10-yl]-4-(5-bromo-1-methyl-3--indolyl)furan-2,5-dione of melting point 215-220°C.
Example 68 In a manner analogous to that desceibed in Example 2, from the product of Example 67 there was prepared 3-[8-(aminomethyl)-6,7,8.9-~tetrahydropyrido[1,2-a]indol-10--yl]-4-(5-bromo-1-methyl-3-indolyl)-lt-I-.pyrrole-2,5-dione hydrochloride of melting point >310°C.
Example 69 ~1 solution of 200 mg of 3-[7-(2-acetoxyethyl)-6,7,8,9--tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)---furan-2,5-dione in 2 ml of DMF and 1 ml of 33% aqueous ammonia was heated to 140°C. Then 1 ml of a 2M solution of sodium hydroxide was added to the cooled solution and the mixture Was stirred for 2 hours. The mixture was acidified with 2M hydrochloric acid and evaporated. 'The residue was partitioned between ethyl acetate and of water and the organic phase was dried. The solvent was evaporated and the solid obtained was triturated with ethyl acetate to give 115 mg of 3-[6.7,8,9-tetrahydro-7-(2-hydroxyethyl)-pyrido[1,2-a]indol--10-y1]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 236-238°C.
The furandione starting material was prepared as follows:
a) 400 mg of a 60% dispersion of sodium hydride in mineral oil were added to a solution of 2.24 g of triethyl phosphonoacetate in 40 ml of dimethoxyethane under a nitrogen atmosphere. Then the solution was cooled to 0°C
and 1.85 g of the product of Example 35d) in l0 ml of dimethoxyethane were added. The mixture was stirred 67 - zo~.os3s overnight and then evaporated. The residue was dissolved in dichloromethane and the solution was washed with water, dried and concentrated. The residue was purified by chromatography on silica gel with diethyl ether/petroleum ether (1:3), there being obtained 1.55 g of a mixture of ethyl (E) and (Z)-(6,7,8,9-tetrahydropyrido[1,2-a]-indol-7-ylidene)acetate. 1.4 g were dissolved in ethanol and the solution was shaken with 280 mg of 10% Pd/C under a hydrogen atmosphere. The catalyst was then filtered off and the filtrate was evaporated to give 1.2 g of ethyl 6,7.8,9-tetrahydropyrido[1,2-a]indole-7-acetate of melting point 66-68°C after crystalli2ation from diethyl ether/
petroleum ether.
b) A solution of 1.2 g of the product of a) in 100 ml of diethyl ether was treated with 3.5 ml of a 1M solution of lithium aluminium hydride in diethyl ether. After stirring for 1 hour the mixture was quenched with 50 ml of aqueous ammonium chloride. The mixture was extracted with of diethyl ether and the organic phase was dried and evaporated to give 1.01 g of 6,7,8,9-tetrahydro-7--(2-hydroxyethyl)pyrido[1,2-a]indo2e of melting point 70-72°C after crystallization from diethyl ether/petroleum ether.
c) A solution of 1.04 g of the product of b), in 30 ml of dichloromethane was treated with 6 ml of acetic anhydride and 3 ml of pyridine and the solution was stirred under a nitrogen atmosphere. The mixture was then evaporated to dryness and the residue was dissolved in dichloromethane.
The organic phase was washed with 2M hydrochloric acid and with water, dried and evaporated. The residue was purified by chromatography on silica gel with diethyl ether/
petroleum ether (1:4) to give 670 mg of 7-(2-acetoxy-ethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole.

d) 250 ul of oxalyl chloride were added to a solution of 670 mg of the proeuct of c) in 12 ml of dichloromethane under a nitrogen atmosphere. Then the solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. 493 mg of 1-methyl-3-indolylacetic acid and 527 mg of triethylamine were added to this solution and the mixture was stirred. Then the solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel with ethyl acetate/petcoleum ether (1:2) to give 350 mg of 3-[7-(2-acetoxy-ethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-yl]-4-(1--methyl-3-indolyl)furan-2,5-dione of melting point 182-184°C after crystallization from ethyl acetate.
Example 70 In a manner analogous to that described in Example 2, from the product of Example 69 there was prepared 3-(7-(2-aminoethyl)-6.7.8.9-tetrahydropyrido--f1,2-a]indol-10-yl]-4-(1-.methyl-3-indolyl)--1H-pyrrole -2.5-dione hydrochloride of melting point 240-242°C.
Example 71 in a manner analogous to that described in the first paragraph of Example 1, from 3-(8-(acetoxymethyl)-6,7,8,9--tetrahydro-2-methoxy-pyrido(1,2-a]indol-10-yl]-4-(1--methyl-3-indolyl)furan-2,5-dione thore was preparod 3-(6,7,8,9-tetrahydro-8-(hydroxymethyl)-2-methoxypyrido-~0 [1.2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-lEI-pyrrole-2,5--dione of melting point 195-197°C.
The furandione starting material was prepared as follows:
a) 2 g of a 60% sodium hydride dispersion in mineral oil was washed with n-hexane by decantation and suspended in 20.0636 100 ml of DMF under a nitrogen atmosphere. A solution of g of ethyl 5-methoxyindole-2-carboxylate in 100 ml of DMF was added and the mixture was stirred. Then 9.8 g of ethyl 4-bromobutyrate were added and the mixture was 5 stirred for 2 hours. The mixture was cooled and treated with 50 ml of 1M hydrochloric acid and 400 ml of water.
The mixture was extracted with diethyl ether and the combined extracts were washed with sodium chloride solution. The organic phase was dried and evaporated. The obtained oil was dissolved in TEIF and added to a mixture of 5.2 g of potassium t-butoxide in 200 ml of THF under a nitrogen atmosphere. Then the mixture was cooled and neutralized with 1M hydrochloric acid. Water was added and the mixture was extracted with diethyl ether. The combined extracts were washed with water and sodium chloride solution and then dried. Evaporation of the solvent and crystallization of the cesidue fcom,ethyl acetate gave 6.7 g of ethyl 6,7-dihydro-9-~hydtoxy-2-methoxypyrido-[1.2-a]indole-e-carboxylate of melting point 157-160°C.
b) 5 g of the product of a) in 200 ml of ethanol were .
treated under a nitrogen atmosphere with 10 spoon spatula measures of Raney nickel and 100 ml of water. The suspension was heated at reflux, then cooled and filtered.
The solid was washed with ethyl acetate and volatile constituents were removed in a vacuum from the combined filtrate and washings. The aqueous suspension was extracted with ethyl acetate and the combined extracts were washed with sodium chloride solution and dried.
Evaporation of the solvent and crystallization of the residue from methanol gave 2.41 g of ethyl 6,7,8,9-tetra-hydro-2-methoxypyrido(1,2-a]indole-e-carboxylate of melting point 104-105°C.
c) A solution of 2.3 g of the product of b) in 25 ml of THF was added to a suspension of 260 mg of lithium aluminium hydride in 20 ml of THF under a nitrogen 70 _ zo~.os3s atmosphere. Then the mixture was treated with 10 ml of ethyl acetate followed by 20 ml of water. The mixture was acidified to pH 3 with 1M hydrochloric acid and extracted with diethyl ether. The combined extracts were washed with water and dried. Removal of the solvent by evaporation gave 1.85 g of 6,7,8,9-tetrahydro-2-methoxypyrido-[1,2-a]indole-8-methanol. A sample crystallized from ethyl acetate/n-hexane melted at 95-96°C.
d) 1 g of the product of c) in 10 ml of pyridine was treated with 1.5 g of acetic anhydride. Then the solvent was evaporated and the residue was partitioned between diethyl ether and 5% aqueous ammonium chloride. The organic phase was washed with sodium chloride solution, dried and evaporated. Crystallization of the residue from diethyl ether/n-hexane gave O.B4 g of 8-acetoxymethyl--6.7.8.9-tetrahydro-2-methoxypyrido[1,2-a]indole of melting point 98-100°C.
e) A suspension of 800 mg of the product of d) in 25 ml of diethyl ether was treated with 0.27 ml of oxalyl chloride under a nitrogen atmosphere. Then the solvent was evaporated, the residue was 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 Was stirred for 65 hours and then the solvent was removed under ceduced pressure. Chromatography of the cesidue on silica gel with ethyl acetate/n-hexane (1:1) gave 380 mg of 3-[e-(acetoxymethyl)-6,7,8,9-tetrahydro-2-methoxy-~0 pyrido[1,Z-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5--dione. A sample crystallized from toluene/n-hexane melted at 131-133°C (decomposition).
Example 72 3~5 In a manner analogous to that described in Example 2, from the product of Example 71 there was prepared 3-[8-(aminomethyl)-6.7.8,9-tetrahydro-2-methoxypyrido-[1,2-a]indol-10-yl]]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5--dione hydrochloride of melting point 235-238°C
(decomposition).
Example 73 a) A solution of 150 mg of the product of Example 20 in dichloromethane under a nitrogen atmosphere was treated with 135 mg of 1.1~-thiocarbonyldiimidazole, After 17 hours, the solution was washed with water and dcied.
The solvent was evaporated and the residue was crystallized fcom ethyl acetate to give 150 mg of 3-[1,2,3,4-tetrahydro-2-(1-imidazolylthiocarbonyl)--pYrazino[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-lI-I--pyrrole-2,5-dione of melting point 244-247°C.
b) A solution of 140 mg of the product of a) in 10 ml of DME' was treated with 20 ml of 33~ aqueous ammonia. After 17 hours, the suspension was filtered and the solid was washed with water. The solid was dried to give 95 mg of 3-[1.2,3,4-tetrahydro-2-thiocarbamoylpyrazino[1.2-a]indol--10-yl]-4-(1-methyl-3-indolyl)-lI-I-pyrrole-2,5-dione of melting point 278°C (decomposition).
Examv_le 74 A solution of 150 mg of the product of Example 20 in 50 ml of dichloromethane was treated with 3 ml of acetic anhydride and 3 ml of triethylamine. After 17 hours, the solution was washed with water. The organic phase was dried and evaporated. The residue was dissolved in dichloromethane and treated with 0.08 ml of diethylamine, After 17 hours the solution was evaporated. Crystalli-zation of the residue from dichloromethane/n-hexane gave 80 mg of 3-[2-acetyl-1,2.3,4-tetrahydro-pyrazino-[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-20~.0~36 -. 7 2 _ -dione of melting point 308-310°C.
Example 75 In a manner analogous to that described in Example 74, from the product of Example 2 there was prepared 3-[8-(acetamidomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]-indol-10-yl ]-4-~ ( 1-methyl- 3-~ indolyl )-lEI- pyrrole--2, 5-~dione of melting point 270-273°C.
Examine 76 A solution of 150 mg of the product of Example 20 in 40 ml of dichloromethane was treated with 40 mg of triethylamine and 44 mg of methanesulphonyl chloride.
After 17 hours the solution was washed with water. The organic phase was dried and evaporated. Chromatography of the residue on silica gel with ethyl acetate/n-hexane (2:1) and ethyl acetate gave 95 mg of 3-[1.2,3,4--tetra-hydro-2-methanesulphonylpyrazino[1.2-a]indol-10-yl]-4--(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 298-301°C (decomposition).
Examyle 77 2b 3.0 g of the product of Example 1 were dissolved in 100 ml of THF and the solution was added to a suspension of 1.8 g of lithium aluminium hydride in 50 ml of THF at 0°C. Then the mixture was heated at reflux for 16 hours.
The mixture was then cooled, treated with 10 ml of water and extracted with dichloromethane. The combined dichloromethane extracts were washed with aqueous sodium bicarbonate solution, dried and concentrated to give a solid. Chromatography on silica gel with dichloromethane/
methanol (95:5) gave a solid which was purified further by chromatography to give 20.0636 _. ~3 _ a) 400 mg of 1,5-dihydro-3-[6,7,8,9--tetrahydro--8--(hydroxymethyl)pyrido[1,2-a]indol-10-yl]-4-(1-methyl--3-indolyl)-2H-pyrrole-2-one of melting point 205-207°C.
There were also obtained b) 160 mg of 1,5-dihydro-4-~[6,7,8,9-tetrahydro-8--(hydroxymethyl)pyrido[1,2-a)indol-10-yl]-3-(1-methyl-3--indolyl)-2H-pyrrole-2-one of melting point 201-203°C.
Example 78 In a manner analogous to that described in the first paragraph of Example 1. from 0.5 g of 3-[8-(acetoxy-methyl)-6,7,8,9-tetrahydropyrido[1,2-a)indol-10-yl]-4--(3-trifluoromethylphenyl)furan-2,5-dione there were obtained 110 mg of 3-[6,7,8,9-tetrahydro--8-(hydroxy-methyl)pyrido[1,2-a]indol-10-yl]-4-(3-trifluoromethyl-phenyl)-1fI-pyrrole-2,5-dione solid of, melting point 77-79°C. .
The furandione starting material was prepared as follows:
1.7 g of oxalyl chloride were added to a cold (0-4°C) solution of 3.0 g of B-(acetoxymethyl)-6,7,8,9-tetra-hydropyrido[1,2-a]indole in 50 ml of dichloromethane.
After 2 hours the solvent was evaporated and the residue was dissolved in dichlocomethane. The solution was added to a solution of 2.7 g of (a,a,a-trifluoro-m-tolyl)-acetic acid and 3.2 g of triethylamine in 70 ml of dichloromethane. The mixture was stirred for 16 hours and then concentrated. The residue was chromatographed on silica gel with dichloromethane/methanol (95:5). There were obtained 700 mg of 3-[8-(acetoxymethyl)-6,7,8,9--tetcahydropyrido[1,2-a]indol-10-yl]-4-(3-trifluoromethyl-phenyl)furan-2,5-dione of melting point 176-177°C.

20.0636 Example 79 In a manner analogous to that described in the first paragraph of Example 1, from 1.0 g of 3-[8-(acetoxy-methyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4---(4-methoxyphenyl)furan-2,5-dione there were obtained 150 mg of 3-[6,7,8,9-~tetrahydto-8-(hydroxymethyl)--pyrido[1,2-a]indol--10-yl]-4-(4-methoxyphenyl)-lEI--pyrrole-2,5-dione of melting point 228°C (decomposition).
The furandione starting material was prepared as follows:
1.7 g of oxalyl chloride were added to a cold (0-4°C) solution of 3.0 g of 8-(acetoxymethyl)-6,7,8,9-tetrahydro-pyrido[1.2-a]indole in 50 ml of dichloromethane. After 2 hours the solvent was evaporated and the residue was dissolved in dichloromethane. This solution was added to a solution of 2.24 g of p-methoxyphenylacetic acid and 3.2 g of triethylamine in 70 ml of dichloromethane. The mixture was stirred for 16 hours and then concentrated. Chromato-graphy of the residue on silica gel With dichloromethane/
methanol (95:5) gave 2 g of 3-[8-(acetoxymethyl)-6,7,8,9--tetrahydropyrido[1,2-a]indol-10--yl]-4-(4-methoxyphenyl)--furan-2.5-dione of melting point 79-82°C.
Examele 80 In a manner analogous to that described in the first paragraph of Example 1, from 0.8 g of 3-[8-(acetoxy-methyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol--10-yl]-4-(2-chlorophenyl)furan-2.5-dione there were obtained 120 mg of 3-(2-chlorophenyl)-4-[6,7.8,9-tetra-hydro-8-(hydroxymethyl)pyrido[1,2-a]indol-10-yl]-lEI--pyrrole-2,5-dione of melting point 232-233°C.

_ 75 -The furandione starting material was pcepared as follows:
2.2 g of oxalyl chloride were added to an ice-cold solution of 4 g of 8-(acetoxymethyl)-6,7,8.9-tetcahydro-pycido[1.2-a]indole in 50 ml of dichloromethane. After 2 hours the solvent was evaporated and the residue was dissolved in diahloromethane. This solution was added to a solution of 3.0 g of 2-chlocophenylacetic acid and 4.0 g of triethylamine in dichloromethane. The mixture was stirred for 16 hours and then concentrated. Chromatography of the residue on silica gel with dichloromethane/methanol (95:5) yielded 0.9 g of 3-[8-(acetoxymethyl)-6.7.8.9--tetrahydropyrido[1,2-a]indol-10-yl]-4-(2-chlorophenyl)-fucan-2.5-dione of melting point 168-171°C.
Examule 81 In a manner analogous to that described in Example 51, from 80 mg of the product of Example 78 there were obtained 30 mg of 3-[8-(aminomethyl)-6,7.8,9-tetra--hydropyrido[1.2-a]indol-10-yl]-4-(3-trifluoromethylphenyl)--1H-pyrrole-2.5-dione of melting point 202--204°C.
z5 Examule 82 In a manner analogous to that described in Example 51, fcam 100 mg of the product of Example 79 there were obtained 88 mg of 3-[B-(aminomethyl)-6.7.8.9-tetta-hydropyrido[1,2-a]indol-10-yl]-4-(4-methoxyphenyl)-1H--pyrrole-2,5-dione of melting point 195-19S°C.
Examvle 83 3,5 In a manner analogous to that described in Example 53.
from 80 mg of the product of Example 80 there were obtained 57 mg of 3-[8-(aminomethyl)-6.7.8.9-tetrahydro-pyrido[1,2-a]indol-10-yl]-4-(2-chlorophenyl)-1H-pyrrole-2,5-dione of melting point 206-208°C (decomposition).
The following Examples illustrate typical pharmaceutical preparations containing compounds provided by the present invention:
Example A
1p Tablets containing the following ingredients may be produced in a conventional manner:
Incrredient Per tablet Compound of formula I 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 mc~
Example B
Capsules containing the following ingredients may be produced in a conventional manner:
Inaredient Per capsule Compound of formula I 10.0 mg Lactose 165.0 mg Maize starch 20.0 mg Talc 5.0 ma Capsule fill weight 200.0 and

Claims (21)

1. Compounds of the general formula wherein R represents hydrogen or hydroxy, R1 and R2 together represent a group of the formula -(CH2)n- and R7 represents hydrogen or R1 and R7 together represent a group of the formula -(CH2)n- and R2 represents hydrogen; R3 represents an aryl or heteroaryl group; R4, R5 and R6 each independently represent hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulphinyl or alkylsulphonyl;
R8 represents a group of the formula -(CH2)p-R9 or -(CH2)Q-R10; R9 represents hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkylsulphonyl, aminocarbonyl or aminothiocarbonyl; R10 represents hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, sulphonylamino, alkylarylsulphonylamino, alkylthio, alkoxycarbonylamino, aminoacylamino, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulphonyloxy or arylsulphonyloxy, a 5- or 6-membered saturated nitrogen-containing heterocycle attached via the nitrogen atom or a group of the formula -U-C(V)-W; U

represents S or NH; V represents NH, NNO2, NCN, CHNO2; W
represents amino, monoalkylamino or dialkylamino; one of X and Y represents O and the other represents O or (H,H); Z
represents CH or N; m stands for 0-5, n stands for 1-5; p stands for 0-5; and q stands for 0-5, with the proviso that q and m stand for 2-5 when Z stands for N;
"alkyl", alone or in combination, means a straight-chain or branched-chain alkyl group containing a maximum of 7 carbon atoms, "alkoxy", alone or in combination, means a alkyl group as defined before which is attached via an oxygen atom, "acyl"
means an acyl group derived from an alkanoic acid containing a maximum of 7 carbon atom, "aryl", alone or in combination, means a monocyclic or polycyclic group which is unsubstituted or substituted with one or more substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulphinyl and alkylsulphonyl, and "heteroaryl" means a 5-or 6-membered heterocyclic aromatic group which can optionally carry a fused benzene ring and which is unsubstituted or substituted with one or more substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulphinyl and alkylsulphonyl;
as well as pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids.

-78a-

2. Compounds according to claim 1, wherein R
represents hydrogen, R9 represents hydrogen, alkylcarbonyl, cyano, amidino, alkoxycarbonyl, alkylsulphonyl, aminocarbonyl or aminothiocarbonyl and R10 represents hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylsulphonylamino, arylsulphonylamino, alkylthio, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulphonyloxy or arylsulphonyloxy or a group of the formula -U-C(V)-W and R1. R2, R3. R4, R5, R6, R7, R8, U, V, W, X, Y, Z, m, n, p and q have the significance given in claim 1.

3. Compounds according to claim 1 or claim 2, wherein R1 and R2 together represent -CH2- and R7 represents hydrogen, m stands for 1 or 2 and Z represents CH.

4. Compounds according to claim 1 or claim 2, wherein R1 and R2 together represent -(CH2)2- and R7 represents hydrogen, m stands for 1 and Z represents CH.

5. Compounds according to claim 1 or claim 2, wherein R1 and R2 together represent -CH2- and R7 represents hydrogen, m stands for 2 and Z represents N.

6. Compounds according to claim 1 or claim 2, wherein R1 and R7 together represent -CH2- and R2 represents hydrogen, m stands for 1 and Z represents CH.

7. Compounds according to claim 1 or claim 2, wherein R1 and R7 together represent -(CH2)2- and R2 represents hydrogen, m stands for O and Z represents CH.

8. Compounds according to any one of claims 1 to 6, wherein R3 represents phenyl, naphthyl, 3-benzothienyl, 3-benzofuranyl or 3-indolyl which is optionally substituted with one or more substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulphinyl and alkylsulphonyl.

9. Compounds according to claim 8, wherein R3 represents 1-methyl-3-indolyl.

10. Compounds according to any one of claims 1 to 9, wherein R4, R5 and R6 each represent hydrogen.

11. Compounds according to any one of claims 1 to 10, wherein R8 represents a group of the formula -(CH2)q-R10.

12. Compounds according to claim 11, wherein q stands for 1 or 2.

13. Compounds according to claim 11 or claim 12, wherein R10 represents hydroxy, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylcarbonyloxy or alkylsulphonyloxy or a group of the formula -U-C(V)-W.

14. Compounds according to claim 13, wherein U
represents S, V represents NH and W represents amino.

15. Compounds according to any one of claims 1 to 14, wherein X and Y both represent O.

16. Compounds according to claim 1 or 2 of the group 3-[8-(Aminomethyl)-6,7,8,9-tetrahydropyrido-[1,2-a)indol-10-yl)-4-(1-methyl-3-indolyl)-1H-pyrrole--2,5-dione, 3-[7-(Amidinothiomethyl)-6,7,8,9-tetrahydropyrido-[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole--2,5-dione, 3-[6,7,8,9-Tetrahydro-8-[(dimethylamino)methyl]-pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H--pyrrole-2,5-dione and its pharmaceutically acceptable acid addition salts.

17. Compounds of the general formula wherein R1, R2, R3, R4, R5, R6, R7, R8, Z and m have the significance given in claim 1.

18. Compounds according to any one of claims 1 to 16, for use as antiinflammatory, immunological, oncological, bronchopulmonary and cardiovascular active substances or as active substances in the treatment of asthma or AIDS.

19. A process for the manufacture of the compounds according to any one of claims 1 to 16, which process comprises (a) for the manufacture of a compound of formula I in which X and Y both represent O, 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
represents hydrogen or with hydroxylamine to give a compound of formula I in which R represents hydroxy, or (b) for the manufacture of a compound of formula I in which one of X and Y represents O and the other represents (H,H), reducing a compound of formula I in which X and Y
both represent O with lithium aluminium hydride, or (c) if desired, functionally modifying a reactive centre present in a compound of formula I obtained, and (d) also if desired, converting an acidic compound of formula I into a pharmaceutically acceptable salt with a base or converting a basic compound of formula I into a pharmaceutically acceptable salt with an acid.

20. An antiinflammatory, immunological, ontological, bronchopulmonary or cardiovascular medicament or a medicament for the treatment of asthma or of AIDS, containing a compound according to any one of claims 1 to 16 together with a therapeutically inert carrier or excipient material.

21. The use of a compound according to any one of claims 1 to 16 for the manufacture of a medicament against inflammatory, immunological, ontological, bronchopulmonary or cardiovascular disorders or against asthma or AIDS.