AU633051B2 - Substituted pyrroles - Google Patents

Abstract

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

Description

u7.~~iUill-I PYTT. irll I Our Ref: 307134 FORM

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art: Applicant(s): F Hoffmann-La Roche AG 124 Grenzacherstrasse CH-4002 Basle

SWITZERLAND

Address for Service: ARTHUR S. CAVE CO.

Patent Trade Mark Attornerys Level 10, 10 Barrack Street SYDNEY NSW 2000 Complete specification for the invention entitled "Substituted pyrroles".

The following statement is a full description of this invention, including the best method of performing it kncon to me:- -1 5020

A

I i Y- RAN 4070/77 la The present invention relates to substituted pyrroles.

More particularly, the invention is concerned with compounds of the general formula

R

I

R N R R7 1 R (CH2)m and represents hydrogen R R together represent a group of the formula represents an aryl or heeroary group; R, R and 25 Reach independently represent hydrogen or R andlogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulphinyl or alkyl- 78 sulR together represent a group of the formula 9 2 3 or (C 2 R rep; esents hydrogen; 30 hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkylrepresents amin o arbonyl or aminothiocarbonyl; R 25 R6 each independently represent hydrogen, halogen, alkyrepresents hydroxy, alkoxy, haloalky, nitro, amnoalkyl acylamino, alkylamthio, alkylsulphino, azido, acylaino, sulphonyl; R represents a group of the formula -(CH )p-R or -(CH )q-R10; R represents 30 hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkylsulphonyl, aminocarbonyl or aminothiocarbonyl; R represents hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, Me/8.1.90

L-

2 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 represents S or NH; V represents NH, NNO 2

NCN,

CHNO

2 W represents amino, monoalkylamino or dialkylamino; one of X and Y represents O and the other represents O or Z represents CH or N; m stands for 0-5, with the proviso that m stands for 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 S. stands for 2-5 when Z stands for N; S 15 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 intermediates useful in said process; medicaments containing said compounds and saits and the manufacture of these 25 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, oncological, bronchopulmonary and cardiovascular disorders or in the treatment of asthma or AIDS, or for the manufacture of a medicament against inflammatory, immunological, oncological, bronchopulmonary and cardiovascular disorders or against asthma or AIDS.

As used herein, the term "alkyl", alone or in combination, means a straight-chain or branched-chain alkyl group containing a maximum of 7, preferably a c i I -1 I 1 r13 9 c" -3 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 "acyl" means an acyl group derived from an alkanoic acid containing a maximum of 7, preferably a maximum of 4, carbon atoms formyl acetyl, propionyl, butyryl etc) or from an aromatic carboxylic acid 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, nitro, amino, acylamino, alkylthio, 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-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-nitrophenyl, 25 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 4-aminophenyl, 4-methylthiophenyl, 4-methylsulphinylphenyl, 4-methylsulphonylphenyl, 1-naphthyl, 2-naphthyl and the S like. The term "heteroaryl" means a 5-membered or 6-membered heterocyclic aromatic group which can S 30 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, nitro, amino, acylamino, alkylthio, alkylsulphinyl and alkylsulphonyl.

Examples of such heteroaryl groups are 2-thienyl, 3-thienyl, 3-benzothienyl, 3-benzofuranyl, 2-pyrrolyl, -own" 4 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

8 9 and R represents a group of the formula -(CH2)p-R 10 in which p stands for 1-5 or -(CH 2 )q-R contain an asymmetric carbon atom and can therefore exist in racemic Sor optically active form. The present invention includes S 15 within its scope not only the racemic compounds, but also the optically active isomers.

In preferred classes of compounds of formula I, R and R together represent -CH 2 and R represents 1 hydrogen, m stands for 1 or 2 and Z represents CH; or R 2 7 and R together represent -(CH2) 2 and R represents hydrogen, m stands for 1 and Z represents CH; *1 2 7 or R and R together represent -CH and R 2 represents hydrogen, m stands for 2 and Z represents N; or 1 7 2 I 25 R and R together represent -CH 2 and R represents hydrogen, m stands for 1 and Z represents CH; 1 7 2 or R and R together represent -(CH2) 2 and R represents hydrogen, m stands for O and Z represents CH.

3 R preferably represents phenyl, naphthyl, 3-benzo- 0 thienyl, 3-benzofuranyl or 3-indolyl which is optionally substituted as defined earlier, especially l-methyl-3- -indolyl. Preferably, R, R and R each represent hydrogen. R 8 preferably represents a group of the 10 formula -(CH 2 )q-R Preferably, q stands for 1 or 2. R 0 preferably represents hydroxy, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, a. a.

a a. a.

a a.

a a *a.a a a.

a. a a a alkylcarbonyloxy or alkylsulphonyloxy or a group of the formula Preferably, U represents S, V represents NH and W represents amino.

Especially preferred compounds provided by the invention are: 3-[B (Aminomethyl) 9-tetrahydropyr ido indol-1O-ylJ-4-(1--methiyl-3-indolyl)-H-pyrrole-2,5-.diole, 3-[7-(amidinotlhiomethyl)-6,7,8,9-tetrahiydropyridoindol-10-yl]-4--(1-methyl--3-indolyl)-1HI-pyrroleand 3-[6,7,8,9-tetrahydro-B--[(dimethylamino)methiyl]pyridoindol-10-ylJ-4-(1-methyl-3-indolyl)-lH-pyrrole-2,5- -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 pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids are manufactured by for the manufacture of a compound of formula I in 25 which X and Y both represent 0, reacting a compound of the general formula R 0 0

R

7CE1 z R 1 "R8 i II i iig r *p fe e 6 wherein R 1 R R 3 R R R R R 8 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 for the manufacture of a compound of formula I in which one of X and Y represents 0 and the other represents reducing a compound of formula I in which X and Y both represent O with lithium aluminium hydride, or if desired, functionally modifying a reactive centre present in a compound of formula I obtained, and 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 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 dimethylformamide or the like. The reaction is preferably carried out at an elevated temperature, for example a temperature in the range of about 100 0 C to about 150 0

C.

The reaction of a compound of formula II with hexamethyldisilazane and methanol, also in accordance with embodiment of the process, is conveniently carried out in an inert organic solvent such as a halogenated hydrocarbon chloroform, carbon tetrachloride or chlorobenzene) or an aromatic hydrocarbon benzene, toluene 0 0 00 0 i I I r Ir3 II i i i 7 or a xylene) and at an elevated temperature a temperature between about 40 0 C and 110 0

C.

The reaction of a compound of formula II with hydroxylamine, also in accordance with embodiment 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 about 100 0

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 sodium or potassium carbonate).

a 0* S a 15 The reduction of a compound of formula I in which X and Y both represent 0 with lithium aluminium hydride in accordance with embodiment of the process is Sexpediently carried out in an inert organic solvent such as an aliphatic or cyclic ether diethyl ether, tetrahydrofuran etc) at a temperature between about 0 C and the reflux temperature of the reaction mixture.

4 0 A reactive centre present in a compound of formula I can be modified, if desired, in accordance with embodiment 25 of the process. All of these modifications can be carried out according to methods known per se. For example, when R represents a group of the formula 9 9 -(CH -R in which R represents alkoxycarbonyl and p stands for 0, this group can be converted into a corresponding group in which R represents hydrogen by treatment with an acid. Again, for example, a group of the formula -(CH 2 )q R10 in which R 10 represents alkylcarbonyloxy can be converted into a corresponding group in which R10 represents hydroxy by appropriate base 10 treatment. A group of the formula -(CH )q-R in 10 which R represents hydroxy can be converted into a

L_

I

8 a..

a a o a 10 corresponding group in which R1 represents amino, monoalkylamino, 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 -(CHq-R 10 in which R0 represents hydroxy can be reacted with an alkanesulphonic anhydride to give a corresponding group in which R 10 represents alkylsulphonyloxy. A group of the formula -(CH2)q-R in which R represents alkylsulphonyloxy can be converted into a corresponding group in which represents formamido by reaction with ammonia in dimethylformamide or in which R represents azido by reaction 10 with an alkali metal azide or in which R represents a group of the formula 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 10 20 in which R represents azido can be converted by catalytic hydrogenation into a corresponding group in which R10 represents amino. A group of the formula in which R10 represents alkoxycarbonylamino can be converted into a corresponding group 25 in which R represents amino by treatment with an acid.

A group of the formula -(CH 2 )q-R10 in which R1 represents amino can be acylated to give a corresponding group in which R10 represents acylamino or can be reacted with 3,5-dimethyl-N -nitro-l-pyrazole-l-carboxamide to give a corresponding group in which represents a group of the formula wherein U represents NH, V represents NH and W represents NNO 2 10 Further, a group of the formula -(CH -R in which 10 q R represents amino can be converted into a corresponding group in which R10 represents isothiocyanato by reaction with 1,1-thiocarbonyldiimidazole. A I I i ~I~V~lp" -9 9 9 group of the formula -(CH 2 )p-R in which R represents cyano can be treated with hydrogen chloride and subsequently with ammonia to give a corresponding group in 9 which R represents amidino. Again, for example, a 8 compound of formula I in which Z represents N and R 9 represents a group of the formula -(CH 2 )p-R wherein p stands for 0 and R represents hydrogen can be 9 converted into a corresponding compound in which R represents alkylcarbonyl, alkoxycarbonyl or aralkoxycarbonyl by appropriate acylation, into a corresponding 9 compound in which R represents alkylsulphonyl by reaction with an alkanesulphonyl chloride, into a 9 corresponding compound in which R represents aminoalkylcarbonyl by treatment with a trifluoroacetamidoalkanoyl chloride and subsequent reaction with ammonia, 9 into a corresponding compound in which R represents aminocarbonyl by treatment with 1,1-carbonyldiimidazole and subsequent reaction with ammonia or into a 9 corresponding compound in which R represents aminothiocarbonyl by treatment with l,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 I into a pharmaceutically acceptable salt in accordance with embodiment 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 of the process, can be carried out by i I I I i 0 10 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-toluenesulphonates and the like.

The compounds of formula II which are used as starting materials in embodiment 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 0 0 *.0 wherein R, R, R 4

R

5

R

6 R R Z and m have the significance given earlier, with a compound of the general formula

HOOC-CH

2

-R

3 wherein R 3 has the significance given earlier, and, where required, functionally modifying a reactive centre present in a compound of formula II obtained.

i i I 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 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.

15 The compounds of formula III can be prepared, in turn, by reacting a compound of the general formula

R

4 R R 2 7

V

R R 1 2 4 5 6 7 8 herein R R R ,R R R R 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 reflux temperature of the solvent. The resulting compound of formula III can be reacted in situ with the

I

fa -12 compound of formula IV or can be isolated and purified 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 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 tion, 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 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 bronchopulmonary disorders. Further, they are also useful in 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 IC 50 figures in the following Table, represent that concentration of test compound which reduces by 32 the protein kinase-induced incorporation of P from P]ATP into histone.

W

V

-13- Table Compound IC 3-[8-(TAminomethyl)--6,7,8,9--tetrahiydropyrido[1, 2-a] indol-10-yl]-4--(i-metlyl-3hydrochlo ride 8 nD4 3-[7-(Amidinothiomethiyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-ylj-4-(l-methyl- -3-indolyl)-1H--pyrrole-2, 5-dione methanesuiphonate 15 nM 3-j2-(Aminoacetyl)-1,2,3,4-tetrahydropyrazino[l, 2-a] indol-10-yl]--4-(l-methylindolyl)-l1H-pyrrole--2,5-dione hydrochloride 50 nM 3-L7-(2-Aminoethyl)--6,7,8,9-tetrahydro- -3-indolyl)--lH-pyrrole-2,5-dione hydrachloride 20 nM 3-[6,7,8,9-Tetrahiydro-8--[(l-piperidino)methyl~pyridafl,2-ajindol-10-yl]-4-(l- -methyl-3-indolyl)-lH-pyrrale-2,5-diane 30 nM 3-f 2.3-Dihiydro-2-(dimethiylaminamethyl).

-iR--pyrrolo[1, 2-a] indal-9-ylj-4-(l-methyl- -3-indalyl)-lHE-pyrrole-2, 5-diane trifluaromethanesuiphanate 20 nM 14 3-[8-Amidino-6,7,8,9-tetrahydropyrido- [1,2-a]indol-10-yl]-4-(l-methyl-3- -indolyl)-1H-pyrrole-2,5-dione hydrochloride 60 nM 3-[7-(Amidinothiomethyl)-6,7,8,9-tetrahydropyrido[l,2-a]indol-10-yl]-4- -(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione methanesulphonate 10 nM The compounds of formula I and their aforementioned Ssalts can be used as medicaments, for example, in the form *5 15 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 in the form of suppositories) or parenterally 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 the 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 I i I i ~aexample, 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 varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically 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 o" of the present invention. This process comprises bringing e 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, 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 S* prevention of illnesses, especially in the control or prevention of inflammatory, immunological, bronchopulmonary 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 general, in the case of oral administration to adults, a daily dosage ot 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: L i I I I a 16 Example 1 A solution of 2.90 g of 3-[8-(acetoxymethyl)-6,7,8,9- -tetrahydropyrido[l,2-a]indol-10-yl]-4-(l-methyl-3- -indolyl)furan-2,5-dione in 30 ml of DMF and 23 ml of 33% aqueous ammonia was heated to 1400C 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-(l-methyl-3-indolyl)-1H-pyrrole-2,5o* -dione in the form of a red solid of melting point 262-263 0

C.

The furandione starting material was prepared as follows: a) A solution of 25 g of ethyl indole-2-carboxylate in 20 400 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 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 200 ml of water and then 92 ml of 2M hydrochloric acid were added. The mixture was concentrated and the resulting precipitate was filtered

II

17 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 0

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 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 Sdecanted 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 15 of ethyl 6,7,8,9-tetrahydropyrido[l,2-a]indole-8- -carboxylate.. A sample was crystallized from methanol to give a solid of melting point 70-72 0

C.

c) 16.2 g of the carboxylate of b) in 200 ml of THF were 20 added to a suspension of 2.00 g of lithium aluminium hydride in 600 ml of THF at 0 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 Sdiethyl ether/n-hexane gave 11.5 g of 6,7,8,9-tetrahydro-8-(hydroxymethyl)pyrido[l,2-a]indole of melting point 110-111c.

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 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 Oh 3 1 I 18 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[l,2-a]indole of melting point 63-64 0

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 and the residue was dissolved in 330 ml of dichloromethane. 6.34 g of 1-methyl-3-indolylacetic acid and 9.20 ml of triethylamine were added to this solution and e the mixture was stirred overnight. A further 4.60 ml of triethylamine were added. After 48 hours, the solvent was 15 removed under reduced pressure and the residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether Crystallization from ethyl acetate gave 4.02 g of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[l,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)furan- 20 -2,5-dione of melting point 174-178 0

C.

Example 2 2.50 g of trifluoromethanesulphonic anhydride in 330 ml of dichloromethane were treated at o0C under a nitrogen atmosphere with a suspension of 1.87 g of pyrroledione product of Example 1 and 0.94 g of collidine in 280 ml of dichloromethane. After 2.5 hours, the mixture was allowed to warm to 10 0 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 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]indolsh- II 1111~-- 19- -10-yl]-4-(l-methyl-3-indolyl)-H-pyrrole-2,5-dione hydrochloride of melting point 310-313 0

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 hours 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-tetrahydro-8-[(trimethylammonio)methyl]pyrido[l,2-a]indol--10-yl]- 15 4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione trifluoromethanesulphonate of melting point 320-324 0

C.

Example 4 20 265 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 ml 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 then added. After 4 hours, the solvent was removed by evaporation and the precipitate was filtered off and purified by chromatography 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[l,2-a]indol-10-yl]-4-(l-methyl--3-indolyl)-Hhydrochloride of melting point 337-340 0

C.

c MOA MUI O -20 Example 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-tetrahydro-8-[(dimethylamino)methyl]pyrido[1,2-a]indol-10-yl]- S 15 -4-(l-methyl-3-indolyl)-IH-pyrrole-2,5-dione hydrochloride of melting point 335-336 0

C.

Example 6 20 A solution of 170 mg of the pyrroledione product of Example 1 in 55 ml of dichloromethane was treated with S87 mg of methanesulphonic anhydride and 1 ml of pyridine.

The resulting solution was stirred under nitrogen for S1 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 S" residue from ethyl acetate/n-hexane gave 150 mg of 3-[6,7,8,9-tetrahydro-8-(methylsulphonyloxymethyl)pyrido- [1,2-a]indol-l0-yl]-4-(l-methyl-3-indolyl)-iH-pyrrole-2,5- -dione of melting point 259-261 0

C.

Example 7 A solution of 120 mg of the pyrroledione product of Example 6 in 6 ml of DMF and 6 ml of 33% aqueous ammonia was heated to 140 0 C for 6 hours. The cooled mixture was poured into water and the precipitate was filtered off.

-21 The product was purified by chromatography on silica gel with d ichloromethane/acetic ac id/methano 1/water (60:18:2:3). Trituration with ethyl acetate gave 50 mg of 3-[8-(for-mamidomethyl)--6,7,8,9-tetrahiydropyrido[1,2-a]indol- 10-ylj--4-(l-methyl-3-indolyl)-i--pyrrole-2,5--dione of melting point 332-334 0

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 0 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-- Smethane/methanol/acetic acid/water (90:18:3:2). The residue was triturated with ethyl acetate to give 80 mg of 3-8-(m d n t i~ e h l ,8 9-e r fy r p r d j indol-10-ylJ-4-(1-methyl-3-indolyl)-1I-Ipyrrole-2,5--dione methanesulphonate of melting point 200-205 0

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,2-a~indol1-yl4(methyl-3 -indolyl)furan-2,5-dione there was prepared 3-[6,7,8,9tetrahydro-7-(hydroxymethyl)pyrido1,2ajindol0yl]p4.

-(1--methyl-3-indolyl)-lHpyrrole-2,s..dione of melting point 239-242 0

C.

The furandione starting material was prepared as follows: a) 6.6 ml of a 1.6M solution of n-butyllithium in n-hexane were added to a stirred solution of 1.11 g of diisopropylamine in 150 ml of TI-F at -78 0 C under nitrogen.

The mixture was allowed to warm to -20 0 C for 5 minutes and -22 was then again cooled to -78 0 C. 1.85 g of 6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one in 10 ml of THF were then added dropwise. After stirring at -78 0 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-tetrahydr-6o-6-oxopyrido[l,2-a]indole-7-carboxylate of melting point 82-84 0

C.

15 b) 30 ml of a IM solution of borane in THF 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 gel were added to the cooled solution and the 20 solvent was removed by evaporation. The residue was purified by chromatography on silica gel with ethyl acetate/n-hexane 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 18 hours, the 25 solution was washed with 60 ml of 2M hydrochloric acid and ml of saturated sodium bicarbonate solution, dried and Sevaporated 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 0* 30 under reduced pressure and the residue was dissolved in 100 ml of dichloromethane. 920 mg of l-methyl-3-indolylacetic 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 on silica gel with ethyl acetate/n-hexane Crystallization from ethyl acetate gave 390 mg of 3-[7-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4ii 23 0* -(l-methyl-3-indolyl)furan-2,5-dione of melting point 190-1930C.

Example 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 dichloromethane. After 2 hours 4 ml of 33% aqueous ammonia were added and the mixture was left to warm to room temperature overnight. The mixture was washed with water, dried and evaporated to dryness. The residue was purified by chromatography on silica gel with dichloromethane/ 15 methanol/acetone/water (90:18:3:2). Crystallization from dichloromethane/n-hexane gave 85 mg of 3-[7-(aminomethyl)- -6,7,8,9-tetrahydropyrido[l,2-a]indol-10-yl]-4-(1-methyl- -3-indolyl)-lH-pyrrole-2,5-dione of melting point 160-165 0

C.

Example 11 A solution of 120 mg of the pyrroledione product of Example 9 in 80 ml of dichloromethane was treated with 25 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 the 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-(amidinothiomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4- -(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione methanesul- 0 00000 I :r 1 3 -1 24 phonate of melting point 195-198 0

C.

Example 12 A solution of 72 mg of 3-(6,7,8,9-tetrahydropyrido- [l,2-a]indol-10-yl)-4-(l-methyl-3-indolyl)furan-2,5-dione in 5 ml of DMF and 5 ml of 33% aqueous ammonia was heated to 140 0 C for 4 hours. The resulting crystals were filtered off and dried to give 50 mg of 3-(6,7,8,9-tetrahydropyrido[l,2-a]indol-10-yl)-4-(l-methyl-3-indolyl)-LH-pyrroleof melting point 286-289 0

C.

The furandione starting material was prepared as follows: a) A solution of 1.03 g of ethyl 6,7-dihydro-9- -hydroxypyrido[l,2-a]indole-8-carboxylate in 20 ml of ethanol, 10 ml of water and 10 ml of concentrated hydrochloric acid was heated at 80 0 C for 3 hours. The solvents 20 were evaporated to give 740 mg of 7,8-dihydropyrido- [1,2-a]indol-9(6H)-one of melting point 138-140 0

C.

b) A solution of 740 mg of the product of 600 mg of hydrazine hydrate and 440 mg of potassium hydroxide in S 25 2 ml of ethanol and 4 ml of diethylene glycol was heated at 100 0 C under reflux for 1.5 hours. Then the mixture was S* heated at 180 0 C for 2 hours. 50 ml of dichloromethane were added and the organic phase was washed with 2M hydrochloric acid and water. The solvent was removed by S 30 evaporation to give 405 mg of 6,7,8,9-tetrahydropyrido- [1,2-a]indole.

c) 350 mg of oxalyl chloride were added dropwise to a solution of 450 mg of the product of b) in 13 ml of dichloromethane at 0 0 C. After stirring for 2 hours the solvent was removed by evaporation and the residue was dissolved in dichloromethane, 497 mg of l-methyl-3- 25 0** *0 -indolylacetic acid and J.73 ml of triethylamine were added to this soluticai aind the mixture was stirred at room temperature for 60 htou:,'. 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-tetrahydropyridofl,2-a~indol-10-yl)-4-(1--methyl-3-indolyl)furan-2,5- -dione in the form of a red solid of melting point 276-27 8 0

C.

Example 13 In a manner analogous to hat desc 'hed in the first paragraph of Example 1. from toxyethyl)- '1 9-tetrahydropyrido[l,2-aJ indol- 10- yl]-4--(l-methyl- 3--indolyl)furan-2,5-dione there was prepared 3-[6,7,8,9- -tetrahydro-8-(2-hydroxyethyl)pyrido[,2-a]indol-0-yl]-4- -(1-methyl-3-indolyl)--1H-pyrrole--2,5-dione of melting point 261-263 0

C.

The furandione starting material was prepared as follows: a) A solution of 6.5.2 q of 8-(2-acetoxyethyl)-6,7,8,9-- 25 -tetrahydro-9-oxopyrido[1,2-ajindole in 48 ml of dichloromethane was treated with 2.5 ml of ethanedithiol arid 3.13 ml of titanium tetrachloride. The resulting solution was heated at reflux under nitrogen for 18 hours.

A further 4 ml of ethanedithiol and 9 ml of titanium tetrachloride were added and heating was continued for 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 to give 7.7 g of 8'-(2-acetoxyethyl)-7,8-dihydrospiro- [1,3-dithiolane-2',91(6)-pyrido[1,2-ajindole].

0 0* 0 4* 0 *0 i 26 *v al ft f ft tf f f f f ft 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 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 0 C. After 2.5 hours the solvent was removed by evaporation and the residue was dissolved in dichloromethane. 1.68 g of l-methyl-3-indolylacetic acid 15 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 Crystallization from ethyl acetate gave 625 mg of 3-[8-(2-acetoxyethyl)-6,7,8,9- -tetrahydropyrido[1,2-a]indol-10--yl]-4-(l-methyl-3-indolyl)furan-2,5-dione of melting point 159-161 0

C.

Example 14 A solution of 115 mg of 3-[8-(2-acetoxyethyl)-6,7,8,9- -tetrahydropyrido[l,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione in 1 ml of DMF and 2 ml of 33% aqueous ammonia was heated to 140 0 C for 4 hours. The cooled 30 mixture was evaporated aid the residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether Crystallization from ethyl acetate/petroleum ether gave 13 mg of 3-[8-(2-acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H- -Flrrole-2,5-dione of melting point 272-274 0

C.

oa f ft ft ftf r ii~l r.

27 Example 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/petroleum ether gave 540 mg of 3-[6,7,8,9-tetrahydro-8-(2-methylsulphonyloxy-ethyl)pyrido- [l,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-iH-pyrrole-2,5- -dione of melting point 244-245 0

C.

Example 16 A solution of 500 mg of the pyrroledione product of S* Example 15 and 250 mg of sodium azide in 10 ml of DMF was 20 heated at 70 0 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-[8-(2-azidoethyl)-6,7,8,9- -tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)- S* 25 1H-pyrrole-2,5-dione of melting point 262-264 0

C.

Example 17 200 mg of the pyrroledione product of Example 16 in S 30 70 ml of methanol containing 40 mg of 10% 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 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 28 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 0

C.

Example 18 In a manner analogous to that described in the first paragraph of Example 12, from 3-[2,3-dihydro-1H-pyrrolo- [1,2-a]indol-9-yl]-4-(-methyl-3-indolyl)furan-2,5-dione there was obtained 3-[2,3-dihydro-lH-pyrrolo[l,2-a]indol- -9-yl]-4-(-methyl-3-indolyl)-H-pyrrole-2,5-dione of melting point 260-270 0

C.

The furandione starting material was prepared as S 15 follows: we 175 mg of oxalyl chloride were added dropwise to a solution of 200 mg of 2,3-dihydro-1H--pyrrolo[1,2-a]indole in 7 ml of diethyl ether at 0 0 C under a nitrogen 20 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 Crystallization from ethyl acetate gave 70 mg of 3-[2,3-dihydro- -1H-pyrrolo[1,2-a]indol-9-yl]-4-(1-methyl-3-indolyl)furan- 30 -2,5-dione of melting point 125-130 0

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-3there was prepared 3-[2,3- I IM M -29 -dihydro-2-(hydroxymethyl)-lH-pyrrolo[l,2-a]indol-9-yl]-4- -(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione of melting point 238-240 0

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-l-oxo-1H- -pyrrolo[l,2-a]indole-2-carboxylate in 180 ml of ethanol and 90 ml of water. The mixture was heated to reflux for hours and then a further 3 spoon spatula measures of Raney nickel were added. Heating was continued for hours, whereupon the mixture was cooled and filtered.

S 15 The 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 ether/petroleum ether Crystallization from methanol gave 635 mg of ethyl 20 2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-carboxylate of melting point 55-57 0

C.

b) 4 ml of a 1M solution of lithium aluminium hydride in THF were added to a solution of 750 mg of ethyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-carboxylate in 30 ml of THF. 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 the S 30 residue from diethyl ether/petroleum ether gave 355 mg of S* 2,3-dihydro-2-(hydroxymethyl)-lH-pyrrolo[1,2-a]indole of melting point 76-78 0

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 L i cn~ 30 dichloromethane and water. The organic phase was dried and evaporated to give 420 mg of 2-(acetoxymethyl)-2,3- -dihydro-lH-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 l-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 Crystallization from ethyl acetate gave 90 mg of 3-[2-(acetoxymethyl)-2,3-dihydro- 1H-pyrrolo[1,2-a]indol-9-yl]-4-(l-methyl-3-indolyl)furan- -2,5-dione of melting point 208-211 0

C.

Example A solution of 150 mg of 3-[2-t-butoxycarbonyl-1,2,3,4- -tetrahydropyrazino[l,2-a]indol-10-yl]-4- (1-methyl-3- -indolyl)furan-2,5-dione in 4 ml of DMF and 8 ml of 33% aqueous ammonia was heated to 140 0 C for 4 hours. The 25 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 imide 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-l0-yl]-4-(l-methyl-3-indolyl)-IH-pyrrole- -2,5-dione hydrochloride of melting point 268-270 0

C.

r

"I*

31 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 0 C under a nitrogen atmosphere with 303 mg of triethylamine and 615 mg of di(t-butyl) dicarbonate. The mixture was stirred at OOC 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 0

C.

b) 230 mg of oxalyl chloride were added dropwise to a S* 15 stirred solution of 450 mg of the product of a) in 30 ml of diethyl ether at 0 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 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-l0-yl]-4-(-methyl-3-indolyl)furan-2,5- -dione of melting point 125-127 0

C.

Exampe 21 30 In a manner analogous to that described in the first paragraph of Example 12, from 3-(5,6-dihydro-4H-pyrrolo- [3,2,1-ij]quinolin-l-yl)-4-(l-methyl-3-indolyl)furan-2,5- -dione there was prepared 3-(5,6-dihydro-4H-pyrrolo- [3,2,1-ij]quinolin-l-yl)-4-(l-methyl-3-indoly)-lH-pyrrole- -2,5-dione of melting point 285-288 0

C.

i i I 32 o 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 Further purificat'on 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- -(l-methyl-3-indolyl)furan-2,5-dione of melting point 217-2190C.

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-l-yl]-4-(1-methyl-3there was prepared 3-[5,6- -dihydro-5-(hydroxymethyl)-4H-pyrrolo[3,2,1-ij]quinolin-l- -yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 223-225 0

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 THF at -78 0 C under a nitrogen atmosphere. After hour 4.6 g of 1,2,5,6-tetrahydro-4-oxo-4H-pyrrolo- 0 0 00 0 0 0 0 0 L C i I 33 [3,2,1-ij]quinoline were added and the mixture was stirred at -78 0 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 Crystallization from diethyl ether gave 2.8 g of ethyl 1,2,5,6- -tetrahydro-4-oxo-4H-pyrrolo[3,2,1-ij]quinoline-5- -carboxylate of melting point 88-90 0

C.

b) 15 ml of a IM solution of borane in THF were added to a solution of 2.8 g of the product of a) in 100 ml of THF and the resulting solution was heated to reflux for 2 hours. A further 55 ml of borane were added and heating S 15 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 IM 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- 25 -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 4 ml of acetic anhydride and 2 ml of pyridine. After 4 hours a further 4 ml of 30 acetic anhydride were added and the mixture was stirred for 18 hours. The 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 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

L

i I "-Lrr: 34 and the filtrate was evaporated. The residue obtained was purified by chromatography on silica gel with ethyl acetate/petroleum ether to give 350 mg of 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 chromatography on silica gel with dichloromethane. Crystallization 15 from ethyl acetate/n-hexane gave 140 mg of methyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl]-4- -(l-methyl-3-indolyl)furan-2,5-dione solid of melting point 198-200 0

C.

V* Example 23 p *4 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- [3,2,1-ij]quinolin-1-yl]-4-(l-methyl-3-indolyl)-1H-pyrrole- -2,5-dione methanesulphonate of melting point 190-195 0

C.

Example 24 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-ijjquinolin-1-yl]-4-(l-methy-3-indolyl)-1H-pyrrolehydrochloride of melting point 248-2500C.

L 35 Exapl In a manner analogous to that described in the first paragraph of Example 1, from 3-[8-(acetoxymethyl)-6,7,8,9- -tetrahydropyrido[l,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- -tetrahydro-8-(hydroxymethyl)pyrido[1,2-ajindol-10-yl]-4- -phenyl--1H-pyrrole-2,5-dione of melting point 276-278 0

C.

Example 26 In a manner analogous to that described in the first 15paragraph of Example 1, from 4-[8-(acetoxymethtyl)-6,7,8,9- (obtained as described in the last paragraph of Example I by using 3-benzo[bjthienylacetic acid in place of 1l-methyl-3-indolylacetic acid) there was prepared 3-(3-benzo[bjthienyl)-4-[6,7, 8, 9-tetrahiydro-8- -(hydroxymethyl)pyrido[1,2-ajindol-10-yl]J1?Jpyrroe.2,5- -,-dione of melting point 226-227 0

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- -tetrahydropyrido1,2aindoloyly-4-(lnaphthyl)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 7 8 ,9-tetrahlydro-8-(hydroxymethyl)pyridor,2-ajindol- -lO-ylj-4-(l-aphthyl)-1-pyrrole2,5-dione of melting point 221-222 0

C.

I IBT: 36 Example 28 In a manner analogous to that described in Example from the pyrroledione product of Example 19, there was prepared 3-[2-(aminomethyl)-2,3-dihydro-1H-pyrrolo[1,2-ajindol-9-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 208-211 0

C.

Example 29 In an analogous manner to that described in Example 10, from the pyrroledione product of Example there was prepared 3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-phenyl-1H-pyrrole-2,5-dione of 6 melting point 249-250 0

C.

Example A suspension of 100 mg of the pyrroledione 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) 25 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[l,2-a]indol-l1-yl]-4-(l-methyl- -3-indolyl)-lH-pyrrole-2,5-dione of melting point 160-165 0

C.

II R" 37 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 dichloromethane. 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 and crystallization from ethyl acetate/n-hexane gave mg of 3-[2-[(trifluoroacetamido)acetyl]-1,2,3,4-tetrahydropyrazino[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)- -1H-pyrrole-2,5-dione of melting point 170-172 0

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 removed 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 1M hydrochloric acid. Evaporation of 25 the solvent and trituration of the residue with diethyl ether gave 35 mg of 3-[2-(aminoacetyl)-1,2,3,4-tetrahydropyrazino[l,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-1H- -pyrrole-2,5-dione hydrochloride of melting point 235 0

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 I i I I ICP- 38 the residue with ethyl acetate gave 84 mg of 3-[1,2,3,4- -tetrahydro-2-(l-imidazolylcarbonyl)pyrazino[l,2-a]indol-10yl]-4-(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 295 0 C (decomposition).

b) 80 mg of the product of a) were dissolved in a mixture of 20 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 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-

*S

-10-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione of melting point 295 0 C (decomposition).

000a 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 oo* was purified by chromatography on silica gel with methanol/dichloromethane Trituration with n-hexane gave 297 mg of 3-[6,7,8,9-tetrahydro-8-isothiocyanato- S 25 pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrolein the form of a red solid of melting point 285-287 0

C.

Example 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 for 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 39 by trituration with n-hexane gave 220 mg of 3-[8-(benzamidomethyl)-6,7,8,9-tetrahydropyridol1,2-a]indol-10-yl]- -4-(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 297-303 0

C.

Example A solution of 150 mg of 3-[7-acetoxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-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

S

S* with water, dried and evaporated. Crystallization of the residue from ethyl acetate gave 120 mg of 3-[6,7,8,9- 15 -tetrahydro-7-hydroxypyrido[l,2-a]indol-10-yl]-4- (-methyl- -3-indolyl)-1H-pyrrole-2,5-dione of melting point 252-255 0

C.

The furandione starting material was prepared as 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 S 25 off and washed with dichloromethane. The combined washings were concentrated and 33 g of (carbethoxymethylene)triphenylphosphorane were added. The resulting solution Swas heated to reflux under a nitrogen atmosphere. The solvent was evaporated to give an oil which was purified by chromatography on silica gel with ethyl acetate/ n-hexane 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 0

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 i I I1P-- 40 *0 S

S*

S S 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 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 0

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 THF. The solution was added to a solution of 2.8 g of potassium t-butoxide in THF under a nitrogen 20 atmosphere. Then the mixture was left to stir for I hour and the solvent was evaporated. The residue was partitioned 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 There are obtained 4.55 g of t-butyl 6,7,8,9-tetrahydro-7-oxo- -pyrido[l,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 0

C.

c L, i i C EI 41 e) 190 mg of sodium borohydride were added to a stirred solution of 650 mg of 8,9-dihydropyrido[1,2-a]indol- -7(6H)-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 0

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 15 hydrochloric acid and extracted with ethyl acetate. The combined organic 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[l,2-a]indole of melting point 90-95 0

C.

Sg) 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-indolylacetic 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 Crystallization from ethyl acetate gave 160 mg of 3-[7-acetoxy-6,7,8,9-tetrahydropyrido- [1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione of melting point 272-275 0

C.

c I i 42 Example 36 A solution of 85 mg of 3-[7-t-butoxyformamido-6,7,8,9- -tetrahydropyrido[l,2-a]indol-10-yl]-4-(l-methyl-3- -indolyl)furan-2,5-dione in 5 ml of DMF and 5 ml of 33% aqueous ammonia was heated to 100 0 C for 1 hour. The cooled mixture was partitioned 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-tetrahydropyrido[l,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-1H-pyrroleof melting point 159-163 0

C.

a The furandione starting material was prepared as 5 follows: a) A suspension of 555 mg of 8,9-dihydropyrido[l,2-a]r indol-7(6H)-one and 4.62 g of ammonium acetate in 15 ml of methanol was treated with 250 mg of sodium cyanoborohydride. 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 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 toluene. The combined Sfiltrate 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 dichloromethane at 0°C under a nitrogen atmosphere. After 18 hours the solution was 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- 43 -tetrahydropyrido[l,2--a]indole of melting point 137-139 0

C.

c) 127 mg of oxalyl chloride were added to a golution of 240 mg of the product of b) in 30 ml of diethyl ether 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- :qeegraphy on silica gel with ethyl acetate/n-htexane a Crystallization from ethyl acetate/n-htexane gave 100 mg of 3-[7-t-butoxyformamido-6,7,8,9--tetrahydropyrido[l,2-ajindol- 15 l0-ylJ--4-(l-methyl--3-indolyl)furan-2,5-dione of melting point 141-145 0

C.

a 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 residue was triturated with ethyl acetate to give 35 mg of 3-[7-amino-6,7,8,9-tetrahiydropyrido[1,2-ajindol-10-ylJ-4-(lmethyl-3-indolyl)-lH-pyrrole--2,5-dione hydrochloride of melting point 260-265 0

C.

Example 38 A solution of 80 mg of 3-[8-t-butoxytormamido-6,7,8,9- -tetrahiydropyrido 2-a] indol-l0-yl l-methyl--3-indolyl) in 2 ml of DMF and 2 ml of 33% aqueous ammonia was heated to 100 0 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-lo-yl]-4-(-methyl-3-indolyl)i I 3 1 44 1H-pyrrole-2,5-dione of melting point 153-155 0

C.

The furandione starting material was prepared as follows: 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 lb) 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[l,2-a]indole-8-car- .boxylic acid of melting point 244-246 0

C.

15 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 576 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 dichloromethane. The extracts were evaporated and the residue was S. purified by chromatography on silica gel with dichloromethane. The obtained solid was dissolved in 10 ml of 25 toluene and heated to 100 0 C for 4 hours under a nitrogen atmosphere. The solvent was evaporated to give 700 mg of 6,7,8,9-tetrahydropyrido[l,2-a]indole-8-isocyanate of melting point 87-89 0

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 extract was evaporated to give an amine which was redissol'red in dichloromethane. 645 mg of di-t-butyl dicarbonate and 300 mg of triethylamine were added at 0 C 1 i i Irr- 45 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-butoxyformamido-6,7,8,9-tetrahydropyrido[l.2-a]indole of melting point 155-157 0

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 0C under a nitrogen atmosphere. After 1 hour the solvent was removed under reduced pressure and the residue was 15 dissolved in dichloromethane. 363 mg of 1-methyl-3o ~-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 Crystallization from diethyl ether/petroleum ether gave 200 mg of 3-[8-t-butoxyformamido-6,7,8,9-tetrahydropyrido[l,2-a]indol- 10-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione of melting point 155-160 0

C.

Example 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-(l-methyl-3-indolyl)-lH-pyrrole-2.5-dione hydrochloride of melting point 310-315 0

C.

Example A solution of 320 mg of 3-[4-(2-acetoxyethyl)-5,6- -dihydro-4H-pyrrolo[3,2,l1-ij]quinolin-l-yl]-4-(l-methyl-3- 46in 2 ml of DMFand 2 ml of 33% aqueous ammonia was heated to 1400C 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-l-yl)-4-(l-methyl-3- -indolyl)-1H-pyrrole-2,5-dione of melting point 214-215 0

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 20 ml of THF at 0°C under nitrogen. After 10 minutes the 15 stirred solution was cooled to -78 0 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-4-one in 20 ml of THF was added followed by 8 ml of boron trifluoride diethyl etherate.

The mixture was stirred at -78 0 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 S 25 on silica gel with ethyl acetate/petroleum ether There were obtained 4.1 g of t-butyl (E)-(1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-ylidene)acetate of melting point 105-107 0

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 S. 0.

0 0 0 a :0 acetate. The ethyl acetate extracts were dried and concentrated under reduced pressure to give 1.44 g of 1,2,5,6-te rahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-ethanol.

c) 1.44 g of the product of b) in 40 ml of dichloromethane were treated with 10 ml of acetic anhydride and ml of pyridine. The solution obtained was stirred and then evaporated. The residue was dissolved in dichloromethane, 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 15 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.

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 of l-methyl-3-indolylacetic acid and 1.48 g of triethylamine 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 chromatography on silica gel with ethyl acetate/petroleum ether Crystallization from methanol/water gave 280 mg of 3-[4-(2-acetoxyethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-l-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione of melting point 143-146 0

C.

r ~r lir~ 48 Example 41 A solution of 400 mg of 3-[8-[(t-butoxyformamido)methyl]-6,7,8,9-tetrahydropyrido[l,2-a]indol-10-yl]-4- -(l-methyl-3-indolyl)furan-2,5-dione in 50 ml of DMF and 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 0 C. The solvents were evaporated and the residue was dissolved in dichloromethane, 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-ylJ-l-hydroxy-4-(1-methyl- 15 -3-indolyl)pyrrole-2,5-dione of melting point 238-240 0

C.

o The furandione starting material was prepared as follows: 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[l,2-a]indole-8-methanol in 40 ml of dichloromethane under a nitrogen atmosphere.

After 18 hours the mixture was washed with saturated 25 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 0 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-tetrahydropyrido[1,2-a]indole of mnelting point 85-90 0

C.

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-tetrahydropyrido[l,2-a]indole and 920 mg of triethylamine in

L

S-49ml of dichloromethane at 0°C under a nitrogen atmosphere. After 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 0

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 9. was dissolved in dichloromethane. 630 mg of l-methyl-3- -indolylacetic acid and 920 1 l of triethylamine were 15 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 2 gel with ethyl acetate/petroleum. ether 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 0

C.

*9 S 25 Example 42 In a manner analogous to that described in Example 37, .0 from the product of Example 41 there was prepared 3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol- -10-yl]-l-hydroxy-4-(l-methyl-3-indolyl)pyrrole-2,5-dione hydrochloride of melting point 280-282 0

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-pyrroloso methanesuiphonate of melting point 185-190'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-ijjhydrochloride of melting point 193-195 0

C.

In a manner analogous to that described in Example 2, i from the product of Example 26 there was obtained (aminomethyl)-6,7,8,9-tetrahydropyrido[l,2-aj indol- -10--ylJ-4-(3-be-nzo[bjthienyl)-I-1-pyrrole-2, 5-dione hydrochloride of melting point 285-287 0

C.

Example 46 In a manner analogous to that described in the first paragraph of Example 1, from 3-[8-(acetoxymethiyl)- -6,7,8,9-tetrahiydropyrido[l,2-alindol-l0-yl]-4-(2- -naphthyl)furan-2,5-dione (obtained as described in the last paragraph of Example 1 by using 2-naphthylacetic acid in place of 1-methyl--3-indolylacetic acid) there was prepared 3-[6,7,8,9-tetrahydro-8-(hydroxymethyl)pyrido- 'S [l,2-a]indol--10-yl]-4-(2-naphthyl)-lH--pyrrole--2,5-dione of melting point 260-263 0

C.

Example 47 In a manner analogous to that described in Example 2, from the product of Example 46 there was obtained 3-[8- -(aminomethyl)-6, 7,8, 9-tetrahydropyrido[1, 2-a) -4-(2-naphthyl)-111-pyrrole-2, 5-dione hydrochloride of I i CC 51 melting point >300 0

C.

Example 48 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)-1H-pyrrole-2,5-dione of melting point 167-169 0

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- 0*9* 5 methyl)-7,8,9,10-tetrahydro-6H-azepino[ 1,2-a]indol-11-yl]-4- (l-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-1l-yl]-4-(l-methyl-3-indolyl)-1Hof melting point 268-270 0

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 g 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-ethoxycarbonylbutyl)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 II I 7ii-"~Ee S-52mixture of water and diethyl ether. The organic phase was dried and concentrated. Chromatography of the residue on silica gel with dichloromethane/methanol 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[l,2-a]indole-9-carboxylate of melting point 74-81 0

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 0 the residue was washed with ethyl acetate. The filtrate S• was extracted with ethyl acetate. The combined extracts 15 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[l,2-a]indole-9-carboxylat.e of melting point 69-70 0

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 20 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 1.90 g of 7,8,9,10-tetrahydro-9-(hydroxymethyl)-6H-azepino[1,2-a]indole of melting point 109-111 0

C.

e) 1.8 g of this solid were dissolved in 100 ml of diethyl ether at OOC and treated with 1.70 g of acetic anhydride and 0.66 g of pyridine. After 8 hours a further g of pyridine were added and the mixture was stirred for 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

I~

53 9-(acetoxymethyl)-7,8,9,10-tetcahydro-6H-azepino[1, 2 indole of melting point 65 0

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 l-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)- 15 7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-ll-yl]-4- 15 -(i-methyl-3-indolyl)furan-2,5-dione of melting point 164-166 0

C.

Example In a manner analogous to that described in Example 12, fron 0.50 g of 3-[7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-ll-yl]-3-(l-methyl-3-indolyl)furan-2,5-dione there was obtained 0.43 g of 3-[7,8,9,10-tetrahydro-6H-azepino- [l,2-a]indol-1l-yl]-3-(l-methyl-3-indolyl)-1H-pyrrole-2,5- -dione of melting point >300 0

C.

a The furandione starting material was prepared as follows: 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 Org. Chem. 33, 1968, 4286) in 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 l-methyl-3-

-A

i S-54- -indolylacetic acid and 2.73 g of triethylamine in 50 ml of dichloromethane. The mixture was stired 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[l,2-a]indol-ll-yl]-3- (l-methyl-3-indolyl)fucan-2,5-dione of melting point 257-259 0

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 15 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 0

C

(decomposition).

o Example 52 A mixture of 40 mg of the product of Example 51, 20 mg of sodium bicarbonate and 25 mg of 3,5-dimethyl-N 2 -nitro-l-pyrazole-l-carboxamide 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 There were obtained 15 mg of 3-(l-methyl-3-indolyl)-4-[7,8,9,10- -tetrahydro-9-[(2-nitroguanidino)methyl]-6H-azepino[l,2-aindol-ll-yl]-1H-pyrrole-2,5-dione of melting point 177-178 0

C.

i I I i -O CF- 55 Example 53 In a manner analogous to that described in the first paragraph of Example 1, from 0.20 g of 3-[8-(acetoxymethyl)-7,8,9,10-tetrahydro-6H-azepino[l,2-a]indol-1l-yl]- 4 (l-methyl-3-indolyl)furan-2,5-dione there were obtained mg of 3-[7,8,9,10-tetrahydro-8-(hydroxymethyl)-6H- -azepino[l,2-a]indol-ll-yl]-4-(l-methyl-3-indolyl)-1Hof melting point 109-111 0

C.

The furandione starting material was prepared as Sfollows: a) A solution of 5 g of ethyl 6,7-dihydro-9-hyd oxy- 15 pyrido[l,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-(ethoxycarbonyl)-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 dichloromethane/methanol (95:5) to give 3.0 g of diethyl 7,8-dihydro-10-hydroxy-6H-azepino[1,2-a]indole- -8,9-dicarboxylate.

ILI

L-

I I 56 c) A mixture of 2.8 g of the product of b) and 0.5 g of boric acid was heated at 150 0 C for 1 hour and at 170 0 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 dichloromethane/methanol There were obtained 2.1 g of ethyl 7,8,9,10-tetrahydro-10-oxo-6H-azepino[1,2-a]indole-8-carboxylate.

d) 2.1 g of the product of c) were dissolved in 80 ml of *9 ethanol and treated with 4 spoon spatula measures of Raney nickel and 50 ml of water. The mixture was heated at reflux for 4 hours, cooled and filtered, and the residue 15 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-8-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 mg 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 dichloromethane/methanol (95:5) gave 0.70 g of 7,8,9,10-tetrahydro-8-(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 on silica gel with dichloromethane, there being obtained 0.60 g of 8-(acetoxymethyl)c 3 ~iT 57 *0 *r

C

0*c *0 .6 .r 4 6 66a 06co 6 6 r4 6 06a 6 .6 -7,8,9,10-tetrahydro-6H-azepino[l,2-a]indole of melting point 77-79 0

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 0 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 l-methylindole-3-acetic acid and 0.59 g of triethylamine in dichloromethane. After 16 hours the mixture was concentrated and the residue was chromatographed on silica gel with dichloromethane/methanol There was obtained 0.51 g of 3-[8-(acetoxymethyl)- 8 ,9,10-tetrahydro-6H-azepino[1,2-a]indol-11-yl]--4- 15 -(1-methyl-3-indolyl)furan-2,5-dione of melting point 70 0

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 trifluoromethanesulphonic 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 concentrated. Chromatography of the residue on silica gel gave mg of 3-[8-(aminomethyl)-7,8,9,10-tetrahydro-6H- -azepino[1,2-a]indol-1l-yl]-4-(1-methyl-3-indolyl)-1H- -pyrrole-2,5-dione acetate of melting point 162-163 0

C.

Example 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 trifluoromethanesulphonic 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 i 58 chromatography of the residue on silica gel with dichloromethane/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-(l-methyl-3-indolyl)-1H-pyrrole-2,5- -dione. This was converted into the hydrochloride of melting point 294 0 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- *0 0* 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 260 mg of 3-[6,7,8,9- -tetrahydro-8-[(diisopropylamino)methyl]pyrido[l,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of melting point 187 0 C (decomposition).

Example 57 A solution of 1.0 g of 3-[8-(acetoxymethyl)-6,7,8,9- S"e -tetrahydropyrido[l,2-a]indol-lO-ylj-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 0 C while stirring under a nitrogen atmosphere for 6 hours. A further 13.8 ml of hexamethyldisilazane and 2.73 ml of methanol were added and the heating was continued for 16 hours. Two further additions of the same quantities of hexamethyldisilazane and methanol were effected and the i

I

59 temperature of the mixture was held at 50 0 C for a further 24 hours. 20 ml of methanol were added and the mixture was heated to reflux for 15 minutes, c :oled and concenLrated.

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-tetrahydropyrido[l,2-a]indol-10-yl]-4-(3-benzofuranyl)-IHof melting point 234-237 0

C.

The furandione starting material was prepared as follows: S1.7 g of oxalyl chloride were added dropwise to a solution of 3.3 g of 8-(acetoxymethyl)-6,7,8,9-tetra- 15 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-benzofuranylacetic 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 purified by chromatography on silica gel with ethyl acetate/petroleum ether Crystallization of the residue from ethyl acetate/petroleum ether gave 1.62 g of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol- -10-yl]-4-(3-benzofuranyl)furan-2,5-dione of melting point 214-215 0

C.

Example 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 ml of 2M hydrochloric acid and the methanol was removed 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

I

60 solution and dried. The solution was concentrated and the precipitate was filtered off to give 190 mg of 3-(3-benzofuranyl)-4-[6,7,8,9-tetrahydro-3-(hydroxymethyl)pyrido- [1,2-a]indol-10-yl]-lH-pyrrole-2,5-dione of melting point 246-248 0

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[l,2-ajindol- -10-yl]-4-(3-benzofuranyl)-lH-pyrrole-2,5-dione hydrochloride of melting point 210-212 0

C.

15 Example 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 dichloromethane. After 45 minutes 0.41 ml of a 40% solution of dimethylamine in water was added and the mixture was Sstirred 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- .0 aminomethyl)pyrido[l,2-a]indol-10-yl]-1H-pyrrole-2,5-dione of melting point 285-286 0

C.

Example 61 546 mg of trifluoromethanesulphonic anhydride in 80 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 dichloromethane. After 1 hour 1.9 ml of 40% aqueous dimethylamine MMMNMW7"- 61 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)-lH-pyrrolo[l,2-a]indol-9-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione trifluoromethanesulphonate of melting point 323-325 0

C.

Example 62 A solution of 400 mg of 3-[8-cyano-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)furan- -2,5-dione in 12 ml of DMF and 12 ml of 33% aqueous 15 ammonia was heated to 140 0 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-(1l-methyl-3-indolyl)-1H-pyrrole-2,5- -dione of melting point 312-3130C.

The furandione starting material was prepared as follows: a) A suspension of 4.0 g of the product of Example 38a) in 4.4 ml of water and 84 ml of acetone was cooled to 0°C and 2.18 g of triethylamine 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 0

C.

i 4C: 62 9 999* 99 b) 991 mg of trifluoroacetic anhydride were added dropwise to a suspension of 1.0 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxamide in 15 ml of dioxan at 0 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 There were obtained 740 mg of 6,7,8,9-tetrahydropyrido[l,2-ajindole-8-carbonitrile of melting point 116-118 0

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-carbonitrile in 100 ml of diethyl ether under a nitrogen atmosphere. The solvent was evaporation and the residue was dissolved in of dichloromethane. 771 mg of l-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 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-[8-cyano-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4- -(l-methyl-3-indolyl)furan-2,5-dione of melting point 309-311 0

C.

*99*99 9. Example 63 Hydrogen chloride gas was bubbled through a solution of 200 mg of the product of Example 62 in 250 ml of methanol at 0 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 through the solution and the solvent was then evaporated.

The residue was purified by chromatography on silica gel with dichloromethane/methanol/acetic acid/water

L

1 3 LE-* 63 (90:18:3:2). Trituration with ethyl acetate gave 75 mg of 3-18-amidino-6,7,8,9-tetrahydropyrido1,2-a]indol-10-yl]- -4-(l-methyl-3-indolyl)-1H-pyrrole-2.,5-dione hydrochloride of melting point 237-239 0

C.

Example 64 A solution of 50 mg of 3-[8-carbamoyl-6,7,89-tetrahydropyrido[l,2-a]indol-10-yl]-4--(l-methyl-3-indolyl)furan- -2,5-dione in 4 ml of DMF and 4 ml of 33% aqueous ammonia was heated to 140 0 C. The mixture was extracted with of n 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.

15 There were obtained 20 mg of 3-[8-carbamoyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl-4-(1-methyl-3-indolyl)-1H- -pyrrole-2,5-dione of melting point 315-316 0

C.

The furandione starting material was prepared as follows: 178 mg of oxalyl chloride were added to a solution of S* 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 l-methyl-3- S -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 methanol in dichloromethane. Crystallization from ethyl acetate gave 70 mg of 3-[8-carbamoyl-67,8,9-tetrahydropyrido[1,2-aindol-10o-yl]-4-(l-methyl-3-indolyl) of melting point 307-309 0

C.

64 Example In a manner analogous to that described in the first paragraph of Example 1, from 3-[B-(acetoxymethyl)-6,7,8,9- -tetrahydropyriLdo[1,2-aindol-0-yl]-4-(5-methoxy-1- -methyl-3-indolyl)furan-2,5-dione there was prepared 3-.[6,7,8,9-tetrahydro-8-(hydroxymetyl)pyridol1,2-a~ildol- -10-ylJ-4-(5--methoxy-l--methyl-3-indolyl)-liH-pyrrole-2,5- -diane of melting point 300-303 0

C.

The furandione starting material was prepared as follows: 0.4 ml of oxalyl chloride were added to a solution of 15 906 mg of 8-(acetoxymethiyl)-6,7,8,9-tetrahydropyrido- [1,2-ajindole 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 dichloromethane. 940 mg of 5-methoxy-l-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 chromatography on silica gel with ethyl acetate/n-hexane Crystallization from ethyl acetate/petroleum ether gave 250 mg of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido- [1,2-a~indol-10--ylJ--4-(5-methoxy-l-methyl-3-indolyl)furcanof melting point 259-261 0

C.

Example 66 In a manner analogous to that described in Example 2, from the product of Example 65 there was prepared 3-[B-(aminiomethyl)-6,7,8,9-tetrahydropyridofl,2-a~indol-10- -yl]-4-(5-methoxy-1--methyl-3-indolyl)-lH-pyrrole-2,5-dione hyvdrochloride of melting point 268-270 0

C.

-A

I Ir i 65 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[l,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-l-methyl-3-indolyl)-lH-pyrrole-2,5-dione of melting point 316-318 0

C.

The furandione starting material was prepared as follows: e c a) 500 mg of a 60% dispersion of sodium hydride in 15 mineral oil were added to solution of 1 g of indole-3-acetic acid in 50 ml of THF and the mixture was S. 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 S 25 5-bromo-l-methyl-3-indolylacetic acid of melting point 192-194 0

C.

b) 500 mg of oxalyl chloride were added to a solution of 900 mg of the product of a) in 100 ml of diethyl ether under a nitrogen atmosphere. Then the solvent was evaporated and the residue was dissolved in dichloromethane. 880 mg of 5-bromo-l-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 chromatography on silica gel with ethyl acetate/n-hexane to give 400 mg of a solid. A sample was recrystallized from I, I I 66 ethyl acetate to give 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(5-bromo--methyl-3of melting point 215-220 0

C.

Example 68 In a manner analogous to that described 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- -ylj-4-(5-bromo-l-methyl-3-indolyl)-1H-.pyrrole-2,5-dione hydrochlcride of melting point >310 0

C.

*t Example 69 Se 15 A solution of 200 mg of 3-[7-(2-acetoxyethyl)-6,7,8,9- -tetrahydropyrido[1,2-a]indol-10-yl]-4- (l-methyl-3-indolyl)in 2 ml of DMF and 1 ml of 33% aqueous ammonia was heated to 140 0 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 S* organic phase was dried. The solvent was evaporated and S 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-yl-4-(1-methyl-3-indolyl)-lH-pyrrole- 2,5-dione of melting point 236-238 0

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 0

C

and 1.85 g of the product of Example 35d) in 10 ml of dimethoxyethane were added. The mixture was stirred 3r -67 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 there being obtained 1.55 g of a mixture of ethyl 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 0 C after crystallization from diethyl ether/ d petroleum ether.

S

15 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 IM solution of 0O lithium aluminium hydride in diethyl ether. After stirring for I 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]indole of melting point 70-72 0 C after crystallization from diethyl ether/petroleum bo ether.

c) A solution of 1.04 g of the product of in 30 ml of dichloromethane was treated with 6 ml of acetic anhydride Sand 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 to give 670 mg of 7-(2-acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole.

-68 d) 250 jii of oxalyl chloride were added to a solution of 670 mg of the proeuct of c) in 12 ml of dichioromethane 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/petroleum ether to give 350 mg of 3-[7-(2-acetoxyethiyl)-6,7, 8,9-tetrahiydropyrido[1,2-ajindole-10-ylJ-4- (1- -methyl- 3-indolyl)furan-2,5-dione of melting point o 182-1840C after crystallization from ethyl acetate.

Example 0:In a manner analogous to that described in Example 2, from the product of Example 69 there was prepared 3-[7-(2-aminoethiyl)-6,7,8,9-tetrahydropyrido- [1,2-ajindol-10-ylJ-4-(1-methyl-3-indolyl)-1H-pyrrole- *0*0 -2,5-dione hydrochloride of melting point 240-242 0

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-ajindol-10-yl--4-(.- *0 -methyl-3-indolyl)furan-2,5--dione there was prepared 3-[6,7,8,9-tetrahydro-8-(hydroxymetyl)-2-metoxypyrido- [1,2-a~indol-1o-ylJ-4-c1--methyl-3-indolyl)-lH--pyrrole-2,5- -dione of melting point 195-197 0

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 i I i i 69 100 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 stirred for 2 hours. The mixture was cooled and treated with 50 ml of IM 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 THF 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 15 extracts were washed with water and sodium chloride solution and then dried. Evaporation of the solvent and crystallization of the residue from ethyl acetate gave 6,7 g of ethyl 6,7-dihydro-9-hydroxy-2-methoxypyrido- [1,2-a]indole-8-carboxylate of melting point 157-160 0

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 Sextracted 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-tetrahydro-2-methoxypyrido[l,2-a]indole-8-carboxylate of melting point 104-105 0

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 i I' 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 0

C.

d) 1 g of the product of c) in 10 ml of pyridine was treated with 1.5 g of acetic anhyd:ide. Then the solvent was evaporated and the residue was partitioned between Sdiethyl ether and 5% aqueous ammonium chloride. The organic phase was washed with sodium chloride solution, 15 dried and evaporated. Crystallization of the residue from diethyl ether/n-hexane gave 0.84 g of 8-acetoxymethyl- -6,7,8,9-tetrahydro-2-methoxypyrido[1,2-a]indole of melting point 98-100 0

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 hloride 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- 0* -3-acetic acid and 0.8 ml of triethylamine. The mixture was stirred for 65 hours and then the solvent was removed S under reduced pressure. Chromatography of the residue on Ssilica gel with ethyl acetate/n-hexane gave 380 mg of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydro-2-methoxypyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)furan-2,5- -dione. A sample crystallized from toluene/n-hexane melted at 131-133 0 C (decomposition).

Example 72 In a manner analogous to that described in Example 2, from the product of Example 71 there was prepared e i i I'---CP 71 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 0

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 dried.

.The solvent was evaporated and the residue was crystallized from 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)-I- -pyrrole-2,5-dione of melting point 244-247 0

C.

b) A solution of 140 mg of the product of a) in 10 ml of DMF 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-aJindol- -10-yl-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 278C (decomposition).

Example 74 A solution of 150 mg of the product of Example 20 in 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. Crystallization of the residue from dichloromethane/n-hexane gave mg of 3 -[2-acetyl-1.2,3,4-tetrahydro-pyrazino- [1,2-ajindol-O-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole2,5- L L i -72 -dione of melting point 308-310 0

C.

Example 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-tetrahvdropyrido[1,2-ajindol-10-ylj-4- (1-methyl-3-indolyl)-l of melting point 270-273 0

C.

Example 76 A solution of 150 mg of the product of Example 20 in 40 ml of dichloromethane was treated with 40 mg of 15 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 and ethyl acetate gave 95 mg of 3-[1,2,3,4-tetrahydro-2-methanesulphonylpyrazino[1,2-a]indol-10-yl]-4- -(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 298-301 0 C (decomposition).

Example 77 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 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 0 -73 a) 400 mg of l.5-dihydro-3--f6,7,8,9-tetrahydro-8-- -(hiydroxymethyl)pyrido[l,2-ajindol-lo-yl]-4-(l-methlyl- -3-indolyl)-2H-pyrrole-2--one of melting point 205-207 0

C.

There were also obtained b) 160 mg of l,5-dihydro-4-[6,7,8,9--tetrahydro-8- (hydroxymethyl) pvrido l, 2-a] indol-10-.yl]-3-(l--methiyl- 3- -indolyl)-2H-pyrrole-2-one of melting point 201-203 0

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- *0methyl)-6,7,8,9-tetraydropyrido1,2-aindol10ylj4- -(3-trifluoromethylphienyl)furan-2,5-dione there were obtained 110 mg of 3-[6,7,8,9-tetrahydro-8-(hydroxy- 0. methyl)pyrido[l,2-ajindol-10-yl]-4-(3- trifluoromethylsolid of melting point 77 79 0

C.

The furandione starting material was prepared as follows: 1.7 g of oxalyl chloride were added. to a cold (0-4 0

C)

solution of 3.0 g of 8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[l,2-a~indole in 50 ml of dichloromethane.

After 2 hours the solvent was evaporated and the residue :was dissolved in dichloromethane. The solution was added to a solution of 2.7 g of (a.cz.,x-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 There were obtained 700 mg of 3-[8-(acetoxymethyl)-6,7,8,9-- -tetrahydropyrido[,2-aindol10yl-4-(3-trifluoromethyl of melting point 176-177 0

C.

74 Example 79 In a manner analogous to that described in the first paragraph of Example 1, from 1.0 g of 3-[8-(acetoxymethyl)-6,7,8,9- tetrahydropyrido[l,2-aJindol-l0-yl]-4- -(4-methioxyphienyl)furan-2,5-dione there were obtained 150 mg of 3-[6,7,8,9-tetrahydro-8-(hiydroxymethyl)pyridlo[1,2-ajindol-10-yl]-4-(4-methoxyphenyl)-1Hof melting point 228 0 C (decomposition).

The furandione starting material was prepared as *follows: 0 1.7 g of oxalyl chloride were added to a cold (0-4 0

C)

solution of 3.0 g of 8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[l,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-methioxyphenylacetic acid and 3.2 q of triethylamine in 70 ml of dichloromethane. The mixture was stirred for 16 hours and then concentrated. Chromatography of the residue on silica gel with dichloromethane/ methanol (95:5) gave 2 g of 3-[8-(acetoxymethyl)-6,7,8,9-- 0: -tetrahydropyridoVL,2-ajindol-lO-yl]-4-(4-methoxyphenyl)furan-2,5--dione of melting point 79-82 0

C.

Example In a manner analogous to that described in the first paragraph of Example 1, from 0.8 g of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido1,2-a~indol- -l.0-ylJ-4-(2-chlorophienyl)furan-2,5-dione there were obtained 120 mg of 3-(2--chlorophenyl)-4-[6,7,8,9-tetrahydro-8-(hydroxymethyl)pyrido[,--aindol-10-ylj--l-- -pyrrole-2,5--dione of melting point 232-233 0

C.

75 The furandione starting material was prepared 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--tetrahydropyrido[l,2-aJindole in 50 ml of dichioromethane. After 2 hours the solvent was evaporated and the residue was dissolved in dichloromethane. This solution was added to a solution of 3.0 g of 2-chilorophenylacetic 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-(acetoxymetftyl)--6,7,8,9- S -tetrahydropyrido[l. 2-a] indol-10--ylj-4- (2-chilorophienyl)furan-2,5-dione of melting point 168-171-C.

.~.Example 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-tetrahydropyrido[1,2-a]indol-10-yl]-4-(3-trifluorometylhenyl)-.

of melting point 202--204 0

C.

Example 82 5:5.0:In a manner analogous to that described in Example 51, from 100 mg of the product of Example 79 there were obtained 88 mg of 3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a~indol-1--ylj-4-(4methoxypenyl)-I.

of melting point 195-196 0

C.

Example 83 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- I I i L i il_ ~Sa -76 pyrido[l,2-a]indol-10-yl]-4-(2-chlorophenyl)-1H-pyrrole-2,5dione of melting point 206-208 0 C (decomposition).

The following Examples illustrate typical pharmaceutical preparations containing compounds provided by the present invention: Example A Tablets containing the following ingredients may be produced in a conventional manner: 9. 9w t 9 *09S Ingredient Compound of formula I Lactose Maize starch Talc Magnesium stearate Tablet weight Per tablet 5.0 mg 125.0 mg 75.0 mg 4.0 mg 1.0 mg 210.0 mq .6 9 99 9 0 9* a« a w Example B Capsules containing the following ingredients may be produced in a conventional manner: *9499.

99 a Ingredient Compound of formula I Lactose Maize starch Talc Capsul Per capsule 10.0 mg 165.0 mg 20.0 mg 5.0 mg e fill weight 200.0 mq

Claims (26)

1. Compounds of the general formula R N R4 XR Y RSR R6 N R2 R R 7 (CH2,)m I RI 'R' wherein R represents hydrogen or hydroxy, R'and R 2 together represent a group of the formula -(CH 2 and R 7 represents hydrogen or R' and R 7 together represent a group of the formula -(CH 2 and R 2 represents hydrogen: R 3 represents an optionally substituted aryl (as hereinbefore described) or an optionally substituted heteroaryl (as hereinbefore described) group: R 4 R 5 and R 6 each independently represent hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acyl-amino, alkylthio, alkylsulphinyl or alkylsulphonyl: R 8 represents a group of the formula -(CH 2 )p-R 9 or -(CH 2 )q-R R represents hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkylsulphonyl, aminocarbonyl or aminothiocarbonyl; R' 1 represents hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkyla.-_no, azido, acylamino, alkylsulphonylamino, arylsulphonylamino, alkylthio, alkoxycarbonylamino, aminoacylamino, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulphonyloxy or arylsulphonyloxy, a or 6-membered saturated nitrogen-containing heterocycle attached via the nitrogen atom or a group of the formula -U- U c i 78 represents S or NH; V represents NH, NNO2, NCN, CHNO 2 W represents amino, monoalkylamino or dialkylamino; one of X and Y represents 0 and the other represents 0 or Z represents CH or N; m stands for 0-5, n stands for 1-5; p stands for and q stands for 0-5, with the proviso that q and m stand 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.

2. Compounds according to claim 1, wherein R S represents hydrogen, R represents hydrogen, alkyl- carbonyl, cyano, amidino, alkoxycarbonyl, alkylsulphonyl, 10 15 aminocarbonyl or aminothiocarbonyl and R represents hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkyl- s* amino, trialkylamino, azido, acylamino, alkylsulphonyl- amino, arylsulphonylamino, alkylthio, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulphonyloxy or arylsulphonyloxy or a group of the formula and R 1 R 2 R 3 R 4 R R R R U, V, W, S0 X, Y, Z, m, n, p and q have the significance given in claim 1.

3. Compounds according to claim 1 or claim 2, represents hydrogen, m stands for 1 or 2 and Z represents SCH. C 6 *5

4. Compounds according to claim 1 or claim 2, 1 2 wherein R and R together represent -(CH 2 2 and 7 R represents hydrogen, m stands for 1 and Z represents CH. i 79 Compounds according to claim 1 or claim 2, 1 2 7 wherein R and R together represent -CH 2 and R represents hydrogen, m stands for 2 and Z represents N.

6. Compounds according to claim 1 or claim 2, 1 7 2 wherein R and R together represent -CH 2 and R 2 represents hydrogen, m stands for 1 and Z represents CH.

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

8. Compounds according to any one of claims 1 to 6, 3 S 15 wherein R 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, So acylamino, alkylthio, alkylsulphinyl and alkylsulphonyl.

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

10. Compounds according to any one of claims 1 to 9, 25 wherein R R and R each represent hydrogen.

11. Compounds according to any one of claims 1 to 8 wherein R represents a group of the formula -(CH 2 )q -R

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

13. Compounds according to claim 11 or claim 12, wherein R1 0 represents hydroxy, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkyl- L 80 carbonyloxy or alkylsulphonyloxy or a group of the formula -W.

14. Compounds according to claim 13, wherein U represents S, V represents NH and W represents amino. Compounds according to any one of claims 1 to 14, wherein X and Y both represent 0.

16. Compounds according to claim 1 or 2 of the group 3-f8-(Aminomethyl)-6,7,8,9-tetrahydropyrido- *[1,2-ajindoll10yl]-4i(lmethyl-3indolyl)lH-pyrrole- 15 3-[7-(Amidinothtiomethyl)-6,7,8,9-tetrahydropyrido- 2-a] indol-10-ylJ-4-(l--methyl-3--indolyl)-lH--pyrrole- 3-[6,7,8,9-Tetrahydro-8-[(dimethylamino)methylJ- pyrido[1,2-alindol-10-ylJ-4-(l-methyl-3-indolyl)-1H- -pyrrole-2,5-dione and its pharmaceutically acceptable acid addition salts.

17. Compounds of the general formula 2 R RN 8 R R3 i I ~~TLT. 81 wherein R 2 R 3 R 4 R 5 R R, R 7 R 8 Z and m have the significance given in claim 1.

18. A method for the prophylaxis or treatment of a condition responsive to protein kinase inhibition, in a subject, which comprises administering to said subject a compound according to any one of claims 1 to 16.

19. The method according to claim 18, for the control or prevention of aninflammatory disorder. The method according to claim 19, wherein the inflammatory disorder is selected from arthritis, immune diseases, conditions in conjunction with organ transplants, or in oncology.

21. The method according to claim 18, wherein the condition is AIDS.

22. The method according to claim 18, wherein the condition is asthma.

23. The method according to claim 18 wherein the condition is a cardiovascular of bronchopulmonary disorder.

24. A process for the manufacture of the compounds according to any one of claims 1 to 16, which process comprises for the manufacture of a compound of formula I in which X and Y both represent 0, reacting a compound of the general formula 0 R4 0 0 RN 2 II Z 82 wherein R 2 R 3 R 4 R 5 R 6 R 7 R 8 Z and m have the significance given in claim 1, with ammonia under pressure or with hexamethyldisilazane and methanol to give a compound of formula I in which R represents hydrogen or with hydroxylamine to give a compound of formula I in which R represents hydroxy, or for the manufacture of a compound of formula I in which one of X and Y represents 0 and the other represents reducing a compound of formula I in which X and Y both represent 0 with lithium aluminium hydride, or if desired, functionally modifying a reactive centre present in a compound of formula I obtained, and 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.

25. A medicament, particularly an anti-inflammatory, immunological, oncological, 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 and a therapeutically inert carrier material.

26. A method for the manufacture of a medicament against the 4. use of a compound according to any one of claims 1 to 16 for the manufacture of a medicament against inflammatory, immunological, oncological, bronchopulmonary or cardiovascular disorders or against asthma or AIDS.

27. The compounds of claims 1-16 whenever prepared by the process of claim 24 or by an obvious chemical equivalent thereof. 1 83

28. A compound of general formula as shown in claim 1, said compound substantially as herein described with reference to any one of Examples 1 to 83.

29. A pharmaceutical composition substantially as herein described with reference to any one of Examples A or B. DATED this 27th day of October 1990. F.HOFFMANN-LA ROCHE AG By their Patent Attorneys DAVIES COLLISON CAVE e e *l 06