MC2096A1 - 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

1

SUBSTITUTED PYRROLES

The present invention relates to substituted pyrroles. More particularly, the invention relates to compounds of general formula

10

l/ \ 8 R R

where R represents a hydrogen or a hydroxyl, R

2

R together represent a group of formula

7 1

~^CH2^n~ and R represents a hydrogen or R

R^ together represent a group of formula

2 3

-(CH0) - and R represents a hydrogen; R

4

represents an aryl or heteroaryl group; R ( 5 6

R and R each independently represent one and

%

hydrogen, halogen, alkyl, hydroxy, alkoxy,

haloalkyl, nitro, amino, acylamino, alkylthio,

8

alkylsulfonyl or alkylsulfonyl; R represents

9 10

a group of formula -(CH.-) -R or -(CH9) -R;

g / P Z q

R represents hydrogen, alkylcarbonyl, amino-alkylcarbonyl> cyano, amidino, alkyloxycarbonyl, aryloxycarbonyl, alkylsulfonyl, aminocarbonyl or aminothiocarbonyl; R"^ represents a hydroxy, alkoxy, halogen, amino, monoalkoylamino, dialkoylamino, trialkoylamino, azido, acylamino, alkylsulfonylamino, arylsulfonylamino, alkylthio, alkoxycarbonylamino, aminoacylamino, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulfonyloxy, or arylsulfonyloxy, a heterocycle containing saturated nitrogen with 5 or 6 bonds attached via the nitrogen atom, or a group of the formula -U-C-(V)-W; U represents S or NH; V represents NH, NNC>2 i NCN, CHN02; W represents an amino, monoalkoylamino, or dialkoylamino; one of the radicals x and Y represents O and the other represents O or (H,H); Z represents CH or N; m represents 0-5, with the precision that m equals 2-5 when Z represents N; n represents 1-5; p represents 0-5; and q represents 0-5, with the clarification that q represents 2-5 when Z represents N?

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

The objects of the invention are the compounds of formula I and their salts mentioned above, both as such and as therapeutically active substances; a process for the preparation of said compounds and salts and of new intermediates.

3

useful in the said process; medicines containing the said compounds and salts and the preparation of these medicines; and the application of these compounds and salts to combat or prevent diseases, in particular to combat or prevent inflammatory, immunological, oncological, bronchopulmonary and cardiovascular diseases or in the treatment of asthma or AIDS or for the preparation of a medicine against inflammatory, immunological, oncological, bronchopulmonary and cardiovascular diseases or against asthma or AIDS.

As used here, the term "alcohol", alone or in combination, denotes a straight-chain or branched-chain alkyl group containing a maximum of 7, preferably a maximum of 4, carbon atoms.

such as methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, tert.butyl, pentyl, etc. The term "alkoxy", alone or in combination, designates an alkyl group as defined above which is attached via an oxygen atom, examples of alkoxy groups being methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert.butoxy etc.

A haloalkoyl group may bear one or more halogen atoms, examples of such groups 25 being chloromethyl, trifluoromethyl, etc. The term "acyl" designates an acyl group derived from an alkanoic acid containing a maximum of 7, preferably a maximum of 4, carbon atoms (e.g. formyl, acetyl, propionyl, butyryl, etc.) 30 or from an aromatic carboxylic acid (e.g.

benzoyl, etc). The term "aryl" alone or in

combination refers to a monocyclic or polycyclic group, preferably a monocyclic or bicyclic group, i.e., phenyl or naphthyl, which may be substituted or unsubstituted, for example, with one or more, preferably 1 to 3 substituents, selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfonyl, and alkylsulfonyl. Examples of such aryl groups include phenyl, 2-chlorophenyl,

3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 2-methylphenyl, 3-methylphenyl, 2,5-dimethylphenyl,

4-methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 4-aminophenyl, 4-methylthiophenyl, 4-methylsulfinylphenyl, 4-methylsulfonylphenyl, 1-naphthyl, 2-naphthyl, etc.

The term "heteroaryl" refers to a heterocyclic aromatic group with 5 or 6 members, which may optionally bear a condensed benzene ring, and which may be substituted or unsubstituted, for example, with one or more, preferably 1 to 3, substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl, and alkylsulfonyl. Examples of such heteroaryl groups include 2-thienyl, 3-thienyl, 3-benzothienyl, 3-benzofuranyl, 2-pyrrole, 3-mololyl, etc., which may be unsubstituted or substituted as indicated. The saturated nitrogen heterocycle with 5 or 6 members attached via the nitrogen atom may contain another nitrogen atom or a

5

oxygen or sulfur atoms; examples of these heterocycles are pyrrolidino, piperidino, piperazino, morpholino, and thiamorpholino. The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

5. Compounds of formula I where Z represents

8 9

CH and R represent a group of formula -(CH~) -R

10 ^ P

where p ranges from 1 to 5 or -(CH9) -R contain an asymmetric carbon atom z. q and can therefore exist in racemic or optically active form. Invention 10 includes within its scope not only racemic compounds, but also optically active isomers.

In the preferred classes of compounds of 1 2

formula I, R and R together represent -CH„- and

•y ^

15 R represents a hydrogen atom, m is equal to 1 or 2 and Z

12

represents CH; or R and R together represent

7

-(CH»).,- and R represents a hydrogen, m is equal to 1 and

12

Z represents CH; or R and R together represent

7

-CH»- and R represents a hydrogen, m is 2 and Z

* 17

20 represents N; or R and R together represent o

-CH2~ and R represents a hydrogen atom, m equals 1 and Z

represents CH;

17 - 2

or R and R together represent -(CH2)2~ and R

represents a hydrogen atom, m is 0, and Z represents

25 CH.

3

R preferably represents a phenyl group,

naphthyl, 3-benzothienyl, 3-benzofuranyl, or 3-indolyl which is possibly substituted as defined above, in particular l-methyl-3-indolyl.

A £ G

30 Preferably, R, R and R each represent a

8 ✓

hydrogen. R preferably represents a group of i

formula -(CH9) -R. Preferably, q equals 1 or 2.

10^4

R preferably represents a hydroxyl group, an amino group,

a monoalkylamino, dialkylamino, trialkylamino,

azido, acylamino, alkylcarbonyloxy, or alkylsulfonyl-

oxy or a group with the formula -U-C(V)-W. Preferably,

U represents S, V represents NH and W represents an amino.

Particularly preferred compounds provided by the invention include:

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

3-[7-(amidinothiomethyl)-6,7,8,9-tetrahydropyrido-1,2-a]indol-10-yl1-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione and

3-16,7,8,9-tetrahydro-8-[(dimethylamino)methyl1 pyrido- [ 1, 2-a ] inçiol-10-yl ]-4- ( l-methyl-3-indolyl ) -1H-pyrrole-2,5-dione and their pharmaceutically acceptable acid addition salts.

According to the method provided by the invention,

We prepare compounds of formula I and pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids (a) to prepare a compound of formula I where X and Y both represent 0, by reacting a compound of general formula

where R1, R2, R3, R4, R5, R6, R7, R8, Z and m have the i

meaning given above,

with pressurized ammonia or with hexamethyldisilazane and methanol to give a compound of formula I, where R represents a hydrogen, or with 11-hydroxylamine to give a compound of formula I, where R represents a hydroxy, or

(b) to prepare a compound of formula I where one of the radicals X and Y represents 0 and the other represents (H,H), by reducing a compound of formula I where X and Y both represent 0 with lithium-aluminum hydride, or

(c) if desired, by functionally modifying a reactive center present in a compound of formula I obtained, and

(d) also if desired, by transforming an acidic compound of formula I into a pharmaceutically acceptable salt with a base or by transforming 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 according to embodiment (a) of the process is conveniently carried out using ammonia (preferably 33% ammonia) and in the presence of an inert, water-miscible organic solvent such as dimethylformamide, etc. The reaction is preferably carried out at a high temperature, for example, a temperature in the range of about 100°C to about 150°C.

The reaction of a compound of formula II with hexamethyldisilazane and methanol, also according to embodiment (a) of the process, is conveniently carried out in an inert organic solvent, such as a halogenated hydrocarbon (e.g., chloroform, tetrachloride).

8

of carbon or chlorobenzene) or an aromatic hydrocarbon (e.g. benzene, toluene or xylene) and at a high temperature (e.g. a temperature between about 40°C and 110°C).

The reaction of a compound of formula II with hydroxylamine, also according to embodiment (a) of the process, is conveniently carried out in an inert organic solvent such as dimethylformamide, etc., and at room temperature or at an elevated temperature, preferably at an elevated temperature (e.g., about 100°C). It is convenient to use hydroxylamine in the form of a salt such as the hydrochloride, and the reaction is carried out in the presence of a base such as an alkali metal carbonate (e.g., sodium or potassium carbonate).

The reduction of a compound of formula I where X and Y both represent 0 with lithium aluminum hydride according to embodiment (b) of the process is conveniently carried out in an inert organic solvent such as an aliphatic or cyclic ether (e.g. diethyl ether, tetrahydrofuran) at a temperature between about 0°C and the reflux temperature of the reaction mixture.

If desired, a reactive center present in a compound of formula I can be modified according to embodiment (c) of the process. All these modifications can be carried out according to con-

8

bare. For example, when R represents a group of

9 9

formula -(ÇH ) -R where R represents an alkoxycarbonyl

£, P

and p equals 0, this group can be transformed into a rou-

9

corresponding pe where R represents a hydrogen by

9

treatment with an acid. Here again, for example, a group of the formula -(CH») -R"^ where R"^ represents an alkoi-carbonyloxy can be transformed into a corresponding group where R"^ represents a hydroxyl by approximate treatment.

5 prayed with a base. A formula group ~(CH») -R10 10 , ^4

where R represents a hydroxyl group can be transformed into a corresponding group where R^ represents an amino group,

monoalcoylamino, dialcoylamino, trialcoylamino, or a heterocycle containing nitrogen saturated at 5 or 6 chains

10 non-attached via the nitrogen atom by a treatment first with anhydrous tri-

fluoromethanesulfonic acid and then with ammonia, a monoalkylamine, a dialkylamine, a trialkylamine, or a suitable heterocycle, respectively. One can

15. To react a group of formula -(CH») -R^ where 10

R represents a hydroxyl group with an alkane-sulfonic anhydride to give a corresponding group where R"^ represents an alkoxide-sulfonyloxyl group. A group with the formula -(CH») -R"^ can be transformed where R"^ represents a

"10

20 alkoolsulfonyloxy in a corresponding group where R

represents a formamido by reaction with ammonia in dimethylformamide, or where R^ represents an azido by reaction with an alkali metal azide, or R"^ represents a group of formula -U-C(V)-W 25 where U represents S, V represents NH, and W represents an amino by reaction with thiourea. Furthermore, one can transform a group of formula -(CH») -R"^ where

10 *

R represents an azido by catalytic hydrogenation into a corresponding group where R1^ represents an amino.

30. We can transform a group of formula -(CH») -R10 10

where R represents an alkoxycarbonylamino in a corresponding group where R^ represents an amino by treatment

10

with an acid. A group of formula can be acylated

-(CH9) -R"^ where R"^ represents an amino to give

"10

a corresponding group where R represents an acylamino, or it can be reacted with 3,5-dimethyl-2

N-nitro-l-pyrazole-l-carboxamide to give a corresponding group where R^ represents a group of formula -U-(C(V)-W where U represents NH, V represents NH, and W represents NNO2. Furthermore, a group of formula -(CH~)-R^ can be transformed where R^ represents an amino

X 10

in a corresponding group where R represents an iso-thiocyanate by reaction with 1,1-thiocarbonyl di-

9

xmidazole. We treat a group of formula -(CH„) -R

9 P

where R represents a cyanoacrylate with hydrochloric acid and then with ammonia to give a corresponding group

pondant where R represents an amidino. Here again, for example, we can transform a compound of formula

✓ 8

I where Z represents N and R represents a group of g 9

formula -(CH9) -R where p represents 0 and R is a

% I? ^ 9

hydrogen in a corresponding compound where R represents an alkylcarbonyl, alkoxycarbonyl, or alkoxycarbonyl by appropriate acylation, in a compound

^ Q

corresponding where R represents an alkalisulfonyl by reaction with an alkanesulfonyl chloride, in a

9

corresponding compound where R represents an aminoalkoyl-carbonyl by treatment with a trifluoroacetamidoalcanoyl chloride and then by reaction with ammonia-

9

that, in a corresponding compound where R represents an aminocarbonyl by treatment with 1,1-carbonyl-diimidazole and then by reaction with ammonia or in a corresponding compound where R represents an aminothiocarbonyl by treatment with 1,1-thio-carbonyldiimidazole and then by reaction with

11

ammonia. It should be noted that the preceding modifications are given only as examples and that other modifications within the competence of specialists are also possible.

The transformation of an acidic compound of formula I into a pharmaceutically acceptable salt according to embodiment (d) of the process can be carried out by treatment with a suitable base in a known manner. Suitable salts are those derived not only from inorganic bases, for example sodium salts, potassium salts, calcium salts, etc., but also from organic bases such as ethylenodiamine, mcjnoethanolamine, diethanolamine, etc. The transformation of a basic compound of formula I into a pharmaceutically acceptable salt, also according to embodiment (d) of the process, can be carried out by treatment with a suitable acid in a known manner. Suitable salts are those derived not only from inorganic acids, for example hydrochlorides, hydrobromides, phosphates, sulfates, etc., but also from organic acids, for example acetates, citrates, fumarates, tartrates, maleates, methanesulfonates, p-toluenesulfonates, etc.

The compounds of formula II, which are used as starting materials in embodiment (a) of the process, are novel and constitute another object of the invention. They can be prepared by reacting a compound of general formula

12

ILI

2 4 5 6 7 8 where R, R, R, R, R, R, R, Z and m have the meaning given above,

with a compound of general formula

HOOC-CH2-R3

IV

3

where R has the meaning given above, and if desired, by functionally modifying a reactive center present in a compound of formula II obtained.

The reaction of a compound of formula III with a compound of formula IV is preferably carried out in the presence of an acid-binding agent, conveniently a tertiary 10-amine such as a trialcoylamine (e.g.

triethylamine, diisopropylethylamine, etc.), and in an inert organic solvent such as a halogenated aliphatic hydrocarbon (dichloromethane, etc.) at around room temperature.

15 The optional functional modification of a reactive substituent present in a compound of formula II can be carried out in the same way as described above in relation to the functional modification of a reactive center present in a compound of formula 20 I.

n

13

Compounds of formula III can, in turn, be prepared by reacting a compound of general formula

V

where R1, R2,

R4, R^, R^, R7, R8, Z and m have the meaning

5. cation given above,

with oxalyl chloride, conveniently in an inert organic solvent, such as a halogenated aliphatic hydrocarbon (e.g., dichloromethane, etc.) at a temperature ranging from about 0°C to the reflux temperature of the solvent. The resulting compound of formula III can be reacted in situ with the compound of formula IV, or it can be isolated and purified (e.g., by concentration followed by crystallization) before reaction with the compound of formula IV. The compounds of formula V above are known compounds or analogs of known compounds that can be prepared in a manner analogous to the known compounds. In addition, some of the following examples contain detailed information on 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,

25

14

For example, they inhibit proliferation and can be used to combat or prevent diseases, such as inflammatory diseases like arthritis, immune diseases, in conjunction with organ transplants, and also in oncology. They inhibit the infection of cells by a human immunodeficiency virus and are thus useful in the treatment of AIDS. The compounds and salts of the invention also inhibit the contraction of smooth muscles and can therefore be used against cardiovascular and bronchopulmonary diseases. In addition, they are also useful in the treatment of asthma.

The activity of the present compounds to inhibit protein kinase C can be demonstrated by means of the in vitro assay system described e.g. in BBRC 19 (1979) 1218.

The CI^q figures in the table below represent the concentration of experimental compound that reduces incorporation by 50%, induced by the

32 32

20 protein kinase of P from [y- PlATP in the histone.

25

30

15

PAINTING

Compound CIc„

OF

I

3-[8-(aminomethyl1)-6,7,8,9-tetrahydropyrido[1,2-a]indol-5 10-yl]-4-(l-methyl-3-indolyl)-1H- hydrochloride

pyrrole-2,5-dione 8 nM

3-[7-(amidinothio-methyl)-6,7,8,9-tetrahydropyridox,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-1H-10 pyrrole-2,5-dione methanesulfonate 15 nM

3-[2-(aminoacetyl)-1,2, hydrochloride

3,4-tetrahydropyrazino.[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-

2.5-dione 50 nM

15 3-[7-(2-aminoethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione hydrochloride 20 nM

3-[6,7,8,9-tetrahydro-8-[(1-piperidino)-20 methyl]pyrido[1,2-a]indol-10-yl]-4-(1-

methyl-3-indolyl-1H-pyrrole-2,5-dione 30 nM

3-[2,3-di-hydro-2-(dimethylaminomethyl)-1H-pyrrolo [1,2-a]indol-9-yl]-4-(l-methyl-3-indolyl)-25 lH-pyrrole-2,5-dione trifluoromethanesulfonate 20 nM

16

3-[8-amidino-6,7,8,9-tetrahydropyrido-[1,2-alindol-10-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione hydrochloride

5

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

10

The compounds of formula I and their salts mentioned above must be used as medicinal products, for example in the form of pharmaceutical preparations. Pharmaceutical preparations may be administered orally, for example as tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, or suspensions. However, they may also be administered rectally (e.g., as suppositories) or parenterally (e.g., as injectable solutions).

For the preparation of pharmaceutical preparations, compounds of formula I and those mentioned above may be formulated with therapeutically inert inorganic or organic carriers. For example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., may be used as such carriers for tablets, coated tablets, dragees, and hard gelatin capsules. Suitable carriers for soft gelatin capsules include, for example, vegetable oils,

60 nM

10 nM

17

Waxes, fats, semi-solid and liquid polyols, etc., are suitable carriers. Depending on the nature of the active substance, however, carriers are not necessary for soft gelatin capsules. Suitable carriers for preparing solutions and syrups include water, polyols, sucrose, invert sugar, glucose, etc. Suitable carriers for injectable solutions include water, alcohols, polyols, glycerin, vegetable oils, etc. Suitable carriers for suppositories include natural or hardened oils, waxes, fats, semi-liquid polyols, etc.

Pharmaceutical preparations may also contain preservatives, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, softening agents, coloring agents, perfumes, salts to vary osmotic pressure, buffers, coating agents, or antioxidants.

They may also contain other therapeutically interesting substances. The invention also covers medicinal products containing a compound of formula I or one of its salts as defined above and a therapeutically inert carrier, as well as a method for preparing such medicinal products. This method involves placing a compound of formula I or one of its salts, as defined above, into a pharmaceutical dosage form with a therapeutically inert carrier and, if desired,

one or more other therapeutically active substances.

18

As mentioned above, the compounds of formula I and their salts mentioned above can be used to combat or prevent diseases, in particular to combat or prevent inflammatory, immunological, bronchopulmonary, and cardiovascular diseases, and for the treatment of asthma or AIDS. The dosage can vary within wide limits and is naturally adjusted to individual needs in each particular case. In general, for oral administration to adults, a daily dose of about 5 mg to about 500 mg should be appropriate, although the upper limit may be exceeded when expedient. The daily dose may be administered all at once or in divided doses. The following examples further specify the invention:

EXAMPLE 1

A solution of 2.90 g of 3-[8-(acetoxymethyl)-6,7,8,9-20 tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-

indolyl)furan-2,5-dione and 23 ml of 33% ammonia. The mixture is extracted with ethyl acetate and the combined organic extracts are washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness. Crystallization of the residue from the acetate gives 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-2,5-dione as a red solid at 262-263°C. The starting material pyranedione is prepared as follows:

19

a) 25 g of ethyl indole-2-carboxylate is added in 400 ml of DMF 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.

5. Then add drop by drop to the mixture at 0°C

30.9 g of ethyl bromobutyrate is mixed, and the resulting mixture is left at room temperature for 18 hours. The reaction is stopped with 100 mL of water and 30 mL of 2 M hydrochloric acid, and the mixture is extracted with dichloromethane. The combined organic extracts are washed with water, dried over anhydrous sodium sulfate, and evaporated to give 49 g of an oil. This oil is dissolved in ethyl acetate, and the solution is washed with water, dried over anhydrous sodium sulfate, and then...

Evaporate to give 39 g of an oil. This oil is added dropwise to a stirred suspension of 20.5 g of potassium t-butoxide in 750 mL of THF under a nitrogen atmosphere. After one hour, 20200 mL of water is added, followed by 92 mL of 2 M hydrochloric acid. The mixture is concentrated, and the resulting precipitate is separated by filtration and dried to give 25.3 g of ethyl 6,7-dihydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate. A 25 g sample is crystallized from methanol, giving crystals with a boiling point of 101–103 °C.

b) A suspension of 19.4 g of Raney nickel carboxylate is heated under reflux for 3 hours (a) and 6 spoonfuls of spatula-sized amounts in 48.0 ml of ethanol.

30,240 ml of water. Then add another 4 scoops of Raney nickel and heat the mixture at reflux for another 1 hour. Remove

20

The supernatant is decanted and the catalyst is washed with ethyl acetate. The combined organic phases are concentrated and the precipitate is separated by filtration to give 16.3 g of ethyl 6,7,8,9-tetrahydro-5-pycido[1,2-a]indole-8-carboxylate. A sample is crystallized from methanol to give a solid with a boiling point of 70-72°C.

c) 16.2 g of carboxylate from b) in 200 mL of THF is added to a suspension of 2.00 g of lithium-10 aluminum hydride in 600 mL of THF at 0°C under a nitrogen atmosphere. After 10 hours, the reaction is stopped by successive additions of ethyl acetate, water, and 2 M hydrochloric acid, and the mixture is extracted with diethyl ether. The combined organic extracts are dried and evaporated. Crystallization of the residue from diethyl ether/n-hexane gives 11.5 g of 6,7,8,9-tetrahydro-8-(hydroxymethyl)pyrido[1,2-a]indole at 110–111°C.

d) 11.4 g of acetic anhydride is added to a solution of 11.0 g of pyridoindole from c) in 100 mL of pyridine, and the resulting solution is stirred under a nitrogen atmosphere for 18 hours. Most of the pyridine is removed by evaporation, and the residue is acidified with 2 M hydrochloric acid. The mixture is extracted with diethyl ether, and the combined extracts are washed with a sodium bicarbonate solution and water. The extracts are dried and evaporated to dryness to give 11.25 g of 8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole at 30 pf. 63–64°C.

21

e) 4.13 g of oxalyl chloride is added dropwise to a solution of 8.2 g of tetrahydropyridoindole from d) in 160 mL of diethyl ether under a nitrogen atmosphere. After 10 minutes, solvent 5 is removed at reduced pressure and the residue is dissolved in

330 mL of dichloromethane. 6.34 g of l-methyl-3-indolylacetic acid and 9.20 mL of triethylamine are added to this solution, and the mixture is stirred overnight. A further 4.60 mL of triethylamine is added. After 48 hours, the solvent is removed under reduced pressure, and the residue is purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2). Crystallization from ethyl acetate yields 4.02 g of 3-[8-(acetoxymethyl)-6,7,8,9-15 tetrahydropyrido[1,2-a]indol-10-yl1-4-(l-methyl-3-indolyl)furan-2,5-dione at Pf. 174–178°C.

EXAMPLE 2

2.50 g of trifluoromethanesulfonic anhydride is treated in 330 mL of dichloromethane at 0°C under a nitrogen atmosphere with a suspension of 1.87 g of pyrroledione product from Example 1 and 0.94 g of collidine in 280 mL of dichloromethane. After 2 hours, the mixture is allowed to warm to 10°C. Then, 37 mL of 33% ammonia is added, and the mixture is allowed to warm to room temperature overnight. The mixture is washed with water, dried, and evaporated. The residue is subjected to silica gel chromatography with dichloromethane/methanol/acetic acid/water (90:18:3:2). The fractions containing the combined product are treated with 2 M hydrochloric acid and evaporated to give 930 mg of

22

3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione hydrochloride Pf■310-313°C.

EXAMPLE 3

265 mg of trifluoromethanesulfonic anhydride is treated in 40 mL of dichloromethane at 0°C under a nitrogen atmosphere with a suspension of 200 mg of the pyrroledione product from Example 1 and 100 mg of collidine in 30 mL of dichloromethane. After 5 hours, 0.5 mL of a 33% trimethylamine solution in ethanol is added, and the mixture is stirred for 18 hours. The resulting precipitate is separated by filtration and dried to give 237 mg of trifluoromethanesulfonate of 3-[6,7,8,9-tetrahydro-8-[(trimethylammonio)methyl]pyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione at 320-324°C.

EXAMPLE 4

265 mg of trifluoromethanesulfonic anhydride is treated in 40 mL of dichloromethane at 0°C under a nitrogen atmosphere with a suspension of 200 mg of the pyrroledione product from Example 1 and 100 mg of collidine in 30 mL of dichloromethane. After 5 hours, 0.75 mL of a 33% methylamine solution in denatured alcohol is added, and the mixture is stirred for 18 hours. Then, another 0.5 mL of the aforementioned methylamine solution is added. After 4 hours, the solvent is removed by evaporation, and the precipitate is removed by filtration and purified by silica gel chromatography with dichloromethane/methanol/acetic acid/water (90:18:3:2). The solid product is shaken with ethyl acetate saturated with hydrochloric acid.

for 2 hours. The resulting solid is separated by filtration and dried to give 5 mg of 3-[6,7,8,9-tetrahydro-8-[(methylamino)-methyl]pyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione hydrochloride at Pf 337-340°C.

EXAMPLE 5

185 mg of trifluoromethanesulfonic anhydride is treated in 30 mL of dichloromethane at 0°C under a nitrogen atmosphere with a suspension of 140 mg of the pyrroledione product from Example 1 and 70 mg of collidine in 25 mL of dichloromethane. After 1 h, 0.8 mL of a 33% dimethylamine solution in ethanol is added, and the mixture is stirred for 2 h. The solvent is removed under reduced pressure, and the residue is triturated with methanol to give a solid, which is then stirred with ethyl acetate saturated with hydrochloric acid. The solid is removed by filtration and dried to give 70 mg of 3-[6,7,8,9-tetrahydro-8-[(di-methylamino)methyl]pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride at Pf. 335-336 °C.

EXAMPLE 6

A solution of 170 mg of the pyrroledione product from Example 1 in 55 mL of dichloromethane is treated with 87 mg of methanesulfonic anhydride and 1 mL of pyridine. The resulting solution is stirred under nitrogen for 1 hour. Then, 30 mg of methanesulfonic anhydride is added. After one hour, the mixture is washed with water, dried, and evaporated. Crystallization of the residue at par-

24

The reaction of ethyl acetate/n-hexane yields 150 mg of 3-16,7,8/9-tetrahydro-8-(methylsulfonyloxymethyl)pyrido-[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione at a temperature of 259-261°C. EXAMPLE 7

A solution of 120 mg of the pyrroledione product from Example 6 in 6 mL of DMF and 6 mL of 33% ammonia is heated at 140°C for 6 hours. The cooled mixture is poured into water, and the precipitate is separated by filtration. The product is purified by silica gel chromatography with dichloromethane/ethyl acetate/methanol/water (60:18:2:3). Trituration with ethyl acetate gives 50 mg of 3-[8-(formamidomethyl)-6,7,8,9-15-tetrahydropyridol-1,2-α]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione at Pf. 332–334°C.

EXAMPLE 8

A solution of 100 mg of product 20 of pyrroledione from Example 6 and 75 mg of thiourea in 5 ml of DMF is heated to 80°C under a nitrogen atmosphere for 18 hours. The solvent is removed by evaporation and the residue is purified by silica gel chromatography with dichloromethane/methanol/acetic acid/water (90:18:3:2). The residue is triturated with 25 of ethyl acetate to give 80 mg of methanesulfonate of 3-[8-[(amidinothio)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]-indol-10-yl]-4-(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione at 200-205°C.

EXAMPLE 9

30. In a manner analogous to what is described in the first paragraph of example 1, starting from the

25

3-[7-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-r-methyl-3-indolyl)furan-2,5-dione is prepared. 3-[6,7,8,9-tetrahydro-7-(hydroxymethyl)pyrido-[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-5,2,5-dione is prepared at Pf. 239-242°C.

The furanedione starting material is prepared as follows: i a) 6.6 mL of a 1.6 M n-butyllithium in n-hexane solution is added to a stirred solution of

10 µg of diisopropylamine is dissolved in 150 mL of THF at -78°C under nitrogen. The mixture is allowed to warm to -20°C for 5 minutes and then cooled again to -78°C. 1.85 g of 6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one is then added dropwise to 10 mL of THF. After stirring at -78°C for 1 hour, 1.19 g of ethyl chloroformate is added, and the mixture is allowed to warm to room temperature. The solvent is removed by evaporation, and the residue is divided between diethyl ether and 2 M hydroxychloride. The ether extracts are washed with a saturated sodium bicarbonate solution and concentrated to yield an oil. This oil is purified by silica gel chromatography with dichloromethane. Crystallization of the product from methanol 25 gives 1.35 g of 6,7,8,9-tetrahydro-6-oxo-pyrido

[1,2-a]ethyl indole-7-carboxylate Pf. 82-84°C.

b) 30 ml of a 1 M borane solution in THF is added to a stirred solution of 1.25 g of carboxylate from a) and the resulting solution is heated under reflux

30 for two hours under a nitrogen atmosphere. Six spatula-sized scoops of silica gel are added to the cooled solution, and the solvent is removed.

26

by evaporation. The residue is purified by silica gel chromatography with ethyl acetate/n-hexane (1:1) to give an oil. This oil is dissolved in 60 mL of dichloromethane containing 8 mL of pyridine and 2 mL of acetic anhydride. After 18 hours, the solution is washed with 60 mL of 2 M hydrochloric acid and 20 mL of saturated sodium bicarbonate solution, dried, and evaporated to give an oil. A solution of this oil is treated in 60 mL of diethyl ether with 630 mg of oxalyl chloride under a nitrogen atmosphere. The solvent is then removed at reduced pressure, and the residue is dissolved in 100 mL of dichloromethane. 920 mg of l-methyl-3-indolyl acetic acid and 975 mg of triethylamine are added to this solution. After 72 hours, the solvent is removed by evaporation and the residue is purified by silica gel chromatography with ethyl acetate/n-hexane (1:1). Crystallization from ethyl acetate gives 390 mg of 3-[7-(acetoxymethyl)-6,7,8,9-tetrahydropyridox,2-α]indol-10-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione at Pf. 190-193°C.

EXAMPLE 10

200 mg of trifluoromethanesulfonic anhydride in 50 mL of dichloromethane is treated at 0°C under a nitrogen atmosphere with a suspension of 150 mg of the pyrroledione product from Example 9 and 75 mg of collidine in 50 mL of dichloromethane. After 2 hours, 4 mL of 33% ammonia is added, and the mixture is allowed to warm to room temperature overnight. The mixture is washed with water, dried, and evaporated to dryness. It is purified

27

the residue by silica gel chromatography with dichloromethane/methanol/acetone/water (90:18:3:2).

Crystallization from dichloromethane/n-hexane gives 85 mg of 3-[7-(aminomethyl)-6,7,8,9-5 tetrahydropyrido|1,2-a]indol-10-yl]-4-(1-methyl-

3-indolyl)-1H-pyrrole-2,5-dione, m.p. 160-165°C.

EXAMPLE 11

A solution of 120 mg of the pyrroledione product from Example 9 in 80 mL of dichloromethane with 2 mL of pyridine and 100 mg of methanesulfonic anhydride is treated under a nitrogen atmosphere. After stirring for 18 hours, the mixture is washed with 2 M hydrochloric acid and a saturated sodium bicarbonate solution, dried, and evaporated to give 130 mg of a gum. This gum is dissolved in 40 mL of ethanol containing 200 mg of thiourea, and the mixture is heated under reflux for 72 hours. The solvent is removed by evaporation, and the residue is purified by silica gel chromatography with dichloromethane/methanol/acetone/water (90:18:3:2). Crystallization from methanol/dichloromethane gives 30 mg of 3-[7-(amidino-thiomethyl)-6,7,8,9-tetrahydropyridol-1,2-α]indol-10-yl methanesulfonate

4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione of 25 Pf. 195-198 °C.

EXAMPLE 12

A solution of 72 mg of 3-(6,7,8,9-tetrahydropyrido[1,2-a]in-dol-10-yl)-4-(l-methyl-3-indolyl)furan-2,5-dione is heated at 140°C for 4 hours in 305 ml of DMF and 5 ml of 33% ammonia. The resulting crystals are separated by filtration and dried to give 50 mg of 3-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione with a Pf. of 286-289°C.

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The starting product furanedione is prepared as follows:

a) A solution of 1.03 g of 6,7-dihydro-9-hydroxypyrido[1,2-α1-indole-8-

5 carboxylate in 20 ml of ethanol, 10 ml of water and 10 ml of concentrated hydrochloric acid. The solvent is evaporated to give 740 mg of 7,8-dihydropyrido-[1,2-α1indol-9(6H)-one at Pf 138-140°C.

b) A solution of 740 mg of product of a), 600 mg of hydrated hydrazine, and 440 mg of potassium hydroxide in 2 mL of ethanol and 4 mL of diethylene glycol is heated at 100°C under reflux for 1 hour. The mixture is then heated at 180°C for 2 hours. 50 mL of dichloromethane is added, and the organic phase is washed with 2 M hydrochloric acid and water. The solvent is removed by evaporation to give 405 mg of 6,7,8,9-tetrahydropyrido-[1,2-alindole].

c) Add 350 mg of oxalyl chloride dropwise to a solution of 450 mg of product from b) in 13 ml

20 ml of dichloromethane at 0°C. After stirring for 2 hours, the solvent is removed by evaporation and the residue is dissolved in dichloromethane. 497 mg of 3-methylindoleacetic acid and 0.73 ml of triethylamine are added to this solution, and the mixture is stirred at 25°C room temperature for 60 hours.

The solvent is evaporated and the residue is purified by silica gel chromatography with dichloromethane. Trituration of the product with ethyl acetate gives 100 mg of 3-(6,7,8,9-tetrahydropyrido[1,2-a]indol-30 10-yl)-4-(l-methyl-3-indolyl)furan-2,5-dione as a red solid with a boiling point of 276-278°C.

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EXAMPLE 13

In a manner analogous to what is described in the first paragraph of example 1, from 3-[8-(2-acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-a] 5 indol-10-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione,

we prepare 3-[6,7,8,9-tetrahydro-8-(2-hydroxyethyl)pyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione at Pf 261-263°C.

The starting product furanedione 10 is prepared as follows:

a) A solution of 6.52 g of 8-(2-acetoxyethyl)-6,7,8,9-tetrahydro-9-oxopyrido11,2-α-indole in 48 mL of dichloromethane is treated with 2.5 mL of ethanedithiol and 3.13 mL of titanium tetrachloride. The resulting solution is heated under reflux in nitrogen for 18 hours. An additional 4 mL of ethanedithiol and 9 mL of titanium tetrachloride are added, and the mixture is heated for another 4 hours. The mixture is washed with water, dried, and evaporated. The residue 20 is purified by silica gel chromatography with ethyl acetate/petroleum ether (1:3) to give 7.7 g of 8'-(2-acetoxyethyl)-71,81-dihydrospiro[1,3-dithio-lane-21,91(6'H)-pyrido[1,2-a]indole].

b) A solution of 5 g of the product of a) is stirred in 25,200 ml of ethanol with 8 scoops of Raney nickel for 3 hours. h- The mixture is filtered and the filtration residue is washed with ethanol. The filtrate and the combined wash water are evaporated to dryness and the residue is purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) to give 620 mg of 8-(2-acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole.

30

c) 1.19 g of oxalyl chloride is added dropwise to a solution of 2.29 g of the product of b)

in 50 mL of diethyl ether at 0°C. After 2 hours, the solvent is removed by evaporation and the residue is dissolved in dichloromethane. 168 g of 1-methyl-3-indolylacetic acid and 2.45 mL of triethylamine are added to this solution, and the mixture is heated under reflux in nitrogen for 18 hours. The solvent is evaporated, and the residue is purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2). Crystallization from ethyl acetate yields 625 mg of 3-[8-(2-acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-furan-2,5-dione at a boiling point of 159-161°C. 15 EXAMPLE 14

A solution of 115 mg of 3-[8-(2-acetoxyethyl)-6,7,8,9-tetrahydropyridol1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-furan-2,5-dione is heated at 140°C for 4 hours in 1 ml of DMF and 2 ml 20 of 33% ammonia. The cooled mixture is evaporated and the residue is purified by silica gel chromatography with ethyl acetate/petroleum ether (2:1). Crystallization from ethyl acetate/petroleum ether gives 13 mg of 3-(8-(2-acetoxyethyl)-25 6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]—4—(1—methyl-3-indolyl)-1H-pyrrole-2,5-dione at Pf 272-274°C.

EXAMPLE 15

A solution of 500 mg of product 30 of pyrroledione from Example 13 in 50 mL of dichloromethane is treated with 218 mg of methanesulfonic anhydride and 1 mL of pyridine. The resulting solution is shaken at

31

room temperature under a nitrogen atmosphere for 1 hour. Then 20 mg of methanesulfonic anhydride is added and stirring continues for another hour. The mixture is washed with water, dried, and evaporated. Crystallization of the residue from ethyl acetate/petroleum ether gives 540 mg of 3-[6,7,8,9-tetrahydro-8-(2-methylsulfonyloxyethyl)pyrido-[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione at Pf. 244-245°C.

EXAMPLE 16

A solution of 500 mg of pyrroledione product from Example 15 and 250 mg of sodium azide in 10 ml of DMF is heated to 70°C for 3 hours. The solvent is removed by evaporation and the solid is distributed between ethyl acetate and water. The insoluble material is separated by filtration and dried to give 425 mg of 3-[8-(2-azidoethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione at Pf. 262-264°C.

EXAMPLE 17

200 mg of the pyrroledione product from Example 16 is stirred in 70 mL of methanol containing 40 mg of 10% Pd under a hydrogen atmosphere at a pressure of 3 atmospheres for 48 hours. The supernatant is removed by decantation and evaporated. The residue is treated with 50 mL of a saturated solution of hydrochloric acid in ethyl acetate and then purified by silica gel chromatography with dichloromethane/methanol/acetic acid/water (60:18:2:3). Crystallization from ethyl acetate gives 20 mg of 3-[8-(2-aminoethyl)6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl) lH-pyrrole-2,5-dione at Pf. 160-165°C.

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EXAMPLE 18

Similar to what is described in the first paragraph of Example 12, from 3-[2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl]-4-(1,5-methyl-3-indolyl)furan-2,5-dione we obtain the

3-[2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl]— 4 —(1 — methyl-3-indolyl)-1H-pyrrole-2,5-dione de Pf 260-270°C.

The starting product furanedione 10 is prepared as follows:

175 mg of oxalyl chloride is 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°C under a nitrogen atmosphere. After one hour, the solvent is removed under reduced pressure and the residue is dissolved in 14 mL of dichloromethane. 245 mg of 1-methyl-3-indolylacetic acid and 265 mg of triethylamine are added to this solution, and the mixture is stirred at room temperature for 72 hours. The solvent is removed under reduced pressure, and the residue is purified by pure silica gel chromatography with ethyl acetate/petroleum ether (1:2). Crystallization from ethyl acetate gives 70 mg of 2 —[2,3 — dihydro-1H-pyrrolo[1,2-a]indol-9-yl]-4-(1-methyl-3-25 indolyl)furan-2,5-dione at Pf. 125-130°C.

EXAMPLE 19

In a manner analogous to what is described in the first paragraph of example 1, from the 3-[2-(acetoxymethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-30 yl]-4-(l-methyl-3-indolyl)furan-2,5-dione, the 3-[2,3-dihydro-2-(hydroxymethyl)-1H-pyrrolo[1,2-a]indol-9-yl]-4-(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione is prepared at Pf 238-240°C.

33

The starting product furanedione is prepared as follows:

a) Add 6 spatula-sized measures of Raney nickel to a 5.08 g solution of ethyl 2,3-dihydro-l-oxo-lH-pyrrolo[1,2-a,]indole-2-carboxylate in

180 ml of ethanol and 90 ml of water. The mixture is heated under reflux for 10 hours, then 3 more spatula-sized measures of Raney nickel are added. Heating continues for 5 hours, after which the mixture is cooled and filtered. The filter residue is washed with ethyl acetate and dichloromethane. The filtrate and combined wash water are evaporated, and the residue is purified by silica gel chromatography with diethyl ether/petroleum ether (1:2). Crystallization from methanol yields 635 mg of ethyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-carboxylate at 55-57°C.

b) Four mL of a 1 M lithium-aluminum hydride solution are 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 one hour, 30 mL of saturated ammonium chloride solution are added, and the mixture is evaporated. The residue is extracted with dichloromethane, and the organic extract is dried and evaporated. Crystallization of the residue from diethyl ether/petroleum ether yields 355 mg of 2,3-dihydro-2-(hydroxymethyl)-1H-pyrrolo[1,2-a]indole of Pf. 76–78°C.

c) A solution of 355 mg of the product from b) is stirred for 2 hours in 20 mL of dichloromethane containing 2 mL of acetic anhydride and 2 mL of pyridine. The solvents are evaporated, and the residue is distributed between the dichloromethane and water. The phase is dried.

34

organic compound is evaporated to give 420 mg of 2-(acetoxymethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole. d) 290 mg of oxalyl chloride is added dropwise to a solution of 420 mg of the product of c) in 5 14 mL of diethyl ether under a nitrogen atmosphere. After one hour, the solvent is removed at reduced pressure and the residue is dissolved in dichloromethane. 420 mg of 1-methyl-3-indolylacetic acid and 485 mg of triethylamine are added to this solution and the mixture is stirred for 72 hours. The solvent is evaporated and the residue is purified by silica gel chromatography with ethyl acetate/petroleum ether (1:1). Crystallization from ethyl acetate gives 90 mg of 3-[2-(acetoxymethyl)-2,3-dihydro-15 lH-pyrrolo[1,2-a]indol-9-yl]-4-(1-methyl-3-indolyl) furan-2,5-dione at Pf. 208-211°C.

EXAMPLE 20

A solution of 150 mg of 3-[2-t-butoxycarbonyl-l,2,3,4-20 tetrahydropyrazino. [1,2-a]indol-10-yl]-4-(l-methyl-3-

indolyl)furan-2,5-dione in 4 mL of DMF and 8 mL of 33% ammonia. The mixture is extracted with ethyl acetate, and the organic extract is washed with water, dried, and evaporated to give a gum. 25 Purification is carried out by silica gel chromatography with dichloromethane/methanol/acetic acid/water. The resulting imide is dissolved in 30 mL of ethanol and 5 mL of 2 M hydrochloric acid, and the resulting solution is heated under reflux for 2 hours 30 minutes. Removal of the solvent by evaporation and trituration of the residue with ethyl acetate give 35 mg of 3-[1,2,3,4-tetrahydropyrazino-

35

[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2, 5-dione Pf 268-270°C.

The starting product furanedione is prepared as follows:

5 a) a 450 mg solution of 1,2,3,4-tetra-

Hydropyrazino[1,2-a]indole in 30 mL of dichloromethane at 0°C under a nitrogen atmosphere with 303 mg of triethylamine and 615 mg of di(t-butyl) dicarbonate. The mixture is stirred at 0°C for 4 hours, then washed with a saturated sodium bicarbonate solution, dried, and evaporated to give an oil. Crystallization from methanol gives 580 mg of t-butyl 1,2,3,4-tetrahydropyrazino[1,2-a]indole-2-carboxylate at 103–105°C. b) 230 mg of oxalyl chloride is added dropwise to a stirred solution of 450 mg of the product of a) in 30 mL of diethyl ether at 0°C. After stirring, the solution is evaporated and the residue is dissolved in 50 mL of dichloromethane. 20,360 mg of l-methyl-3-indolylacetic acid and 350 mg of triethylamine are added, and the mixture is stirred for 90 hours. The solvent is evaporated, and the residue is purified by silica gel chromatography with ethyl acetate/petroleum ether (2:3) to give 180 mg of a gum. A sample is crystallized from l-ethyl acetate/n-hexane to give 3-I2-t-butoxycarbonyl-l,2,3,4-tetrahydropyrazino[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione at 125–127°C. 30 • EXAMPLE 21

Similar to what is described in the first paragraph of Example 12, from 3-(5,6-dihydro-4H-pyrrolo-[3,2,1-ij]quinolin-1-yl)-4-(l-methyl-3-indolyl)furan-2,3-dione we prepare

36

3-(5,6-dihydro-4H-pyrrolo-13,2,[-11-quinoline-1-yl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of Pf. 285-288 °C.

The starting product furanedione is prepared as follows:

One hundred and twenty-two grams of oxalyl chloride is added dropwise to a solution of 1.5 grams of 5,6-dihydro-4H-pyr-rolol-3,2,1-11J-quinoline in 60 mL of dichloromethane under a nitrogen atmosphere. After one hour, the solvent is removed under reduced pressure, and the residue is dissolved in 120 mL of dichloromethane. One hundred and nine grams of 1-methyl-3-indolylacetic acid and 2.02 grams of triethylamine are added to this solution, and the mixture is stirred for 18 hours. The solvent is removed under reduced pressure, and the residue is purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2). Further purification is carried out by chromatography with dichloromethane. Crystallization from ethyl acetate gives 690 mg of 3 — (5,6 — dihydro-4H-pyrrolo13,2,1 —ij]quinolin- 1 -yl)-4-(1-methyl-3-indolyl)furan-2,5-dione at Pf. 217-219°C.

EXAMPLE 22

In a manner analogous to what is described in the first paragraph of example 1, from 3-[5-(acetoxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1—111 quinolin-1-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione, 3-[5,6-dihydro-5-(hydroxymethyl)-4H-pyrrolo[3,2,1—111 quinolin-1-yl1-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione is prepared at Pf. 223-225°C.

The starting product furanedione is prepared as follows:

a) 33.4 mL of a 1.6 M n-butyllithium in hexane solution is added to an 8.13 mL solution of

diisopropylamine in 420 ml of THF at -78°C under a nitrogen atmosphere. After h hours, 4.6 g of 1,2,5,6-tetrahydro-4-oxo-pyrrolo-[3,2,1-ij]quinoline are added and the mixture is stirred at -78°C for % hours.

2.77 mL of ethyl chloroformate is added and stirring continues for 1 hour. The reaction is stopped with water and the mixture is evaporated. The residue is purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2). Crystallization from the diethyl ether gives 2.8 g of ethyl 1,2,5,6-tetrahydro-4-oxo-4H-pyrrolo[3,2,1-1]quinoline-5-carboxylate at 88-90°C.

b) 15 mL of a 1 M borane solution in THF is added to a solution of 2.8 g of the product of a) in 100 mL of THF, and the resulting solution is heated under reflux for 2 hours. A further 55 mL of borane is added, and heating continues for 12 hours. The solvent is removed under reduced pressure, water and 2 M hydrochloric acid are added, and the mixture is extracted with dichloromethane. The solvent is evaporated, and the residue is dissolved in diethyl ether.

The resulting solution is heated with 12 mL of a 1 M lithium-aluminum hydride solution in diethyl ether, and the mixture is stirred under a nitrogen atmosphere for 18 hours. Water is added, and the mixture is extracted with dichloromethane. Removal of the solvent under reduced pressure yields 1.4 g of 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-111quinoline-5-methanol.

c) A 1.4 g solution of the product from b) is treated

in 50 ml of dichloromethane with 4 ml of acetic anhydride and 2 ml of pyridine. After 4 hours, add another 4 ml of acetic anhydride and shake.

38

The mixture is heated for 18 hours. The solvent is removed under reduced pressure, and the residue is divided between water and dichloromethane. The organic phase is evaporated, and the residue is dissolved in 5-to-luene and heated under reflux in the presence of 250 mg of 10% Pd for 18 hours. Another 250 mg of 10% Pd is then added, and heating continues for a further 20 hours. The mixture is filtered, and the filtrate is evaporated. The resulting residue is purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) to give 350 mg of 5-(acetoxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-1]quinoline.

d) 315 mg of oxalyl chloride is added to a solution of 570 mg of the product of c) in 15 mL of dichloromethane under a nitrogen atmosphere. The solvent is removed at reduced pressure and the residue is dissolved in the dichloromethane. 472 mg of 1-methyl-3-indolylacetic acid and 505 mg of triethylamine are added and the mixture is stirred for 72 hours. The solvent is removed at

pressure reduced and the residue is purified by silica gel chromatography with dichloromethane. Crystallization from ethyl acetate/n-hexane gives 140 mg of 3-[5-(acetoxymethyl)-5,6-dihydro-4H-25pyrrolol3,2,1-ij]quinolin-1-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione solid at Pf. 198-200°C.

EXAMPLE 23

In a manner analogous to what is described in example 11, from the pyrroledione product of 30 in example 22, the methanesulfonate of 3 —[5— amidinothiometh^l)-5,6-dihydro-4H-pyrrolo-[3,2,1-i j1 quinolin- 1 -yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione is prepared at Pf. 190-195°C.

39

EXAMPLE 24

In a manner analogous to what is described in example 2, from the pyrroledione product of example 22, the hydrochloride of 3-[5-(amino-methyl)-5,6-dihydro-4H-pyrrolo[3,2,1—1]quinoline-1-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione is prepared at Pf. 248-250°C.

EXAMPLE 25

Similar to what is described in the first paragraph of Example 1, from 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-phenylfuran-2,5-dione (obtained as stated in the last paragraph of Example 1 using phenylacetic acid instead of i

l-methyl-3-indolylacetic acid) is prepared

3-[6,7,8,9-tetrahydro-8-(hydroxymethyl)pyrido[1,2-a]indol-10-yl]-4-phenyl-1H-pyrrole-2,5-dione de Pf. 276-278 °C.

EXAMPLE 26

Similar to what is described in the first paragraph of example 1, starting from the

4-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-3-(3-benzo[b]thienyl)-furan-2,5-dione (obtained as stated in the last paragraph of Example 1 using 3-benzo[b]thienyl-acetic acid instead of 1-methyl-3-indolylacetic acid) prepares the 3-(3-benzo[b]thienyl)-4-[6,7,8,9-tetrahydro-8-(hydroxymethyl)pyrido[1,2-a]indol-10-yl]-1H-pyrrole-2,5-dione of Pf. 226-227°C.

40

EXAMPLE 27

In a manner analogous to what is described in the first paragraph of Example 1 from 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-5 10-yl]-4-(1-naphthyl)furan-2,5-dione (obtained as described in the last paragraph of Example 1 using 1-naphthylacetic acid instead of 1-methyl-3-indolylacetic acid) 3-[6,7,8,9-tetrahydro-8-(hydroxymethyl)pyrido[1,2-a]indol-10-yl]-10 4-(1-naphthyl)-1H-pyrrole-2,5-dione is prepared at Pf. 221-222°C.

EXAMPLE 28

In a manner analogous to what is described in example 10, from the pyrroledione product of example 19, the 3-[2-(aminomethyl)-2,3-di-15 hydro-1H-pyrrolo[1,2-a]indol-9-yl]-4-(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione of Pf. 208-211°C is prepared.

EXAMPLE 2 9

Similar to what is described in Example 10, from the pyrroledione product 20 of Example 25, 3-[8-(aminomethyl)- is prepared

6,7,8,9-tetrahydro-pyrido[1,2-a]indol-10-yl]-4-phenyl-1H-pyrrole-2,5-dione de Pf. 249-250°C.

EXAMPLE 30

A suspension of 100 mg of pyrroledione product 25 from Example 20 in 10 mL of dichloromethane under nitrogen is treated with 0.08 mL of triethylamine and 86 mg of phenyl chloroformate. The mixture is stirred for 2 hours, and then the solvent is evaporated. Silica gel chromatography of the residue with ethyl acetate/n-hexane (1:1) yields a gum, which is dissolved in a mixture of 5 mL of isopropanol and 10 mL of 33% ammonia. The mixture is then diluted with

41

water and it is extracted with dichloromethane. The combined dichloromethane extracts are dried and evaporated. Crystallization of the residue from ethyl acetate/n-hexane gives 45 mg of 3-[1,2,3,4-tetra-hydro-2-(phenoxycarbonyl)pyrazino[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,3-dione at Pf. 160-165°C.

EXAMPLE 31

a) A solution of 80 mg of the pyrroledione product from Example 20 in 20 mL of dichloromethane is treated with 10 mL of 5% aqueous sodium bicarbonate. The stirred mixture is then treated with a solution of 125 mg of trifluoroacetamidoacetyl chloride in 5 mL of dichloromethane. After 17 hours, the phases are separated, and the organic phase is dried and evaporated. Silica gel chromatography of the residue with ethyl acetate/n-hexane (2:1) and crystallization from ethyl acetate/n-hexane yielded 70 mg of 3-[2-[(trifluoroacetamido)acetyl]-1,2,3,4-tetrahydropyrazino[1,2-a]indol-10-yl1-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione with a Pf 17 0-

172 °C.

b) A solution of 65 mg of the product of a) is treated

in 10 ml of methanol with 5 ml of 33% ammonia. After 4 hours, the solvent is removed by evaporation and the residue is divided between dichloromethane and water. The organic phase is washed with water, dried, and evaporated. The residue is then analyzed by chromatography on silica gel with chloroform/methanol/

Acetic acid/water (60:18:2:3) gives a gum which is dissolved in glacial acetic acid and treated with 20 ml of 1 M hydrochloric acid. Evaporation of

42

solvent and trituration of the residue with diethyl ether give 35 mg of 3-12-(aminoacetyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride at Pf. 235°C (decomposition).

EXAMPLE 32

a) A solution of 100 mg of the pyrroledione product from Example 20 in 40 ml of dichloromethane under a nitrogen atmosphere is treated with 125 mg of 1,1-carbonyldi-

10 imidazole and the mixture is stirred for 24 hours. The solution is washed with water, dried and evaporated. Trituration of the residue with ethyl acetate gives 84 mg of 3-[1,2,3,4-tetrahydro-2-(1-imidazolyl-carbonylDpyrazinol1,2-a]indol-10-yl]-4-(1-methyl-3-15 indolyl)-1H-pyrrole-2,5-dione at Pf. 295°C (decomposition).

b) 80 mg of the product from a) is dissolved in a mixture of 20 mL of DMF and 20 mL of 33% ammonia. The mixture is stirred for 17 hours and the solvent is evaporated. Silica gel chromatography of the residue is performed.

20 with methanol/ethyl acetate (1:9) gives a solid which is crystallized from the methanol. 45 mg of 3-[2-carbamoyl-1,2,3,4-tetrahydropyrazino[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione is obtained at a decomposition temperature of 295°C. 25 EXAMPLE 33

A 505 mg solution of the pyrroledione product from Example 2 in 20 mL of DMF is treated with a 222 mg solution of 1,1-thiocarbonyldiimidazole in 5 mL of THF. After 17 hours, 30% of the solvent is evaporated and the residue is purified by silica gel chromatography with methanol/dichloromethane (1:99).

43

Trituration with n-hexane gives 297 mg of 3-(6,7,8,9-tetrahydro-8-isothiocyanato-pyrido[1,2-a-jindol-10-ylJ-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione as a red solid at 285-287°C. EXAMPLE 34

250 mg of the pyrroledione product from Example 2 is stirred in a mixture of 25 mL of dichloromethane and 15 mL of 5% aqueous sodium bicarbonate. The mixture is treated with 1 mL of benzoyl chloride and stirred for 17 hours. The phases are separated, and the organic phase is dried and evaporated. Silica gel chromatography of the residue with methanol/dichloromethane (7:93) followed by trituration with n-hexane gives 220 mg of 3-[8-(benz-15 amidomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione with a boiling point of 297–303°C.

EXAMPLE 35

A solution of 150 mg of 3-[7-acetoxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione is heated at 150°C for 6 hours in 6 ml of DMF and 6 ml of 33% ammonia. The mixture is extracted with ethyl acetate and the organic extracts are washed with water, dried, and evaporated. Crystallization of the residue from ethyl acetate gives 120 mg of 3-[6,7,8,9-tetrahydro-7-hydroxypyrido[1,2-a]indol-10-yl1-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione at Pf. 252-255°C.

The starting product furanedione 30 is prepared as follows:

a) A solution of 14.0 g of indole-2-methanol in 500 ml of dichloromethane is stirred with 76.4 g of activated manganese-IV oxide. After one hour, the

S

44

The solid is filtered and washed with dichloromethane. The collected wash water is concentrated, and 33 g of (carbethoxymethylene)-triphenylphosphorane is added. The resulting solution is heated under reflux in a nitrogen atmosphere. The solvent is evaporated to give an oil, which is purified by silica gel chromatography with ethyl acetate/n-hexane (1:3). The product is obtained as a 20:1 mixture of E/Z isomers. Crystallization from methanol gives 11.3 g of ethyl (E)-2-indolyl-2-propenoate at 120–122°C.

b) A solution of 7.2 g of ethyl (E)-2-indolyl-2-propenoate in 120 ml of DMF is treated with 1.47 g of a 60% sodium hydride dispersion in oil

15. Mineral. The resulting solution is cooled to 0°C and 7.17 g of t-butyl bromoacetate is added under a nitrogen atmosphere. After 2 hours, the mixture is poured into 100 mL of 2 M hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are washed with water, dried, and...

evaporate to give an oil. This oil is purified by silica gel chromatography with diethyl ether/petroleum ether (1:3). Crystallization from diethyl ether/n-hexane gives 8.1 g of ethyl (E)-3-(1-25t-butoxycarbonylmethyl)-2-indolyl]-2-propenoate at Pf. 66-68°C.

c) A solution of 8.0 g of the product from b) is stirred in 300 ml of ethanol with 800 mg of 10% Pd under a hydrogen atmosphere. The catalyst is separated by

30 filtration and it is washed with ethyl acetate.

The filtrate and wash waters are evaporated together to produce an oil which is then dissolved in the THF.

1

45

The solution is added to a 2.8 g solution of t-but potassium oxide in THF under a nitrogen atmosphere. The mixture is then stirred for 0.1 hour and the solvent is evaporated. The residue is divided between ethyl acetate and 2 M hydrochloric acid. The organic phase is washed with water, dried, and evaporated. The residue is purified by silica gel chromatography with diethyl ether/h-nexane (1:4). 4.55 g of t-butyl 6,7,8,9-tetrahydro-7-oxo-pyrido[1,2-a]indole-6-carboxylate is obtained.

d) A solution of 4.5 g of the product of c) in 200 ml of toluene is treated with four spoonfuls of silica gel and the mixture is heated under reflux for 3 hours under a nitrogen atmosphere.

The solid is removed by filtration and washed with toluene. The filtrate and wash water are evaporated to give a solid. Crystallization from diethyl ether/n-hexane yields 2.5 g of 8,9-dihydropyridol-1,2-α-indol-7(6H)-one with a boiling point of 126–128°C.

e) 190 mg of sodium borohydride is added to a stirred solution of 650 mg of 8,9-dihydropyrido[1,2-a]indole-7(6H)-one in 50 mL of methanol under a nitrogen atmosphere. The mixture is stirred and then poured into 100 mL of saturated ammonium chloride solution. The mixture is extracted with ethyl acetate, and the combined extracts are dried and evaporated to give a solid. This is crystallized from diethyl ether/n-hexane to give 500 mg of 6,7,8,9-tetrahydro-7-hydroxypyrido[1,2-a]indole at 99–100°C.

f) A solution of 500 mg of the product of e) in 5 ml of pyridine and 2 ml of acetic anhydride is shaken for 8 hours. The mixture is then poured into 50 ml of acid

46

2 M hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are washed with a 5% sodium bicarbonate solution and water, dried, and evaporated to give 520 mg of an oil. A sample is crystallized from diethyl ether/n-hexane to obtain 7-acetoxy-6,7,8,9-tetrahydropyrido[1,2-alindole at 90-95°C.

(g) 320 mg of oxalyl chloride is added to a solution of 500 mg of product of (f) in 50 mL of diethyl-10 ether under a nitrogen atmosphere. The solvent is then removed under reduced pressure, and the residue is dissolved in 50 mL of dichloromethane. 378 mg of l-methyl-3-indolylacetic acid and 505 mg of triethylamine are added to this solution, and the mixture is stirred for 72 hours and 15 minutes. The solvent is then removed under reduced pressure, and the residue is purified by silica gel chromatography with ethyl acetate/n-hexane (1:1). Crystallization from ethyl acetate gives 160 mg of 3-[7-acetoxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-20 yl]-4-(l-methyl-3-indolyl)furan-2,5-dione at Pf. 272-275°C.

EXAMPLE 36

A solution of 85 mg of 3-[7-t-butoxyformamido-6,7,8,9-tetrahydro-25-pyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione is heated at 100°C for 1 hour in 5 mL of DMF and 5 mL of 33% ammonia. The cooled mixture is divided between ethyl acetate and water. The organic phase is washed with water, dried, and evaporated. Crystallization from 30% of ethyl acetate.n-hexane yields 70 mg of 3-[7-t-butoxyformamido-6,7,8,9-tetrahydro-25-pyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione.

t-butoxyformamido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl] -4- (l-methyl-3-indolyl) -lH-pyrrole-2, 5-dione, mp. 159-163°C.

47

The starting product furanedione is prepared as follows:

a) A suspension of 555 mg of 8,9-dihydropyrido[lf2-a]indol-7(6H)-one and 4.62 g of ammo- acetate is treated

5-nium in 15 mL of methanol with 250 mg of sodium cyanoborohydride. The mixture is stirred and then distributed between ethyl acetate and water. The organic phase is dried and the solvent is removed under reduced pressure. The residual oil is subjected to silica gel chromatography with 10% methanol in dichloromethane. The resulting indoline is dissolved in toluene and heated under reflux with 50 mg of 10% Pd for 4 hours. The catalyst is separated by filtration and washed with toluene. The filter and combined wash waters are evaporated to give 170 mg of 7-amino-6,7,8-S-tetrahydropyrido[1,2-a]indole.

b) 225 mg of di-t-butyl dicarbonate is 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 is washed with a saturated sodium bicarbonate solution, dried, and evaporated to give an oil. Crystallization from the diethyl ether gives 240 mg of 7-t-butoxyformamido-6,7,8,9-tetrahydropyrido 25 11,2-α-indole at 137–139°C.

c) 127 mg of oxalyl chloride is added to a solution of 240 mg of the product from b) in 30 mL of diethyl ether under a nitrogen atmosphere. After 10 minutes, the solvent is removed at reduced pressure and the solution is dissolved.

The residue is dissolved in 30 mL of dichloromethane. 170 mg of l-methyl-3-indolylacetic acid and 200 mg of triethylamine are added to the resulting solution, and the mixture is stirred for 72 hours. The solvent is removed under reduced pressure, and the residue is purified by chromatography on

48

silica gel with ethyl-n-hexane acetate (1:2). Crystallization from ethyl/n-hexane acetate gives 100 mg of 3-[7-t-butoxyformamido-6,7,8,9-tetrahydropyridol1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl) 5 furan-2,5-dione at Pf. 141-145°C.

EXAMPLE 37

A saturated solution of hydrochloric acid in 30 ml of ethyl acetate is added to a stirred suspension of 60 mg of the pyrroledione 10 product of Example 36 in 50 ml of ethyl acetate, and the mixture is stirred for 18 hours. The solvent is removed under reduced pressure, and the residue is triturated with ethyl acetate to give 35 mg of 3-[7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-15 yl]-4-(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride at Pf. 260-265°C.

EXAMPLE 38

A solution of 80 mg of 3-[8-t-butoxyformamido-6,7,8,9-20 tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indol-lyl)-furan-2,5-dione is heated to 100°C for 1 hour in 2 ml of DMF and 2 ml of 33% ammonia. The solution is then cooled, yielding 60 mg of 3-[8-t-butoxyformamido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-1H-pyrrole-25 2,5-dione with a Pf. of 153-155°C.

The starting product furanedione is prepared as follows:

a) A solution of 300 mg of sodium hydroxide in 5 mL of water is added to a stirred solution of 1.35 g of the carboxylate product from example b) in 25 mL of ethanol, and the mixture is heated under reflux for 15 minutes. 2 mL of 2 M hydrochloric acid and 10 mL of water are added, and the precipitate is separated by filtration.

1

49

obtained and dried to give 1.14 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxylic acid at Pf. 244-246°C.

b) A suspension of 900 mg of product from a) in 1 ml of water and 20 ml of acetone is cooled to 0°C and treated with 490 mg of triethylamine followed by 576 ml of ethyl chloroformate. After 1 hour, 345 mg of sodium azide in 1 ml of water is added, and the mixture is stirred at 0°C for 1 hour. The solvent is removed under reduced pressure, and the residue is extracted with dichloromethane. The extracts are evaporated, and the residue is purified by silica gel chromatography with dichloromethane. The resulting solid is dissolved in 10 ml of toluene and heated at 100°C for 4 hours under a nitrogen atmosphere. The solvent is evaporated to give 700 mg of 6,7,8,9-tetrahydropyridol1,2-α-indole-8-isocyanate of Pf. 87-89 °C.

c) 4 mL of a 2 M sodium hydroxide solution are added to a 700 mg solution of the product from b) in

50 mL of THF is added, and the resulting solution is stirred overnight. The solvent is removed under reduced pressure, and the residue is extracted with dichloromethane. The dichloromethane extract is evaporated to give a 25-amine, which is then redissolved in dichloromethane. 645 mg of di-t-butyl dicarbonate and 300 mg of triethylamine are added at 0°C, and the mixture is allowed to warm to room temperature while being stirred for 72 hours. The mixture is washed with a 30-molecular-weight sodium bicarbonate solution, and the organic phase is dried. The solvent is removed under reduced pressure, and the residue is extracted with diethyl ether. The

1

50

ethereal extracts and the solid obtained is triturated with petroleum ether to give 550 mg of 8-t-butoxy-formamido-6,7,8,9-tetrahydropyrido(1,2-a1indole of Pf. 155-157°C.

5 d) 256 mg of oxalyl chloride is added to a solution of 550 mg of the product of c) in 10 mL of diethyl ether at 0°C under a nitrogen atmosphere. After one hour, the solvent is removed under reduced pressure and the residue is dissolved in dichloromethane. 10,363 mg of 1-methyl-3-indolylacetic acid and 390 mg of triethylamine are added, and the mixture is stirred for 40 hours. The solvent is removed under reduced pressure, and the residue is purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2). Crystallization from diethyl ether/petroleum ether gives 200 mg of 3-[8-t-butoxyformamido-6,7,8,9-tetrahydropyrido (1,2-a J indol-10-yl J-4-(l-methyl-3-indolyl)furan-2,5-dione at Pf. 155-160°C.

EXAMPLE 39

20. Analogously to what is described in Example 37 from the pyrroledione product of Example 38, the hydrochloride of 3-(8-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione is prepared at a temperature of 310-315°C. 25. 1 EXAMPLE 40

A solution of 320 mg of 3-|4-(2-acetoxyethyl)-5,6-dihydro-4H-pyrrolo[2,2-11-quinolin-1-1-11-11-(1-methyl-3-indolyl)furan-2,5-dione is heated at 140°C for 12 hours in 2 ml of DMP and 2 ml of 33% ammonia. Water is added to the cooled mixture, which is then filtered to yield 210 mg of a solid. A sample is crystallized from ethyl acetate to give 3-[4-(2-hydroxyethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione at Pf. 214-215°C.

51

The starting product furanedione is prepared as follows:

a) 25 mL of a 1.6 M n-butyllithium in n-hexane solution is added to a 4.04 g solution of

5 diisopropylamine is added to 20 mL of THF at 0°C under nitrogen. After 10 minutes, the stirred solution is cooled to -78°C and a solution of 9.28 g of t-butyl acetate is added to 20 mL of THF. After another 10 minutes, 3.46 g of 1,2,5,6-tetrahydro-4H-pyrrolo 10 [3,2,1-1j]quinolin-1-one is added to 20 mL of THF, followed by 8 mL of boron trifluoride diethyl etherate. The mixture is stirred at -78°C and then 20 mL of pyrrolidine is added. The mixture is divided between methyl acetate and water, and the organic extracts are washed with 15% water and a sodium chloride solution, then dried and evaporated. The residue is purified by silica gel chromatography with ethyl acetate.

petroleum ether (1:3). 4.1 g of (E)-1,2,5,6-tetrahydro-4H-pyrrolo13,2,[-ij]quinolin-1 -ylidene) 20 t-butyl acetate is obtained at Pf. 105-107°C.

b) A solution of 4 g of the product from a) in 400 ml of methanol with 280 mg of 10% Pd is stirred under a hydrogen atmosphere for 18 hours. The catalyst is separated by filtration and the filtrate is evaporated.

25 to give an oil. 1.99 g of this oil is treated in 100 ml of diethyl ether with 5 ml of a 1 M lithium-aluminum hydride solution in diethyl ether, and the mixture is stirred for 2 hours. Water is added, and the product is extracted with ethyl acetate and concentrated under reduced pressure to give

1.44 g of 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolei-ne-4-ethanol.

52

c) 1.44 g of the product from b) is treated in 40 ml of dichloromethane with 10 ml of acetic anhydride and 5 ml of pyridine. The resulting solution is stirred and then evaporated. The residue is dissolved in dichloromethane.

5. We wash the solution with water, separate the organic phase, dry and concentrate to give 1.65 g of 4-(2-acetoxyethyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-111quinoline.

d) A solution of 1.6 g of the product of c) is heated under reflux for 12 hours in 50 ml of xylene and 100 mg of 10%/C Pd. The catalyst is separated by filtration and the filtrate is evaporated to give 1.7 g of 4-(2-acetoxyethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline.

15 e) 935 mg of oxalyl chloride is added to a stirred solution of 1.7 g of the product of c) in 45 mL of dichloromethane under a nitrogen atmosphere. After one hour, the solvent is removed under reduced pressure and the residue is dissolved in 90 mL of dichloromethane. 20 1.38 g of l-methyl-3-indolyl acetic acid and 1.48 g of triethylamine are added to this solution and the resulting mixture is stirred for 18 hours. The solvent is removed under reduced pressure and the residue is purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2). 25 Crystallization from methanol/water gives 280 mg of 3-[4-(2-acetoxyethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione at Pf. 143-146°C.

EXAMPLE 41

30 A 400 mg solution of 3 —[8 — is treated

[(t-butoxyformamido)-methyl]-6,7,8,9-tetrahydropyrido-[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione in 50 ml of DMF and 50 ml of water with 2.5 g of hydrochloride

53

d1-hydroxylamine and 2.5 g of potassium carbonate are added, and the resulting solution is heated to 100°C. The solvents are evaporated, and the residue is dissolved in dichloromethane. The mixture is washed with water and dried. The sol-5 is removed by heating under reduced pressure, and the residue is crystallized from ethyl acetate/petroleum ether to give 190 mg of 3-[8-[(t-butoxyformamido)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-1-hydroxy-4-(l-methyl-3-indolyl)pyrrole-2,5-dione at 238-240°C. The furanedione starting material is prepared as follows:

a) Add 2/4 g of methanesulfonic anhydride and

2 mL of triethylamine is added to a stirred solution of 2.01 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-methanol in 40 mL of dichloromethane under a nitrogen atmosphere. After 18 hours, the mixture is washed with a saturated sodium bicarbonate solution, dried, and evaporated to yield an oil. 1.8 g of this oil is dissolved in 10 mL of propanol and 5.2 mL of 33% ammonia, and the mixture is heated to 80°C.

for 10 hours. The solvent is removed under reduced pressure and the residue is divided between dichloromethane and a saturated sodium bicarbonate solution. The organic phase is dried and evaporated to give 1.3 g of 8-aminomethyl-6,7,8,9-tetrahydropyrido[1,2-a]indole at 85-90°C.

b) 1.09 g of di-t-butyl dicarbonate is added to a stirred solution of 890 mg of 8-aminomethyl-6,7,8,9-tetrahydropyrido[1,2-a]indole and 920 mg of triethylamine

30 in 60 ml of dichloromethane at 0°C under a nitrogen atmosphere. After 72 hours, the organic phase is washed with a saturated sodium bicarbonate solution.

54

The mixture is dried and evaporated. The residue is crystallized from petroleum ether to give 1.03 g of 8-[(t-butoxyformamido)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indole at 5°C. 445 mg of oxalyl chloride is added dropwise to a solution of 1 g of the product from step b) in 20 mL of diethyl ether under a nitrogen atmosphere at 0°C. After one hour, the solvent is removed under reduced pressure and the residue is dissolved in dichloromethane. 630 mL of 1-methyl-3-indolylacetic acid and 920 mL of triethylamine are added to this solution and the mixture is stirred for 72 hours. The solvent is removed under reduced pressure and the residue is purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2). The resulting solid is crystallized from the diethyl ether, yielding 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 at 124-126°C. 20 EXAMPLE 42

In a manner analogous to what is described in example 37, from the product of example 41, the hydrochloride of 3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-l-hydroxy-4-(1-methyl-25 3-indolyl)pyrrole-2,5-dione is prepared at Pf. 280-282°C.

EXAMPLE 43

In a manner analogous to what is described in example 11, from the product of example 40, the methanesulfonate of 3-[4-[1-(amidinothio) 30 ethyl]-5,6-dihydro-4H-pyrrolo[3,2,1-1 j]quinoline-l-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione is prepared at Pf. 185-190 °C.

55

EXAMPLE 44

In a manner analogous to what is described in example 2, from the product of example 40 is prepared the hydrochloride of 3-[4-(2-aminoethyl)-5,6-5 dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of Pf. 193-195°C.

EXAMPLE 45

In a manner analogous to what is described in example 2, from the product of example 26, we obtain 10 the hydrochloride of 3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(3-benzo[b]thienyl)-1H-pyrrole-2,5-dione with a Pf. 285-287°C.

EXAMPLE 46

In a manner analogous to what is described in the first paragraph of Example 1, from the 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(2-naphthyl)furan-2,5-dione ((obtained as described in the last paragraph of Example 1 using 2-naphthylacetic acid instead of 20 l-methyl-3-indolylacetic acid) we prepare the 3-[6,7,8,9-tetrahydro-8-(hydroxymethyl)pyrido-[1,2-a]indol-10-yl]-4-(2-naphthyl)-lH-pyrrole-2,5-dione of Pf. 260-263°C.

EXAMPLE 47

25. Analogously to what is described in Example 2, from the product of Example 46, we obtain the hydrochloride of 3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(2-naphthyl)-1H-pyrrole-2,5-dione with a boiling point >300°C. 30. EXAMPLE 48

Similar to what is described in example 10, starting from the product of example 27, we

56

prepares 3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido-[1,2-a]indol-l-yl]-4-(1-naphthyl)-lH-pyrrole-2,5-dione at Pf. 167-169°C.

EXAMPLE 4 9

In a manner analogous to what is described in the first paragraph of example 1, from 1.3 g of 3~[9-(acetoxymethyl)-7,8,9,10-tetrahydro-6H-azepino 1,2-a]indol-ll-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione we obtain 520 mg of 3-[7,8,9,10-tetrahydro-9-(hydroxymethyl) -6H-azepino [1,2-a]indol-ll-yl]-4-(1-methyl-3-indolyl)-lH-pyrrole-2,5-dione with a Pf. 268-270°C.

The starting product furanedione is prepared as follows:

a) A solution of 18.9 g of ethyl indole-2-carboxylate in 100 ml of DMF is added to a suspension of 2.64 g of sodium hydride in 50 ml of DMF. After one hour, a solution of 20.9 g of ethyl bromovalerate in 100 ml of DMF is added dropwise.

After 48 hours, the mixture is poured into water, extracted with dichloromethane, and the combined dichloromethane extracts are washed with water, dried, and concentrated to give 26.2 g of ethyl 1-(4-ethoxycarbonyl-butyl)indole-2-carboxylate.

b) This oil is dissolved in 50 mL of THF, and the solution is then added to a stirred suspension of 11.2 g of potassium t-butoxide in 150 mL of THF. After 36 hours, the mixture is concentrated, and the residue is poured into a mixture of water and diethyl ether. The organic phase is dried and concentrated. Silica gel chromatography with dichloromethane/methanol (9:1) yields a solid, which is recrystallized from

57

ethyl acetate/n-hexane and 6.1 g of ethyl 7,8-dihydro-10-hydroxy-6H-azepino[1,2-a]indole-9-carboxylate is obtained at Pf. 74-81°C.

5 c) 5.5 g of this solid is dissolved in 200 ml of ethanol and treated with 11 spatula-sized measures of Raney nickel and 400 ml of water. The mixture is heated under reflux for 4 hours. The cooled mixture is filtered and the residue is washed with ethyl acetate. The filtrate is extracted with ethyl acetate. The combined extracts and wash waters are dried and concentrated to give an oil, which is purified by silica gel chromatography with dichloromethane, yielding 2.5 g of ethyl 7,8,9,10-tetrahydro-6H-15 azepino[l,2-a]indole-9-carboxylate, with a boiling point of 69-70°C.

d) This solid is dissolved in 50 ml of THF and added dropwise to a mixture of 0.45 g of lithium-aluminum hydride in 20 ml of THF. The

The mixture is stirred for 2 hours, then water is added. The resulting mixture is extracted with diethyl ether, and the combined extracts are dried and concentrated. Silica gel chromatography of the residue with dichloromethane yields 1.90 g of 7,8,9,10-tetrahydro-9-25(hydroxymethyl)-6H-azepino[1,2-a]indole at 109-111°C

e) 1.8 g of this solid is dissolved in 100 ml of diethyl ether at 0°C and treated with 1.70 g of acetic anhydride and 0.66 g of pyridine. After 8 hours, a further 5 g of pyridine is added and the mixture is stirred for

30 76 hours. The solvents are removed under reduced pressure and the residue is chromatographed on silica gel with dichloromethane and 1.98 g of 9-(acetoxymethyl)-7,8,9,10-tetrahydro-6H~azepino[1,2-a]indole of Pf. 65°C is obtained.

58

f) 1.90 g of this solid is dissolved in 50 mL of dichloromethane, the solution is cooled to 0°C, and it is treated with 1.03 g of oxalyl chloride. After 2 hours, the solvent is removed by evaporation, and the residue is dissolved in dichloromethane and added dropwise to a solution of 1.5 g of 1-methylindole-3-acetic acid and 1.86 g of triethylamine in dichloromethane. The mixture is concentrated, and the residue is chromatographed on silica gel with dichloromethane containing 5% by volume methanol.

The solid obtained from ethyl/n-hexane acetate is recrystallized to give 1.55 g of 3-[9-(acetoxymethyl)-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-ll-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione at Pf. 164-15 166 °C.

EXAMPLE 50

Similar to what is described in example 12, from 0.50 g of 3-[7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-ll-yl]-3-(l-methyl-3-indolyl) 20 furan-2,5-dione we obtain 0.43 g of 3-[7,8,9,10-tetra-hydro-6H-azepino-[1,2-a]indol-ll-yl]-3-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione with Pf >300°C.

The starting product furanedione is prepared as follows:

25. One 1.5 g of oxalyl chloride is added dropwise to an ice-cold solution of 2.0 g of 7,8,9,10-tetrahydro-6H-azepino[1,2-a]indole (J. Org. Chem. 33, 1968, 4286) in 50 mL of dichloromethane. The mixture is stirred for 12 hours. The solvent is removed under vacuum and the residue is dissolved in dichloromethane. The resulting solution is added to a solution of 2.2 g of 1-methyl-3-indolylacetic acid and 2.73 g of triethylamine in 50 mL of dichloromethane. The

S

59

mix and then concentrate. The residue is chromatographed on silica gel with dichloromethane and 1.0 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 is obtained at Pf. 257-259°C.

EXAMPLE 51

A solution of 150 mg of the product from Example 49 and 146 mg of 2,6-lutidine in 15 mL of dichloromethane is added to a solution of 290 mg of trifluoromethanesulfonic anhydride at 0°C. After 3 hours, 25 mL of 33% ammonia is added, and the mixture is stirred for 16 hours. The mixture is extracted with dichloromethane, and the combined extracts are dried and concentrated. Chromatography of the residue on silica gel with dichloromethane/methanol/acetic acid/water (90:18:3:2) gives 50 mg of 3-[9-(aminomethyl) 7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-ll-yl]- 4 —(1 — methyl-3-indolyl)-lH-pyrrole-2,5-dione acetate at Pf. 215°C (decomposition).

EXAMPLE 52

A mixture of 40 mg of the product from Example 51, 20 mg of sodium bicarbonate, and 25 mg of 3,5-dimethyl-N-nitro-1-pyrazole-1-carboxamide in 10 mL of ethanol is heated under reflux for 16 hours. The mixture is concentrated, and the residue is chromatographed on silica gel with dichloromethane/methanol (9:1). This yields 15 mg of 3-(1-methyl-3-indolyl)-4-[7,8,9,10 tetrahydro-9-[(2-nitroguanidino)methyl]-6H-azepino[1,2-a]indol-11-yl]-1H-pyrrole-2,5-dione from Pf. 177-178

EXAMPLE 53

Similar to what is described in the first paragraph of example 1 starting from 0.20

60

from 3-[8-(acetoxymethyl)-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-ll-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione we obtain 60 mg of 3-(7,8,9,10-8-(hydroxymethyl)-6H-azepino[1,2-a]indol-ll-yl]-4-(l-methyl-3-indolyl)-5 lH-pyrrole-2,5-dione with a Pf. 109-111°C.

The starting product furanedione is prepared as follows:

a) A 5 g solution of 6,7-9-hydroxypyrido[1,2-a]indole-8-carboxylate is treated (prepared as described

10 (in example 1) in 200 mL of DMF with 550 mg of sodium hydroxide. The mixture is stirred under a nitrogen atmosphere, then a solution of 3.6 g of ethyl bromoacetate in 50 mL of DMF is added. After 16 hours, the mixture is poured into water and extracted with diethyl ether. The combined extracts are washed with water, dried, and concentrated to give 4.4 g of 8-(ethoxycarbonyl)-6,7,8,9-tetrahydro-9-oxopyrido[1,2-a]indole-8-ethyl acetate.

b) A 5.0 g solution is added drop by drop

20 of the product from a) in 200 mL of THF is added to a stirred solution of 2.0 g of potassium t-butoxide in 50 mL of THF. The mixture is stirred, and then 1 mL of glacial acetic acid is added. The mixture is poured into water and extracted with dichloromethane. The combined extracts are dried and concentrated. The residue is 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.

c) A mixture of 2.8 g of the product from b) and 0.5 g of boric acid is heated to 150°C for 1 hour and to 170°C for 3 hours. Ice water is added to the cooled mixture, and the whole is extracted with dichloromethane.

61

The combined dichloromethane extracts are dried and concentrated. The residue is chromatographed on silica gel with dichloromethane/methanol (95:5). 2.1 g of ethyl 7,8,9,10-tetrahydro-10-oxo-6H-azepino[1,2-a]-5-indole-8-carboxylate is obtained.

d) Dissolve 2.1 g of the product from c) in 80 ml of ethanol and treat with 4 spatula-sized scoops of Raney nickel and 50 ml of water. Heat the mixture under reflux for 4 hours, then cool and

10. The residue is filtered and washed with ethyl acetate. The filtrate is extracted with ethyl acetate. The combined extracts and wash waters are dried and concentrated. Silica gel chromatography of the residue with dichloromethane yields 0.89 g of ethyl 15,7,8,9,10-tetrahydro-6H-azepino[1,2-a]indole-8-carboxylate.

e) Dissolve 0.85 g of the product from d) in 50 ml of THF and add it dropwise to a shaken suspension of 140 mg of lithium-aluminum hydride in 50 ml

20 of THF. After adding water, the mixture is extracted with diethyl ether. The combined extracts are dried and concentrated. Silica gel chromatography of the residue with dichloromethane/methanol (95:5) gives 0.70 g of 7,8,9,10-tetrahydro-8-(hydroxymethyl)-6H-azepino[1,2-25 a]indole at Pf. 90-91 °C.

f) 0.70 g of the product of e) is 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 1 g of acetic acid are added, and the mixture is stirred for 16 hours.

30 then concentrates the mixture and the residue is chromatographed on silica gel with dichloromethane, yielding 0.60 g of 8-(acetoxymethyl)-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indole at Pf. 77-79°C.

62

(g) A solution of 0.60 g of the product from (f) in 50 mL of dichloromethane is treated dropwise with 0.33 g of oxalyl chloride. After allowing the solution to stand at 10°C for 2 hours, the solution is concentrated and the residue is dissolved in dichloromethane. This solution is added to a solution of 0.49 g of 1-methylindole-3-acetic acid and 0.59 g of triethylamine in dichloromethane. After 16 hours, the mixture is concentrated and the residue is chromatographed on sili-10 ce with dichloromethane/methanol (95:5). We obtain 0.51 g of 3-[8-(acetoxymethyl)-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-ll-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione at Pf. 70°C.

EXAMPLE 54

15. A solution of 60 mg of the product from Example 53 and 60 mg of 2,6-lutidine in 25 mL of dichloromethane is added dropwise to a solution of 116 mg of trifluoromethanesulfonic anhydride in 25 mL of dichloromethane at 0°C. After 3 hours, 20-25 mL of ammonia is added to the solution. The organic phase is dried and concentrated. Silica gel chromatography of the residue gives 30 mg of 3-[8-(aminomethyl)-7,8,§,10-tetrahydro-6H-azepinol[1,2-a]indol-11-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione acetate at 25 Pf. 162-163°C.

EXAMPLE 55

A solution of 0.64 g of the product from Example 1 and 0.4 mL of 2,4,6-collidin in 20 mL of dichloromethane is added dropwise to a solution of 0.75 g of trifluoromethanesulfonic anhydride in 10 mL of dichloromethane at 0°C. After 2 hours, the mixture is treated with 3 mL of piperidine and stirred for 16 hours. The concentration

(

63

Chromatography of the residue on silica gel with dichloromethane/methanol (gradient from 98:2 to 50:50) yields 340 mg of 3-[6,7,8,9-tetrahydro-8-[(1-piperidino)methyl]pyrido-[1,2-α]indol-10-yl]-4-(1-methyl1-3-indolyl)1H-pyrrole-2,5-dione. This is transformed to give Pf hydrochloride at 294°C (decomposition) by treatment with a saturated solution of hydrochloric acid in ethyl acetate.

EXAMPLE 56

A solution of 0.8 g of the product from Example 1 and 0.44 g of 2,4,6-collidin in 30 mL of dichloromethane is added to a solution of 0.9 g of trifluoromethanesulfonic anhydride in 10 mL of dichloromethane at 0°C. After one hour, the mixture is treated with 3.64 g of diisopropylamine and stirred for 16 hours. The mixture is washed with water and then with a saturated solution of aqueous sodium bicarbonate, dried, and concentrated. The resulting solid is dissolved in ethyl acetate and treated with a saturated solution of hydrochloric acid in ethyl acetate. Removal of solvent under vacuum gives 260 mg of 3-[6,7,8,9-tetrahydro-8-[(diisopropylamino)methyl]pyrido [,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione hydrochloride at Pf. 187°C (decomposition).

EXAMPLE 57

A solution of 1.0 g of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(3-benzofuranyl)-furan-2,5-dione in 100 ml of chloroform is treated with 13.8 ml of hexamethyldisilazane and 2.73 ml of methanol and heated to 50°C while stirring under a nitrogen atmosphere for 6 hours. A further 13.8 ml of hexamethyl-

64

Disilazane and 2.73 mL of methanol are added, and heating continues for 16 hours. Two further additions of the same quantities of hexamethyldiilazane and methanol are made, and the mixture is maintained at 50°C for another 24 hours. 20 mL of methanol is added, and the mixture is heated under reflux, cooled, and concentrated. The precipitate is separated by filtration and triturated successively with ethyl acetate and methanol. 630 mg of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydrpyrido[1,2-a]indol-10-yl]-4-(3-benzofuranyl)-1H-pyrrole-2,5-dione is obtained at a temperature of 234-237°C.

The starting product furanedione is prepared as follows:

1.7 g of oxalyl chloride is added dropwise to a solution of 3.3 g of 8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole in 200 mL of diethyl ether under a nitrogen atmosphere. After 15 minutes, the solvent is removed under reduced pressure and dissolved in dichloromethane. 2.4 g of 3-benzofuranyacetic acid and 5.6 mL of triethylamine are added to this solution, and the mixture is stirred overnight. The solvent is removed under reduced pressure, and the residue is purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2). Crystallization of the residue from ethyl acetate/

petroleum ether gives 1.62 g of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(3-benzo-furanyl)furan-2,5-dione at Pf. 214-215°C.

EXAMPLE 58

A solution of 300 mg of the product from Example 57 in 40 mL of methanol is treated with 5 mL of 2 M sodium hydroxide. After 10 minutes, it is acidified.

65

The mixture is combined with 5 mL of 2 M hydrochloric acid, and the methanol is removed under reduced pressure. The residue is distributed between ethyl acetate and water. The phases are separated, and the organic phase is washed with a sodium bicarbonate solution and dried. The solution is concentrated, and the precipitate is separated by filtration to give 190 mg of 3-(3-benzofuranyl)-4-[6,7,8,9-tetrahydro-8-(hydroxymethyl)pyrido-[1,2-a]indol-10-yl]-1H-pyrrole-2,5-dione at 246-248°C. 10 EXAMPLE 59

In a manner analogous to what is described in example 2, from the product of example 58, the hydrochloride of 3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(3-benzofuranyl)-15 lH-pyrrole-2,5-dione is prepared at Pf. 210-212°C.

EXAMPLE 60

118 mg of trifluoromethanesulfonic anhydride is treated in 20 mL of dichloromethane at 0°C under a nitrogen atmosphere with a suspension of 90 mg of product from Example 26 and 45 mg of collidine in 20 mL of dichloromethane. After 45 minutes, 0.41 mL of a 40% diethylamine solution in water is added, and the mixture is stirred for 1 hour. The resulting solution is washed with water and a sodium bicarbonate solution, and then dried. The solution is concentrated and the resulting crystals are separated by filtration and dried to give 60 mg of 3-(3-benzo[b]thienyl)-4-[6,7,8,9-tetrahydro-8-(dimethyl-aminomethyl)pyrido-1,2-a]indol-10-yl]-1H-pyrrole-2,5-30 dione at Pf. 285-286°C.

66

EXAMPLE 61

546 mg of trifluoromethanesulfonic anhydride in 80 mL of dichloromethane at 0°C under a nitrogen atmosphere is treated with a suspension of 400 mg of product 5 from Example 19 and 208 mg of collidine in 120 mL of dichloromethane. After one hour, 1.9 mL of 40% aqueous dimethylamine is added, and the mixture is stirred for 3 hours. The solvent is removed, and the residue is subjected to silica gel chromatography with 10 dichloromethane/methanol/acetone (88:10:2). Crystallization with ethyl acetate followed by recrystallization from methanol gives 295 mg of tri-fluoromethanesulfonate of 3-[2,3-dihydro-3-(dimethylamino-methyl)-1H-pyrrolo[1,2-a]indol-9-yl]-4-(l-methyl-3-15 indolyl)-1H-pyrrole-2,5-dione at Pf. 323-325°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-2,5-20 dione in 12 ml of DMF and 12 ml of 33% ammonia is heated at 140°C for 3 hours.

The mixture is cooled and the resulting solid is separated by filtration and dried to give 275 mg of 3-[8-cyano-6,7,8,9-tetrahydropyrido-[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione at Pf. 25, 312-313°C.■

The starting product furanedione is prepared as follows:

a) A 4.0 g suspension of the product from Example 38a) is cooled in 4.4 mL of water and 84 mL of acetone to 300°C and 2.18 g of triethylamine is added. Then 2.56 g of ethyl chloroformate is added and the resulting solution is stirred under a nitrogen atmosphere.

I

67

Add 0.9 mL of 33% ammonia and allow the mixture to warm to room temperature. Add another 0.5 mL of 33% ammonia and continue stirring. Evaporate the solvent and extract the residue with dichloromethane. Wash the organic phase with water, dry, and concentrate to give 2.8 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxamide at 179-181°C.

b) 991 mg of 10-trifluoracetic anhydride is 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 dioxane at 10°C. The mixture is divided between dichloromethane and water, and the organic phase is dried. The solvent is removed under reduced pressure to give an oil that

15. We subject to silica gel chromatography with ethyl acetate/petroleum ether (1:1). We obtain 740 mg of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carbonitrile at Pf. 116-118°C.

(c) 518 mg of oxalyl chloride is 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 is evaporated and the residue is dissolved in dichloromethane. 771 mg of l-methyl-3-indolylacetic acid and 1.24 g of triethylamine are added to this solution and the mixture is stirred overnight. The solvent is removed at reduced pressure and the residue is purified by silica gel chromatography with 10% methanol in dichloromethane. The fractions containing the desired products are concentrated and the resulting crystals are separated by filtration 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-indo-lyl)furan-2,5-dione at Pf. 309-311°C.

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EXAMPLE 63

Hydrochloric acid gas is bubbled through a solution of 200 mg of the product from Example 62 in 250 mL of methanol at 0°C. Solvent 5 is then removed under reduced pressure, and the residue is dissolved in 50 mL of dichloromethane and 250 mL of ethanol. Ammonia is bubbled through the solution, and the solvent is evaporated. The residue is purified by silica gel chromatography with dichloromethane/methanol/10 acetic acid/water (90:18:3:2). Trituration with ethyl acetate gives 75 mg of 3-[8-amidino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione hydrochloride at Pf. 237-239°C.

15 EXAMPLE 64

A solution of 50 mg of 3-[8-carbamoyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione is heated to 140°C in 4 mL of DMF and 4 mL of 33% ammonia. The mixture is extracted with ethyl acetate, and the organic phase is washed with water and then dried. Most of the solvent is evaporated, and the resulting precipitate is separated by filtration and dried. 20 mg of 3-[8-carbamoyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-25-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione is obtained.

315-316°C.

The starting product furanedione is prepared as follows:

178 mg of oxalyl chloride is added to a 30 mg solution of the product from Example 62a) in

40 ml of dichloromethane under a nitrogen atmosphere. The solvent is then removed at reduced pressure and the residue is dissolved in the dichloromethane. Adding

69

265 mg of l-methyl-3-indolylacetic acid and 424 mg of triethylamine are stirred for approximately 60 hours. The solvent is removed under reduced pressure, and the residue is purified by silica gel chromatography with 10% methanol in dichloromethane. Crystallization from ethyl acetate yields 70 mg of 3-[8-carbamoyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione at Pf. 307-309°C.

10 EXAMPLE 65

In a manner analogous to what is described in the first paragraph of example 1, from the 3-[8-(acetoxymethyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(5-methoxy-l-methyl-3-indolyl)furan-2,5-15 dione the 3-[6,7,8,9-tetrahydro-8-(hydroxymethyl)pyrido[1r 2-a]indol-10-yl]-4-(5-methoxy-l-methyl-3-indolyl)-1H-pyrrole-2,5-dione of Pf. 300-303°C is prepared.

The starting product furanedione is prepared as follows:

20. 0.4 mL of oxalyl chloride is added to a solution of 906 mg of 8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido-[1,2-a]indole in 35 mL of diethyl ether under a nitrogen atmosphere. The solvent is then removed under reduced pressure, and the residue is dissolved in dichloromethane. 25. 940 mg of 5-methoxy-1-methyl-3-indolylacetic acid and 1.16 mL of triethylamine are added, and the mixture is stirred for 40 hours. The solvent is removed under reduced pressure, and the residue is purified by silica gel chromatography with 1:2 d1-ethyl/n-hexane acetate. 30. Crystallization from ethyl acetate/petroleum ether gives 250 mg of

70

3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido-[1,2-a]indol-10-yl]-4-(5-methoxy-l-methyl-3-indolyl)furan-2,5-dione de Pf. 259-261°C.

EXAMPLE 66

5. In a manner analogous to that described in Example 2, from the product of Example 65, the hydrochloride of 3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(5-methoxy-1-methyl 3-indolyl)-1H-pyrrole-2,5-dione is prepared at a temperature of 268-270°C. 10. EXAMPLE 67

In a manner analogous to what is described in the first paragraph of example 1, from 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(5-bromo-l-methyl-3-indolyl)furan-2,5-15 dione is 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 Pf. 316-318°C.

The starting product furanedione is prepared as follows:

20 a) 500 mg of a 60% sodium hydride dispersion in mineral oil is added to a solution of 1 g of 5-bromoindole-3-acetic acid in 50 mL of THF, and the mixture is stirred under a nitrogen atmosphere for one hour. Then, 820 mg (5.8 mmol) of methyl iodide-25 is added, and the mixture is stirred under a nitrogen atmosphere for 24 hours. 5 mL of water is added, and the solvent is removed under reduced pressure. The residue is treated with 2 M hydrochloric acid, and the precipitate formed is separated by filtration, washed with 30 n-hexane, and dried. The resulting solid is recrystallized from diethyl ether to give 5-bromo-1-methyl-3-indolylacetic acid with a boiling point of 192–194°C.

71

b) 500 mg of oxalyl chloride is added to a solution of 900 mg of the product of a) in 100 mL of diethyl ether under a nitrogen atmosphere. The solvent is then evaporated, and the residue is dissolved in dichloromethane. 5) 880 mg of 5-bromo-l-methyl-3-indolylacetic acid and 810 mg of triethylamine are stirred, and the mixture is stirred for 48 hours. The solvent is removed under reduced pressure, and the residue is purified by silica gel chromatography with ethyl acetate/n-hexane (1:1) to give 400 mg of a solid. A sample is recrystallized from ethyl acetate to give 3-18-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(5-bromo-l-methyl-3-indolyl)furan-2,5-dione at Pf. 215-220°C.

15 EXAMPLE 68

In a manner analogous to what is described in example 2, from the product of example 67, the hydrochloride of 3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido [1,2-a]indol-10-yl]-4-(5-bromo-l-methyl-3-indolyl)-1H-20 pyrrole-2,5-dione is prepared with a pf. >310°C.

EXAMPLE 69

A solution of 200 mg of 3-[7-(2-acetoxyethyl)=-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)furan-2,5-dione is heated to 140°C in 252 ml of DMF and 1 ml of 33% ammonia. Then

Add 1 ml of a 2 M sodium hydroxide solution to the cooled solution and stir the mixture for 2 hours. Acidify the mixture with hydrochloric acid.

2 M and evaporate. The residue is divided between ethyl acetate and water, and the organic phase is dried. The solvent is evaporated, and the resulting solid is triturated with ethyl acetate to give

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115 mg of 3-[6,7,8,9-tetrahydro-7-(2-hydroxyethyl)-pyrido[1,2-a J indol-10-yl]-4-(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione at Pf. 236-238°C.

The starting product furanedione is prepared as follows:

a) 400 mg of a 60% sodium hydride dispersion in oil is added to a solution of 2.24 g of triethyl phos-phonoacetate in 40 mL of dimethoxyethane under a nitrogen atmosphere. The solution is then cooled to 0°C and 1.85 g of the product from Example 35d) is added to 10 mL of dimethoxyethane. The mixture is stirred overnight and then evaporated. The residue is dissolved in dichloromethane and the solution is washed with water, dried, and concentrated. The residue is purified by silica gel chromatography with diethyl ether/petroleum ether (1:3).

and 1.5 g of a mixture of (E) and (Z)-(6,7,8,9-tetrahydropyrido[1,2-a]indol-7-ylidene)ethyl acetate is obtained. 1.4 g of this is dissolved in ethanol and the solution is stirred with 280 mg of 10% Pd under a hydrogen atmosphere. The catalyst is then separated by filtration and the filtrate is evaporated to give 1.2 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-7-ethyl acetate of Pf. 66-68°C after crystallization from diethyl ether/petroleum ether;

b) A 1.2 g solution of the product of a) is treated

in 100 mL of diethyl ether with 3.5 mL of a 1 M lithium-aluminum hydride solution in diethyl ether. After stirring for one hour, the mixture is extinguished with 50 mL of aqueous ammonium chloride. The mixture is extracted with diethyl ether, and the organic phase is dried and evaporated to

73

give 1.01 g of 6,7,8,9-tetrahydro-7-(2-hydroxyethyl)pyrido[1,2-a]indole of Pf. 70-72°C after crystallization from diethyl ether/petroleum ether.

c) A solution of 1.04 g of product from b) 5 in 30 mL of dichloromethane is treated with 6 mL of acetic anhydride and 3 mL of pyridine, and the solution is stirred under a nitrogen atmosphere. The mixture is then evaporated to dryness, and the residue is dissolved in dichloromethane. The organic phase is washed with 10 mL of 2 M hydrochloric acid and with water, dried, and evaporated. The residue is purified by silica gel chromatography with diethyl ether/petroleum ether (1:4) to give 670 mg of 7-(2-acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-α]indole

15 d) 250 yl of oxalyl chloride is added to a solution of 670 mg of the product of c) in 12 mL of dichloromethane under a nitrogen atmosphere. The solvent is then removed under reduced pressure and the residue is dissolved in dichloromethane. 493 mg of l-methyl-3,20-indolelyacetic acid and 527 mg of triethylamine are added to this solution and the mixture is stirred. The solvent is then removed under reduced pressure and the residue is purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) to give 350 mg of 25 3-[7-(2-acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-a]

indole-10-yl]-46(l-methyl-3-indolyl)furan-2,5-dione of Pf. 182-184°C after crystallization from ethyl acetate.

EXAMPLE 70

30. In a manner analogous to what is described in Example 2, from the product of Example 69, the hydrochloride of 3-[7-(2-aminoethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-

%

74

lH-pyrrole-2,5-dione, m.p. 240-242°C.

EXAMPLE 71

Similar to what is described in the first paragraph of Example 1, from the 5 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 is prepared. 3-[6,7,8,9-tetrahydro-8-(hydroxymethyl)-2-methoxypyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-lH-pyrrole-2,5-dione is prepared at a temperature of 195-197°C. The starting material furanedione is prepared as follows:

a) Two g of a 60% sodium hydride dispersion in mineral oil are washed with n-hexane by decantation and suspended in 100 mL of DMF under a nitrogen atmosphere. A solution of 10 g of 5-methoxyindole-2-carboxylate is added to 100 mL of DMF and the mixture is stirred. Then, 9.8 g of ethyl 4-bromobutyrate is added and the mixture is stirred for 2 hours. The mixture is cooled and treated with 20 50 mL of 1 M hydrochloric acid and 400 mL of water. The mixture is extracted with diethyl ether and the combined extracts are washed with a sodium chloride solution. The organic phase is dried and evaporated. The oil obtained is 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. The mixture is then cooled and neutralized with 1 M hydrochloric acid. Water is added, and the mixture is extracted with diethyl ether. The combined extracts are washed with water and sodium chloride solution and then dried. The solvent evaporates, and the residue crystallizes from the acetate.

75

ethyl gives 6.7 g 6,7-dihydro-9-hydroxy-2-methoxy-pyridox1,2-α-indole-8-carboxylate of Pf. 157-160°C.

(i) b) 5 g of the product from (a) is treated in 200 ml of ethanol under a nitrogen atmosphere with 10 scoops of Raney nickel and 100 ml of water. The suspension is heated under reflux, then cooled and filtered. The solid is washed with ethyl acetate and the volatile components are removed under vacuum from the combination of the filtrate and the wash water.

The aqueous suspension is extracted with ethyl acetate and the combined extracts are washed with a sodium chloride solution and dried. Evaporation of the solvent and crystallization of the residue from methanol give 2.41 g of ethyl 6,7,8,9-tetrahydro-2-methoxy-pyridol,2-α-indole-8-carboxylate at Pf. 104-105 °C.

c) A solution of 2.3 g of the product from b) is added

In 25 mL of THF, a suspension of 260 mg of lithium-aluminum hydride in 20 mL of THF was mixed under a nitrogen atmosphere. The mixture was then treated with 10 mL of ethyl acetate followed by 20 mL of water. The mixture was acidified to pH 3 with 1 M hydrochloric acid and extracted with diethyl ether. The combined extracts were washed with water and dried. Removal of the solvent by evaporation yielded 1.85 g of 6,7,8,9-tetrahydro-2-methoxypyrido[l,2-a]indole-8-methanol. A sample crystallized from ethyl acetate/n-hexane melted at 95–96°C.

d) 1 g of the product from c) is treated in 10 ml of pyridine with 1.5 g of acetic anhydride. The solvent is then evaporated and the residue is divided between diethyl ether and 5% aqueous ammonium chloride.

76

The organic phase is washed with a sodium chloride solution, dried, and evaporated. Crystallization of the residue from diethyl ether/n-hexane gives 0.84 g of 8-acetoxymethyl-6,7,8,9-tetrahydro-2-methoxy-5-pyrido[1,2-a]indole with a melting point of 98-100°C.

e) A suspension of 800 mg of the product of d) is treated

in 25 ml of diethyl ether with 0.27 ml of oxalyl chloride under a nitrogen atmosphere. The solvent is evaporated, the residue is dissolved in 20 ml of dichloromethane, and it is treated with 555 mg of N-methyl-

indole-3-acetic acid and 0.8 mL of triethylamine. The mixture is stirred for 65 hours, then the solvent is removed under reduced pressure. Silica gel chromatography of the residue with ethyl acetate/n-hexane (1:1) 15 gives 380 mg of 3-[8-(acetoxymethyl)-6,7,8,9-tetra-

hydro-2-methoxy-pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione. A sample crystallized from toluene/n-hexane melts at 131-133°C (decomposition).

20 EXAMPLE 72

In a manner analogous to what is described in example 2, from the product of example 71 the hydrochloride of 3-[8-(aminomethyl)-6,7,8,9-tetrahydro-2-methoxypyrido[1,2-a]indol-10-yl]-4-(1-25 methyl-3-indolyl)-1H-pyrrole-2,5-dione is prepared at Pf. 235-238°C (decomposition).

EXAMPLE 73

a) A solution of 150 mg of the product of example 20 in dichloromethane under a nitrogen atmosphere 30 is treated with 135 mg of 1,1'-thiocarbonyldiimidazole.

After 17 hours, the solution is washed with water and dried. The solvent is evaporated, and the residue is crystallized from ethyl acetate to give

77

150 mg of 3-[1,2,3,4-tetrahydro-2-(1-imidazolylthio-carbonyl)-pyrazino[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione is heated to 244-247°C. b) 140 mg of the product from a) is treated in 10 ml of DMF 5 with 20 ml of 33% ammonia. After 17 hours, the suspension is filtered and the solid is washed with water. The solid is dried to give 95 mg of 3-[1,2,3,4-tetrahydro-2-thiocarbamoylpyrazino[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione at Pf. 278°C 10 (decomposition).

EXAMPLE 74

A solution of 150 mg of the product from Example 20 in 50 mL of dichloromethane is treated with 3 mL of acetic anhydride and 3 mL of triethylamine. After 15 to 17 hours, the solution is washed with water. The organic phase is dried and evaporated. The residue is dissolved in dichloromethane and treated with 0.08 mL of diethylamine. After 17 hours, the solution is evaporated. Crystallization of residue 20 from dichloromethane/n-hexane gives 80 mg of 3-[2-acetyl-1,2,3,4-tetrahydro-pyrazino-[1,2-a]indol-10-yl1-4-(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione with a boiling point of 308–310°C.

EXAMPLE 75

25 In a manner similar to what is described in the example

74, from the product of example 2, we prepare the 3-[8-(acetamidomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]-indol-10-yl]-4-(l-methyl-3-indolyl)-lH-pyrrole-2,5-dione of Pf. 270-273°C.

30

78

EXAMPLE 76

A solution of 150 mg of the product from Example 20 in 40 mL of dichloromethane is treated with 40 mg of triethylamine and 44 mg of methanesulfonyl chloride. After 17 hours, the solution is washed with water. The organic phase is dried and evaporated. Silica gel chromatography of the residue with ethyl acetate/n-hexane (2:1) and ethyl acetate gives 95 mg of 3-[1,2,3,4-tetrahydro-2-methanesulfonyl-pyrazino[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-1H-pyrrole-2,5-dione with a decomposition temperature of 298–301°C.

EXAMPLE 77

3.0 g of the product from Example 1 is dissolved in 100 mL of THF, and the solution is added to a suspension of 1.8 g of lithium-aluminum hydride in 50 mL of THF at 0°C. The mixture is then heated under reflux for 16 hours. Afterward, the mixture is cooled, treated with 10 mL of water, and extracted with dichloromethane. The combined dichloromethane extracts are washed with an aqueous solution of sodium bicarbonate, dried, and concentrated to a solid. Silica gel chromatography with dichloromethane/methanol (95:5) gives a solid which is further purified by chromatography to give a) 400 mg of 1,5-dihydro-3-[6,7,8,9-tetrahydro-8-(hydroxymethyl)pyrido[1,2-a]indol-10-yl]-4-(l-methyl-3-indolyl)-2H-pyrrole-2-one at Pf. 205-207°C.

We also obtain b) 160 mg of 1,5-dihydro-4-[6,7,8,9-tetrahydro-8-

(hydroxymethyl)pyrido[1,2-a]indol-10-yl]-3-(1-methyl-3-indolyl)-2H-pyrrole-2-one de Pf. 201-203°C.

EXAMPLE 78

In a manner analogous to what is described in the first paragraph of the example there, starting from 0.5 g of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(3-trifluoromethylphenyl)furan-2,5-dione, we obtain 110 mg of 3-[6,7,8,9-tetrahydro-8-(hydroxymethyl)pyrido[1,2-a]indol-10-yl]-4-(3-trifluoromethylphenyl)-1H-pyrrole-2,5-dione solid at Pf. 77-79°C.

The starting product furanedione is prepared as follows:

One hundred and seventy-one-seven (1.7 g) of oxalyl chloride is added to a cold (0-4°C) solution of 3.0 g of 8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole in 50 mL of dichloromethane. After two hours, the solvent is evaporated, and the residue is dissolved in dichloromethane. This solution is added to a solution of 2.7 g of (a,a,a-trifluoro-m-tolyl)acetic acid and 3.2 g of triethylamine in 70 mL of dichloromethane. The mixture is stirred for 16 hours and then concentrated. The residue is chromatographed on silica gel with dichloromethane/ethanol (95:5). We obtain 700 mg of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2- a]indol-10-yl]-4-(3-trifluoromethylphenyl)furan-2,5-dione at Pf. 176-177°C.

EXAMPLE 79

In a manner analogous to what is described in the first paragraph of example 1, from 1.0 g of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(4-methoxyphenyl)furan-2,5-dione, 150 mg of 3-[6,7,8,9-tetrahydro-8-(hydroxymethyl)-pyrido[1,2-a]indol-10-yl]-4-(4-methoxyphenyl)-1H-pyrrole-2,5-dione of Pf. 228°G (decomposition).

80

The starting product furanedione is prepared as follows:

One hundred and seventy-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-one-of ... Silica gel chromatography of the residue with dichloromethane/methanol (95:5) gives 2 g of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-15 4-(5-methoxyphenyl)furan-2,5-dione at Pf. 79-82°C.

EXAMPLE 80

In a manner analogous to what is described in the first paragraph of example 1, from 0.8 g of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-20 a]indol-10-yl]-2-(2-chlorophenyl)furan-2,5-dione we obtain 120 mg of 3-(2-chlorophenyl)-4-[6,7,8,9-tetra-hydro-8-(hydroxymethyl)pyrido[1,2-a]indol-10-yl]-1H-pyrrole-2,5-dione at Pf. 232-233°C.

The starting product furanedione 25 is prepared as follows:

2.2 g of oxalyl chloride is added to an ice-cold solution of 4 g of 8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole in 50 mL of dichloromethane. After 2 hours, the sol-30 is evaporated and the residue is dissolved in dichloromethane.

This solution is added to a solution of 3.0 g of 2-chlorophenylacetic acid and 4.0 g of triethylamine in dichloromethane. The mixture is stirred for 16 hours.

81

and we concentrate. Silica gel chromatography with dichloromethane/methanol (95:5) gives 0.9 g of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(2-chlorophenylfuran-2,5-dione of Pf. 5 168-171°C.

EXAMPLE 81

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

EXAMPLE 82

Similar to what is described in Example 51, starting from 100 mg of the product of 15 in Example 79, we obtain 88 mg of 3-[8-(aminomethyl)-

6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(4-methoxyphenyl)-1H-pyrrole-2,5-dione Pf. 195-196°C.

EXAMPLE 83

In a manner analogous to what is described in 20 example 53, from 80 mg of the product of example 80, 57 mg of 3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-ylI-4-(2-chlorophenyl)-1H-pyrrole-2,5-dione is obtained at Pf. 206-208°C (decomposition).

The following examples present typical pharmaceutical preparations containing compounds provided by the invention:

30

82

EXAMPLE A

Tablets containing the following ingredients can be produced using conventional methods:

Ingredient per tablet

Formula I compound 5.0 mg

Lactose 125.0 mg

Corn starch 75.0 mg

Talc 4.0 mg

Magnesium stearate 1.0 mg

10 Weight of one tablet 210.0 mg

EXAMPLE B

Capsules containing the following ingredients can be produced using conventional methods:

Ingredient per capsule

15 Compound of formula I 10.0 mg

Lactose 165.0 mg

Corn starch 20.0 mg

Talc 5.0 mg

20

Weight of one filled capsule: 200.0 mg

83

EV 4070/77

general

Claims (1)

DEMANDS Method for preparing compounds of formula 10 8 R R x where R represents a hydrogen or a hydroxyl, R and 2 R together represent a group of formula 7 1 -(CH-j) - and R represents a hydrogen or R and n M n R together represent a formula group 2 n 3 -(CH0) - and R represents a hydrogen; R / 4 represents an aryl or heteroaryl group; R, 5 6 R and R each independently represent a 84 hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, 0 alkylsulfonyl or alkylsulfonyl; R represents 9 10 a group of formula -(CH~) -R or -(CH~) -R; Q ^ P ^ Si R represents hydrogen, alkylcarbonyl, amino-alkylcarbonyl, cyano, amidino, alkyloxycarbonyl, aryloxycarbonyl, alkylsulfonyl, aminocarbonyl or aminothiocarbonyl; R represents a hydroxy, alkoxy, halogen, amino, monoalkoylamino, dialkoylamino, trikoylamino, azido, acylamino, alkylsulfonylamino, arylsulfonylamino, alkylthio, alkoxycarbonylamino, aminoacylamino, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulfonyloxy, or arylsulfonyloxy, a heterocycle containing saturated nitrogen with 5 or 6 bonds attached via the nitrogen atom, or a group of formula -U-C(V)-W; U represents S or NH; V represents NH, NCN, CHNC; W represents an amino, monoalkoylamino, or dialkoylamino; one of the radicals is Y, and Y represents O and the other represents O or (H,H); Z represents CH or N; m represents O-5, with the precision that m equals 2-5 when Z represents N; n represents 1-5; p represents 0-5; and q represents 0-5, with the clarification that q represents 2-5 when Z represents N; as well as pharmaceutically acceptable selti of acidic compounds of formula I with bases and of basic compounds of formula I with acids, process in which one proceeds 85 (a) to prepare a compound of formula I where X and Y both represent 0, by reacting a compound of general formula where r\ R^, R^, R4, R5, R^, R7, R8, Z and m have the meaning given above, with pressurized ammonia or with hexamethyldisilazane and methanol to give a compound of formula I, where R represents a hydrogen, or with hydroxylamine to give a compound of formula I where R represents a hydroxy, or (b) to prepare a compound of formula I where one of the radicals X and Y represents 0 and the other represents (H,H), by reducing a compound of formula I where X and Y both represent 0 with lithium-aluminum hydride, or (c) if desired, by functionally modifying a reactive center present in a compound of formula I obtained, and (d) also if desired, by transforming a 20 acidic compound of formula I into a pharmaceutically acceptable salt with a base or by transforming a basic compound of formula I into a pharmaceutically acceptable salt with an acid. 86 2. A method according to claim 1, wherein R represents a hydrogen, R represents a hydrogen, alkylcarbonyl, cyano, amidino, alkylcarbonyl, alkylsulfonyl, aminocarbonyl or aminothiocarbonyl and R"^ represents a hydroxy, alkyloxy, halogen, amino, monoalkylamino, dialalkylamino, trialkylamino, azido, acylamino, alkylsulfonylamino, arylsulfonylamino, alkylthio, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulfonyloxy or arylsulfonyloxy or a group of formula -U-C(V)-W and R1, R2, R3, R4, R5, R6, R7, R8, U, V, W, X, Y, Z, m, n, p and q have the meanings given in claim 1. 3. Method according to claim 1 or 2, 12 ✓ 7 where R and R together represent -CH^- and R represents a hydrogen, m is 1 or 2 and Z represents CH. 4. Method according to claim 1 or 2, 12 7 where R and R • together represent -(C^^- and R represents a hydrogen, m is 1 and Z represents CH. 5. Method according to claim 1 or 2, 1 2 7 where R and R together represent -C^- and R represents a hydrogen, m is 2 and Z represents N. 6. Method according to claim 1 or 17 2 2, where R and R together represent -C^- and R represents a hydrogen, m is 1 and Z represents CH. 7. A method according to claim 1 or 2, where 17 2 R and R together represent -(^2)2" and R represents a hydrogen, m is 0 and Z represents CH. 8. Procedure according to any one of the claims 3 indications 1 to 6, where R represents a phenyl, naph-tyl, 3-benzothienyl, 3-benzofuranyl, or 3-indolyl 87 which is possibly substituted by one or more substituents chosen from halogen, alkoyl, hydroxy, alkoxy, haloalkoyl, nitro, amino, acylamino, alkoylthio, alkoylsulfinyl and alkoylsulfonyl. 3 5.9. Method according to claim 8, where R represents l-methyl-3-indolyl. 10. Method according to any one of claims 1 to 9, where R, R and R each represent a hydrogen. 10 11. Procedure according to any one of the N 8 claims 1 to 10, where R represents a group of formula -(CH9 ) -R^. 4 12. Method according to claim 11, where q is 1 or 2. 15 13. Method according to claim 11 or 12, where R"^ represents a hydroxy, amino, monoalcoylamino, dialcoylamino, trialcoylamino, azido, acylamino, alcoyl-carbonyloxy or alcoylsulfonyloxy or a group of formula -U-C(V)-W. 20 14. Method according to claim 13, where U represents S, V represents NH and W represents an amino. 15. A method according to any one of claims 1 to 14, wherein X and Y both represent 25 0. 16. Method according to claim 1 or 2, in which compounds belonging to the following group of compounds are prepared: 30 88 3-|8-(aminomethyl)-6,7,8,9-tetrahydropyrido (1,2-a|-indo1-10-y1I-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, 3-I7-(amidinothiomethyl)-6,7,8,9-tetrahydropyrido-5[1,2-a]indol-10-ylI-4-(1-methyl-3-indoly1)-lH-pyrrole-2,5-dione 3-16,7,8,9-tetrahydro-8-[(dimethylamino)methyl]pyrido-[1,2-α|indol-10-yl-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione 10 and their pharmaceutically acceptable acid addition salts. 17. A method for preparing a medicinal product, in particular an anti-inflammatory, immunological, oncological, bronchopulmonary or cardiovascular medicinal product or a medicinal product for the treatment of asthma and AIDS, a method in which a product according to claim 1 is placed in a pharmaceutical administration form with a therapeutically inert carrier, and, if desired, one or more therapeutically active substances. 19. Application of a product according to claim 1 to the preparation of a drug against inflammatory, immunological, oncological, bronchopulmonary or cardiovascular diseases or against asthma or AIDS. 36. The invention as described above. 30 89 37. Compounds of general formula II _i^ V.8 n « or R, R, R^, R4 / R^# R**, R7, R®, z and m have the meaning given in claim 1. ******** ORIGINAL ! in —-- containing Reference* added —word crossed out “ul” Josfe CURA] Council ej Property)*0krielle 26'ki », Blvd. fE-CARLO Pat procuiattOH da dlo. XL(Û.IU^_ LlX docile ^ C)lf