WO1998011103A1 - New pharmaceutically active compounds - Google Patents

Abstract

The present invention provides compounds of formula (I) wherein each R20, which may be the same of different, is a hydrogen or halogen; R' is methyl, hydrogen or R; R is a group of formula (II) wherein Z is a single or a double bond; n is 1-3; R1 is hydroxy, hydroxymethyl, amino, N-((C1-C5)alkyl)amino, aminomethyl, N-((C1-C5)alkyl)aminomethyl, N,N-di((C1-C5)alkyl)aminomethyl, (C1-C5)acyloxy or N-((C1-C5)acyl)amino, and R2 and R3 are hydrogen and, when Z is a single bond, R4 and R5, which may be the same or different, are each hydrogen or hydroxy; and pharmaceutically acceptable salts thereof; and the use of such compounds in medical therapy.

Description

NEW PHARMACEUTICALLY ACTIVE COMPOUNDS

Field of the invention

The present invention relates to novel bisindolylmaleimides, methods for their preparation, intermediates therefor and pharmaceutical compositions comprising them.

Background and prior art

Protein kinase C (PKC) is a family of phospholipid-dependent serine /threonine- specific protein kinases which play an important role in cellular growth control, regulation and differentiation.

Since the activation of PKC has been implicated in several human disease processes, including various forms of cancer, different forms of inflammatory and /or immunological disorders as well as some neurological disorders, inhibition of PKC could be of therapeutic value in treating these conditions.

Several classes of compounds have been identified as PKC inhibitors, e.g. isoquinoline sulphonamides, sphingosine and related sphingolipids and indolocarbazoles.

EP, Bl, 0328026 discloses the use of bisindolylmaleimides, a class of compounds related to the indolocarbazoles, in medicaments for the treatment of various diseases.

WO 95/17182(Eli Lilly and Company) purports to describe bis-indolemaleimides which are protein kinase inhibitors. Although PKC inhibitors are described in the prior art, there is an urgent need for specific anti-inflammatory and im unosuppressive compounds which are suitable for oral administration, and for inhalation.

Outline of the invention

We have found a group of novel bisindolylmaleimides which are PKC inhibitors. The compounds of formula (I) and pharmaceutically acceptable salts, stereoisomers, either pure or as racemates, or mixtures of stereoisomers, thereof are active topically, moreover, they have a systemic activity when administred orally, and certain of them have enhanced anti-inflammatory effect.

Compounds of the present invention have improved PKC inhibiting properties -and /or improved solubility and /or improved oral activity and /or improved ability to inhibit the pro-inflammatory cytokine, IL-lβ in human blood momocytes an/or improved ability to enhance the production of the anti-inflammatory cytokine IL-10, in human blood monocytes.

The object of the present invention is to provide these novel bisindolylmaleimides, methods for their preparation and intermediates used for their preparation.

Another object of the present invention is the use of the novel compounds for the treatment of inflammatory and immunological disorders and preferably for oral or topical treatment of inflammatory and immunological disorders, such as the oral or topical treatment of airway diseases involving inflammatory conditions, e.g. asthma; bronchitis and atopic diseases, e.g. rhinitis and atopic dermatitis; psoriasis; inflammatory bowel diseases, e.g. Crohn's disease and colitis; rheumatoid arthritis and malignant diseases (e.g. skin and lung cancer).

Still another object of the invention is a pharmaceutical composition comprising a compound according to the invention, as active ingredient, together with a pharmaceutically acceptable adjuvant, diluent or carrier.

Detailed description of the invention

According to the present invention we provide compounds of formula (I)

wherein

each R₂₀, which may be the same or different, is a hydrogen or halogen;

R' is methyl, hydrogen or R;

R is a group of formula (II)

(π) wherein

Z is a single or a double bond;

n is 1-3;

R, is hydroxy, hydroxymethyl, amino, N-((C₁-C₅)alkyl)amino, aminomethyl,

N-((C₁-C₅)alkyl)aminomethyl, N,N-di((C₁-C₅)alkyl)aminomethyl,

(C^C^acyloxy or N-^C^C^ cy^amino, and

R, and R₃ are hydrogen and, when Z is a single bond, R₄ and R₅ , which may be the same or different, are each hydrogen or hydroxy; and

pharmaceutically acceptable salts, as well as all possible stereoisomers either pure or as racemates or mixtures of stereoisomers, thereof.

Methods of preparation

The compounds of formula (I) and pharmaceutically acceptable salts, as well as all possible stereoisomers either pure or as racemates or mixtures of stereoisomers, thereof may be prepared by

a) production of a compound of formula (I) in which R₁ is hydroxyl or hydroxymethyl, and when Z is a single bond, R₄ and R_s are each hydrogen, by deprotecting a corresponding compound of formula (I) in which R_j is a protected hydroxyl group or a methylene carrying a protected hydroxyl group, or

b) production of a compound of formula (I) in which R_: is amino or aminomethyl, and when Z is a single bond, R₄ and R₅ are each hydrogen, by i) reduction of a corresponding compound in which R, is azide or azidomethyl, or

ii) deprotection of a corresponding compound of formula (I) in which R. is a protected amino group or a methylene carrying a protected amino group, or

c) production of a compound of formula (I) in which R, is amino, N-((C₁-C₅)alkyl)amino, aminomethyl, N-((C₁-C₅)alkyl)aminomethyl,

N,N-di((C₁-C₅)alkyl)aminomethyl, and when Z is a single bond, R₄ and R₅ are each hydrogen, by reaction of ammonia or an appropriate amine with a corresponding compound of formula (I) in which R₁ is a good leaving group or a methylene group carrying a good leaving group respectively, or

d) production of a compound of formula (I) in which , is (C_j-C₅)acyloxy or N-((C₁-C₅)acyl)amino, and when Z is a single bond, R₄ and R₅ are each hydrogen, by acylation of a corresponding compound of formula (I) in which R^ is hydroxy or amino respectively, or

e) production of a compound of formula (I) in which ^ is hydroxy, hydroxymethyl, amino, aminomethyl, and when Z is a single bond, R₄ and R_s are each hydrogen, by reaction of a compound of formula (III)

in which R₂₀, R' and R are defined as in formula (I), but in which R_t is a protected hydroxyl group, a methylene carrying a protected hydroxyl group, a protected amino group, or a methylene carrying a protected amino group, with

i) ammonia, or ammonia followed by treatment with an appropriate deprotecting agent; or

ii) ammonium acetate followed by treatment with an appropriate deprotecting agent; or

iii) hexamethyldisilazane-methanol, followed by treatment with an appropriate deprotecting agent; or

f) production of a compound of formula (I) in which R₄ and R₅ are hydroxyl, by hydroxylation of a compound of formula (I) in which Z is a double bond, in the presence of e.g. a metal oxidant, or

g) converting

i) a compound of formula (I) to a pharmaceutically acceptable salt thereof, or vice versa; or

ii) a pharmaceutically acceptable salt of a compound of formula (I) into a different pharmaceutically acceptable salt.

In process a) the conditions for deprotection are well known for similar reactions. Preferred conditions are: i) the protecting group may be a silylether, e.g. tertbutyldimethylsilyloxy, and the deprotecting agent may be fluoride ions or acid, e.g. acetic acid. The deprotecting step may be carried out in a suitable solvent, e.g. a mixture of

0 tetrahydrofuran and water at from about 40-70 C; ii) the protecting group may be an acyl group, e.g. a chloracetate ester, and the deprotecting agent may be a base, e.g. ammonium hydroxide (25% by volume) or ammonia in methanol. The deprotecting step may be carried out in a o suitable solvent, e.g. dimethylformamide at from about 100-140 C or in o methanol at about 10-30 C.

In process b) i) the conditions for the reduction are well known for similar reactions. Preferred conditions are: A) hydrogenation over Pd/C or Lindlar catalyst, e.g. at atmospheric pressure and at a temperature of 10-30°C and using a protic solvent, e.g. ethanol or a mixture of ethanol and ethyl acetate;

B) a sulphide in a suitable solvent, e.g. hydrogen sulphide in a mixture of pyridine and water;

C) triphenyl phosphine in a suitable solvent, e.g. tetrahydrofuran at a temperature of 10-30°C, followed by treatment with sodium hydroxide, e.g. IM, or ammonium hydroxide (e.g. 25% by volume) at a temperature of 10- 30°C, e.g. overnight.

In process b) ii) the protecting groups and conditions for deprotection are well known for similar reactions. Preferred conditions are:

A) the protecting group may be a phthaloyl group and the deprotecting agent may be methylamine in ethanol. The deprotecting step may be carried out in a suitable solvent, e.g. tetrahydrofuran at about 10-30°C;

B) the protecting group may be a trifluoroacetamide group and the deprotecting agent may be a base, e.g. potassium hydroxide or potassium carbonate. The deprotecting step may be carried out in a suitable solvent, e.g. methanol-water (e.g. 10:1) at about 10-30°C;

C) the protecting group may be a tertbutoxycarbonyl group and deprotecting agent may be an acid, e.g. trifluoroacetic acid.

In process c) the good leaving group may be a sulphonate group or a methylene carrying a sulphonate group, e.g. trifluoromethanesulphonate. After transformation may treatment with an amine, e.g. ammonia, methylamine or dimethylamine, follow. Suitable leaving groups are well known to those skilled in the art. A preferred leaving group is trifluoromethanesulphonate group. The intermediate compound possessing a good leaving group may be isolated or generated in situ.

In process d) the compound of formula (I) in which R_t is hydroxyl or amino may be converted to the corresponding amide or ester by reaction with an acylating agent, e.g. acetic anhydride, in the presence of a base, e.g. triethylamine.

In process e) the preferred protecting groups and the preferred deprotecting agents may be as defined above in a) and in b) ii), and preferred conditions for the reaction are: i) reaction with ammonia at elevated temperature, optionally followed by treatment with a deprotecting agent, e.g aqueous acetic acid; or

ii) reaction with ammonium acetate, e.g. at elevated temperature followed by treatment with a deprotecting agent, e.g aqueous acetic acid.; or

iii) reaction with hexamethyldisilazane-methanol in a polar solvent, e.g. N,N-dimethylformamide at a temperature of 10-30°C followed by treatment with a deprotecting agent, e.g. aqueous acetic acid. In process f) the conditions are well known to those skilled in the art. The hydroxylating agent may be a nitrogen oxide, e.g. N-methylmorpholine N-oxide monohydrate, and the hydroxylation may be carried out in a suitable solvent mixture, e.g. acetone-water, at e.g. 10-30°C, in the presence of a metal oxidant, e.g. osmium tetroxide.

In processes g) i) and g) ii) the conversion may be carried out by conventional processes known per se. e.g. reaction of the free base with an acid containing the desired anion, or by careful basification of the salt. The reaction may be carried out in a suitable solvent, e.g. ethanol or methylene chloride.

The starting materials for the above processes may be made by the methods set out in the Examples or by methods analogous thereto. Other conventional methods for making the starting materials will be evident to those skilled in the art.

In cases were Z is a single bond there is need for a transformation of a double bond into a single bond. Conditions for this transformation are well known to those skilled in the art. A preferred method of reducing the double bond is catalytic hydrogenation over palladium catalyst.

Within the methods set out in the Examples the following general intermediates, which also are an object of the invention, are disclosed:

i) A compound of formula (I A) defined as in formula (I) above, but in which R, is a protected hydroxyl group, a methylene carrying a protected hydroxyl, an azide, an azidomethyl group, a protected amino group, a methylene carrying a protected amino group, a good leaving group or a methylene group carrying a good leaving group. ii) A compound of formula (IIIA)

which is defined as formula (HI) above, but wherein Y is oxygen or a nitrogen substituted with a methyl group.

iii) A compound of formula (IVA)

wherein

R₂₀ is a hydrogen or halogen;

X is an halogen atom, preferably chlorine;

R is as defined above in formula (ELI).

iv) A compound of formula (V A)

wherein

R₂₀ is a hydrogen or halogen;

R is as defined above in formula (III).

The preferred protecting groups for i), ii), iii) and iv) immediately above, are as defined above under processes a) and b) ii) above.

The compounds of formula (UI) may be prepared by reacting a compound of formula (IV) with a compound of formula (VI)

wherein

R is R or R' as defined above, and

R₂₀ and R are defined as in formula (I) above, but in which R₁ is a protected hydroxyl group, a methylene carrying a protected hydroxyl group, a protected amino group, or a methylene carrying a protected amino group,. in the presence of an amine base, e.g. triethylamine.

Certain compounds of formula (III) may also be prepared by reacting an anion of a compound of formula (VII)

wherein each R₂₀, which may be the same or different, is a hydrogen or halogen;

R" is a methyl group or tertbutoxycarbonyl group;

Y is an oxygen or a nitrogen carrying a methyl group;

with a compound of formula (VIII)

wherein n is 1-3; Q is an acetoxy group, N-(4-methylphenylsulphonyl)-4- methylphenylsulphonamide, a diethyl phosphate group or an equivalent leaving group;

R_j is a protected hydroxyl group, a methylene carrying a protected hydroxyl group, a protected amino group or a methylene carrying a protected amino group,

in the presence of a transition metal catalyst, and

the double bond, originating from the double bond in the compound of the formula (VIII), may optionally be transformed to a single bond, by methods well known from similar reactions.

The tertbutoxycarbonyl group can be removed by heating in υacuo or by treatment with acid, e.g. trifluoroacetic acid.

The maleimide nitrogen carrying a methyl group may be transformed into an oxygen by treatment with an aqueous base, e.g. sodium hydroxide, followed by treatment with an aqueous acid, e.g. hydrochloric acid.

Compounds of formula (VII) are known from the literature.

Compounds of formula (VIII) are either known from the literature or may be prepared by methods analogous to known, well established methods.

Certain compounds of formula (HI) may also be prepared by reacting an anion of the compound of formula (VII) with a compound of formula (IX)

wherein n, and R, is as defined above in formula (VIII); and

Q_a is a good leaving group, e.g. methanesulfonyloxy;

in a polar aprotic solvent.

The compounds of formula (I) and pharmaceutically acceptable salts, as well as stereoisomers either pure or as racemates or mixtures of stereoisomers, thereof are useful because they demonstrate pharmacological activity. In particular they demonstrate activity as PKC inhibitors, e.g. as is shown by their activity in the in vitro assays described in Granet, R.A. et al, Analyt. Biochem. 1987; 163.458-463; Olsson, H. et al, Cell Signal 1989, 1, 405-410; and Chakravarthy, B.R. et al, Analyt. Biochem. 1991, 196, 144-150. The compounds are generally active in the above test with IC_jo-values ranging from 1-1000 nM.

The compounds of the invention are active topically, moreover, they have a systemic activity when administred orally, and certain of them have enhanced anti-inflammatory effect.

The compounds of the invention are indicated for use in the treatment of inflammatory and immunological disorders, e.g. topical or systemic treatment of airway diseases involving inflammatory conditions, e.g. asthma; bronchitis and atopic diseases, e.g. rhinitis and atopic dermatitis; psoriasis; inflammatory bowel diseases, e.g. Crohn's disease and colitis; rheumatoid arthritis and malignant diseases (e.g. skin and lung cancer). For the treatment of the above conditions the compounds may be administered at a dosage from about 10 μg to 10 mg per day either as a single dose or in divided doses 2 to 4 times per day. Thus unit doses comprise from 2.5 μg to 10 mg of a compound according to the invention. The compounds may be administered topically, e.g. to the lung and/or the airways, in the form of solutions, suspensions, HFA areosols and dry powder formulations,

® e.g. Turbuhaler formulations; or systemically, e.g. by oral administration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral administration in the form of sterile parenteral solutions or suspensions, or by rectal administration in the form of suppositories.

The compounds of the invention may be administered on their own or as a pharmaceutical composition comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are compositions not containing material capable of causing an adverse, e.g. an allergic, reaction.

Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administred by oral or nasal inhalation. For inhalation the compound is desireably finely divided. The finely divided compound preferably has a mass median diameter of less than 10 μm, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C₈-C₂₀ fatty acid or salt thereof, (e.g. oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.

The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.

One possibility is to mix the finely divided compound with a carrier substance, e.g. a mono-, di- or polysaccharide, a sugar alcohol or another polyols. Suitable carriers are sugars, e.g. lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.

Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled

® into the drug reservoir of a multidose inhaler, e.g. that known as the Turbuhaler in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active compound with or without a carrier substance is delivered to the patient.

The pharmaceutical composition comprising the compound of the invention may conveniently be tablets, pills, capsules, syrups, powders or granules for oral administration; sterile parenteral solutions or suspensions for parenteral administration or suppositories for rectal administration.

For oral administration the active compound may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent. For the preparation of soft gelatine capsules, the compound may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets, e.g. lactose, saccharose, sorbitol , mannitol, starches, cellulose derivatives or gelatine. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules.

Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

The compounds of the invention may also be administered tn conjunction with other compounds used for the treatment of the above conditions.

Preferred compounds of the formula (I) are those, wherein

R_j is hydroxy, hydroxymethyl, amino or aminomethyl.

Particularly preferred compounds of the formula (I) are those, wherein

n is 1 or 2; and

R_j is hydroxy or amino.

The most preferred compounds of the formula (I) are those, wherein n is 1 or 2; and

R_j is amino.

The most preferred compounds of the present invention include the following:

3-[l-((lS,3S)-3-amino-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-2,5- dione,

3-[l-((lK,3R)-3-amino-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-2,5- dione, 3-[l-(frflπs-4-amino-l-cyclohexyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-2,5- dione,

(+)-3-[l-((lR,4R)-4-amino-2-cyclopenten-l-yl)-3-indolyl]-4-[l-methyl-3- indolyl]pyrrol-2,5-dione,

3-[l-((lS,4S)-4-amino-2-cyclohexen-l-yl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol- 2,5-dione,

3-[l-((lK,2S,3R,4K)-4-amino-2,3-dihydroxy-l-cyclopentyl)-3-indolyl]-4-[l-methyl-

3-indolyl]-pyrrol-2,5-dione ,

3-[l-((lS,3R)-3-amino-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-2,5- dione, 3-[l-((lR,3S)-3-amino-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-2,5- dione,

3-[l-((lR,2S,3 ,4S)-4-amino-2,3-dihydroxy-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3- indolyl]-pyrrol-2,5-dione,

3-[l-((lR,4S)-4-amino-2-cyclopenten-l-yl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol- 2,5-dione ,

3-[l-((lS,4R)-4-(aminomethyl)-2-cyclopenten-l-yl)-3-indolyl]-4-[l-methyl-3- indolyl]pyrrol-2,5-dione,

and pharmaceutically acceptable salts, in particular hydrochloride salts thereof. The most preferred compound of the present invention is: 3-[l-((lS,3S)-3-amino-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-2,5- dione, and pharmaceutically acceptable salts, in particular hydrochloride salts thereof.

Pharmaceutically acceptable salts of the compounds of the formula (I) include the hydrochlorides, hydrobromides, phosphates, nitrates, acetates, benzoates and sulphonates, also included are all possible stereoisomers, either pure or as racemates or mixtures of stereoisomers.

The optical isomers may be prepared by stereospecific synthesis or by resolution of mixtures, e.g. racemic mixtures, containing them. The resolution may be carried out using processes known per se.

The following Examples illustrate, but in no way limit the invention.

All reactions were performed in dried glassware under Ar or N₂, and at a temperature of about 10-30°C, unless otherwise noted. Tetrahydrofuran was distilled from sodium/benzophenone. N,N-Dimethyl formamide and dichloromethane were distilled from calcium hydride, or dried over molecular sieves. The ammonium hydroxide used had a concentration of 25 % v/v, unless otherwise stated, and all commercial reagents were used as received.

Chromatography was carried out using a Chromatotron® (a centrifugally accelerated, radial preparative thin-layer chromatograph), the plates used were prepared using Merck Silica Gel PF^ containing gypsum.

'H - NMR spectra were recorded on a Varian XL-300 or Unity-500+ instrument. The central solvent peaks of chloroform-^ (δ 7.24 ppm), methanol-rf₄ (δ 3.34 ppm) and DMSO-d₆ (δ_H 2.50 ppm) were used as internal references. Low- resolution mass spectra and accurate mass determinations were recorded on an Autospec-Q, Fisons Analytical, double focusing sector instrument equiped with a LSIMS interface.

Example 1 3-[l-((lS,3R)-3-hydroxy-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-

2,5-dione

aUlS.4RV4-0-Acetyl-l-Q-(tert-butyldimethylsilyl ycloρenten-3.5-diol

(lS,4R)-cis-4-Acetoxy-2-cyclopenten-l-ol (0.25 g, 1.76 mmol), imidazole (0.13 g, 1.93 mmol) and tert-butyldimethylchlorosilane (0.29 g, 1.93 mmol) were dissolved in dry tetrahydrofuran (5 ml) and stirred overnight at room temperature. Diethyl ether (5 ml) was added and the solution filtered and evaporated, the resulting crude product was chromatographed through a short silica column to yield the sub-title compound (0.43 g, 95 %) as a viscous oil.

H-NMR (500 MHz, CDC1₃): δ 0.09 (3H, s), 0.09 (3H, s), 0.90 (9H, s), 1.61 (2H, dt, /

5.0, 13.7 Hz), 2.05 (3H, s) 2.81 (2H, dt, / 7.5, 13.9 Hz), 4.72 (1H, t, / 6.2 Hz), 5.46 (1H, t, / 6.6 Hz), 5.89 (1H, d, / 6.0 Hz), 5.98 (1H, d, / 6.0 Hz).

b^ S-ll-fdR S ^førtbutyldimethylsilyloxy^^-cyclopenten-l-yD-S-indolyll^-fl- methyl-3-indolyl]-pyrrol-2.5-dione

3-(l-methyl-3-indolyl)-4-(3-indolyl)furan-2,5-dione (1.00 g, 2.92 mmol) and lithiumhydride (0.047 g, 5.85 mmol) were dissolved in dry dimethylformamide (25 ml) and stirred for ten minutes. The deep purple solution was degassed in vacuo and the product from step a) (0.75 g, 2.92 mmol) added followed by tefrαfcistriphenylpalladium(O) (0.33 g, 0.29 mmol). The reaction was allowed to proceed for four hours at 70°C. After cooling diethyl ether (25 ml) and acetic acid

TM

(1 M, 25 ml) was added followed by filtration trough Celite , the phases were separated and the aqueous phase washed with an additional portion of ether (25 ml). The combined organic phases were washed with water (2 x 25 ml), dried over

Na₂S0₄, evaporated and chromatographed through silica yielding crude

3-[l-((lR,4S)-4-ferfbutyldimethylsilyloxy-2-cycloρenten-l-yl)-3-indolyl]-4-[l- methyl-3-indolyl]-furan-2,5-dione (1.2 g), which was used without further purification.

This compound was dissolved in dimethylformamide (10 ml) in a sealed tube vessel. Ammonium hydroxide (10 ml) was added followed by heating to 120°C for two hours. After cooling the remaining ammonia was removed by stirring in vacuo for ten minutes, the remaining solution was extracted with diethyl ether (2 x 20 ml). The combined ethereal phases were washed with water (2 x 10 ml), dried over

Na₂S0₄, evaporated and chromatographed through silica obtaining the sub-title product as a red solid (1.02 g, 64%).

^αH-NMR (500 MHz, CDC1₃): δ 0.06 (3H, s), 0.10 (3H, s), 0.87 (9H, s), 1.77 (IH, dt, / 5.6 Hz, 14.3), 2.89 (IH, dt, J 7.7 Hz, 13.8), 3.82 (3H, s), 4.84 (IH, brs), 5.28 (IH, brs), 5.82 (IH, d, / 5.6 Hz), 6.01 (IH, brs), 6.70 (IH, t, / 7.8 Hz), 6.73 (IH, d, / 7.7 Hz), 6.83 (IH, t, / 7.7 Hz), 7.06-7.11 (2H, m), 7.17 (IH, d, / 7.7 Hz), 7.25 (IH, d, / 9.6 Hz), 7.41 (IH, brs), 7.46 (IH, d, / 9.0 Hz), 7.59 (IH, s), 7.70 (IH, s). HRMS (FAB) calcd for

C₃₂H₃₅N₃θ₃Si 537.2477, found 537.2447 [M+].

c) The product from step b) (0.80g, 1.49 mmol) was dissolved in a mixture of ethanol (10 ml) and ethyl acetate (10 ml). Palladium on charcoal (0.062 g, 10% Pd) was added and the solution hydrogenated for 20 hours. The palladium catalyst was filtered off and the solvent removed in vacuo. The crude product was dissolved in tetrahydrofuran (5 ml), acetic acid (15 ml) and water (5 ml). Heating to 55 °C for five hours, evaporation of solvent and chromatography yields the title compound (0.61 g, 96%) as a red solid.

H-NMR (500 MHz, CDC1₃): δ 1.70-1.83 (3H, m), 2.01-2.10 (IH, m), 2.15-2.23 (IH, m), 2.41 (IH, dq, J 5.6, 9.4, 14.6 Hz), 3.84 (3H, s), 4.31 (IH, brs), 4.79-4.84 (IH, m), 6.70-6.76 (2H, m), 6.94 (IH, t, / 7.5 Hz), 7.11 (IH, dq, / 3.0, 5.3, 8.2 Hz), 7.15 (IH, / 7.5 Hz), 7.29 (IH, d, / 8.1 Hz), 7.37 (IH, d, / 8.1 Hz), 7.41 (IH, d, / 8.6 Hz), 7.50 (IH),

7.67 (IH, s), 7.72 (IH, s). HRMS (FAB) calcd for C₂₆H₂₄N₃0₃426.1818, found 426.1809 [M+].

Example 2

S-ll-tdS^SΪ-S-amino-l-cyclopentyD-S-indolyll^-ll-methyl-S-indolyll-pyrrol^S- dione hydrochloride.

The title compound of Example 1 (0.56 g, 1.32 mmol) and triphenylphosphine (0.52 g, 1.98 mmol) was dissolved in dry dichloromethane (20 ml). To this solution (ice cooled) was added hydrogen azide (1.52 ml, 2.5 M in benzene, 3.96 mmol) followed by diethyl azodicarboxylate (0.31 ml, 1.98 mmol). The solution was stirred for one hour at room temperature followed by the addition of methanol (0.1 ml) and stirring for 15 minutes. Removal of the solvent in vacuo and chromatography yielded crude 3-[l-((lS,3S)-3-azido-l-cyclopentyl)-3-indolyl]-4-[l- methyl-3-indolyl]-pyrrol-2,5-dione hydrochloride (0.65 g).

Η-NMR (500, MHz, CDC1₃): δ 1.77-1.85 (IH, m), 1.86-1.94 (IH, m), 1.98-2.14 (2H, m), 2.23-2-29 (IH, m), 2.34-2.43 (IH, m), 3.86 (3H, s), 3.99-4.04 (IH, m), 4.98 (IH, p, / 7.2, 14.5 Hz), 6.70-6.76 (2H, m), 6.90 (IH, t, / 7.5 Hz), 7.10-7.18 (2H, m), 7.26-7.32 (2H, m), 7.35 (IH, d, / 8.1 Hz), 7.49 (IH, s), 7.64 (IH, br s), 7.75 (IH, s). The crude azide, which was used without further purification, was dissolved in pyridine (25 ml) and water (25 ml). Hydrogen sulphide was bubbled through the solution until all the azide was consumed as monitored by TLC. The solvent was removed in vacuo, chromatography, treatment with ethanolic hydrogen chloride and freeze drying furnished the title compound (0.35 g, 59%) as a red solid.

^!H-NMR (500 MHz, CD₃OD): δ 1.76-1.85 (IH, m), 2.03-2.12 (1H, m), 2.27-2.50 (4H, m), 3.76 (IH, dt, / 7.3), 3.89 (3H, s), 5.19 (IH, dt, / 7.5, 14.8 Hz), 6.64 (IH, t, / 7.8 Hz), 6.68 (IH, d, / 7.8 Hz), 6.80 (IH, t, J 7.8 Hz), 7.06-7.16 (3H, m), 7.40 (IH, d, J 8.5 Hz), 7.47 (IH, d, 7.8 Hz), 7.64 (IH, s), 7.81 (IH, s). HRMS (FAB) calcd for

C₂₆H₂₅C1N₄0₂ - HCl 424.1899, found 424.1930 [M+].

Example 3

3-[l-((lR,3R)-3-amino-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyτrol- 2,5-dione hydrochloride

a 3-ri-((lR3SV3-hydroxy-l-cyclopentyl -3-indolyl1-4-ri-methyl-3-indolyl1-pyrrol- 2,5-dione

The sub-title compound was prepared as described in Example 1 starting from (lS, R)-l-0-diethylphosphat cyclopenten-l,4-diol.

b) The title compound was prepared from the product of step a) as described in Example 2.

FAB-MS: m/z 425 [MH+]

Example 4

3-[l-(4-cts-hydroxy-l-cyclohexyl)-3-indolyl]-4-(l-methyl-3-indolyl)-p-yrrole-2,5 dione This compound was prepared in analogous manner to that descibed in Example 1, starting from the previously known (lR,4S)-4-acetoxy-2-cyclohexenol.

-NMR (500 MHz, CDC1₃): δ 1.30 (IH, d, J 2.9 Hz), 1.71 (2H, t, J 14.0 Hz), 1.84 (2H, br d, 712.6 Hz), 1.91 (2H, br d, J 12.6 Hz), 2.07 (2H, dq, J 2.9, 13.1 Hz), 3.83 (3H, s), 4.12 (IH, br s), 4.21 (IH, tt, J 3.7, 11.9 Hz), 6.68 (IH, dt, / 0.8, 8.0 Hz), 6.73 (IH, d, J 7.9 Hz), 6.84 (IH, t, J 75 Hz), 7.04-7.13 (2H, ), 7.21 (IH, d, J 8.1 Hz), 7.25 (IH, d, J 8.1 Hz), 7.33 (IH, d, } 8.1 Hz), 7.40 (IH, br s), 7.63 (IH, s), 7.70 (IH, s). HRMS calcd. for C₂₇H₂₅N₃0₃439.1882, found 439.1896 [MH+].

Example 5

3-[l-(-tr ns-4-amino-l-cyclohexyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-2,5- dione hydrochloride

This compound was prepared in analogous manner to that described in Example 2, starting from 3-[l-(4-cfs-hydroxy-l-cyclohexyl)-3-indolyl]-4-(l-methyl-3- indolyl)-pyrrole-2,5-dione.

Η-NMR (500 MHz, CDC1₃): δ 1.69-1.79 (2H, m), 1.79-1.90 (2H, m), 2.17 (4H, t, J 13.9

Hz), 3.22 (IH, tt, 73.2, 11.7 Hz), 3.86 (3H, s), 4.44 (IH, tt, J 3.2, 11.7 Hz), 6.63 (IH, t, / 7.7 Hz), 6.67 (IH, d, J 7.7 Hz), 6.76 (IH, t, J 7.7 Hz), 7.05-7.10 (2H, m), 7.11 (IH, t, J 7.6 Hz), 7.37 (IH, d, J 8.4 Hz), 7.48 (IH, d, J 8.4 Hz), 7.65 (IH, s), 7.76 (IH, s). HRMS calcd. for

439.2056, found 439.2039 [MH+].

Example 6

3-ll-((lS,3S)-3-(N-acetylamino)-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]- pyrrol-2,5-dione. The title compound from Example 2 (0.015 g, 1.32 mmol) was dissolved in acetic anhydride (0.5 ml) and triethylamine (0.05 ml) and was stirred overnight at room temperature. The solvent was removed and the residue chromatographed yielding the title compound (0.016 g, quant) was obtained as a red solid.

H-NMR (500 MHz, CDC1₃): δ 1.46-1.54 (IH, m), 1.75-1.84 (IH, m), 1.94 (3H, s),

2.00-2.30 (4H, m), 4.23 (IH, hex, } 7.0 Hz), 4.85 (3H, s), 5.75 (IH, br d, J 6.8 Hz), 6.66- 6.72 (2H, m), 6.86 (IH, t, J 75 Hz), 7.04-7.12 (3H, m), 7.25 (IH, d, } 7.2 Hz), 7.29 (IH, d, 78.4 Hz), 7.47 (IH, s), 7.69 (IH, s). HRMS (FAB) calcd for C₂₈H₂₆C1N₄0₃466.2005 found 466.2040 [MH+].

Example 7

3-[l-((lS,3S)-3-hydroxy-cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-2,5- dione.

The title compound from Example 1 (0.075 g, 0.18 mmol), triphenylphosphine (0.069 g, 0.26 mmol) and chloracetic acid (0.050 g, 0.53 mmol) was dissolved in dry methylene chloride (1.5 ml) and cooled on ice. Diethyl azodicarboxylate (0.046 g, 41 μl, 0.26 mmol) was added dropwise. The temperature was maintained at 0°C for 1 h, then allowed to rise to ambient temperature and stirred overnight. The resulting chloracetate ester, 3-[l-((lS,3S)-3-(chloroacetoxy)-l-cyclopentyl)-3- indolyl]-4-[l-methyl-3-indolyl]-pyrrol-2,5-dione, was purified by chromatography in to a yield of 0.064 g (73%) as a red solid. HRMS (FAB) calcd for C₂₈H₂₄C1N₃0₄ 501.1455 found 501.1459.

The chloracetate ester (0.065 g, ) was hydrolysed by treating it with ammonia in methanol (2 ml) for 5 minutes. The solvent was evaporated and the residue purified by chromatography yielding 0.025 g of the title compound (46%, total 33%) as a red solid. H-NMR (500 MHz, DMSO-d₆): δ 1.54-1.63 (IH, m), 1.66-1.74 (IH, m), 1.86-1.98

(2H, m), 2.04-2.10 (IH, m), 2.26-2.34 (IH, m), 3.88 (IH, s), 4.25 (IH, br s), 4.74 (IH, d, 74.0 Hz), 5.10 (IH, p, J 7.7, 15.3 Hz), 6.59 (IH, d, J 8.2 Hz), 6.65 (IH, t, J 7.6 Hz), 6.79 (IH, t, 77.6 Hz), 7.05-7.12 (IH, m), 7.45 (IH, d, J 8.3 Hz), 7.52 (IH, d, J 8.3 Hz),

7.62 (IH, s), 7.88 (IH, s), 10.93 (IH, s). HRMS (FD) calcd for C₂₆H₂₃N₃0₃425.1739 found 425.1759 [MH+].

Example 8

3-[l-((lR,4S)-4-hydroxy-2-cyclopenten-l-yl)-3-indolyll-4-[l-methyl-3- indolyl]pyrrol-2,5-dione.

The sub-title product from Example 1 a) (0.14 g, 0.26 mmol) was dissolved in tetrahydrofuran (1 ml), acetic acid (3 ml) and water (1 ml). Heating at 55 °C for five hours yields, after evaporation of solvent and chromatography, yielding the title compund (0.11 g, 96%) as a red solid.

^XH-NMR (500 MHz, CDC1₃): δ 1.64 (IH, dt, J 4.5, 14.5 Hz), 2.98 (IH, dt, J 7.2,14.5 Hz), 3.82 (3H, s), 4.79 (IH, br s), 5.33 (IH, br s), 5.92 (IH, d, J 4.5 Hz), 6.10-6.14 (IH, m), 6.70-6.75 (2H, m), 6.89 (IH, t, J 7.9 Hz), 7.07-7.13 (IH, m), 7.14 (IH, t, J 7.4 Hz), 7.25-7.30 (2H, m), 7.40 (IH, d, J 7.9 Hz), 7.49 (IH, s), 7.59 (IH, br s), 7.71 (IH, s).

HRMS (FAB) calcd for C₂₆H₂₁N₃0₃423.1583 found 423.1611 [MH+].

Example 9

3-[l-((lS,4R)-4-hydroxy-2-cyclohexen-l-yl)-3-indolyl]-4-[l-methyl-3-indolyll- pyrrol-2,5-dione 27

a) 3-fl-f(lS.4R)-4-(tgrfeutyldimethylsilyloxy)-2-cyclohexen-l-yn-3-indolyll-4-fl- methyl-3-indolyl]-pyrrol-2,5-dioneThe sub-title compound was prepared in analogue manner to that described in Example lb) starting from (lR,4S)-4-acetoxy- 2-cyclohexenol.

Η-NMR (500 MHz, CDC1₃): δ 0.09 (3H, s), 0.11 (3H, s), 0.92 (9H, s), 1.54-1.62 (IH, m), 1.71-1.78 (IH, m), 1.92-1.99 (IH, m), 2.14-2.22 (IH, m), 3.85 (3H, s), 4.23 (IH, br s), 4.87 (IH, br s), 5.70 (IH, dd, ] 2.9, 10.3 Hz), 5.97 (IH, dt, J 2.7, 10.3 Hz), 6.70-6.76 (2H, m), 6.89 (IH, t, J 7.7 Hz), 7.08-7.15 (2H, m), 7.27 (2H, m), 7.39 (IH, br s), 7.45

(IH, d, 78.4 Hz), 7.56 (IH, s), 7.24 (IH, s). HRMS calcd. for C₃₃H₃₇N₃0₃Si 551.767, found 551.767 [M+].

b) The title compound was prepared from the product of step a) in analogous manner to that described in Example 8.

-NMR (500 MHz, CDC1₃): δ 1.52-1.60 (IH, m), 1.74 (IH, br d, } 6.0 Hz), 1.83-1.91

(IH, m), 1.97-2.08 (2H, m), 3.86 (3H, s), 4.24 (IH, br s), 4.94 (IH, br s), 5.82 (IH, dd, 2.9, 10.1 Hz), 6.09 (IH, dt, J 2.1, 10.1 Hz), 6.71-6.79 (2H, m), 6.91 (IH, t, J 75 Hz), 7.12 (IH, t, 77.5 Hz), 7.16 (IH, t, J 75 Hz), 7.29 (IH, d, J 8.1 Hz), 7.30 (IH, d, J 8.1

Hz), 7.37 (IH, d, J 8.1 Hz), 7.57 (IH, s), 7.74 (IH, s). HRMS calcd. for C-^H^O.,

437.1739, found 437.1710 [M+].

Example 10

3-[l-((lS,4R)-4-hydroxy-2-cyclohepten-l-yl)-3-indolyll-4-[l-methyl-3-indolyll- pyrrol-2,5-dione a) 3-ri-((15.4 )-4-(ferfeutyldimethylsilyloxy 2-cyclohepten-l-yl 3-indolyll-4-ri- methyl-3-indolyl1-pyrrol-2,5-dione

The sub-title compound was prepared in analogue manner to that described in Example lb) starting from (lR,4S)-4-acetoxy-2-cycloheptenol.

Η-NMR (500 MHz, CDC1₃): δ 0.09 (3H, s), 0.09 (3H, s), 0.90 (9H, s), 1.59-1.78 (2H, m), 1.82-1.88 (IH, m), 1.90-1.96 (2H, m), 1.99-2.06 (IH, m), 3.84 (3H, s), 4.42 (IH, br d, 79.9 Hz), 4.94 (IH, br s), 5.63 (IH, dt, J 3.0, 12.1 Hz), 5.82 (IH, dt, J 2.6, 12.0 Hz), 6.68 (IH, t, 78.0 Hz), 6.73 (IH, d, J 8.0 Hz), 6.82 (IH, t, J 7.6 Hz), 7.05-7.11 (2H, m), 7.16 (IH, d, 78.0 Hz), 7.25 (IH, d, J 8.1 Hz), 7.30 (IH, d, } 8.4 Hz), 7.45 (IH, br s),

7.58 (IH, s), 7.72 (IH, s). HRMS(FAB) calcd. for C₃₄H₃₉N₃0₃Si 565.2761, found

565.2749 [M+].

b) The title compound was prepared from the product of step a) in analogous manner to that described in Example 8.

'H-NMR (500 MHz, CDC1₃): δ 1.64 (IH, dq, J 2.7, 12.3 Hz), 1.71 (IH, d, } 4.8 Hz,

OH), 1.72-1.82 (IH, m), 1.90-1.99 (3H, m), 2.01-2.09 (IH, m), 3.84 (3H, s), 4.49 (IH, br d, 79.2 Hz), 4.95 (IH, br s), 5.69 (IH, dt, ] 2.9, 12.1 Hz), 5.84 (IH, br d, ] 11.9 Hz), 6.68 (IH, t, 77.7 Hz), 6.73 (IH, d, J 7.7 Hz), 6.82 (IH, t, J 7 A Hz), 7.05-7.12 (2H, m), 7.15 (IH, d, 78.5 Hz), 7.26 (IH, d, J 8.5 Hz), 7.29 (IH, d, } 7.8 Hz), 7.46 (IH, br s, NH), 7.59 (IH, s), 7.72 (IH, s).

HRMS calcd. for C₂₈H_2SN₃0₃451.1896, found 451.1915 [M+].

Example 11

(+)-3-[l-((ljR,4R)-4-amino-2-cyclopenten-l-yl)-3-indolyl]-4-[l-methyl-3- indolyllpyrrol-2,5-dione hydrochloride. The title compound from Example 8 (0.011 g, 0.026 mmol), triphenylphosphine (0.014 g, 0.051 mmol) and phthalimide (0.010 g, 0.064 mmol) were dissolved in dry methylene chloride (0.5 ml). Diethyl azodicarboxylate was added dropwise and the reaction was allowed to proceed overnight at room temperature. The solvent was removed in vacuo and the residue chromatographed. Impure 3-[l-((lR,4R)-4- (isoindol-2,3-dione-l-yl)-2-cyclopenten-l-yl)-3-indolyl]-4-[l-methyl-3-indolyl]- pyrrol-2,5-dione was obtained as a red solid and was, without further purification, dissolved in tetrahydrofuran (0.5 ml), followed by the addition of methylamine in ethanol (0.5 ml, 30%). After stirring for 20 hours the solvent was removed in vacuo and the residue chromatographed. 3-[l-((lR,4R)-4-amino-2-cyclopenten-l-yl)-3- indolyl]-4-[l-methyl-3-indolyl]pyrrol-2,5-dione was obtained as a red solid wich was treated with ethanolic hydrogen chloride (1.5 M, 1 ml), evaporated twice with absolute ethanol, dissolved in water and freeze dried to yield the title compound (0.0084 g, 71%) as a red solid.

H-NMR (500 MHz, CD₃OD): δ 2.31 (IH, ddd, J 3.6, 7.6, 14,8 Hz), 2.56 (IH, ddd, }

3.3, 7.9, 14.8 Hz), 3.89 (3H, s), 4.33 (IH, br s), 5.95 ( IH, br s), 6.20 (IH, br s), 6.32 (IH, br s), 6.64-6.70 (2H, m), 6.83 (IH, t, J 7.9 Hz), 7.11 (IH, t, J 8.1 Hz), 7.15 ( IH, t, / 7.6 Hz), 7.19 (IH, d, J 7.6 Hz), 7.39 (IH, s), 7.41 (IH, d, J 7.6 Hz), 7.48 (IH, d, J 8.6

Hz), 7.79 (IH, s). HRMS calcd. for

422.1743, found 422.1763

[M+].

Example 12 3-[l-((lS,4S)-4-amino-2-cyclohexen-l-yl)-3-indolyl]-4-[l-methyl-3-indolyl]- pyτrol-2,5-dione hydrochloride

This compound was prepared in analogous manner to that descibed in Example 11, starting from 3-[l-((lS,4R)-4-hydroxy-2-cyclohexen-l-yl)-3-indolyl]-4-[l- methyl-3-indolyl]-pyrrol-2,5-dione. 'H-NMR (500 MHz, CDC1₃): δ 1.82-1.92 (IH, m), 1.93-2.02 (IH, m), 2.20-2.27 (IH, m), 2.33-2.40 (IH, m), 3.89 (3H, s), 4.02 (IH, br s), 5.27 (IH, br s), 6.00 (IH, br d, J 10.3 Hz), 6.12 (IH, br d, J 10.3 Hz), 6.65 (IH, t, J 7.8 Hz), 6.69 (IH, d, J 8.0 Hz), 6.79 (IH, t, 77.6 Hz), 7.06-7.14 (3H, m), 7.39 (IH, d, J 8.4 Hz), 7.48 (IH, d, J 8.4 Hz), 7.54

(IH, s), 7.79 (IH, s). HRMS calcd. for C₂₇H₂₅N₄0₂-HC1436.1899, found 436.1898

[M+l.

Example 13 3-[l-((lR,2S,3R,4R)-4-amino-2,3-dihydroxy-l-cyclopentyl)-3-indolyl]-4-[l-methyl- 3-indolyl]-pyrrol-2,5-dione hydrochloride.

The title compound from Example 11 (0.028 g, 0.067 mmol) and triethylamine (56 μl, 0.40 mmol) were dissolved in dry methylene chloride (1 ml) and cooled on ice. Trifluoroacetic anhydride (28 μl, 0.20 mmol) was added and the solution stirred for one hour, TLC indicates complete reaction. Water (1 ml) was added and the phases separated, the organic phase was dried over Na₂S0₄, filtered and evaporated. The residue was chromatographed yielding 3-[l-((lR,4S)-4-amino-2- cyclopenten-l-yl)-3-indolyl]-4-[l-methyl-3-indolyl]pyrrol-2,5-dione trifluoroacetamide as a red solid which was used directly.

3-[l-((lR,4S)-4-amino-2-cyclopenten-l-yl)-3-indolyl]-4-[l-methyl-3-indolyl]pyrrol- 2,5-dione trifluoracetamide and N-methylmorpholine N-oxide monohydrate (0.012 g, 0.087 mmol) were dissolved in acetone-water (10:1, 1.1 ml), osmium tetroxide

(42 μl, 2.5% in BuOH, 0.003 mmol) was added and the reaction was allowed to proceed overnight. The reaction was quenched by stirring with sodium pyrosulphite for one hour. Ethyl acetate (2 ml) was added and the organic phase was washed with water (3 x 1 ml) and evaporated. The residue was dissolved in methanol-water (10:1, 1.1 ml) and K₂C0₃ (0.046 g, 0.34 mmol) added, and stirring at room temperature for one hour gave complete deprotection. Ethyl acetate (2 ml) was added and the organic phase were washed with water (3 x 1 ml) and evaporated. The residue was purified by preparative HPLC and the title compound (0.010 g, 30 %) was obtained as a red solid after treatment with ethanolic hydrogen chloride and freeze drying from water.

^-NMR (500MHz, CDC1₃): δ 2.28-2.37 (IH, m), 2.47-2.55 (IH, m), 3.85-3.95 (4H, m), 4.23 (IH, t, J 3.9 Hz), 4.44 (IH, dd, J 8.1, 10.1 Hz), 6.67 (IH, t, J 7.8 Hz), 6.74 (IH, t, 77.8 Hz), 6.78 (IH, d, } 7.8 Hz), 6.99 (IH, d, J 7.8 Hz), 7.08 (IH, t, J 7.8 Hz), 7.10 (IH, t, 77.8 Hz), 7.38 (IH, d, J 8.9 Hz), 7.50 (IH, d, J 8.1 Hz), 7.78 (IH, s), 7.80 (IH, s). HRMS (FAB) calcd for C^H^CIN^-HCI 456.1797 found 456.1827 [M+].

Example 14

3-[l-((lS,3R)-3-amino-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-ρyrrol-2,5- dione hydrochloride.

a^-ll-fflR^SI^-acetoxy^-cvclopenten-l-yD-S-indolyll^-ri-methyl-S-indolyn- pyrrol-2,5-dione

3-[l-((lR,4S)-4-(tertbutyldimethylsilyloxy)-2-cyclopenten-l-yl)-3-indolyl]-4-[l- methyl-3-indolyl]-pyrrol-2,5-dione (0.21 g, 0.39 mmol) was dissolved in a mixture of acetic acid, tetrahydrofuran and H₂0 (3:1:1, 5.0 ml) the solution was heated at 55

°C for five hours. After cooling the solvent was removed in vacuo and the residue dried by azeoptropic removal of water with toluene. The precipitated solid was dissolved in acetic acid anhydride (2.5 ml) and pyridine (0.25 ml). Stirring overnight followed by removal of solvent and chromatography affords the subtitle compund (0.19 g, quantitative) as a red solid. ^XH-NMR (500 MHz, CDC1₃): δ 1.89 (IH, dt, J 4.5, 15.0 Hz), 2.04 (3H, s), 3.07 (IH, dt,

77.9, 14.6 Hz), 3.85 (3H, s), 5.43 (IH, br s), 5.69 (IH, br s), 6.10 (IH, br d, J 5.6 Hz), 6.19 (IH, br d, J 5.6 Hz), 6.72 (IH, t, J 72 Hz), 6.76 (IH, d, J 8.0 Hz), 6.84 (IH, t, J 7.6 Hz), 7.08-7.15 (3H, m), 7.28 (IH, d, J 8.3 Hz), 7.39 (IH, br s), 7.41 (IH, d, J 8.7 Hz),

7.61 (IH, s), 7.74 (IH, s). HRMS (FAB) calcd for C₂₈H₂₃N₃0₄465.1689 found

465.1715 [M+].

b'l 3-fl-((lR.4SV4-azido-2-cyclopenten-l-yl)-3-indolyn-4-ri-methyl-3-indolyll- pyrrol-2,5-dione

The product from step a) (0.16 g, 0.34 mmol) and sodium azide (0.044 g, 0.68 mmol) was dissolved in tetrahydrofuran-water (2:1, 2.25 ml). The solution was degassed in vacuo and te αfø^'striphenylpalladium(O) (0.039 g, 0.03 mmol) added. The reaction was allowed to proceed for 1.5 hour. The solvent was removed in vacuo and the residue chromatographed to yield the sub-title compound (0.12 g, 80%) as a red solid.

H-NMR (500 MHz, CDC1₃): δ 1.80 (IH, dt, J 5.3, 14.4 Hz), 3.00 (IH, dt, } 8.1, 14.4

Hz), 3.86 (3H, s), 4.49 (IH, br t, J 6.2 Hz), 5.43 (IH, br t, J 6.7 Hz), 6.03 (IH, br d, J 5.6 Hz), 6.09 (IH, dt, J 2.1, 5.6 Hz), 6.70-6.76 (2H, m), 6.92 (IH, t, J 7.2 Hz), 7.12 (IH, dq, 72.0, 6.1 Hz), 7.16 (IH, t, J 7.6 Hz), 7.30 (2H, d, J 8.8 Hz), 7.39 (IH, d, J 8.4 Hz),

7.47 (IH, s), 7.74 (IH, s). HRMS (FAB) calcd for C₂₅H₂₀N₆O₂448.1648 found

448.1667 [M+].

c) The product from step b) was dissolved in ethyl acetate (0.5 ml) and ethanol (0.5 ml), palladium on charcoal (30 mg, 10%) was added followed by hydrogenation for 56 hours at ambient pressure and temperature. The catalyst was removed by

TM filtration through Celite , the solvent was removed in vacuo, chromatography, treatment with ethanolic hydrogen chloride and freeze drying furnished the title compound (0.0073 g, 22%) as a red solid.

Η-NMR (500 MHz, CDC1₃): δ 1.92-2.02 (2H, m), 2.15-2.23 (IH, m), 2.29-2.42 (2H, m), 2.80 (IH, dt, J 7.2, 12.9 Hz), 3.81 (IH, pent, J 7.74 Hz), 3.89 (3H, s), 5.07 (IH, pent, 78.74 Hz), 6.63 (IH, t, J 7.8 Hz), 6.71-6.76 (2H, m), 6.98 (IH, d, J 8.2 Hz), 7.06- 7.13 (2H, m), 7.39 (IH, d, J 8.2 Hz), 7.49 (IH, d, J 8.2 Hz), 7.80 (IH, s), 7.82 (IH, s).

HRMS (FAB) calcd for C^H^CIN^ - HCl 424.1899 found 424.1912 [M+].

Example 15

3-[l-((lR,3S)-3-amino-l-cyclopentyl)-3-indolyll-4-[l-methyl-3-indolyl]-pyrrol-2,5- dione hydrochloride

The title compound was prepared in analogous manner to that described in Example 14, starting from the previously known (lS,4R)-l-0-diethylphosphate cyclopenten- 1 ,4-diol.

H-NMR identical to that of the title compound of Example 14. HRMS (FAB) calcd

for C -,26,H-^l --^*„25C^v-1-"N^,-<r-)^*,2 - HCl 424.1899 found 424.1891 [M+].

Example 16

3-[l-((lR,2S,3R_/4S)-4-amino-2,3-dihydroxy-l-cyclopentyl)-3-indolyl]-4-[l-methyl- 3-indolyl]-pyrrol-2,5-dione hydrochloride

a) 3-ri-((lR.2S.3R.4S)-4-azido-2.3-dihydroxy-l-cyclopentyD-3-indolyll-4-fl-methyl- 3-indolyl^"l-pyrrol-2,5-dione

The sub-title product from Example 14 b) (0.090 g, 0.20 mmol) and N- methylmorpholine N-oxide monohydrate (0.036 g, 0.26 mmol) was dissolved in acetone-water (10:1, 2,2 ml). Osmium tetroxide (0.13 ml, 2.5% in ΕuOH, 0.01 mmol) was added and the reaction allowed to proceed for four hours. The reaction was quenched by stirring with sodium pyrosulphite overnight. Water (2 ml) and ethyl acetate (5 ml) was added and the phases separated, and the aqueous phase was washed with ethyl acetate (2 x 5 ml). The organic phases were dried over

Na₂S0₄, evaporated and chromatographed to yield the sub-title compound (0.76 g,

78%) as a red solid.

H-NMR (500 MHz, CDC1₃): δ 1.69 (IH, p, J 6.9 Hz), 2.77 (IH, dt, J 8.7, 14.2 Hz), 3.86-3.91 (4H, m), 3.93-3.99 (IH, m), 4.18 (IH, t, J 5.9 Hz), 4.86 (IH, q, J 7.6 Hz),

6.68-6.76 (2H, ), 6.81 (IH, t, } 7.7 Hz), 7.07-7.16 (2H, m), 7.19 (IH, d, J 8.3 Hz), 7.40 (IH, d, 78.3 Hz), 7.53 (IH, d, J 8.3 Hz), 7.66 (IH, s), 7.76 (IH, s). HRMS (FAB) calcd for C₂₆R,₂N₆0₄483.1703 found 483.1718 [M+].

b) The product from step a) (0.037 g, 0.076 mmol) was dissolved in ethanol and indlar catalyst (0.039 g) added. Hydrogenation at normal pressure and temperature for 48 hours, evaporation of the solvent and purification by preparative HPLC afforded 3-[l-((lR,2S,3R,4S)-4-amino-2,3-dihydroxy-l- cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-2,5-dione as its trifluoroacetate salt. Treatment of the trifluoroacetate salt with hydrogen chloride in ethanol, evaporation and freeze drying from water yielded the title compound (0.011 g, 31%) as a red solid.

H-NMR (500 MHz, CDC1₃): δ 1.95 (IH, dt, J 10.2, 13.4 Hz), 2.79 (IH, dt, J 7.8, 13.1 Hz), 3.64 (IH, dt, J 7 A, 9.1 Hz), 3.87 (3H, s), 4.15 (IH, t, J 4.1 Hz), 4.31 (IH, t, J 6.1 Hz), 4.94 (IH, q, J 7.8 Hz), 6.65 (IH, t, J 72 Hz), 6.71 (IH, t, } 7.5 Hz), 6.77 (IH, d, } 8.0 Hz), 6.93 (IH, d, } 8.0 Hz), 7.04-7.13 (2H, m), 7.37 (IH, d, ] 8.5 Hz), 7.55 (IH, d, ]

8.5 Hz), 7.78 (IH, s), 7.82 (IH, s). HRMS (FAB) calcd for C^H^CIN^-HCI 456.1797 found 456.1828 [M+]. Example 17

3-[l-((lR,4S)-4-amino-2-cyclopenten-l-yl)-3-indolyl]-4-[l-methyl-3-indolyl]- ρyrrol-2,5-dione hydrochloride

The sub-product from Example 14 b) (0.028 g, 0.065mmol) was hydrogenated according to the procedure described in Example 16 b), the title product was obtained after chromatography and treatment with ethanolic hydrogen chloride as a red solid (0.009 g, 30%).

H-NMR (500 MHz, CD₃OD): δ 1.81 (IH, dt, J 7.1, 13.5 Hz), 3.29 (IH, dt, J8.0, 13.6

Hz), 3.88 (3H, s), 4.44 (IH, t, J 8.0 Hz), 5.80 (IH, br t, J 6.9 Hz), 6.22 (lH,dt, J 2.0, 5.6 Hz), 6.29-6.32 (IH, m), 6.65 (1 H, t, J 7.6 Hz), 6.72-6.77 (2H, m), 6.98 (IH, d, J 8.4 Hz), 7.07-7.14 (2H, m), 7.39 (1 H, d, J 8.2 Hz), 7.55 (1 H, d, J 8.2 Hz), 7.70 (IH, s), 7.80 (IH, s). HRMS (FAB) calcd for C^H^ClN ^HCl 422.1743 found 422.1763 [M+].

Example 18

3-tl-((lS,4R)-4-(hydroxymethyl)-2-cyclopenten-l-yl)-3-indolyl]-4-[l-methyl-3- indolyl]pyrrol-2,5-dione.

3-(l-methyl-3-indolyl)-4-(3-indolyl)furan-2,5-dione (0.066 g, 0.19 mmol), lithiumhydride (0.003 g, 0.38 mmol) and lithium chloride (0.001 g, 0.029 mmol) was dissolved in dry dimethylformamide (0.5 ml) and the solution stirred for ten minutes. N-[(2S,4R)-4-(acetyloxymethyl)cyclopent-2-enyl]-N-(4- methylphenylsulρhonyl)-4-methylphenylsulphonamide was added and the solution degassed in vacuo before te fostriphenylpalladium(O) (0.022 g, 0.019 mmol) was added. The solution was heated at 70°C for three hours and then allowed to cool to room temperature. Aqueous acetic acid (1 M, 2 ml) and ethyl acetate (2ml) were added and the phases separated, the aqueous phase was extracted with ethyl acetate (2 x 2 ml). The combined organic phases were washed with water (2 x 2 ml). The solvent was removed and the residue dissolved in dimethylformamide (2 ml), ammonium hydroxide (2 ml) added and the solution heated in a sealed tube at 120°C for two hours. After cooling ethyl acetate (2 ml) was added, the phases separated and the organic phase washed with water.

Removal of solvent followed by chromatography yields the title compound (0.031 g, 37 %) as a red solid.

H-NMR (500 MHz, CDC1₃): δ 1.49 (IH, dt, 75.5, 14.1 Hz), 2.67 (IH, dt, J 9.2, 13.6 Hz), 2.93 (IH, br s), 3.41 (2H, s), 3.83 (3H, s), 3.52 (IH, br t, J 6.4 Hz), 5.80-5.83 (IH, m), 6.02-6.05 (IH, m), 6.70-6.76 (2H, m), 6.89 (IH, t, J 8.4 Hz), 7.06-7.12 (IH, m), 7.13 (IH, t, 77.8 Hz), 7.27 (2H, d, J 8.6 Hz), 7.39 (IH, d, / 8.6 Hz), 7.49 (IH, s), 7.52 (IH, br s), 7.71 (IH, s). HRMS (FAB) calcd for C₂₇H₂₃N₃0₃438.1818 found 438.1818

[M+].

Example 19

3-ll-((lS,4Λ)-4-(aminomethyl)-2-cyclopenten-l-yl)-3-indolyl]-4-[l-methyl-3- indolyllpyrrol-2,5-dione hydrochloride

The product from Example 18 (0.031 g, 0.071 mmol) and 2,6-luthidine (35 μl, 0.21 mmol) were dissolved in dry methylene chloride (1 ml), the solution was cooled on ice before the addition of trifluoromethanesulphonic anhydride (25 μl, 0.21 mmol). The reaction was allowed to proceed for 30 minutes, followed by the addition of aqueous ammonium hydroxide (25%, 2 ml). The biphasic mixture was stirred overnight. The phases were separated and the aqueous phase extracted with methylene chloride (2 x 2 ml), the combined organic phases were washed with water (2 ml) and brine (2 ml), dried over Na₂S0₄ and chromatographed yielding the title compound (0.015 g, 45%) as a red solid after treatment of the free amine with ethanolic hydrogen chloride followed by freeze drying from water. Η-NMR (500 MHz, CD₃OD): δ 1.50 (IH, dt, J 6.4, 13.6 Hz), 2.83 (IH, dd, J 8.4, 12.2 Hz), 2.91 (2H, m), 3.15 (IH, br t, } 72 Hz), 3.88 (3H, s), 5.75 (IH, tt, } 2.1, 6.2 Hz), 6.05 (IH, dt, 7 2.1, 5.6 Hz), 6.19 (IH, dt, J 2.1, 5.6 Hz), 6.68 (IH, t, J 8.3 Hz), 6.73 (IH, d, 7.9 Hz), 6.78 (IH, t, J 7.9 Hz), 7.06-7.14 (2H, m), 7.40 (IH, d, J 8.8 Hz),

7.52 (IH, d, 7 8.8 Hz), 7.55 (IH, s), 7.77 (IH, s). HRMS (FAB) calcd for C₂₇H₂₃N₃0₃ -

HCl 438.2056 found 438.2065 [M+].

Example 20

3-[l-((lS,3S)-3-Amino-l-cyclopentyl)-6-fluoro-3-indolyl]-4-[l-methyl-3-indolyl]- pyrrol-2,5-dione hydrochloride.

aHlS,4R)-2-N-fertbutoxycarbonyl-2-azabicyklof2,2,11heptan-3-one

(lR,4S)-2-N-tørtbutoxycarbonyl-2-azabicyklo[2,2,l]-5-hepten-3-one (3.80 g, 18.0 mmol) was dissolved in toluene (15 ml) and palladium on charcoal (5%, 0.10 g) was added and the reaction hydrogenated for 2 hours at 3 bar. The catalyst was filtered off and the solvent removed in vacuo. (lS,4 )-2-N-tertbutoxycarbonyl-2- azabicyklo[2,2,l]heptan-3-one (3.8 g, quantitative) was obained as a white solid.

¹H-NMR(200 MHz, CDC1₃): δ 1.40 (1 H, d), 1.51 (9 H, s), 1.95-1.70 (5 H, m), 2.2 (3 H, s), 2.85 (1 H, m), 4.5 (1 H, s).

b) (lS,3R)-3-acetyl-l-(N-ter butoxycarbonyl^')amino-cyclopentane

Methyl lithium ( 2.2 M in diethyl ether, 9.0 mL) was added dropwise to a cooled solution (-30 °C) of the product of step a) (3.8 g, 18.0 mmol) in toluene (40 mL). The reaction was allowed to proceed for 1 hour at -30 °C after which saturated aqueous ammonium chloride (15 mL) was added. The temperature was allowed to rise and the organic layer was separated off, dried over Na₂S0₄ and evaporated to dryness.

Recrystallisation from diethylether/pentane yielded (2.8 g, 68%) of the sub-title compound.

H-NMR (200 MHz, CDC1₃): δ 1.45 (9 H, s), 2.0-1.5 (5 H, m), 2.10 (1 H, m), 2.2 (3 H, s), 3.0 (1 H, m), 4.0 (1 H, m), 4.9 (1 H, br s).

c (lR,3S)-l-0-methanesulphonate-3-N-ter£butoxycarbonyl-3-amino-l- cyklopentanol

3-chloroperbenzoic acid (70 %, 5.0 g, 20.0 mmol) was added to a 40 °C of the product from step b) (2.3 g, 10.0 mmol) in toluene (25 mL). The reaction was allowed to proceed for 5 days followed by extraction with NaHS0₃ (IM, 2 xlO mL)

and NaHC0₃ (IM, 2 x 10 mL). The organic solution was separated off, cooled on an ice bath, and methanol (1.5 mL) was added followed by portions of sodium methoxide (1.1 g, 20 mmol). After 1 hour the reaction was quenched by addition of aqueous NaHSθ4 (2M, 10 mL). Ethylacetate (15 mL) was added, the water layer separated off and the organic layer extracted with saturated aqueous NaHC0₃ (2 x

10 mL). The organic layer was concentrated to half its volume. The residue was chilled to 0°C and triethylamine (2.0 mL, 15.0 mmol) was added followed by dropwise addition of methanesulphonyl chloride (0.8 mL, 10 mmol). After 2 hours the reaction mixture was extracted with saturated aqueous NaHC0₃ (2 xlO mL).

The organic phase was heated to 35 °C and the product was precipitated by addition of heptane (50 mL). Filtration and recrystallization yielded the sub-title compound (1.8 g, 63%)

H-NMR (200 MHz, CDC1₃): δ 1.4 (9H, s), 2.25-1.5 (5H, m), 2.4 (IH, m), 3.0 (3H, s), 4.1 (IH, m), 4.7 (IH, m), 5.15 (IH, m). d) l-f(lR,3S)-3-(ferf-butoxycarbonylam o yclopentyll-6-fluoroindol

Sodium hydride (60 % in oil, 0.030 g, 1.26 mmol) was added to 6-fluoroindole dissolved in dry N,N-dimethylformamide (7 ml). The mixture was stirred at room temperature for 20 minutes. The product of step c) (0.31 g, 1.09 mmol) was added in one portion. An additional portion of sodium hydride (0.006 g, 0.25 mmol) was added after three hours. The reaction was allowed to proceed overnight, water (120 ml) and ethyl acetate (40 ml) was added and the phases separated, the aqueous phase was washed with ethyl acetate (40 ml). The organic solvent was removed in vacuo, dissolved in ethyl acetate and evaporated once more. Chromatography yielded the sub-title compound (0.17 g, 48%).

'H-NMR (500 MHz, CDC1₃): δ 1.46 (9H, s), 1.67-1.55 (IH, ), 1.98-1.85 (IH, m), 2.13-2.03 (IH, m), 2.40-1.24 (3H, m), 4.24 (IH, br d, } 6.5 Hz), 4.71 (IH, br s), 4.81 (IH, p, 77.3 Hz), 6.47 (IH, d, f 3.2 Hz), 6.86 (IH, t, J 9.0 Hz), 7.02 (IH, d, } 10.3 Hz), 7.14 (IH, d, 3.4 Hz), 7.50 (IH, dd, J 5.5, 8.5 Hz).

e) 3-fl-((lS,3S)-l-teri?butoxycarbonylamino-3-cyclopentyl)-6-fluoro-3-indolyll-4-ri- methyl-3-indolyll-pyrrol-2.5-dione.

Oxalyl chloride (85 μl, 1.0 mmol) was added to an ice cooled solution of the product of step d) (0.17 g, 0.52 mmol) dissolved in dry methylene chloride (4.5 ml). The solution was stirred at room temperature for 20 minutes, evaporated to dryness obtaining the crude [6-fluoro-l-((lS,3S)-3-(N-tert!-butoxycarbonyl- amino)cyclopentyl)-3-indolyl]-glyoxyl chloride as a orange precipitate. This was dissolved in dry methylene chloride (3.5 ml) and slowly added to a methylene chloride (2.5 ml) solution of N-methylindoleacetic acid (0.098 g, 0.52 mmol) and triethylamine (0.14 ml, 1.0 mmol). The solution was stirred at room temperature for 8 hours followed by removal of the solvent in vacuo, the red residue was filtered trough a short Si0₂-column. Crude 3-[l-((lS,3S)-3-tertbutoxycarbonyl- amino-1 -cyclopentyl) -6-fluoro-3-indolyl]-4-[ 1 -methy 1-3-indoly 1] furan-2,5-dione was obtained after evaporation of the solvent and used without further purification.

The cιxιde 3-[l-((lS,3S)-3-terfbutoxycarbonyl-amino-l-cyclopentyl)-6-fluoro-3- indolyl]-4-[l-methyl-3-indolyl]furan-2,5-dione was dissolved in N,N- dimethylformamide (6 ml), ammonium hydroxide (6 ml) was added and the solution stirred at 100 °C for 3 h in a sealed tube. After cooling brine (25 ml) was added and the the solution extracted with ethyl acetate - heptane (2:1, 2 x 75 ml). The organic solvent were removed in vacuo and the residue chromatographed obtaining the sub-title compound (0.047 g, 17%).

Η-NMR (500 MHz, CDC1₃): δ 1.46 (9H, s), 1.60-1.51 (IH, m), 1.92-1.75 (2H, m), 2.22-2.08 (2H, m), 2.38-2.22 (IH, m), 3.84 (3H, s), 4.02 (IH, sext., J 6.8 Hz), 4.71 (IH, br s), 4.79 (IH, p, J 7.7 Hz), 6.61 (IH, t, J 9.4 Hz), 6.74 (2H, m), 6.99 (IH, d, J 9.9 Hz), 7.10 (IH, t, 77.3 Hz), 7.16 (IH, br t, J 7.3 Hz), 7.27 (IH, s), 7.50 (IH, s), 7.74 (IH, s), 8.07 (IH, s).

f 3-π-((lS.3S')-3-Amino-l-cycloρentyn-6-fluoro-3-indolyn-4-ri-methyl-3-indolyn- pyrrol-2,5-dione hydrochloride.

3-[l-((lS,3S)-l-tertbutoxycarbonylamino-3-cyclopentyl)-6-fluoro-3-indolyl]-4-[l- methyl-3-indolyl]-pyrrol-2,5-dione (0.047 g, 0.087 mmol) was dissolved in tetrahydrofurane (4 ml). Water (2 ml) and concentrated hydrochloric acid (2 ml) was added. The solution was deoxygenated in vacuo and heated at 50 °C for 25 minutes. The slightly cooled solution was partitioned between ammonium hydroxide (2.5%, 110 ml) and ethyl acetate (25 ml). The organic phase was evaporated to dryness. Chromatography, followed by treatment with ethanolic hydrogen chloride and freeze drying from water afforded the title compound (0.030 g, 78%) as a red solid.

Η-NMR (500 MHz, CD₃OD): δ 7.86 (IH, s), 7.66 (IH, s), 7.42 (IH, d, J 8.3 Hz), 7.23 (IH, dd, 72.1, 9.9 Hz), 7.11 (IH, t, J 7.3 Hz), 7.08 (IH, dd, J 4.6(5.5) Hz), 6.69-6.64 (2H, m), 6.58 (IH, t, } 9.3 Hz), 5.11 (IH, p, J 7.7 Hz), 3.93 (3H, s), 3.77 (IH, p, J 7.7 Hz), 2.50-2.43 (IH, m), 2.41-2.27 (3H, m), 2.11-2.04 (IH, m), 1.80 (IH, sex., J 7.0 Hz).

Example 21

3-[l-((lS,3S)-3-Amino-l-cyclopentyl)-5-chloro-3-indolyl]-4-[l-methyl-3-indolyl]- pyrrol-2,5-dione hydrochloride.

The title compound was synthesized as described in Example 20 starting from 5- chloroindole.

Η-NMR (500 MHz, CDC1₃): δ 1.77-1.84 (1 H, m), 1.98-2.07 (1 H, m), 2.25-2.38 (3 H, m), 2.41-2.49 (1 H, m), 3.74 (1 H, p, J 71 Hz), 3.94 (3 H, s), 5.17 (1 H, p, J 7.4 Hz), 6.63-6.70 (2 H, m), 7.08-7.14 (3 H, m), 7.45 (2 H, t, J 8.8 Hz), 7.68 (1 H, s), 7.83 (1 H, s).

Example 22

3-[l-((lS,3S)-3-Amino-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol- 2,5-dione hydrochloride

a) (l-Methyl-3-fl-((lS,3S)-3-N-tertbutoxycarbonyl-3-aminocyclopentyl -3-indolyn- 4-fl-methyl-indol-3-yn-pyrrol-2.5-dione

Potassium terfbutoxide (0.13 g, 1.1 mmol) was added to a solution of l-methyl-3- (3-indolyl)-4-(l-methyl-3-indolyl)-pyrrole-2,5-dione (0.39 g, 1.1 mmol) in N,N- 42

dimethylformamide (3.5 mL), and the mixture was stirred for 10 minutes at room temperature. The sub-title product from Example 20 c) (0.28 g, 1.0 mmol) was added and the reaction stirred for 2 hours at 100 °C. The mixture was poured out into 40 mL of saturated aqueous NaHC0₃ and extracted with toluene (50 mL). The

organic layer was washed with water, dried over Na₂S0₄ and evaporated to dryness. Purification on silica-gel column gave the sub-title compound (0.30 g, 56%) as a red solid. H-NMR (200 MHz, CDC1₃): δ 1.44 (9H, s), 1.51 (IH, m), 1.82 (IH, m), 2.35-2.0 (4H, m), 3.16 (3H, s), 3.83 (3H, s), 4.01 (IH, m), 4.53 (IH, s), 4.88 (IH, m), 6.69 (IH, t, J 7.6 Hz), 6.74 (IH, d, J 8.1 Hz), 6.85 (IH, t, J 8.1), 7.08 (IH, t, J 7.6 Hz), 7.11 (IH, t, J 7.6 Hz), 7.24 (IH, s), 7.26 (IH, d, ] 8.3 Hz), 7.30 (IH, d, J 8.3 Hz), 7.50 (IH, s), 7.70 (IH, s).

b1 3-ri-((lS.3S 3-N-terfeutoxycarbonyl-3-aminocyklopentan-l-yD-indol-3-yll-4-(l- methyl-indol-3-yl)-pyrrol-2,5-dione

Potassium hydroxide (0.38 g, 6.7 mmol) dissolved in water (2.5 mL), was added to a solution of the product of step a) (0.30 g, 0.56 mmol) in ethanol (5 mL), and the resulting mixture was heated at reflux for 2 hours. To the cooled solution was 1 M HCl added until pH = 2. The resulting red precipitate was filtered off, washed with water, and redissolved in N,N-dimethylformamide (4 mL). Ammonium hydroxide was added and the reaction refluxed at 120 °C for 2 hours. The reaction was partitioned between ethylacetate and water, and the organic layer evaporated to dryness. Silica gel column chromatography gave the sub-title product (0.18 g, 63%) as a red solid.

H-NMR (200 MHz, CDC1₃): δ 1.4 (9H, s), 2.3-1.4 (6H, m), 3.85 (3H, s), 3.90 (IH, m), 5.0 (IH, ), 7.90-6.60 (10 H, m), 10.9 (1 H, s). c 3-ri-(3-aminocyklopentan-l-yl)-indol-3-yll-4-(l-methyl-indol-3-yl)-pyrrol-2_<5- dione

The title compound was obtained by treatment of the product from step b) with acid as described in Example 20 i).

Example 23

3-[l-((lR,4S)-4-hydroxy-2-cyclopenten-l-yl)-3-indolyl]-4-[3-indolyl]-pyrrol-2_/5- dione.

aU-Methyl-3-[l-(flR.4S)-4-(fe^butyldimethylsilyloxy -2-cyclopenten-l-yD-3- indolyn-4-[l-(ferfbutoxycarbonyl)-3-indolyl1-pyrrol-2,5-dione

4-(3-indolyl)-l-methyl-3-(l-ferfbutoxycarbonyl-3-indolyl)-pyrroll-2,5-dione (0.75 g, 1.70 mmol), lithium chloride (0.005 g, 0.11 mmol) and lithivunhydride (0.26 g, 1.73 mmol) was dissolved in dry dimethyl formamide (17 ml) and stirred for ten minutes. The deep purple solution was degassed and (lS,4R)-4-0-Acetyl-l-0- (tertbutyldimethylsilyl)cyclopenten-3,5-diol (0.44 g, 1.70 mmol) added, followed by addition of fefrαfcistriphenylpalladium(O) (0.20 g, 0.17 mmol). The reaction was allowed to proceed for 45 minutes at 60°C. After cooling was diethyl ether (20 ml) and aqueous acetic acid (1 M, 20 ml) added the phases were separated and the aqueous phase was washed with an additional portion of diethyl ether (20 ml). The combined organic phases was washed with water (2 x 20 ml) and dried over

Na₂S0₄, evaporated and chromatographed. The sub-title compound was obtained as a red solid (0.74 g, 67%).

^lH-NMR (500 Mhz, CDC1₃): δ 0.04 (3H, s), 0.07 (3H, s), 0.86 (9H, s), 1.73 (IH, dt, J

5.1, 13.8 Hz), 2.88 (IH, dt, J 7.5, 13.6 Hz), 3.18 (3H, s), 4.83 (IH, br s), 5.26 (IH, br t, J 6.3 Hz), 5.78 (IH, d, J 5.1 Hz), 6.00-6.04 (IH, m), 6.75-6.93 (2H, m), 7.09 (IH, t, J 7.8 Hz), 7.13-7.17 (2H, m), 7.20 (IH, d, J 8.0 Hz), 7.45 (IH, d, J 8.0 Hz), 7.66 (lH,s), 8.02 (IH, s), 8.07-8.16 (IH, m). HRMS(FD) calcd for C₃₇H₄₃N₃0₅Si 637.2972, found 637.2989 [MH+].

l-Methyl-3,4-di(l-((lR,4S)-4-fertbutyldimethylsilyloxy)-2-cyclopenten-l-yl)-3- indolyl)-pyrrol-2,5-dione was isolated as the major by-product.

b) The title compound was obtained by heating the product of step a) in vacuo to 180°C for 45 minutes. Chromatography yields 3-[l-((lR,4S)-4- (tertbutyldimethylsilyloxy)-2-cyclopenten-l-yl)-3-indolyl]-4-(3-indolyl)-pyrrol-2,5- dione (0.48 g, 70%). A small portion of the product (0.017 g, mmol) was dissolved in ethanol (1 ml) and aqueous sodium hydroxide (2.0 M, 1 ml). The solution was refluxed for 1.5 hours, cooling to room temperature followed by acidification with hydrochloric acid and extraction of the product with ethyl acetate (2 x 1 ml) yields the intermediate 3-[l-((lR,4S)-4-hydroxy-2-cyclopenten-l-yl)-3-indolyl]-4-(3- indolyl)-furan-2,5-dione. This product was dissolved in N,N-dimethylformamide 81 ml and ammonium hydroxide (1 ml), heating to 120 °C for 2 hours in a sealed tube vessel, extraction and evaporation of the solvent yields the title product (0.004 g, 32%) as a red solid after chromatography.

H-NMR (500 MHz, CDC1₃): δ 1.61 (1 H, dt, J 4.7, 13.9 Hz), 1.75 (1 H, br d, J 6.2 Hz,

OH), 2.95 (1 H, dt, J 7.9, 14.3 Hz), 4.79 (1 H, br s), 5.33 (1 H, br s), 5.91 (1 H, d, J 5.2 Hz), 6.09 (1 H, dt, J 1.9, 5.6 Hz), 6.76 (1 H, t, J 7.4 Hz), 6.83 (1 H, d, J 8.1 Hz), 6.88 (1 H, t, J 7.4 Hz), 7.07 (1 H, t, J 7.7 Hz), 7.14 (1 H, t, J 7.7 Hz), 7.26 (1 H, d, J 8.1 Hz), 7.31 (1 H, d, J 8.1 Hz), 7.40 (1 H, d, J 8.4 Hz), 7.52 (1 H, s), 7.67 (1 H, s), 7.70 (1 H, d, J 7.5 Hz), 8.62 (1 H, s). HRMS(FAB) calcd for C₂₅H₁₉N₃0₃409.1426, found 409.1436 [M+l.

Example 24 3,4-Di(l-((lR,4S)-4-hydroxy-2-cyclopenten-l-yl)-3-indolyl)-pyrrol-2,5-dione The major by-product from Example 23 a) (0.051 g, 0.070 mmol) was dissolved in ethanol (4 ml) and aqueous potassium hydroxide (0.9 M, 2 ml). The solution was heated at reflux for 1 hour, cooling to room temperature followed by acidification with hydrochloric acid and extraction of the product with ethyl acetate (2 x 1 ml) yields the intermediate 3,4-Di(l-((lR,4S)-4-hydroxy-2-cyclopenten-l-yl)-3-indolyl)- furan-2,5-dione. This product was dissolved in N,N-dimethylformamide (2 ml) and ammonium hydroxide (2 ml), heating to 120 °C for 2 hours in a sealed tube vessel, extraction and evaporation of the solvent yields the title product (0.015 g, 44%) as a red solid after chromatography.

Η-NMR (500 MHz, CDC1₃): δ 1.72 (2H, dt, J 5.3, 13.5 Hz), 3.08 (2H, dt, } 7.8, 13.8

Hz), 4.87 (2H, br s), 5.51 (2H, br s), 5.99 (2H, d, } 5.3 Hz), 6.19 (2H, d, J 5.3 Hz), 6.73 (2H, t, 77.6 Hz), 6.91 (2H, d, J 8.0 Hz), 7.08 (2H, t, J 7.7 Hz), 7.55 (2H, d, } 8.2 Hz),

7.72 (2 H, s). HRMS(FAB) calcd for C₃₀H₂₅N₃O₄491.1845, found 491.1854 [M+].

Claims

1. A compound of formula (I)

wherein

each R₂₀, which may be the same or different, is a hydrogen or halogen;

R' is methyl, hydrogen or R;

R is a group of formula (II)

wherein

Z is a single or a double bond; n is 1-3;

R. is hydroxy, hydroxymethyl, amino, N-((C₁-C₅)alkyl)amino, aminomethyl,

N-((C₁-C₅)alkyl)aminomethyl, N,N-di((C₁-C₅)alkyl)aminomethyl, (C₁-C₅)acyloxy or N-((C₁-C₅)acyl)amino, and

R₂ and R₃ are hydrogen and, when Z is a single bond, R₄ and R_s , which may be the same or different, are each hydrogen or hydroxy; and

pharmaceutically acceptable salts, as well as all possible stereoisomers either pure or as racemates or mixtures of stereoisomers, thereof.

2. A compound according to claim 1, wherein R_χ is hydroxy, hydroxymethyl, amino or aminomethyl.

3. A compound according to claim 2, wherein n is 1 or 2, and R. is hydroxy or amino.

4. A compound according to claim 3, n is 1 or 2, and R_j is amino.

5. The compounds:

3-[l-((lS,3S)-3-amino-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-2,5- dione, 3-[l-((lR,3R)-3-amino-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-2,5- dione,

3-[l-(trans-4-amino-l-cyclohexyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-2,5- dione,

(+)-3-[l-((lR,4R)-4-amino-2-cyclopenten-l-yl)-3-indolyl]-4-[l-methyl-3- indolyl]pyrrol-2,5-dione, 3-[l-((lS,4S)-4-amino-2-cyclohexen-l-yl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-

2,5-dione,

3-[l-((lR,2S,3R,4R)-4-amino-2,3-dihydroxy-l-cyclopentyl)-3-indolyl]-4-[l-methyl-

3-indolyl]-pyrrol-2,5-dione , 3-[l-((lS,3R)-3-amino-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-2,5- dione,

3-[l-((lR,3S)-3-amino-l-cycloρentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-ρyrrol-2,5- dione,

3-[l-((lR,2S,3R,4S)-4-amino-2,3-dihydroxy-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3- indolyl]-pyrrol-2,5-dione,

3-[l-((lR,4S)-4-amino-2-cyclopenten-l-yl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-

2,5-dione ,

3-[l-((lS,4R)-4-(aminomethyl)-2-cyclopenten-l-yl)-3-indolyl]-4-[l-methyl-3- indolyl]pyrrol-2,5-dione,

and pharmaceutically acceptable salts thereof.

6. The compound:

3-[l-((lS,3S)-3-amino-l-cyclopentyl)-3-indolyl]-4-[l-methyl-3-indolyl]-pyrrol-2,5- dione, and pharmaceutically acceptable salts thereof.

7.The hydrochloride salt of a compound according to any one of claims 1 to 6.

8. A process for the preparation of a compound according to claim 1, comprising

a) production of a compound of formula (I) in which R₁ is hydroxyl or hydroxymethyl, and when Z is a single bond, R₄ and R₅ are each hydrogen, by deprotecting a corresponding compound of formula (I) in which R, is a protected hydroxyl group or a methylene carrying a protected hydroxyl group, or b) production of a compound of formula (I) in which R, is amino or aminomethyl, and when Z is a single bond, R₄ and R₅ are each hydrogen, by i) reduction of a corresponding compound in which R, is azide or azidomethyl, or

ii) deprotection of a corresponding compound of formula (I) in which R, is a protected amino group or a methylene carrying a protected amino group, or

c) production of a compound of formula (I) in which R_j is amino, N-((C₁-C₅)alkyl)amino, aminomethyl, N-((C₁-C₅)alkyl)aminomethyl,

N,N-di((C₁-C₅)alkyl)aminomethyl, and when Z is a single bond, R₄ and R₅ are each hydrogen, by reaction of ammonia or an appropriate amine with a corresponding compound of formula (I) in which R₁ is a good leaving group or a methylene group carrying a good leaving group respectively, or

d) production of a compound of formula (I) in which R₁ is (C_α-C₅)acyloxy or N-((C₁-C₅)acyl)amino, and when Z is a single bond, R₄ and R₅ are each hydrogen, by acylation of a corresponding compound of formula (I) in which ^ is hydroxy or amino respectively, or

e) production of a compound of formula (I) in which R, is hydroxy, hydroxymethyl, amino, aminomethyl, and when Z is a single bond, R₄ and R₅ are each hydrogen, by reaction of a compound of formula (IH) 50

in which R₂₀, R' and R are defined as in formula (I), but in which R_j is a protected hydroxyl group, a methylene carrying a protected hydroxyl group, a protected amino group, or a methylene carrying a protected amino group, with

i) ammonia, or ammonia followed by treatment with an appropriate deprotecting agent; or

ii) ammonium acetate followed by treatment with an appropriate deprotecting agent; or

iii) hexamethyldisilazane-methanol, followed by treatment with an appropriate deprotecting agent; or

f) production of a compound of formula (I) in which R₄ and R₅ are hydroxyl, by hydroxylation of a compound of formula (I) in which Z is a double bond, in the presence of a metal oxidant, or

g) converting

i) a compound of formula (I) to a pharmaceutically acceptable salt thereof, or vice versa: or ii) a pharmaceutically acceptable salt of a compound of formula (I) into a different pharmaceutically acceptable salt.

9. A compound according to any one of claims 1 to 6, for use in therapy.

10. A compound according to claim 9, for use in the treatment of inflammatory or immunlogical disorders.

11. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of inflammatory or immunlogical disorders.

12. A method for the treatment of an inflammatory or immunlogical disorder, wherein a therapeutically effective amount of a compound according to any one of claims 1 to 6 is administered to a mammal in the need of such treatment.

13. A pharmaceutical composition wherein the active ingredient is a compound according to any one of claims 1 to 6.

14. A compound of formula (I A)

wherein

each R₂₀, which may be the same or different, is a hydrogen or halogen; R' is methyl, hydrogen or R;

R is a group of formula (II)

wherein

Z is a single or a double bond;

n is 1-3;

R_j is a protected hydroxyl group, a methylene carrying a protected hydroxyl, an azide, an azidomethyl group, a protected amino group, a methylene carrying a protected amino group, a good leaving group or a methylene group carrying a good leaving group; and

R-, and R₃ are hydrogen and, when Z is a single bond, R₄ and R₅ are hydrogen; or

a compound of formula (IIIA) T/SE97/01506

53

R R ^* (IIIA)

wherein Y is oxygen or a nitrogen substituted with a methyl group, and

R₂₀, R', R, Z and n are as previously defined in this claim, but

R, is a protected hydroxyl group, a methylene carrying a protected hydroxyl group, a protected amino group or a methylene carrying a protected amino group; and

R_j and R₃ are hydrogen and, when Z is a single bond, R₄ and R. are hydrogen; or

a compound of formula (IVA)

wherein

X is an halogen atom; R₂₀ is a hydrogen or halogen; R is as defined above in formula (HI); or a compound of formula (V A)

wherein

R₂₀ is a hydrogen or halogen; R is as defined above in formula (III).