WO1998011105A1

WO1998011105A1 - New pharmaceutically active compounds

Info

Publication number: WO1998011105A1
Application number: PCT/SE1997/001505
Authority: WO
Inventors: Håkan BERGSTRAND; Kostas Karabelas; Matti Lepistö; Margareta Linden; Ghazi Noori; Kristina Stenvall
Original assignee: Astra Aktiebolag
Priority date: 1996-09-10
Filing date: 1997-09-08
Publication date: 1998-03-19
Also published as: AR009733A1; SE9603284D0; ZA977808B; AU4143297A

Abstract

The present invention provides novel compounds of formula (I), wherein X is hydrogen or methyl; R is a group of formula (II) wherein X, R, R2, R4, R6, R7 and n are as described in the specification, 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.

Melnik, S. Y. et al (Russian Journal of Bioorganic Chemistry, Vol. 22, No. 11, 1996, pp. 726-731.) disclose 3-(lH-3-indolyl)- -(l-glycosyl-3-indolyl)-lH-pyrrole-2,5- diones which are purported to have antiproliferative properties on human ovary carcinoma cells.

Melnik, S. Y. et al (Russian Journal of Bioorganic Chemstry: Vol. 22, No.6, 1996, pp. 397-405) disclose bis(indolyl)furan-2,5-dione and bis(indolyl)-lH-pyrrole-2,5- dione N-glycosides which are purported to have antiproliferative properties on human ovary carcinoma cells.

Although PKC inhibitors are described in the prior art, there is an urgent need for specific anti-inflammatory and immunosuppressive 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 thereof are active topically, moreover, they have a systemic activity when administered orally, and certain of them have enhanced anti-inflammatory effect. Compounds of the present invention possess improved ability to inhibit PKC relative to compounds of the closest structural prior art and /or possess improved solubility and /or improved bioavailability and /or improved oral activity.

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

X is hydrogen or methyl;

R is a group of formula (II)

wherein

n is 0 or 1;

R₂ is hydrogen,

R₄ is hydrogen, hydroxy, azide, amino, N-((C₁-C₅)alkyl)amino or N,N-di((C₁- C₅)alkyl)amino,

or R₂ and R₄ may together form a bond,

when n is 1 R₆ may be hydrogen, hydroxy, azide, amino or N,N-di((C₁-C₅)alkyl)amino, and

R₇ is hydrogen, hydroxy methyl, (C₁-C₅)alkoxy methyl, azidomethyl,

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

pharmaceutically acceptable salts thereof. Methods of preparation

The compounds of formula (I), and pharmaceutically acceptable salts thereof, may be prepared by

a) production of a compound of formula (I) in which one or both of R₄ and R₆ is

hydroxyl, and /or R₇ is hydroxymethyl, by deprotecting a corresponding compound of formula (I) in which one or both of R₄ and R₆ is a protected hydroxyl group, and /or R₇ is a methylene carrying a protected hydroxyl group, or

b) production of a compound of formula (I) in which one or both of R₄ and R₆ is amino, and /or R₇ is aminomethyl, by reduction of a corresponding compound of formula (I) in which one or both of R₄ and R₆ is azide, and /or R₇ is azidomethyl, or

c) production of a compound of formula (I) in which one or both of R₄ and R₆ is amino, and /or R₇ is aminomethyl, by deprotecting a compound of formula (I) in which one or both of R₄ and R₆ is a protected amino group, and /or R₇ is a methylene carrying a protected amino group, or

d) production of a compound of formula (I) in which one or both of R₄ and R₆ is amino, and /or R₇ is aminomethyl, by reaction of an appropriate amine with a corresponding compound of formula (I) in which one or both of R₄ and R₆ is a good leaving group, and /or R₇ is a methylene group carrying a good leaving group, or e) production of a compound of formula (I), by reaction of a compound of formula (III)

in which R and X are defined as in formula (I), but

in which one or both of R₄ and R₆ is a protected hydroxyl group or a protected amino group, and/or R₇ is a methylene carrying a protected hydroxyl group or a methylene carrying a protected amino group, with

an appropriate source of ammonia followed by treatment with an appropriate deprotecting agent; or

f) 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 to those skilled in the art. The protecting group may be an acyl group such as acetyl or benzoyl, and the deprotecting agent may be a base such as sodium methoxide. The deprotection step may be carried out in a suitable solvent, e.g. methanol at a temperature between 20°C to reflux for, for example, 1 hour to 24 hours.

In process b) the conditions for the reduction are well known to those skilled in the art. Preferred conditions are: i) 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;

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

iii) triphenyl phosphine in a suitable solvent, e.g. tetrahydrofuran at a temperature of 10-30°C, e.g. for about 30 h followed by either acidic extraction or chromatographic purification.

In process c) the protecting groups and conditions for deprotection are well known to those skilled in the art. 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 for about 22 hours.

In process d) the good leaving group may be obtained by transformation of a corresponding hydroxy or hydroxymethyl to a better leaving group, e.g. p-toluenesulphonyloxy group. An appropriate amine may be ammonia, monoalkylamine or dialkylamine. Suitable leaving groups are well known to those skilled in the art. The intermediate compound possessing a good leaving group may be isolated or generated in situ. In process e) the appropriate source of ammonia may be hexamethyldisilazane, and the reaction may be performed with hexamethyldisilazane and methanol in a polar solvent, e.g. dimethylformamide at a temperature of 10-30°C.

The protecting groups may be acyl or phthaloyl groups, the removal of the protecting groups may be carried out according to conventional methods known per se (e.g. deacylation, catalytic hydrogenation and dephthaloylation), and prefererred conditions for the deprotection step are as defined above under a) and c) above.

In process f) 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.

A) The compounds of formula (III) may be prepared by reacting a compound of formula (IV)

(IV) wherein Hal is a halogen atom, preferably chlorine, and R_χ is R or X, both as defined in formula (III), with

a compound of formula (V)

wherein R is R or X, both as defined in formula (IE), in the presence of an appropriate organic base, e.g. triethylamine.

A compound of the formula (IV) may be prepared by reacting a compound of formula (VI)

(VI)

wherein R_χ is as defined in formula (IV), with

oxalyl chloride in dichloromethane. A compound of formula (VI) in which R_χ is R, may be prepared by reacting a compound of the general formula (VII)

(VII)

wherein R is as defined in formula (III), with

a suitable oxidant, e.g. 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) in a suitable solvent, e.g. toluene.

A compound of formula (VH) may be prepared by reacting a compound of formula (VIII),

(VIII) wherein Y is a hydroxyl, and R₂, R₄, R₆, R₇and n are as defined in formula (III), with

indoline (formula IX)

(IX)

in a mixture of ethanol and toluene.

B) The compounds of formula (III) defined as above, or of formula (EIA)

in which R and X are as defined in formula (El), and Z is NCH^OCH_j H_j,

may be prepared by reacting a compound of formula (VELA), which is as defined in formula (VIII), but wherein Y is hydroxyl, acetoxy or methoxy, with

a compound of formula (BIB), which is as defined in formula (El) or (EIA), but wherein R is hydrogen,

in the presence of a Lewis acid, e.g. boron trifluoride etherate or t-butyldimethylsilalyl trifluoromethanesulphonate in a solvent, e.g. acetonitrile, dichloromethane or a mixture of the two solvents at a temperature between -60°C and ambient temperature. Compounds of formula (EIA) may be converted to a compound of formula (III) by treatment with a strong base, e.g. aqueous sodium hydroxide followed by acidification, e.g. with aqueous hydrogen chloride.

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 one or both of R₄ and R₆ is a protected hydroxyl group, a protected amino group or a good leaving group, and/or R₇ is a methylene carrying a protected hydroxyl group, methylene carrying a protected amino group or a methylene carrying good leaving group.

ii) A compound of formula (El) defined as above.

iii) A compound of formula (IV A)

wherein Hal is an halogen atom, preferably chlorine, and R is as defined in formula (III).

iv) A compound of formula (VIA)

wherein R is as defined in formula (III).

v) A compound of formula (VIEA)

(VIIIA)

wherein

Y_a is methoxy, R_4a is benzoyloxy, R_6a is hydrogen and R_9a is 4-methylphenylsulphonoxy, azide or N-phthalimide; or

Y_a is hydroxy, R_4a is azide, R_6a is hydrogen and R_9a is benzoyloxy.

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

Further compounds in v) may be a compound of formula (VIEA) wherein Y_a is methoxy, R_4a is azide, R_6a is hydrogen or benzoyloxy and R_9a is benzoyloxy; or

Y_a is methoxy, R_4a is benzoyloxy, R_6a is benzoyloxy and R_9a is azide.

Moreover, Y_a may also be an acyloxy group.

The compounds of formula (I), and pharmaceutically acceptable salts 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 i vitro assays described in Granet, R. A. et al, Analyt. Biochem. 1987; 163.458-463;

Olsson, H. et al, Cell Signal 1989, 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_M-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 C_S-C_2Q 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 in conjunction with other compounds used for the treatment of the above conditions.

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

R₄ is hydrogen, hydroxy, azide, amino or N,N-di((C₁-C₃)alkyl)amino,

or R₂ and R₄ may together form a bond,

when n is 1 R₆ may be hydrogen, hydroxy, azide, amino or N,N-di((C C₃)alkyl)amino, and

R₇ is hydrogen, hydroxymethyl, (C₁-C₃)alkoxymethyl, azidomethyl, aminomethyl, N,N- di((C₁-C₃)alkyl)aminomethyl.

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

R₄ is hydroxy, azide, amino or N,N-diethylamino, when n is 1 R₆ may be hydrogen, hydroxy, azide, amino or N,N-diethylamino, and

R₇ is hydroxymethyl, methoxymethyl, azidomethyl, aminomethyl, (N,N- diethylamino)methyl.

The most preferred compounds according to the present invention include:

3-[l-(6-Amino-2,4,6-trideoxy-α-D-threo-hexopyranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)-pyrrole-2,5-dione,

3-{l-(6-Amino -2,4,6-trideoxy-β-D-threo-hexopyranosyl)-indol-3-yl}-4-(l-methyl-3- indolyl)-pyrrole-2,5-dione,

3-[l-(3-Amino-2,3-dideoxy-β-D-threo-pentofuranosyl)-3-indolyl]-4-(l-methyl-3-indolyl)- ρyrrole-2,5-dione ,

3-[l-(3-Aιnino-2,3-dideoxy-α-D-threo-pentofuranosyl)-3-indolyl]-4-(l-methyl-3-indolyl)- pyrrole-2,5-dione,

3-[l-(3-Ami_no-2,3-dideoxy-α-D-erythro-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione , 3-[l-(3-Amino-2,3-dideoxy-β-D-erythro-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione ,

3-[l-(3-Amino-2,3-dideoxy-5-0-methyl-α-D-threo-pentofuranosyl)-3-indolyl]-4-(l- methyl-3-indolyl)pyrrole-2,5-dione,

3-[l-(5-Amino-2,5-dideoxy-α-D-threo-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione,

3-[l-(5-Amino-2,5-dideoxy-β-D-threo-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione ,

3-[l-(5-Amino-2,5-dideoxy-β-D-erythro-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione , and in particular the acetic acid salts thereof.

The most preferred compound according to the present invention is :

3-[l-(6-Amino-2,4,6-trideoxy-α-D-threo-hexopyranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)-pyrrole-2,5-dione, and in particular its acetic acid salt.

Enantiomers and diastereomers of compounds of the formula (I) may be prepared by stereospecific synthesis or by resolution of mixtures containing them. The resolution ma be carried out using processes known per se.

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

General methods

Drying of the acceptor

The bisindolylmaleic anhydride (acceptor) is dissolved in a minimal amount of hot acetonitrile and diluted with an equal volume of toluene. The solvents are distilled off under reduced pressure and the residue is dried overnight at 0.05 torr at room temperature.

Glycosylation

The bisindolylmaleic anhydride (acceptor) is dissolved in the reaction solvent to obtain 20-100 M solution. The reaction solvent is acetonitrile (dried over 3 A molcular sieves) or a mixture of acetonitrile (dried over 3 A molcular sieves) and dichloromethane (dried over 4A molcular sieves) (1:6 - 3:2). When the reaction is to be conducted below the freezing point of acetonitrile, a larger portion of methylene chloride is preferred. Optionally, ground 4A molecular sieves are added (0.1- 0 .5g/ml). The solution is cooled to the indicated temperature (-20 to -60°C) and 1 to 10 equivalents (preferrably 1.5 to 4 equivalents) of the promoter is added. Promoters used are boron trifluoride etherate, trimethylsilyl trifluoromethanesulfonate and dimethyl- t-buty lsily 1 trifluoromethanesulfonate .

The donor (the compound of formula (VIII)) dissolved in reaction solvent (10-20% of the total volume) is then added over the indicated addition time (2min-llh) and the mixture is stirred during the indicated reaction time (lh to 48h).

The reaction is monitored by TLC and /or HPLC and terminated by addition of a base such as triethylamine or aqueous sodium hydrogen carbonate and allowed to attain ambient tempreature. If ground molecular sieves were included, the

TM mixture is filtered through a celite pad. The filtrate is washed with aqueous sodium hydrogen carbonate, water and the organic phases are then dried over sodium sulfate, filtered and the solvents removed under reduced pressure and the residue subjected to either straight or reverse phase column chromatography unless otherwise indicated.

Imide formation

A 0.1-0.25 mM solution of the glycosylated bisindolylmaleic anhydride in dimethylformamide is treated with 5 to 30 equivalents (preferrably 8 to 12 equivalent) of hexamethyldisilazane and 2.5 to 15 equivalents (preferrably 4 to 6 equivalents) of methanol at ambient temperature. When the reaction is complete as indicated by TLC, the solvents and reagents are removed under reduced pressure and the residue crystallized or subjected to column chromatography

Deacylation When appropriate, the ester (25-100 mM) in methanol or a mixture of methanol and t-butyl methyl ether or dichloromethane is treated with 2-3 equivalents of methanolic 0.2 M sodium methoxide. Upon completition of reaction as indicated by TLC the reaction mixture is neutralized with an acidic ion-exchange resin, silica gel or acetic acid, filtered when appropriate (the solids are washed with methanol), the combined filtrates are concentrated under reduced pressure and then crystallized or subjected to column chromatography.

Azide reduction

When appropriate, a 50-250 mM tetrahydrofuran solution of the azide is treated with 5 to 10 equivalents of triphenylphosphine and 10 to 20 equivalents of water in a flask, protected from light, overnight or until the reaction is complete as indicated by TLC. The reaction mixture is then either concentrated under reduced pressure and the residude subjected to chromatography (to afford the free amine) or partitioned between 5% aquous acetic acid and chloroform or ethyl acetate, the aquous phase is washed with another portion of the organic solvent and concentrated under reduced pressure or lyophilized to obtain the acetic acid salt. Alternatively, the aquous solution is made weakly alkaline with sodium hydrogen carbonate and the amine extracted with an organic solvent which is then dried over sodium sulfate and the solvent is removed under reduced pressure. The product is then purified either by crystallization or column chromatography.

Chromatography

Analytical HPLC was run on a Beckman Star System with C-8 or C-18 reverse- phase columns ( Beckman Ultrasphere 4.6 μm, 5x150 mm ) and one of the following eluent systems:

Acetonitrile-water gradients in the range 25-85% acetonitrile with non-basic products and intermediates. Acetonitrile-water with 0.1% trifluoroacetic acid in the range 25-85% acetonitrile with basic products and/or intermediates except furanosides. Acetonitrile-water with 1% acetic acid in the range 25-85% acetonitrile with basic furanoside products and /or intermediates.

Semi-preparative HPLC methods were identical to the analytical methods above except for column size ( 10x250 mm).

TLC was run on pre-coated glass plates ( Merck; DC Kieselgel 60 F^, HPTLC RP-8 Ε_]S4S/ or HPTLC RP-18 F^) with following eluents (unless otherwise indicated):

Silica; t-butyl methyl ether/ toluene (2:1 to 1:40) with most intermediate products, methanol / methylene chloride (1:9 to 1:20 ) with 2% concentrated ammonia with basic products, methanol / t-butyl methyl ether (1:9 to 1:40) with neutral products.

RP-8 and RP-18; acetonitrile / water ( 2:1 to 9:1) with most intermediate products, acetonitrile / water ( 1:4 to 2:1, 1% acetic acid or 0.1% trifluoroacetic acid) with basic products.

Column and flash chromatography with silica ( Grace 35-70 μm ) were used with the same solvent systems as in TLC.

Reverse-phase column chromatography was done with pre-packed columns (

Merck Lobar, LiChroprep RP-8 and RP-18 ) equipped with a peristaltic pump ( Ismatec MS-REGLO ) and UV-detector ( Pharmacia-LKB UVl ) with the same eluent systems described for reverse-phase TLC above.

Example 1 3-[l-(6-Amino-24,6-trideoxy-α-D-threo-hexopyranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)-pyrrole-2,5-dione acetic acid salt

a) Methyl 3-Q-benzoyl-6-phthalimido-2,4 ,6-trideoxy-β-D-threo-hexopyranoside

A mixture of methyl 3-0-benzoyl-2,4-dideoxy-6-p-toluenesulphonyl-β-D-threo- hexopyranoside (This compound is described below as the product in Example 2 step a) ) (2.0 g, 4.8 mmol) and potassium phthalimide (0.98 g, 5.2 mmol) in N,N- dimethylformamide (30 mL) was stirred at 125°C for 45 min. The mixture was taken to dryness under reduced pressure and the residue was dissolved in dichloromethane (250 mL), washed with water (2x200 mL), saturated aqueous sodium chloride (100 mL), dried and concentrated under reduced pressure. Column chromatography (toluene-ethyl acetate, 10:1) afforded the sub-title compound (1.5 g, 80%).

Η-N.m.r. data (CDC1-): 5 8.04 to 7.39 (9 H, Phth and OBz), 5.20 to 5.05 (m, 1 H), 4.41 (dd, 1 H, J 9.7 and 2.0 Hz), 3.97 (dd, 1 H, J 15.7 and 8.9 Hz), 3.89 to 3.78 (m, 2 H), 3.42 (s, 3 H), 2.38 to 2.25 (m,l H), 2.18 to 2.08 (m, 1 H), 1.72 to 1.58 (m,l H), 1.60 to 1.45 (m, 1 H).

b 3-ri-⁽3-0-Benzoyl-6-phthalimido-2_<4_<6-trideoxy-α-D-threo-hexopyranosyπ-3-indolyn- 4-(l-methyl-3-indolylVfuran-2.5-dione

3-Indolyl-4-(l-methyl-3-indolyl)-furan-2,5-dione (533 mg, 1.56 mmol) was dissolved in a mixture of acetonitrile and dichloromethane (18:8, 26 mL) and cooled to -45°. Tert- Butyldimethylsilyl trifluoromethanesulfonate (540 μL, 2.34 mmol) was added, followed by addition of the product from step a) (308 mg, 0.78 mmol) dissolved in a mixture of acetonitrile and dichloromethane (2:5, 7 mL). The mixture was stirred at -45° for 3 h, quenched with triethylamine (420 μL, 3 mmol) and concentrated under reduced pressure. Crystallisation from acetonitrile-water (7:2) gave the sub-title compound (300 mg, 55%). Η-N.m.r. data (CDC ): 6 7.96 to 7.46 (m, 12 H), 7.24 to 7.09 (m, 4 H), 6.83 (m, 1 H), 6.80 to 6.72 (m, 1 H), 6.10 (m, 1 H), 5.99 (bd, 1 H, J 4.4 Hz), 4.02 (dd, 1 H, J 14.1 and 10.3 Hz), 3.71 (s, 3 H, s), 3.60 to 3.48 (m, 3 H), 2.55 (bdd, 1 H, J 14.1 and 4.4 Hz), 1.87 (ddd, 1 H, J 14.0, 11.6 and 5.2 Hz), 1.68 to 1.54 ( , 2 H).

c⁾ 3-fl-⁽3-0-Benzoyl-6-phthalimido-2.4.6-trideoxy-α-D-threo-hexopyranosylV3-indolyll- 4-( 1 -methy l-3-indolyl)-pyrrole-2,5-dione

A solution of the product from step b) (650 mg, 0.92 mmol), hexamethyldisilazane (2 mL, 9.29 mmol) and methanol (190 μL, 4.65 mmol) in dry N,N-dimethylformamide (7 mL) was stirred at room temperature overnight. Precipitation with methanol (7 mL) gave the sub-title compound (514 mg, 79 %), as a powder. The mother liquor was concentrated under reduced pressure , the residue dissolved in boiling tetrahydrofuran (10 mL) and precipitation by adding methanol (10 mL) gave additional sub-title compound (126 mg, 12 %, total yield, 91%).

^lH-N.m.r. data (d-DMSO): δ 10.95 (bs, 1 H), 7.92 to 6.98 (m, 16 H), 6.70 (bt, 1 H, J 7.7 Hz), 6.46 (bd, 1 H, J 7.7 Hz), 6.03 (bd, 1 H, J 4.4 Hz), 5.91 (bt, 1 H, J 7.7 Hz), 3.86 (dd, 1H, J 14.2 and 10.0 Hz), 3.67 (s, 3 H), 3.56 (bd, 1 H, J 14.2 Hz), 3.48 to 3.30 (m, 2 H, ), 2.53 to 2.44 (m, 1 H), 1.88 to 1.74 (m, 1 H), 1.65 to 1.47 (m, 2 H).

d) 3-[l-(6-Amino-2.4,6-trideoxy-α-D-threo-hexopyranosyl)-3-indoIyn-4-fl-methyl-3- indoIy -pyrrole-2.5-dione

A solution of the product from step c) (149 mg, 211 μmol) in tetrahydrofuran (5 mL) and methanolic sodium methoxide (0.02 M, 5 mL) was stirred at 50°C for 3 h. The solution was then neutralised with a cation exchange resin (Bio-Rad, AG 50W-X8, H⁺), filtered and concentrated under reduced pressure. The residue 3-[l-(6-phthalimido-2,4,6-trideoxy-α- D-threo-hexopyranosyl)-3-indolyl]-4-(l-methyl-3-indolyl)-pyrrole-2,5-dione was stirred in ethanolic methylamine (2 M, 5.5 mL) at reflux for 2 h and concentrated under reduced pressure. Column chromatography (toluene-ethanol-ammonium hydroxide, 300:50:1) afforded the crystalline sub-title compound (84 mg, 83%).

^lH-N.m.r. data (CDCI₃-CD₃OD, 2:1): δ 7.48 (s, 1 H), 7.35 (d, 1 H, J 8.4 Hz), 7.18 (s, 1 H), 7.11 (d, 1 H, J 8.4 Hz), 7.08 (d, 1 H, J 8.3 Hz), 6.95 to 6.82 (m, 2 H), 6.73 to 6.66 (m, 1 H), 6.49 to 6.39 (m, 2 H), 5.79 (d, 1 H, J 5.1 Hz), 3.60 (s, 3 H), 3.29 to 3.16 (m, 1 H), 2.80 to 2.68 (m, 1 H), 2.46 to 2.28 (m, 2 H), 2.17 (dd, 1 H, J 14.2 and 4.5 Hz), 1.62 (ddd, 1 H, J 14.3, 11.4 and 5.5 Hz), 1.40 (dd, 1 H, J 12.1 and 4.6 Hz), 1.06 to 0.93 (m, 1 H).

e) The product from step d) (87 mg, 185 μmol) was dissolved in 0.03 M acetic acid in water (30 mL) and lyophilised to afford the amorphous title compound (95 mg, 97 %).

Η-N.m.r. data (CD₃OD): δ 7.81 (s, 1 H), 7.69 (d, 1 H, J 8.4 Hz), 7.45 to 7.39 (m, 3 H), 7.22 to 7.08 (m, 2 H), 6.99 to 6.93 (m, 1 H), 6.72 to 6.62 (m, 2 H), 6.10 (d, 1 H, J 4.8 Hz), 3.89 (s, 3 H), 3.41 to 3.21 (m, 2 H), 2.95 to 2.80 (m, 2 H), 2.41 (dd, 1 H, J 14.2 and 4.5 Hz), 1.90 (s, 3 H), 1.90 to 1.75 (m, 1 H), 1.70 to 1.63 (m, 1 H), 1.35 to 1.16 (m, 1 H).

Example 2

3-{l-(6-Amino -2,4,6-trideoxy-β-D-threo-hexopyranosyl)-indol-3-yl}-4-(l-methyl-3- indolyl)-pyrrole-2,5-dione trifluoroacetic acid salt

a) Methyl 3-0-benzoyl-2.4-dideoxy-6-p-toluenesulphonyl-β-D-threo-hexopyranoside

A solution of p-toluenesulfonic anhydride (6.01 g, 17.9 mmol) in dry dichloromethane (30 L) and pyridine (5.05 mL) was added to a cold (-56°C), stirred solution of methyl 2,4- dideoxy-β-D-threo-hexopyranoside (2.90 g, 17.9 mmol) and pyridine (9.90 g, 125.2 mmol) in dry dichloromethane (100 mL) during a period of 30 min. The temperature was allowed to increase to -10°C during the next 30 min., then a solution of benzoyl chloride (3.02 g, 21.46 mmol) in dichloromethane (15 mL) was added rapidly. After stirring the mixture at 0°C to 10°C for 1 h, additional benzoyl chloride (3.02 g, 21.46 mmol) was added. The mixture was then diluted with dichloromethane (1 volume) and washed with saturated aqueous sodium hydrogen carbonate, water, dried and concentrated under reduced pressure. The residue was subjected to flash chromatography (heptane-ethyl acetate, 3:1), to give the sub-title compound as a syrup (6.36 g, 84.6%). This compound was used in the next step without further purification.

¹H-N.m.r. data (CDCI3): δ 5.14 (m, 1 H), 4.41 (dd, 1 H, J 1.9 and 9.7 Hz), 4.15 (dd, 1 H, J 6.2 and 10.3 Hz), 4.08 (dd, 1 H, J 4.2 Hz). 3.75 (m, 1 H), 3.47 (s, 3 H), 2.44 (s, 3 H), 2.31 (m, 1 H), 2.09 (m, 1 H), 1.59 (m, 1 H), 1.43 (ABq, J_A,B 11-6 Hz).

b) Methyl 6-azido-3-0-benzoyl-2,4,6-trideoxy-β-D-threo-hexopyranoside

A suspension of the product from step a) (8.50 g, 20.2 mmol) and sodium azide (13.14 g, 202.2 mmol) in dry dimethylformamide (100 mL) was heated at 70°C for 16 h, cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was washed twice with water, dried and concentrated under reduced pressure. The residue was subjected to chromatography (heptane-ethyl acetate, 10:1), to give the sub-title compound (5.03 g, 85.4%).

Η-N.m.r. data (CDCI₃): δ 5.18 (m, 1 H), 4.48 (dd, 1 H, J 2.0 and 9.7 Hz), 3.73 (m, 1 H), 3.55 (s, 3 H), 3.49 (dd, 1 H, J 7.7 and 13.0 Hz), 3.16 (dd, 1 H, J 3.2 Hz), 2.34 (m, 1 H), 2.08 (m, 1 H), 1.64 (m, 1 H), 1.48 (ABq, J_A,B 11.6 Hz).

c) 6- Azido-3-Q-benzoyl-2,4.6-trideoxy-α/ β-D-threo-hexopyranose

A solution of the product from step b) (0.50 g, 1.72 mmol) in THF (10 mL) was treated with aqueous 80% acetic acid (5 mL) and the mixture brought to reflux and then aqueous 3 M hydrochloric acid (0.5 mL) was added. After 1 hour the mixture was cooled and extracted with ethyl acetate. The organic extract was washed with water, saturated aqueous sodium hydrogen carbonate and water, dried and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (toluene-acetone, 20:1) to afford the sub-title compound (383 mg, 80.5%) as a mixture of α- and β-hemiacetals.

"C-N.m.r. data (CDCb): δ 165.8, 133.2, 133.0, 129.6, 129.5, 128.4, 128.3, 94.3, 92.6, 71.2, 68.8, 67.0, 66.7, 54.9, 54.4, 38.3, 33.6, 35.5 and 34.4.

d^ S-fl-Cό-Azido-S-O-benzoyl^^.ό-trideoxy-B-D-threo-hexopyranosyD-indoI-S-yD^-Cl- methyl-3-indolyl)- furan-2.5-dione

A solution of 3-Indolyl-4-(l-methyl-3-indolyl)-furan-2,5-dione (189 mg, .500 mmol) in acetonitrile (15 mL) containing ground molecular sieves (3 A, 1.5 g) was stirred at -30°C for lh. Boron trifluoride etherate ( 1.90 mL, 3.00 mmol) was added dropwise during 2 min.The product from step c) (208 mg) in acetonitrile (2 mL) was then added with a peristaltic pump at a rate of 3 μl/min. (total addition time: 11 h) and the mixture was stirred at -30°C overnight. The reaction was quenched with saturated aqueous sodium

TM hydrogen carbonate and filtered through a short celite pad, the pad was washed with acetonitrile and the combined filtrates were concentrated under reduced pressure. The residue was partitioned between chloroform and saturated aqueous sodium chloride, the organic phase was concentrated under reduced pressure and the residue was subjected to chromatography on a 70 g Lobar C-18 column to afford 22.7 mg, 7.6% of the α-anomer (nmr data not shown ) and the sub-title compound (56.8 mg, 19%).

Η-N.m.r. data (CDCL₃): δ 8.10-8.02 (m, 2 H), 7.87 (s, 1 H), 7.79 (s, 1 H), 7.66-6.75 (m, 11 H), 5.72 (dd, 1 H, J 1.9 and 10.9 Hz), 5.40 (m, 1 H), 4.00 (m, 1 H), 3.84 (s, 3 H), 3.46-3.37 (m, 2 H), 2.58 (m, 1 H), 2.30-2.14 (m, 2 H), 1.76 (m, 1 H).

e) 3-fl-(^'6-Azido-3-0-benzoyl-2,4,6-trideoxy-β-D-threo-hexopyranosyl)-indol-3-yl}-4-(l- methyl-3-indolyl)- pyrrolo-2.5-dione The product from step d) (52.0 mg, 86.5 μmol) was subjected to the general method for imide formation. The reaction mixture was concentrated under reduced pressure and the residue was subjected to flash chromatography ( toluene- t-butyl methyl ether, 8:1) to afford the sub-title compound (33.5 mg, 65%).

'H-N.m.r. data (CDCL₃): δ 8.11-8.05 (m, 2 H), 7.87 (bs, 1 H), 7.82 (s, 1 H), 7.72 (s, 1 H), 7.61 (tt, 1 H, J 1.3 and 7.4 Hz), 7.53-7.41 (m, 3 H), 7.31-7.17 (m, 3 H), 7.14 (ddd, 1 H, J 1.2, 7.3 and 8.3 Hz ), 7.07 (ddd, 1 H, J 1.1, 7.2 and 8.1 Hz), 7.02 (d, 1 H, J 8.1 Hz), 6.88 (d, 1 H, J 7.9 Hz), 6.80 (ddd, 1 H), 6.74 (ddd, 1 H), 5.71 (dd, 1 H, J 1.9, 11.0 Hz), 5.40 (m, 1 H), 3.98 (m, 1 H), 3.81 (s, 3 H), 3.46-3.36 (m, 2 H), 2.56 (m, 1 H), 2.31-2.18 (m, 2 H), 1.75 (m, 1 H).

f) The product from step e) (33.0 mg, 54.9 μmol) was deacylated according to the general deacylation procedure, the reaction mixture was neutralised with silica (ca lg), filtered and concentrated under reduced pressure and the residue was subjected to the general procedure for azide reduction. The mixture was directly applied on a 70 g Lobar C-18 column and the red material which eluted with acetonitrile-water 1:4, 0.1% trifluoroacetic acid was collected and concentrated under reduced pressure. The residue was further purified on semi-preparative HPLC (C-18 column, 27-37% acetonitrile in water, 0.1% trifluoroacetic acid) to afford, upon freeze-drying, the title compound (19.6 mg, 61%) as the trifluoraacetate salt.

'H-N.m.r. data (D_zO, rel. to acetonitrile at 1.95 ppm): δ 7.79 (s, 1 H), 7.68 (s, 1 H), 7.46 (d, 1 H, J 8.2 Hz), 7.30 (d, 1 H, J 8.4 Hz), 7.09-6.97 (m, 2 H), 6.78 (d, 1 H, J 8.0 Hz), 6.68-6.55 (m, 3 H), 5.72 (dd, 1 H, J 1.7 and 10.8 Hz), 4.41 (s, 3 H), 4.14-3.93 (m, 2 H), 3.16 and 3.00 (2 dd, 1 H each, J 2.7, 13.5 and 8.7, 13.3 Hz respectively), 2.28 (m, 1 H), 2.08-1.88 (m, 2 H), 1.32 (m, 1 H).

Example 3 A) 3-[l-(3-Azido-2,3-dideoxy-α-D-threo-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)-pyrroIe-2,5-dione,

B) 3-[l-(3-Amino-2,3-dideoxy-β-D-threo-pentofuranosyl⁾-3-indolyl]-4-(l-methyl-3- indolyl)-pyrrole-2,5-dione acetic acid salt and

C) 3-[l-(3-Amino-2,3-dideoxy-α-D-threo-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)-pyrrole-2,5-dione acetic acid salt.

a) Methyl 2-deoxy-5-0-(4-phenylbenzoyl⁾-3-0-p-toluensulfonyl-β-D-erythro- pentofuranoside

p-Toluenesulfonic anhydride (6.9 g, 20.6 mmol) was added to a solution of methyl-2- deoxy-5-O- (4-phenylbenzoyl) -β-D-erythro-pentofuranoside (4.5 g, 13.7 mmol) in pyridine (3.3 mL, 41.2 mmol) and dry dichloromethane (100 mL) at 0° C. The mixture was stirred at 0° C for 1.5 hour, poured on ice-cold saturated aqueous sodium hydrogen carbonate (200 mL), extracted with dichloromethane (2x250 mL), dried and concentrated under reduced pressure. The residue was filtered through a short silica gel column (heptane-ethyl acetate, 1:1) to give the crude sub-title compound (6.3 g, 89%, approx. 90 % pure).

Η-N.m.r. data (CDC1₃): δ 8.13 to 7.21 (m, 13 H), 5.16 to 5.08 (m, 2 H), 4.49 to 4.37 (m, 1 H), 4.36 (dd, 1 H, J 11.5 and 5.6 Hz), 4.20 (dd, 1 H, J 11.5 and 4.9 Hz), 3.30 (s, 3 H), 2.46 to 2.26 (m, 2 H).

b^ Methyl 3-azido-2,3-dideoxy-5-0-(4-phenylbenzoylVβ-D-threo-pentofuranoside

A mixture of the crude product from step a) (6.2 g, 12.1 mmol), sodium azide (7.9 g, 122 mmol) and powdered molecular sieves (3A, 10 g) in dry N,N-dimethylformamide (250 mL) was stirred at 90° for 72 h. The mixture was diluted with dichloromethane TM

(500 mL), filtered through celite , washed with saturated aqueous sodium hydrogen carbonate (200 mL), dried and concentrated under reduced pressure. The residue was subjected to chromatography (heptane-ethyl acetate, 4:1) to afford the crystalline sub-title compound (3.3 g, 77%).

Η-N.m.r. data (CDCy. δ 8.19 to 7.37 (m, 9 H), 5.10 (dd, 1 H, J 5.5 and 1.0 Hz), 4.63 (dd, 1 H, J 11.4 and 5.7 Hz), 4.56 (dd, 1 H, J 11.4 and 6.6 Hz), 4.47 (bq, 1 H), 4.35 to 4.29 (m, 1 H,), 3.42 (s, 3 H), 2.41 (ddd, 1 H, J 14.3, 7.0 and 5.5 Hz), 2.27 (ddd, 1 H, J 14.3, 5.7 and 1.1 Hz).

cl S-n-O-Azido-Σ.S-dideoxy-S-O-^-phenylbenzoyD- -D-threo-pentofuranosyD-S- indolyll-4-(l-methyl-3-indolyl)-furan-2,5-dione and

d⁾ 3-fl-(^,3-Azido-2.3-dideoxy-5-^Q-⁽4-phenylbenzoyl⁾-β-D-threo-pentofuranosyl)-3- indolyl1-4-(l-methyl-3-indolyl)-furan-2,5-dione

A solution of the product from step b) (2.45 g, 6.9 mmol) in dry acetonitrile (50 mL) was slowly added (approx. 40 min.) to a solution of 3-indolyl-4-(l-methyl-3-indolyl)-furan- 2,5-dione (2.85 g, 8.3 mmol) and boron trifluoride etherate (2.1 mL, 8.0 mmol) in dry acetonitrile (650 mL) at -30°. The mixture was stirred at -30° for 1 h, quenched with saturated aqueous sodium hydrogen carbonate (40 mL) and extracted with cold ethyl acetate (500 mL). The organic phase was washed with saturated aqueous sodium hydrogen carbonate(200 mL), water (200 mL), dried and concentrated under reduced pressure. Column chromatography (first with heptane-ethyl acetate, 1:1 and then toluene-ethyl acetate, 10:1) afforded amorphous the sub-title compounds c) (3.0 g, 65%) and d) (approx. 25 %, contaminated with 3-indolyl-4-(l-methyl-3-indolyl)-furan-2,5- dione, purified and characterised as the sub-title compound f) below).

Η-N.m.r. data (CDC1₃) for compound c) : δ 8.15 to 6.75 (m, 19 H), 6.44 (bt, 1 H, J 6.3 Hz), 4.57 to 4.51 (m, 2 H), 4.31 to 4.24 (m, 2 H), 3.83 (s, 3 H), 2.75 to 2.58 (m, 2 H). e) 3-ri-(3-Azido-2,3-dideoxy-5-Q-(4-phenylbenzoyl)-α-D-threo-pentofuranosyl)-3- indolyll-4-(l-methyl-3-indolyl)-pyrrole-2,5-dione

A solution of the product from step c) (2.95 g, 4.44 mmol), hexamethyldisilazane (29 mL, 133 mmol ) and methanol (2.7 mL, 67 mmol) in dry dimethylformamide (50 mL) was stirred at room temperature overnight and concentrated under reduced pressure. The residue was subjected to chromatography (toluene-ethyl acetate, 5:1) to afford the amorphous sub-title compound (2.37 g, 80 %).

Η-N.m.r. data (CDC1₃): δ 8.13 to 8.08 (m, 2 H), 7.91 (bs, 1 H), 7.75 to 7.07 (m, 13 H), 6.99 to 6.92 (m, 2 H), 6.79 to 6.72 (m, 2 H), 6.42 (bt, 1 H, J 6.2 Hz), 4.57 to 4.46 (m, 2 H), 4.26 to 4.15 (m, 2 H), 3.78 (s, 3 H), 2.71 to 2.56 (m, 2 H).

f) 3-ri-(3-Azido-2.3-dideoxy-5-Q-C4-phenyIbenzoyl')-β-D-threo-pentofuranosylV3- indolyll-4-(l-methyl-3-indolyl)-pyrrole-2.5-dione

A solution of the product from step d) (approx. 1.9 mmol, contaminated with 3-Indolyl-4- (l-methyl-3-indolyl)-furan-2,5-dione), hexamethyldisilazane (24 mL, 112.1 mmol) and methanol (2.3 mL, 56.0 mmol) in dimethylformamide (40 mL) was stirred at room temperature overnight and concentrated. The residue was subjected to chromatography (toluene-ethyl acetate, 6:1) to afford the sub-title compound (1.04 g, approx. 80%, 22% of the product from step b) ).

'H-N.m.r data (CDC1₃): δ 8.13 to 8.08 (m, 2 H), 8.81 (bs, 1 H), 7.73 to 6.75 (m, 17 H), 6.26 (dd, 1 H, J 7.9 and 4.0 Hz), 4.55 (dd, 1 H, J 11.6 and 5.1 Hz), 4.44 (dd, 1 H, J 11.6 and 5.8 Hz), 4.39 to 4.30 (m, 2 H), 3.82 (s, 3 H), 2.77 (m, 1 H), 2.26 (m, 1 H).

g⁾ 3-ri-⁽3-Azido-2.3-dideoxy-α-D-threo-pentofuranosyl)-3-indolyll-4-(l-methyl-3- indoly l)-pyrrole-2 ,5-dione The product from step e) (2.3 g, 3.47 mmol) was dissolved in dichloromethane- methanolic 0.01 M sodium methoxide (3:1, 160 mL) and stirred at room temperature overnight. The solution was neutralised with cation exchange resin (Bio-Rad, AG 50W- X8, H^*), filtered and concentrated under reduced pressure. The residue was subjected to chromatography (first with toluene-tert-butyl methyl ether-methanol, 80:20:1, then with heptane-ethyl acetate, 1:1) to afford the title compound 3 A) (1. 48 g, 88%).

'H-N.m.r. data (CDC1₃): δ 8.15 (bs, 1 H), 7.70 (s, 1 H), 7.54 (s, 1 H), 7.39 (bd, 1 H, J 8.4 Hz), 7.29 (bd, 1 H, J 8.1 Hz), 7.24 (bd, 1 H, J 8.1 Hz), 7.19 to 7.09 (m, 2 H), 6.90 (bdd, 1 H), 6.81 to 6.72 (m, 2 H), 6.36 (bt, 1 H, J 5.9 Hz), 4.10 to 4.02 (m, 2 H), 3.80 to 3.78 (m, 1 H), 3.79 (s, 3 H,), 2.66 to 2.50 (m, 2 H).

h) 3-ri-(3-Azido-2.3-dideoxy-B-D-threo-pentofuranosylV3-indolyn-4-(l-methyl-3- indolyl)-pyrrole-2,5-dione

The product from step f) (980 mg, 1.48 mmol) was dissolved in dichloromethane- methanolic 0.03 M sodium methoxide (3:4, 70 mL) and the mixture was stirred at room temperature for 3 h., neutralised with silica gel, filtered and concentrated under reduced pressure. The residue was subjected to chromatography (heptane-ethyl acetate, 3:1) to afford the sub-title compound (695 mg, 97%).

Η-N.m.r. data (CDC1₃): δ 7.82 (s, 1 H), 7.73 (s, 1 H), 7.41 (bd, 1 H, J 8.1 Hz), 7.30 (bd, 1 H), 7.27 (bd, 1 H), 7.20 to 7.10 (m, 2 H), 6.92 (bdd, 1 H), 6.84 to 6.73 (m, 2 H), 6.21 (dd, 1 H, J 7.5 and 4.7 Hz), 4.34 to 4.25 (m, 1 H), 4.16 to 4.08 (m, 1 H), 3.83 (s, 3 H), 2.79 to 2.26 (m, 1 H), 2.34 to 2.24 (m, 1 H).

i^ 3-ri-(3-Amino-2.3-dideoxy-α-D-threo-pentofuranosyl)-3-indolyll-4-fl-methyl-3- indolyl -pyrrole-2,5-dione A solution of the product from step g), i.e. the title compound 3 A), (585 mg, 1.21 mmol) in tetrahydrofuran (30 mL), was treated with triphenylphosphine (1.61 g, 6.06 mmol) and water (218 μL, 12.1 mmol) and the mixture was stirred at room temperature overnight. Additional triphenylphosphine (200 mg, 0.75 mmol) and water (28 μL, 1.55 mmol) were added and reaction was continued for 8 h and then concentrated under reduced pressure. The residue was subjected to chromatography (dichloromethane-methanol- ammonium hydroxide, 100:10:1) to afford the sub-title compound (417 mg, 75 %).

'H-N.m.r. data (CD₃OD): δ 7.62 (s, 1 H), 7.59 (s, 1 H), 7.42 (bd, 1 H, J 8.35), 7.26 (bd, 1 H, J 8.13), 7.09 to 6.98 (m, 3 H), 6.79 to 6.58 (m, 3 H), 6.40 (dd, 1 H, J 6.6 and 4.8 Hz), 4.04 to 3.95 (m, 1 H), 3.74 to 3.68 (m, 1 H), 3.69 (s, 3 H), 3.55 to 3.45 (m, 1 H), 3.33 to 3.29 (m, 1 H).

j) 3-ri-(^'3-Ammo-23-dideoxy-β-D-threo-pentofuranosy -3-indolyll-4-(^,l-methyl-3- indoly l)-py rrole-2 ,5-d ione

A solution of the product from step h) (640 mg, 1.33 mmol) in tetrahydrofuran (30 mL), was treated with triphenylphosphine (1.76 g, 6.63 mmol) and water (240 μL, 13.3 mmol) and the mixture was stirred at room temperature overnight. Additional triphenylphosphine (0.88 g, 3.32 mmol) and water (120 μL, 6.67 mmol) were added and reaction continued for 10 h. The mixture was then concentrated under reduced pressure and the residue was subjected to chromatography (dichloromethane-methanol- ammo ium hydroxide, 100:10:1) to afford the sub-title compound (392 mg, 65 %).

Η N.m.r. data (CD₃OD): δ 7.96 (s, 1 H), 7.74 (s, 1 H), 7.51 (bd, 1 H, J 8.3 Hz), 7.35 (bd, 1 H, J 8.4 Hz), 7.11 to 7.01 (m, 3 H), 6.78 to 6.63 (m, 3 H), 6.23 (bt, 1 H, J 6.8 and 6.6 Hz), 4.07 to 4.00 (m, 1 H), 3.84 (s, 3 H), 2.72 to 2.61 (m, 1 H), 2.19 to 2.08 (m, 1 H).

k) The product from step j) (92 mg, 43.8 μmol) was dissolved in aqueous 0.02 M acetic acid (25 mL) and lyophilised to give the title product 3 B) (98 mg, 94%). ^lH-N.m.r. data (CD₃OD): δ 7.77 (s, 1 H), 7.67 (s, 1 H), 7.48 (bd, 1 H, J 8.1 Hz), 7.36 (bd, 1 H, J 8.4 Hz), 7.13 to 7.03 (m, 3 H), 6.77 (ddd, 1 H), 6.71 to 6.61 (m, 2 H), 6.54 (dd, 1 H, J 6.7 and 4.9 Hz), 4.09 to 4.01 (m, 1 H, m), 3.85 (s, 3 H), 3.85 to 3.77 (m, 3 H), 2.69 (ddd, 1 H, J 14.2, 6.9 and 4.9 Hz), 2.48 (ddd, 1 H, J 14.2, 6.9 and 4.7 Hz), 1.93 (s, 3 H).

1) The product from step i) (100 mg, 219 μmol) was dissolved in aqueous 0.03 M acetic acid (30 mL) and lyophilised to afford the title compound 3 C) (108 mg, 96%).

'H-N.m.r. data (CD₃OD): 6 7.96 (s, 1 H), 7.68 (s, 1 H), 7.48 (bd, 1 H, J 8.4 Hz), 7.28 (bd, 1 H, J 8.4 Hz), 7.08 to 6.98 (m, 2 H), 6.91 (bd, 1 H, J 7.9 Hz), 6.76 to 6.57 (m, 3 H), 6.19 (dd, 1 H, J 7.6 and 6.5 Hz), 4.15 to 4.08 (m, 1 H), 3.99 to 3.89 (m, 1 H), 3.88 (dd, 1 H, J 12.2 and 4.2 Hz), 3.81 (dd, 1 H, J 12.2 and 4.2 Hz), 3.73 (s, 3 H), 2.73 (ddd, 1 H, J 13.5, 7.3 and 6.4 Hz), 2.30 (ddd, 1 H, J 13.6, 7.2 and 7.2 Hz), 1.94 (s, 3 H).

Example 4

The compounds in Example 4 were prepared in analogy with the compounds described in Examples 1, 2 and 3 above.

A) 3-[l-(2,4-Dideoxy-α-D-threo-hexopyranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione

^lH-N.m.r. data (CD₃OD at 40°C): δ 7.76 (s, 1 H), 7.68 (bd, 1 H, J 8.3 Hz), 7.45 (s, 1 H), 7.38 (bd, 1 H, J 8.3 Hz), 7.32 (br, 1 H, J 7.9 Hz), 7.13-7.05 (m, 2 H), 6.89 (ddd, 1 H, J 1.0, 7.1 and 8.1 Hz), 6.70-6.62 (m, 2 H), 6.1? (bd, 1 H, J 4.0 Hz), 3.87 (s, 3 H), 3.56-3.43 (m, 3 H), 3.21- 3.12 (m, 1 H), 2.43 (bdd, 1 H, J 4.6, 9.6 Hz), 1.85 (ddd, 1 H, J 5.2, 11.0 and 14.3 Hz), 1.72 (bd, 1 H, J 12.2 Hz), 1.39-1.26 (m,l H).

BJ S-tl-tZ^-Dideoxy-β-D-threo-hexopyranosyD-S-indolyll-^-d-methyl-S- indolyl)pyrrole-2,5-dione Η-N.m.r. data (CD₃OD): δ 7.82 (s, 1 H), 7.70 (s, 1 H), 7.50 (bd, 1 H, J 8.3 Hz), 7.34 (bd, 1 H, J 8.2 Hz), 7.06 and 7.03 (2 bd, 1 H each, J 7.6, 7.3 Hz), 6.89 (bd, 1 H, J 8.1 Hz), 6.80 (bd, 1 H, J 8.0 Hz), 6.71-6.62 (m, 2 H), 5.70 (bd, 1 H, J 10.9 Hz), 4.05 (m, 1 H), 3.85-3.73 (s and m, 4 H), 3.65-3.59 (m, 2 H), 2.26 (bd, 1 H, J 11.6 Hz), 2.05-1.185 (m, 2 H), 1.44-1.30 (m, 1 H).

C) 3-[l-(2,4-Dideoxy-β-D-threo-hexopyranosyl)-3-indolyl]-4-(3-indolyl)pyrrole-2,5- dione

Η-N.m.r. data (CD₃OD): δ 7.81 (s,l H), 7.74 (s,l H), 7.49 (bd, 1 H, J 8.4 Hz), 7.33 (dt,l H), 7.05 (ddd, 1 H), 6.98 (ddd, 1 H, J 1.1, 7.1 and 8.2 Hz), 6.91 (dt,l H), 6.82 (dt, 1 H), 6.68 (ddd, 1 H), 6.62 (ddd, 1 H, J 1.0, 7.0 and 8.1 Hz), 5.69 (dd, 1 H, J 11.0 and 1.9 Hz), 4.04 (m,l H), 3.78 (m, 1 H), 3.65-3.56 (m, 2 H), 2.25 (m,l H), 2.04-1.85 (m, 2 H), 1.37 (m,l H).

D) 3-[l-(2,4-Dideoxy-β-D-erythro-hexopyranosyl)-3-indolyl]-4-(3-indolyl) pyrrole-2,5- dione

Η-N.m.r. data (CD₃OD): δ 7.82 (s, 1 H), 7.75 (s, IH), 7.54 (bd, 1 H, J 8.4 Hz), 7.34 (dt, 1 H), 7.06 (ddd, IH, J 1.1, 7.1 and 8.2 Hz), 6.99 (ddd, 1 H, J 1.1, 7.1 and 8.2 Hz), 6.91 (dt, 1 H, J 1.1 and 7.7 Hz), 6.82 (dt, 1 H, J 1.1 and 7.8 Hz), 6.69 (ddd, 1 H, J 1.0, 7.1 and 8.0 Hz), 6.63 (ddd, 1 H, J 1.0, 7.0 and 8.1 Hz), 6.1 (dd, 1 H, J 2.1 and 11.2 Hz), 4.41 (m, 1 H), 4.26 (m,l H), 3.65-3.52 (m, 2 H), 2.21 (ddd, 1 H, J 2.8, 11.3 and 13.5 Hz), 2.00 (bd, 1 H, J 12.2 Hz), 1.78-1.62 (m, 2 H).

E) 3-fl-(2,4-Dideoxy-α-D-threo-hexopyranosyl)-3-indolyl]-4-(3-indolyl)pyrrole-2,5- dione

Η-N.m.r. data (CD₃OD): δ 7.84 (s,l H), 7.68 (bd, 1 H, J 8.4 Hz), 7.42-7.34 (m, 3 H), 7.12 (ddd, 1 H, J 1.0, 7.2 and 8.2 Hz), 7.01 (ddd, 1 H, J 2.5, 6.6 and 8.1 Hz), 6.92 (ddd, IH), 6.66-6.57 (m, 2 H), 5.98 (bd, 1 H, J 4.9 Hz), 3.51-3.41 (m,2 H), 3.33 (m,l H), 3.12 (m,l H), 2.37 (bdd, 1 H, J 4.4 and 14.3 Hz), 1.77 (ddd, 1 H, J 5.3, 11.4 and 14.2 Hz), 1.66 (bdd, 1 H, J 4.6 and 11.9 Hz), 1.27 (m, 1 H).

F) 3-[l-(3-Amino-2,3,4-trideoxy-β-D-threo-hexopyranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione trifluoroacetic acid salt

Η N.m.r. data (CD₃OD): δ 7.86 (s, 1 H), 7.76 (s, 1 H), 7.51 (d, 1 H, J 8.4 Hz), 7.35 (d, 1 H, J 8.2 Hz), 7.10-7.01 (m, 2 H), 6.86 (d, 1 H, J 7.6 Hz), 6.78 (d, 1 H, J 8.0 Hz), 5.87 (bd, 1 H, J 10.3 Hz), 3.96-3.61 (m, 7 H), 2.38 (m, 1 H), 2.21-2-06 (m, 2 H), 1.61 (m, 1 H).

G) 3-[l-(6-Diet yla__nino-2,4,6-trideoxy-α-D-threo-hexopvranosyl)-3-indbIyl]-4-(3- indolyl)pyrrole-2,5-dione trifluroacetic acid salt

Η-N.m.r. data ( CD₃OD ): δ 7.86 (s, 1 H), 7.73 (s, 1 H), 7.65 (bd, 1 H, J 8.3 Hz), 7.39 (d, 1 H, J 8.2 Hz), 7.21-7.12 (m,2 H), 7.02 (ddd, 1 H, J 1.0, 6.9 and 8.2 Hz), 6.84 (m, 1 H), 6.74 (d, 1 H, J 7.9 Hz), 6.60 (ddd, 1 H), 6.38 (bd, 1 H, J 5.2 Hz), 4.00 (m, 1 H), 3.61 (m, 1 H), 3.23-3.02 (m, 5 H), 2.68-2.46 (m, 2 H), 2.14-1.88 (m, 2 H), 1.36 (m, 1 H), 1.22 (t, 3 H, J 7.0 Hz ), 0.87 (t, 3 H, J 7.2 Hz ).

H) 3-[l-⁽6-Diethylamino-2,4,6-trideoxy-β-D-threo-hexopyranosyl)-3-indolyl]-4-(3- indolyl)pyrrole-2,5-dione trifluroacetic acid salt

^lH-N.m.r. data ( CD₃OD ): δ 7.84 and 7.81 (2 s, 2 H), 7.55 (bd, 1 H, J 8.4 Hz), 7.34 (dt, 1 H), 7.10 (ddd, 1 H, J 1.1, 7.0 and 8.3 Hz), 6.98 (ddd, 1 H, J 1.1, 7.0 and 8.3 Hz), 6.95 (ddd, 1 H, J 1.1, 1.8 and 8.1 Hz), 6.76 (ddd, 1 H), 6.73 (ddd, 1 H, J 1.0, 7.0 and 8.3 Hz), 6.59 (ddd, 1 H, J 1.0, 7.0 and 8.2 Hz), 5.88 (dd, 1 H, J 2.1 and 11.3 Hz), 4.25 (m, 1 H), 4.12 (m, 1 H), 3.37-3.13 (m, 6 H), 2.32 (m, 1 H), 2.14-1.97 (m, 2 H), 1.39 (m,l H), 1.24 and 1.21 (2 1, 6 H, J 7.3 and 7.3 Hz ). I) 3-[l-(6-Amino-2,6-dideoxy-β-D-lyxo-hexopyranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione trifluroacetic acid salt

Η-N.m.r. data (CD₃OD ): δ 7.88 (s, 1 H), 7.72 (s, 1 H), 7.57 (bd, 1 H, J 8.4 Hz), 7.34 (bd, 1 H, J 8.2 Hz), 7.12-7.02 (m, 2 H), 6.89 (bd, 1 H, J 7.8 Hz), 6.78 (bd, 1 H, J 7.9 Hz), 6.73-6.60 (m, 2 H), 5.84 (dd, 1 H, J 2.0 and 10.4 Hz), 4.07-3.95 (m, 2 H), 3.87-3.81 (overlapping s and m, 4 H), 3.36-3.15 (bm, 2 H), 2.52 (m,l H), 2.02 (m, 1 H).

J) 3-[l-(3-Amino-2,3-dideoxy-α-D-erythro-pentof ranosyl)-3-indolyl]-4-(l-met yl-3- indolyl)pyrrole-2,5-dione acetic acid salt

1H-N.m.r. data (CD₃OD): δ 6.61-7.82 (m, 10 H), 6.44 (t, 1 H, J6.0 Hz), 3.91 (m, 1 H), 3.83 (s, 3 H), 3.54-2.69 (m, 3 H), 2.58 and 2.38 (2 m, 1 H each), 1.94 (s, 3 H).

K) 3-[l-(3-Amino-2,3-dideoxy-β-D-erythro-pentof ranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione acetic acid salt

1H-N.m.r. data (CD₃OD): δ 6.58-7.88 (m, 10 H), 6.39 (dd, 1 H, J6.4 and 77 Hz), 4.04 (m, 1 H), 3.70-3.88 (m, 3 H), 3.79 (s, 3 H), 2.85 and 2.39 (2 m, 1 H each), 1.94 (s, 3 H).

L) 3-[l-(3-Amino-2,3-dideoxy-β-D-arabino-hexopyranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione acetic acid salt

'H N. .r. data (CD₃OD): δ 7.84 (1 H, s); 7.69 (1 H, s); 7.50 (1 H, d, J 8.4 Hz); 7.31 (1 H, d, J 8.4 Hz); 7.09-6.99 (2 H, m); 6.82 (1 H, d, J 7.9 Hz); 6.77 (1 H, d, J 8.1 Hz); 5.88 (1 H, dd, J 1.9, 10.1 Hz); 3.92 (1 H, h, J 6.2 Hz); 3.89 (1 H, dd, J 1.9, 12.3 Hz); 3.78 (4 H, s and dd, J 4.2, 12.3 Hz); 3.65-3.52 (2 H, m); 3.40-3.32 (1 H, ); 2.43-2.21 (2 H, m); 1.92 (3 H, s ); 1.13 (6 H, d). M) 3-[l-(2,3-Dideoxy-α-D-erythro-hex-2-enopyranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione

'H-N.m.r. data (CD₃OD): δ 7.75 and 7.72 (2 s, IH each), 6.42(m, IH), 6.25 (dt, IH, J 1.8 and 10.1 Hz), 4.92 (ddd, IH, J 2.2, 3.0 and 10.1 Hz), 4.24 (dq, IH, J2.0 and 9.2 Hz), 3.82 (s, 3H), 3.68 (dd, IH, J 4.2 and 12.1 Hz), 3.62 (dd, IH, J 2.6 and 12.2 Hz), and 3.37 (m, IH).

N) 3-[l-(3-Amino-2,3-dideoxy-5-0-methyl-α-D-threo-pentofuranosyl)-3-indolyl]-4-(l- methyl-3-indolyl)pyrrole-2,5-dione acetic acid salt

'H-N.m.r. data (CD₃OD): δ 7.75 (s, 1 H), 7.63 (s, 1 H), 7.46 (bd, 1 H, J 8.4 Hz), 7.34 (bd, 1 H, J 8.4 Hz), 7.13 to 7.02 (m, 3 H), 6.78 (m, 1 H), 6.69 to 6.60 (m, 2 H), 6.50 (dd, 1 H, J 6.7 and 5.1 Hz), 4.06 (dd, 1 H, J 9.8 and 4.6 Hz), 3.82 (s, 3 H), 3.77 to 3.70 (m, 1 H), 3.61 (d, 2H, J 4.6 Hz), 3.38 (s, 3 H), 2.64 (ddd, 1 H, J 14.2, 6.9 and 5.1 Hz), 2.44 (ddd, 1 H, J 14.2, 6.9 and 4.4 Hz), 1.93 (s, 3 H).

0) 3-[l-(5-Amino-2,5-dideoxy-α-D-threo-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione acetic acid salt

Η-N.m.r. data (CD₃OD): δ 6.55-7.75 (m, 11 H), 4.54-4.62 (m, 1 H), 4.23-4.30 (m, 1 H), 3.82 (s, 3 H), 3.14-3.28 (m, 2 H), 60-2.71 (m,l H), 2.43-2.54 (m, 1 H, 1.91 (s, 3 H).

P) 3-[l-(5-Amino-2,5-dideoxy-β-D-threo-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione acetic acid salt "H-N.m.r. data (CD₃OD): δ 6.6-8.3 (m, 10 H), 6.47 (dd, 1 H, J 8.6 and 3.5 Hz), 4.54-4.63 (m, 1 H), 4.15-4.21 (m, 1 H), 3.85 (s, 3 H), 3.21-3.34 (m, 2- H), 2.84-2.96 (m, 1 H), 2.32-2.41 (m, 1 H), 1.91 (s, 3 H)

Q) 3-[l-(5-Amino-2,5-dideoxy-β-D-erythro-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione acetic acid salt

H N.m.r. data (CD₃OD): δ 7.79 and 7.78 (2 H, 2 s); 7.49 (1 H, d, J 8.4 Hz); 7.36 (1 H, d, J 8.4 Hz); 7.13-7.02 (2 H, m ,); 6.96 (1 H, d, J 7.9 Hz); 6.77-6.69 (2 H, m); 6.64 (1 H, ddd, J 1.9, 7.2, 7.3 Hz); 6.53 (1 H, t, J 6.6 Hz); 4.30 (1 H, dt, J 4.8, 9.4 Hz); 4.10-4.01 (1 H, m); 3.86 (3 H, s); 3.21 and 2.94 (2 H, 2 dd, J 3.1, 13.0 and 9.4, 13.0 Hz); 2.63 (1 H, dt, J 6.8, 13.8 Hz); 2.44 (1 H, ddd, J 4.8, 6.4, 13.8 Hz); 1.93 (3 H, s ).

R) 3-[l-(6-Amino-2,3,6-trideoxy-β-D-erythro-hexopyranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione acetic acid salt

H-N.m.r. data (CD₃OD): δ 6.59-7.81 (m, 10 H), 5.79 (dd, 1 H, J 10.5 and 2.2 Hz), 3.68-3.82 (m, 4 H), 3.44-3.53 (m, 1 H), 3.36 (dd, 1 H, J 13.2 and 2.9 Hz), 3.00 (dd, 1 H, J 13.2 and 8.6 Hz), 1.7-2.29 (m, 7 H).

Example 5

3-[l-⁽3-O-Benzoyl-6-phthalimido-2,4,6-trideoxy-β-D-threo-hexopyranosyl)-3-indolyl]- 4-(l-methyl-3-indolyl)-pyrrole-2,5-dione

a⁾ 3-0-Benzoyl-6-phthalimido-2.4.6-trideoxy-D-threo-hexopyranose

Methyl 3-0-benzoyl-6-phthalimido-2,4,6-trideoxy-β-D-threo-hexopyranoside (2.2 g, 5.6 mmol) dissolved in acetonitrile (80 mL) and aqueous hydrogen chloride (0.5 M, 80 mL) was stirred at 100° C for 35 min. The mixture was extracted with ethyl acetate (500 mL). The organic phase was washed with saturated aqueous sodium hydrogencarbonate(200 mL), dried and concentraded under reduced pressure to give the sub-title compound (2.1 g, 90%).

¹³C NMR (CDCl,): δ 168.2, 168.2, 165.6, 134.0, 133.9, 133.0, 132.8, 131.9, 131.8, 130.2, 129.7, 129.6, 129.5, 128.9, 128.3, 128.2, 128.1, 125.2, 123.3, 123.3, 94.3, 92.4, 69.4, 68.8, 66.8, 65.6, 42.0, 41.8, 38.4, 35.6, 35.1, 34.2.

b) l-(3-0-Benzoyl-6-phthalimido-2,4,6-trideoxy-D-threo-hexopyranosyl) indoline

The product from step a) (2.7 g, 7.0 mmol) and indoline (1.58 mL, 14.0 mmol) was stirred in toluene-ethanol (60 mL, 5:1) for 2 h at room temperature. The mixture was concentrated under reduced pressure to give the crude sub-title compound, which was used immediately.

c) l-(3-0-Benzoyl-6-phthalimido-2,4,6-trideoxy-β-D-threo-hexopyranosyl) indole

The product from step b) (7.0 mmol) and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (3.2 g, 14.0 mmol) was stirred at room temperature for 1 h, filtered through celite™ and concentrated under reduced pressure. Column chromatography (toluene-ethyl acetate, 40:1) and crystallisation from ethyl acetate-ethanol (10:1) gave the sub-title compound, (2.1 g, 65%).

Η NMR (CDCI₃): δ 8.15 to 6.57 (14 H), 5.65 (1 H, dd, J 11.0 and 2.0 Hz); 5.45 to 5.34 (1 H, m); 4.31 to 4.21 (1 H, m); 4.04 (1 H, dd, J 13.7 and 7.1 Hz); 3.84 (1 H, dd, J 13.7 and 6.3 Hz); 2.61 to 2.53 (1 H, m); 2.37 to 2.25 (2 H, m); 1.79 to 1.67 (1 H, m).

d) 3-ri-⁽3-0-Benzoyl-6-phthalimido-2,4.6-trideoxy-β-D-threo-hexopyranosyD-3- indolyn-4-d-methyl-3-indolyl)-furan-2,5-dione The product from step c) (100 mg, 0.21 mmol) and oxalyl chloride (183 μL, 2.1 mmol) were stirred in dichloromethane (2 mL) at 0° C for 45 min. The mixture was concentrated under reduced pressure and the residue redissolved in dichloromethane (2 mL). It was added to a solution of l-methyl-3-indolyl acetic acid (40 mg, 0.21 mmol) and triethylamine (60μL, 0.42 mmol) in dichloromethane (0.8 mL) and stirred for 4h at room temperature. Evaporation in vacuo gave the crude sub-title compound which was used without further characterization.

e) The crude product from step d) (0.21 mmol) was subjected to the general method for imide formation and the mixture was concentrated under reduced pressure. Column chromatography (toluene-ethyl acetate, 4:1) gave title product (24 mg, 16%).

Η NMR (CDC1₃): δ 8.03 to 6.67 (20 H), 5.65 (1 H, dd, J 11.0 and 1.7 Hz); 5.36 to 5.30 (1 H, m); 4.24 to 4.18 (1 H, m); 4.01 (1 H, dd, J 13.9 and 7.3 Hz); 3.82 to 3.78(1 H); 3.81 (3 H, s); 2.51 to 2.46 (1 H, m); 2.30 to 2.26 (1 H, m); 2.16 to 2.09 (1 H, m); 1.71 to 1.63 (1 H, m).

Claims

1. A compound of formula (I)

wherein

X is hydrogen or methyl;

R is a group of formula (II)

wherein

n is 0 or 1; R₂ is hydrogen,

R₄ is hydrogen, hydroxy, azide, amino,

or N,N-di((C₁-

C₅)alkyl)amino,

or R₂ and R₄ may together form a bond,

when n is 1 R₆ may be hydrogen, hydroxy, azide, amino or N,N-di((C C₅)alkyl)amino, and

R₇ is hydrogen, hydroxymethyl, (C^C_gJalkoxymethyl, azidomethyl,

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

pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein R₄ is hydrogen, hydroxy, azide, amino or N,N-di((C₁-C₃)alkyl)amino,

or R₂ and R₄ may together form a bond,

when n is 1 R₆ may be hydrogen, hydroxy, azide, amino or N,N-di((C.-C₃)alkyl)amino, and

R→ is hydrogen, hydroxymethyl, (C₁-C₃)alkoxymethyl, azidomethyl, aminomethyl, N,N-

di((C_:-C₃)alkyl)aminomethyl.

3. A compound according to claim 2, wherein R₄ is hydroxy, azide, amino or N,N- diethylamino,

when n is 1 R₆ may be hydrogen, hydroxy, azide, amino or N,N-diethylamino, and

4. The compounds:

3-{l-(6- Amino -2,4,6-trideoxy-β-D-threo-hexopyranosyl)-indol-3-yl}-4-(l-methyl-3- indolyl)-pyrrole-2,5-dione,

3-[l-(3-Ammo-2,3-dideoxy-β-D-threo-pentofuranosyl)-3-indolyl]-4-(l-methyl-3-indolyl)- pyrrole-2,5-dione ,

3-[l-(3-Ammo-2,3-dideoxy-α-D-threo-pento_furanosyl)-3-indolyl]-4-(l-methyl-3-indolyl)- pyrrole-2,5-dione,

3-[l-(3-Amino-2,3-dideoxy-α-D-erythro-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione , 3-[l-(3-Amino-2,3-dideoxy-β-D-erythro-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione ,

3-[l-(3-Amino-2,3-dideoxy-5-0-methyl-α-D-threo-pentofuranosyl)-3-indolyl]-4-(l- methyl-3-indolyl)pyrrole-2,5-dione, 3-[l-(5-Amino-2,5-dideoxy-α-D-threo-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione,

3-[l-(5-Amino-2,5-dideoxy-β-D-threo-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione , 3-[l-(5-Am o-2,5-dideoxy-β-D-e_rythro-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)pyrrole-2,5-dione,

and pharmaceutically acceptable salts thereof.

5. The compound:

3-[l-(6-Amino-2,4,6-trideoxy-α-D-threo-hexopyranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)-pyrrole-2,5-dione

and pharmaceutically acceptable salts thereof.

6. The acetic acid salt of a compound according to any one of claims 1 to 5.

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

a) production of a compound of formula (I) in which one or both of R₄ and R, is hydroxyl, and /or R→ is hydroxymethyl, by deprotecting a corresponding

compound of formula (I) in which one or both of R₄ and R₆ is a protected hydroxyl group, and /or R₇ is a methylene carrying a protected hydroxyl group, or

b) production of a compound of formula (I) in which one or both of R₄ and R₆ is

amino, and /or R. is aminomethyl, by reduction of a corresponding compound of

formula (I) in which one or both of R₄ and R₆ is azide, and /or R₇ is azidomethyl, or c) production of a compound of formula (I) in which one or both of R₄ and R₆ is amino, and /or R₇ is aminomethyl, by deprotecting a compound of formula (I) in which one or both of R₄ and R₆ is a protected amino group, and /or R→, is a methylene carrying a protected amino group, or

d) production of a compound of formula (I) in which one or both of R₄ and R₆ is amino, and /or R→ is aminomethyl, by reaction of an appropriate amine with a

corresponding compound of formula (I) in which one or both of R₄ and R₆ is a good leaving group, and /or R₇ is a methylene group carrying a good leaving group, or

e) production of a compound of formula (I), by reaction of a compound of formula

(HI)

in which R and X are defined as in formula (I), but

in which one or both of R₄ and R₆ is a protected hydroxyl group or a protected

amino group, and/or R₇ is a methylene carrying a protected hydroxyl group or a methylene carrying a protected amino group, with an appropriate source of ammonia followed by treatment with an appropriate deprotecting agent; or

f) converting

8. A compound according to any one of claims 1 to 5, for use in therapy.

9. A compound according to claim 8, for use in the treatment of inflammatory or immunlogical disorders.

10. Use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment of inflammatory or immunlogical disorders.

11. 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 5 is administered to a mammal in the need of such treatment.

12. A pharmaceutical composition wherein the active ingredient is a compound according to any one of claims 1 to 5.

13. A compound of formula (I A)

wherein

X is hydrogen or methyl;

R is a group of formula (II)

wherein

n is 0 or 1;

R, is hydrogen, R₄ is a protected hydroxyl group, a protected amino group or a good leaving group,

or R₂ and R₄ may together form a bond,

when n is 1 R₆ may be a protected hydroxyl group, a protected amino group or a good leaving group, and /or

R₇ is a methylene carrying a protected hydroxyl group, methylene carrying a protected amino group or a methylene carrying good leaving group; or

a compound of formula (III).

in which R and X are defined as in formula (I A), but

amino group, and /or R₇ is a methylene carrying a protected hydroxyl group or a methylene carrying a protected amino group; or

a compound of formula (IV A)

wherein Hal is an halogen atom, and R is as defined in formula (III); or

a compound of formula (VIA)

wherein R is as defined in formula (III); or

a compound of formula (VIIIA)

(VIIIA)

wherein Y_a is methoxy, R_4a is benzoyloxy, R_6a is hydrogen and R_9a is 4-methylphenylsulphonoxy, azide or N-phthalimide; or

Y_a is hydroxy, R_4a is azide, R_6a is hydrogen and R_9a is benzoyloxy.