WO1998011105A1 - Nouveaux composes pharmaceutiquement actifs - Google Patents

Nouveaux composes pharmaceutiquement actifs Download PDF

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Publication number
WO1998011105A1
WO1998011105A1 PCT/SE1997/001505 SE9701505W WO9811105A1 WO 1998011105 A1 WO1998011105 A1 WO 1998011105A1 SE 9701505 W SE9701505 W SE 9701505W WO 9811105 A1 WO9811105 A1 WO 9811105A1
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Prior art keywords
indolyl
formula
amino
compound
methyl
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PCT/SE1997/001505
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English (en)
Inventor
Håkan BERGSTRAND
Kostas Karabelas
Matti Lepistö
Margareta Linden
Ghazi Noori
Kristina Stenvall
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Astra Aktiebolag
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Priority to AU41432/97A priority Critical patent/AU4143297A/en
Publication of WO1998011105A1 publication Critical patent/WO1998011105A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom

Definitions

  • the present invention relates to novel bisindolylmaleimides, methods for their preparation, intermediates therefor and pharmaceutical compositions comprising them.
  • PLC Protein kinase C
  • 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.
  • 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).
  • airway diseases involving inflammatory conditions
  • bronchitis and atopic diseases e.g. rhinitis and atopic dermatitis
  • psoriasis e.g. rhinitis and atopic dermatitis
  • psoriasis e.g. Crohn's disease and colitis
  • rheumatoid arthritis and malignant diseases e.g
  • Still another object of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention, as active ingredient, together with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • X is hydrogen or methyl
  • R is a group of formula (II)
  • n 0 or 1
  • R 2 is hydrogen
  • R 4 is hydrogen, hydroxy, azide, amino, N-((C 1 -C 5 )alkyl)amino or N,N-di((C 1 - C 5 )alkyl)amino,
  • R 2 and R 4 may together form a bond
  • R 6 may be hydrogen, hydroxy, azide, amino or N,N-di((C 1 -C 5 )alkyl)amino, and
  • R 7 is hydrogen, hydroxy methyl, (C 1 -C 5 )alkoxy methyl, azidomethyl,
  • R 7 is hydroxymethyl, by deprotecting a corresponding compound of formula (I) in which one or both of R 4 and R 6 is a protected hydroxyl group, and /or R 7 is a methylene carrying a protected hydroxyl group, or
  • R 4 and R 6 is a protected hydroxyl group or a protected amino group
  • R 7 is a methylene carrying a protected hydroxyl group or a methylene carrying a protected amino group
  • the protecting group may be an acyl group such as acetyl or benzoyl
  • 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.
  • 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;
  • sulphide in a suitable solvent, e.g. hydrogen sulphide (gas) in a mixture of pyridine and water;
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compounds of formula (III) may be prepared by reacting a compound of formula (IV)
  • Hal is a halogen atom, preferably chlorine, and R ⁇ is R or X, both as defined in formula (III), with
  • 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)
  • R ⁇ is as defined in formula (IV), with
  • a compound of formula (VI) in which R ⁇ is R, may be prepared by reacting a compound of the general formula (VII)
  • oxidant e.g. 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) in a suitable solvent, e.g. toluene.
  • DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone
  • a compound of formula (VH) may be prepared by reacting a compound of formula (VIII),
  • R and X are as defined in formula (El), and Z is NCH ⁇ OCH j H j ,
  • VELA a compound of formula (VELA), which is as defined in formula (VIII), but wherein Y is hydroxyl, acetoxy or methoxy, with
  • 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.
  • a Lewis acid e.g. boron trifluoride etherate or t-butyldimethylsilalyl trifluoromethanesulphonate
  • 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.
  • Hal is an halogen atom, preferably chlorine, and R is as defined in formula (III).
  • R is as defined in formula (III).
  • 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.
  • 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
  • R 9a is azide
  • 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.
  • 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;
  • 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).
  • the compounds may be administered at a dosage from about 10 ⁇ g to 10 mg per day either as a single dose or in divided doses 2 to 4 times per day.
  • unit doses comprise from 2.5 ⁇ g 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.
  • 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.
  • the compound is desireably finely divided.
  • the finely divided compound preferably has a mass median diameter of less than 10 ⁇ m, 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • R 4 is hydrogen, hydroxy, azide, amino or N,N-di((C 1 -C 3 )alkyl)amino,
  • R 2 and R 4 may together form a bond
  • R 6 may be hydrogen, hydroxy, azide, amino or N,N-di((C C 3 )alkyl)amino, and
  • R 7 is hydrogen, hydroxymethyl, (C 1 -C 3 )alkoxymethyl, azidomethyl, aminomethyl, N,N- di((C 1 -C 3 )alkyl)aminomethyl.
  • Particularly preferred compounds of the formula (I) are those, wherein
  • R 4 is hydroxy, azide, amino or N,N-diethylamino, when n is 1 R 6 may be hydrogen, hydroxy, azide, amino or N,N-diethylamino, and
  • R 7 is hydroxymethyl, methoxymethyl, azidomethyl, aminomethyl, (N,N- diethylamino)methyl.
  • the most preferred compounds according to the present invention include:
  • the most preferred compound according to the present invention is :
  • 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 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.
  • 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).
  • acetonitrile dried over 3 A molcular sieves
  • dichloromethane dried over 4A molcular sieves
  • 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 .
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 3-Indolyl-4-(l-methyl-3-indolyl)-furan-2,5-dione was dissolved in a mixture of acetonitrile and dichloromethane (18:8, 26 mL) and cooled to -45°.
  • Tert- Butyldimethylsilyl trifluoromethanesulfonate (540 ⁇ L, 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).
  • step d) The product from step d) (87 mg, 185 ⁇ mol) was dissolved in 0.03 M acetic acid in water (30 mL) and lyophilised to afford the amorphous title compound (95 mg, 97 %).
  • step d) 3-fl-( ' 6-Azido-3-0-benzoyl-2,4,6-trideoxy- ⁇ -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 ⁇ mol) 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%).
  • step f) The product from step e) (33.0 mg, 54.9 ⁇ mol) 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.
  • Example 3 3-[l-(3-Azido-2,3-dideoxy- ⁇ -D-threo-pentofuranosyl)-3-indolyl]-4-(l-methyl-3- indolyl)-pyrroIe-2,5-dione,
  • p-Toluenesulfonic anhydride (6.9 g, 20.6 mmol) was added to a solution of methyl-2- deoxy-5-O- (4-phenylbenzoyl) - ⁇ -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).
  • step e 3-ri- ( 3-Azido-2.3-dideoxy- ⁇ -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.
  • step f) 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%).
  • step j) The product from step j) (92 mg, 43.8 ⁇ mol) was dissolved in aqueous 0.02 M acetic acid (25 mL) and lyophilised to give the title product 3 B) (98 mg, 94%). l H-N.m.r.
  • step i) The product from step i) (100 mg, 219 ⁇ mol) was dissolved in aqueous 0.03 M acetic acid (30 mL) and lyophilised to afford the title compound 3 C) (108 mg, 96%).
  • Example 4 The compounds in Example 4 were prepared in analogy with the compounds described in Examples 1, 2 and 3 above.
  • Methyl 3-0-benzoyl-6-phthalimido-2,4,6-trideoxy- ⁇ -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%).
  • step a) 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.
  • step b) 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 celiteTM 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%).
  • step c) 3-ri- ( 3-0-Benzoyl-6-phthalimido-2,4.6-trideoxy- ⁇ -D-threo-hexopyranosyD-3- indolyn-4-d-methyl-3-indolyl)-furan-2,5-dione
  • oxalyl chloride 183 ⁇ L, 2.1 mmol
  • step d) 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%).

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Abstract

Nouveaux composés de formule (I), et leurs sels pharmaceutiquement acceptables. Dans ladite formule, X est hydrogène ou méthyle, R est un groupe de formule (II). Dans ladite formule, X, R, R2, R4, R6, R7 et n sont tels que décrits. On décrit l'utilisation de ces composés en thérapie médicale.
PCT/SE1997/001505 1996-09-10 1997-09-08 Nouveaux composes pharmaceutiquement actifs WO1998011105A1 (fr)

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AU41432/97A AU4143297A (en) 1996-09-10 1997-09-08 New pharmaceutically active compounds

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SE9603284-2 1996-09-10
SE9603284A SE9603284D0 (sv) 1996-09-10 1996-09-10 New compounds

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005042002A2 (fr) * 2003-10-30 2005-05-12 Entelos, Inc. Traitement de la polyarthrite rhumatoide a l'aide d'antagonistes de la proteine flip
WO2005097108A1 (fr) * 2004-04-08 2005-10-20 Novartis Ag Inhibiteurs de proteine kinase c destines au traitement de maladies auto-immunes et de rejets de transplantation
CN108264503A (zh) * 2018-02-13 2018-07-10 东华大学 一种3-吲哚马来酰亚胺化合物的制备方法

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EP0328026A1 (fr) * 1988-02-10 1989-08-16 F. Hoffmann-La Roche Ag Pyrroles substitués
WO1991013071A1 (fr) * 1990-02-26 1991-09-05 Boehringer Mannheim Gmbh Nouveaux pyrroles trisubstitues, leur procede de fabrication, et medicaments renfermant ces composes
WO1995017182A1 (fr) * 1993-12-23 1995-06-29 Eli Lilly And Company Inhibiteurs de la proteine-kinase c

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Publication number Priority date Publication date Assignee Title
EP0328026A1 (fr) * 1988-02-10 1989-08-16 F. Hoffmann-La Roche Ag Pyrroles substitués
WO1991013071A1 (fr) * 1990-02-26 1991-09-05 Boehringer Mannheim Gmbh Nouveaux pyrroles trisubstitues, leur procede de fabrication, et medicaments renfermant ces composes
WO1995017182A1 (fr) * 1993-12-23 1995-06-29 Eli Lilly And Company Inhibiteurs de la proteine-kinase c

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Title
C. R. ACAD. SC., PARIS, Volume 283, Sept. 1976, M. TAM HUYNH DINH et al., "CHIMIE ORGANIQUE. - Glycosylation Directe du Noyau Indolique par un Desoxy-2 Ribose", pages 227-228. *
JOURNAL OF HETEROCYCLIC CHEMISTRY, Volume 25, 1988, NABIH S. GIRGIS et al., "Synthesis of 2'-Deoxyribofuranosyl Indole Nucleosides Related to the Antibiotics SF-2140 and Neosidomycin", pages 361-366. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005042002A2 (fr) * 2003-10-30 2005-05-12 Entelos, Inc. Traitement de la polyarthrite rhumatoide a l'aide d'antagonistes de la proteine flip
WO2005042002A3 (fr) * 2003-10-30 2008-01-10 Entelos Inc Traitement de la polyarthrite rhumatoide a l'aide d'antagonistes de la proteine flip
WO2005097108A1 (fr) * 2004-04-08 2005-10-20 Novartis Ag Inhibiteurs de proteine kinase c destines au traitement de maladies auto-immunes et de rejets de transplantation
AU2005230399B2 (en) * 2004-04-08 2009-07-09 Novartis Ag Protein kinase C inhibitors for the treatment of autoimmune diseases and of transplant rejection
CN108264503A (zh) * 2018-02-13 2018-07-10 东华大学 一种3-吲哚马来酰亚胺化合物的制备方法

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AU4143297A (en) 1998-04-02

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