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WO1997033591A1 - Procede de traitement d'affections associees aux cytokines chez les mammiferes - Google Patents

Procede de traitement d'affections associees aux cytokines chez les mammiferes Download PDF

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Publication number
WO1997033591A1
WO1997033591A1 PCT/DK1997/000108 DK9700108W WO9733591A1 WO 1997033591 A1 WO1997033591 A1 WO 1997033591A1 DK 9700108 W DK9700108 W DK 9700108W WO 9733591 A1 WO9733591 A1 WO 9733591A1
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Prior art keywords
alkyl
phenyl
adenosine
mmol
deoxy
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PCT/DK1997/000108
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English (en)
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Lars Knutsen
Uffe Bang Olsen
Andrew Neil Bowler
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Novo Nordisk A/S
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Priority to AU20225/97A priority Critical patent/AU2022597A/en
Publication of WO1997033591A1 publication Critical patent/WO1997033591A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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
    • C07H19/16—Purine radicals

Definitions

  • the present invention relates to a method of treating disorders related to cytokines in humans, including autoimmune disorders, iriflammation, arthritis, type I or type LI diabetes, multiple schlerosis, stroke, osteoporosis, septic shock and menstrual complications.
  • the invention furthermore relates to the use of known and new purine derivatives for the manufacture of a pharmaceutical composition for treating the above diseases as well as new purine derivatives having affinity for subtypes of adenosine receptors and acting as cytokine inhibitors.
  • Adenosine receptors represent a subclass (Pi) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. This subclass has been further classified into distinct receptor types which are now known as Ai, A ⁇ , A 2b and A 3 .
  • Adenosine A 3 receptors Pharmacological Properties, Species Differences and Receptor Functions. ⁇ PS 1994, 15, 298-306; Jacobson, K.A.; Kim, H.A.; Siddiqi, S.M.; Olah, M.E., Stiles, G.L.; von Lubitz, D..K.J.E.; A3 Adenosine Receptors: Design of Selective Ligands and Therapeutic Propects. Drugs of the Future 1995, 20, 689-699; Collis, M.G.; Hourani, S.M.O.; Adenosine Receptor Subtypes, ⁇ PS 1993, 360-366].
  • cytokine production Cerri, M.A.; Beltran-Nunez, A.; Bernasconi, S.; Dejana, E.; Bassi, L.; Bazzoni, G. Inhibition of Cytokine Production and Endothelial Expression of Adhesion Antigens by 5'- Methylthioadenosine. Eur. J. Pharmacol. 1993, 232, 291-294).
  • adenosine agonists R-PIA, NEC A, CPCA, CGS 21680, 2-chloroadenosine and CHA have all been shown to have an inhibitory effect on Tumour Necrosis Factor (TNF) production (Le Vraux, V.; Chen, Y.L.; Masson, M.; De Sousa, M.; Giroud, J P.; Florentin, I.; Chauvelot-Moachon, L. Inhibition of Human Monocyte TNF production by Adenosine Receptor Agonists. Life Sci.
  • TNF Tumour Necrosis Factor
  • Circulatory Shock 1995, 44, 97-103 as has their therapeutic potential (Giroud, J.P.; Lian Chen, Y.; Le Vraux, V.; Chauvelot- Moachon, L. Therapeutic Aspects of Adenosine in Relation to its anti-TNF properties. Bull. Acad Natl. Med (Paris) 1995, 179, 79 -101).
  • TNF- ⁇ inhibitors are useful in the treatment of diabetes (Argiles, J.M., Lopez-Soriano, J. and Lopez-Soriano, F.J. Cytokines and Diabetes: The Final Step. Involvement of TNF- ⁇ in both Type I and Type U Diabetes Mellitus. Horm. Metab. Res., 1994, 26, 447 - 449).
  • TNF- ⁇ levels are increased in obese rodents (Yamakawa, T., Tanaka, S-L, Yamakawa, Y., Kiuchi, Y., Isoda, F., Kawamoto, S, Okuda, K. and Sekihara, H. Augmented Production of Tumor Necrosis Factor- ⁇ Production in Obese Mice. Clin. Immunol, and Immunopath., 1995, 75, 51-56).
  • a clinical study of the expression pattern of TNF- ⁇ in adipose tissue of obese and normal premenopausal women has been carried out (Hotamisligil, G.S., Amer, P. Caro, J.F., Atkinson, R.L.
  • adenosine and adenosine agonists acting via A receptors can be of benefit in for example septic shock or ischaemia-reperfusion injury, where cytokine production by mononuclear phagocytes can be inhibited by these agents (Bouma, M.G., Stad, R.K., van den
  • TNF- ⁇ inhibitors have application in disorders which involve an inflammatory response, but this cytokine has multiple inflammatory, metabolic and immunological activities (Jirillo, E. Pellegrino, N.M. and Antonaci, S. Role of Tumor Necrosis Factor- ⁇ in Physiological and Pathological Conditions. Med Sci. Res., 1995, 23, 75-79).
  • TNF- ⁇ inhibitors such as rolipram, pentoxyfylline and denbufylline are phosphodiesterase (PDE) inhibitors and exert their effects on TNF- ⁇ via control of cAMP (Davidsen, S.K. and Summers, J.B. Inhibitors of TNF- ⁇ Synthesis. Exp. Opin. Ther. Patents 1995, 5, 1087 - 1100).
  • PDE phosphodiesterase
  • Evidence is also available for some synergism between the effects of rolipram and adenosine in reduction of T primed neutrophil oxidative activity, thereby offering protection against inflammatory tissue damage (Sullivan, G, Ca ⁇ er, H.T. and Mandell, GL. Int. J. Immunopharmac. 1995, 17, 793-803).
  • TNF inhibitors in the prevention of neuronal damage following cerebral ischaemia (Firestein, G.Z., Liu, T and Barone, F.C. Cytokines, Inflammation, and Brain Injury: Role of Tumor Necrosis Factor- ⁇ . Cerebrovascular and Brain Metabolism Reviews 1994, 6, 341-360).
  • Examples with hydrogen at the purine 2-position include N-aminoadenosine, N-[(N-methyl-N- phenyl)amino]adenosine, N-hydroxyadenosine, JV-methoxyadenosine and N-benzyloxyadenosine (Kusachi, S., Thompson, R.D. Bugni, W.J., Yamada, N. and Olsson, R.A. Dog Coronary Artery Adenosine Receptor: Structure of the ⁇ -Alkyl Subregion. J.
  • N-ethoxyadenosine (Fuj ⁇ , T., Wu, C.C, Itaya, T., Moro, S. and Saito, T. Purines.
  • XI The Synthesis of N-Alkoxyadenosines and Their 2',3'-O-Isopropylidene Derivatives Chem Pharm.
  • Examples of adenosine derivatives with oxygen or nitrogen atoms bonded to the 6-am ⁇ no substituent, containing an additional purine 2-subst ⁇ tuent are 2-amino-N-hydroxyadenosine (Kikugawa, K , Iizuka, K , Higuchi, Y , Hirayama, H and Ichino, M Platelet Aggregation Inhibitors 2 Inhibition of Platelet Aggregation by 5'-,2-,6-, and 8-substituted Adenosines J.
  • Pfizer Inc. claim a range of heterocycles, including some purine derivatives, as CRF antagonists.
  • ribose moiety in adenosine is chemically modified, and many of those known have poor affinity for the adenosine receptor (Taylor, M.D., Moos, W.H., Hamilton, H.W. Szotek, D.S. PAtt, W.C. Badger, E.W. Bristol, J.W. Bruns, R.F. Heffher, T.G. Mertz, T.E. Ribose-Modified Adenosine Analogues as Adenosine Receptor Agonists. J. Med Chem., 1986, 29, 346-353).
  • adenosine A 3 receptor agonists are 5'-modified adenosine derivatives (Jacobson, K.A.; Kim, HA; Siddiqi, S.M.; Olah, M.E.; Stiles, G.L.; von Lubitz, D..K.J.E.; A 3 Adenosine Receptors: Design of Selective Ligands and Therapeutic Propects. Drugs of the Future 1995, 20, 689-699; Baraldi, P.G., Cacciari, B., Spalluto, G. Ji, X-d, Olah, M.E.
  • EP-A-181,128 and EP-A-181,129 disclose 5 -deoxy adenosine derivatives containing 5'- hydrogen, 5'-halogen and 5 -methylthio, which are claimed to have desirable anti-inflammatory, analgesic as well as CNS and antihypertensive properties respectively.
  • EP-A-232,813 discloses N-substituted adenosines including a larger range of 5'-modified compounds.
  • WO 88/03147 5'-substituted adenosine derivatives with selectivity for the adenosine A 2 receptor are disclosed.
  • EP Publication No. 0 423 777 A2 a method for treating gastrointestinal motility disorders using N(6) (substituted aminoalkyl) adenosine derivatives is disclosed.
  • EP Publication No. 0 490 818 Al describes a new use of 2'-O-methyl adenosine derivatives for a range of ailments including neurodegenerative disorders.
  • the compounds of WO 93/23417 and WO 95/07921 and some closely related compounds have been found to be cytokine inhibitors, for example inhibitors of TNF- ⁇ , and are found to be useful in the treatment of disorders related to cytokines in mammals, including humans. These conditions include inflammation, arthritis, type I and type LI diabetes, autoimmune disorders, multiple schlerosis, stroke, osteoporosis, septic shock and menstrual complications.
  • the present invention relates to a new use of adenosine analogues containing both ribose and modified ribose moieties, some of which are disclosed in WO 93/23417 and WO 95/07921, which show potent binding to adenosine receptors.
  • the present invention relates to a method of treating disorders related to cytokines in mammals comprising administering to a mammal in need thereof an effective amount of a compound of the general formula (I), or a pharmaceutically acceptable salt thereof:
  • X represents hydrogen, halogen, a ino, perhalomethyl, cyano, C w -alkyl, C ⁇ -alkoxy, -s- alkylthio, Ci-6-alkylarn.no or phenyl;
  • A is hydroxymethyl, methyl, chloromethyl, bromomethyl, fluoromethyl, cyanomethyl, aminomethyl, vinyl, methylthiomethyl or methoxymethyl;
  • Ri is selected from the groups consisting of
  • n is 1 to 3 and where the group (a) may be optionally substituted with one or two Ci-s-alkyl groups, C M -alkenyl, C ⁇ -alkynyl, phenoxy, phenylsulphonyl, phenylthio, hydroxy, phenyl, d- ⁇ -alkoxy or C ⁇ -alkoxy- Ci- ⁇ -alkyl, phenylthioalkyl or
  • Y is O, S or NZ, where Z is H, C ⁇ -6-alkyl or phenyl, and where the group (b) may be optionally substituted with C -6-alkenyl, C 2- 6-alkynyl, phenoxy, phenyl, or
  • R s -NR ⁇ or-YR 4 wherein Y is oxygen; R 2 is C ⁇ -alkyl;
  • R 3 is phenyl or which may be substituted by phenyl or phenoxy;
  • R 4 is straight-chain C ⁇ -6-alkyl, branched C3-8-alkyl, C 2 .g-alkenyl or C3.8-cycloalkyl, which may be substituted by phenyl or phenoxy which in turn may be substituted with nitro, halogen or amine.
  • a preferred method of treating disorders involving cytokines comprises administering to a subject in need thereof a compound of the above general formula (I) wherein R 1 is -OR 4 , wherein R 4 is straight-chain branched C 3 .8-a.kyl, C 2 . 8 -alkenyl or C3-g-cycloalkyl, which may be substi ⁇ tuted by phenyl or phenoxy which in turn may be substituted with nitro, halogen or amine.
  • the present invention is furthermore concerned with new compounds of the above formula (I) or pharmaceutically acceptable salts thereof, wherein
  • X represents phenyl
  • A is hydroxymethyl, methyl, chloromethyl, bromomethyl, fluoromethyl, cyanomethyl, aminomethyl, vinyl, methylthiomethyl or methoxymethyl; i is selected from the groups consisting of
  • n is 1 to 3 and where the group (a) may be optionally substituted with one or two Ci-s-alkyl groups, C 2- 6-alkenyl, C 2 ⁇ -alkynyl, phenoxy, phenylsulphonyl, phenylthio, hydroxy, phenyl, C ⁇ -alkoxy or Ci-e-alkoxy-C -alkyl, phenylthioalkyl or
  • Y is O, S or NZ, where Z is H, or phenyl, and where the group (b) may be optionally substituted with Ci- ⁇ -alkyl, C w -alkenyl, C 2 -5-alkynyl, phenoxy, phenyl, C ⁇ -alkoxy or
  • R' is -NR 2 R 3 or -YR 4 , wherein Y is oxygen; R 2 is Cw-alkyl;
  • R 3 is phenyl or C w -alkyl which may be substituted by phenyl or phenoxy;
  • R 4 is straight-chain Ci- ⁇ -alkyi, branched C 3 -8-alkyl, C 2 .8-alkenyl or C3-8-cycloalkyl, which may be substituted by phenyl or phenoxy which in rum may be substituted with nitro, halogen or amine.
  • the present invention is furthermore concerned with new compounds of the above formula (I) or pharmaceutically acceptable salts thereof, wherein
  • X represents hydrogen, halogen, arnino, perhalomethyl, cyano, Cns-alkyl, C 1 - 5 - alkylthio, or phenyl;
  • A is hydroxymethyl, methyl, chloromethyl, bromomethyl, fluoromethyl, cyanomethyl, aminomethyl, vinyl, methylthiomethyl or methoxymethyl;
  • Ri is selected from the groups consisting of
  • n is 1 to 3 and where the group (a) may be optionally substituted with one or two Ci- ⁇ -alkyl groups, C -6-alkenyl, C 2-6 -alkynyl, phenoxy, phenylsulphonyl, phenylthio, hydroxy, phenyl, C ⁇ -alkoxy or Ci- ⁇ -alkoxy- C e -alkyl, phenylthioalkyl or
  • Y is O, S or NZ, where Z is H, or phenyl, and where the group (b) may be optionally substituted with or Ci- ⁇ -alkoxy-Ci- ⁇ -alkyl, or R 1 is -NR 2 R 3 or -YR 4 , wherein Y is oxygen;
  • R 2 is C ⁇ -6-alkyl
  • R 3 is phenyl or C ⁇ -6-alkyl which may be substituted by phenyl or phenoxy;
  • R 4 is branched C 3 .g-alkyl or C 2 .8-alkenyl, which may be substituted by phenyl or phenoxy which in turn may be substituted with nitro, halogen or amine.
  • salts of compounds of formula (I) can be prepared which can be considered physiologically acceptable. These include addition salts derived from inorganic or organic acids, for example, acetates, fumarates, glutarates, glutaconates, lactates, maleates, methanesulphonates, phosphates, salicylates, succinates, sulphates, sulphamates, tartrates and paratoluenesulphonates. In some cases, solvates of either the free nucleosides or the acid addition salts can be isolated and these solvates may, for example, be hydrates or alcoholates.
  • the compounds of formula (I) have affinity for subtypes of adenosine receptors, modulate cyclic AMP and act as cytokine inhibitors. Moreover, these compounds are found to be useful as drugs in the treatment of disorders where damaging effects of cytokines are observed in humans.
  • the compounds according to the invention possess desirable pharmacological properties which can be ascribed to cytokine modulation. For example they inhibit TNF- ⁇ synthesis, as indicated by lowering of plasma TNF- ⁇ following lipopolysaccharide (LPS) challenge in rats.
  • LPS lipopolysaccharide
  • HEK 293 cells were cultured in Dulbecco's modified Eagles media supplemented with 10% fetal bovine serum, 2 MM glutamine, 0 1 mg/mL streptomycin, 0 1 mg/mL penicillin and 0 8 mg/mL G418 in an incubator at 37°C (95% air, 5% CO 2 )
  • HEK 293 cells were seeded in 24-well plates two days before the experiment so that they were 70-80% confluent on the day of the assay Cells were washed twice with 1 mL of assay buffer (the composition was 1 18 mM NaCl, 25 MM NaHCO 3 , 4 7 mM KCI, 1 2 mM KH 2 PO 4 , 1 2 mM CaCl 2 , 3 8 itiM MgCl 2 , 1 2 mM MgSO 4 , 1 1 mM D-glucose and 10 mM HEPES, pH 7 4) The cells were subsequently incubated for 15 min at
  • Test compounds or buffer were added to the cells before [ 125 I]-AB- MECA and incubated for 45 min. at 37°C in a final volume of 500mL.
  • the cells were washed quickly with 2 x 2 mL ice-cold assay buffer, solubilised with 1 mL of NaOH (2 M) and transferred to g-counting vials with 0.5 mL water.
  • Test compounds are dissolved in DMSO, ethanol or water and further diluted in assay buffer. The final concentrations of solvents should be less than 2%. Test solutions should be in the range of pH 6.5 - 7.5. IC50 values were calculated from dose-response curves (3 points minimum) by a non-linear regression analysis using the GraphPad Prism program (GraphPad Software, USA). The results expressed in nM.
  • test compound is dissolved in dimethyl sulphoxide (DMSO) at 8 mg/mL and is diluted with Cremophor in 5% saline (0.9% aqueous NaCl) to 160, 16 and 1.6 ⁇ g/mL. 25 ⁇ L is added to each tube, and 350 mL heparinised (50 iE/mL) rat blood, 25 ⁇ L lipopolysaccharide (LPS) 1.6 mg/mL in saline are introduced, i.e. the concentrations of the test compound is 10, 1 and 0.1 mg uL respectively.
  • the samples are shaken carefully and are placed in a water bath for 5 h. at 37°C.
  • the samples are centrifuged for 10 min. at 3000 ⁇ m at 4°C.
  • the plasma is removed by pipette in plastic tubes and is frozen. TNF- ⁇ levels are determined using a Genzyme ELISA kit.
  • the compounds of the invention together with a conventional adjuvant, carrier or diluent, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets of filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral use (including subcutaneous administration and infusion).
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the adenosine receptor agonist commensurate with the intended daily dosage range to be employed.
  • Tablets containing ten (10) milligrams of active ingredient or, more broadly, ten (10) to hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
  • the compounds of this invention can thus be used for the formulation of pharmaceutical preparation, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
  • excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or enteral application which do not deleteriously react with the active compounds.
  • Such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy- methylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical preparations can be sterilised and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Ampoules are convenient unit dosage forms.
  • a syrup, elixir or the like can be used in cases where a sweetened vehicle can be employed.
  • the compounds of this invention are dispensed in unit form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.
  • the dosage of the compounds according to this invention is 0.1-300 mg/day, preferably 10-100 mg/day, when administered to patients, e.g. humans, as a drug.
  • a typical tablet which may be prepared by conventional tabletting techniques contains:
  • the compounds of the invention are extremely useful in the treatment of related symptoms in mammals, when administered in an amount effective for agonist activity of compounds of the invention.
  • the compounds of the invention may accordingly be administered to a subject, e.g., a living animal body, including a human, in need of adenosine receptor agonist, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof (such as the hydrobromide, hydrochloride, or sulphate), in any event prepared in the usual or conventional manner, e.g., evaporation to dry- ness of the free base in solution together with the acid), ordinarily concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount of adenosine receptor agonist, and in any event an amount which is effective for the treatment diseases related to cytokines, owing to their adenosine receptor agonist activity.
  • a pharmaceutically acceptable acid addition salt thereof such as the hydrobromide, hydrochloride, or sulphate
  • Suitable dosage ranges are 1-200 milligrams daily, 10-100 milligrams daily, and especially 30-70 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
  • TLC thin layer chromatography
  • THF tetrahydrofuran
  • TFA trifluoracetic acid
  • m.p. melting point. Where melting points are given, these are uncorrected.
  • the structures of the compounds are confirmed by assignment of NMR spectra (from which representative peaks are quoted) and by microanalysis where appropriate.
  • Compounds used as starting materials are either known compounds or compounds which can be prepared by methods known per se. Column chromatography was carried out on Merck silica gel 60 (Art 9385).
  • HPLC was carried out on a Waters or Merck chromatograph with a multiwavelength detector and a reversed phase C18 column (250 x 4 mm, 5mm, lOOA; eluent flow rate 1 mL/ min at 35°C). Retention times are given in minutes.
  • Phenylacetaldehyde (24.0 g, 0.20 mol), a 33% solution of methylamine in ethanol (42.35 g, 0.41 mol) and methylamine hydrochloride (10.13 g, 14.8 mmol) were dissolved in methanol (200 mL).
  • Sodium cyanoborohydride (3.77 g, 60 mmol) was introduced and the reaction mixture was stirred at room temperature for 18 h.
  • the reaction mixture was evaporated in vacuo to ca. 50 mL, concentrated hydrochloric acid (40 mL) was added and once the exotherm had subsided the reaction mixture was stirred for 2 h.
  • N-methyl-2-phenylethylamine hydrochloride (6.4 g, 37.3 mmol) was dissolved in water (18 mL), ethanol (11 mL) and 2 N hydrochloric acid ( 4 mL) were introduced and the solution was heated to 70°C.
  • 2,6-dichloro-9H-purine (5.8 g, 30.7 mmol) and 1-O-acetyl-tri-O-benzoyl- ⁇ -D-ribofuranose (16.26 g, 32.2 mmol) were thoroughly mixed (as powdery solids) and fused together at 145-150°C under oil pump vacuum. The resultant oily mixture was stirred gently for 0.75 h (during which time the acetic acid by-product evaporated) and cooled to ca. 50°C before being dissolved in dichloromethane (100 mL) with stirring.
  • This example was prepared by a method similar to that described in Example 1. 9-(2 , ,3 , ,5 , -Tri-O-benzoyl- ⁇ -D-ribofuranosyl)-2,6-dichloro-9H-purine (2.0 g, 3.2 mmol), O-(phenylmethyl)hydroxylamine hydrochloride (0.77 g, 4.8 mmol) and (1.03 g, 8.0 mmol) were dissolved in dioxan (50 mL). The reaction mixture was heated at reflux for 20h, filtered and evaporated in vacuo.
  • the title compound was prepared by reacting O-[(4-nitrophenyl)methyl]hydroxylamine hydro ⁇ chloride (1.43 g, 7 mmol) with 6-chloropurine riboside (i.e. 9- ⁇ -D-ribofi ⁇ ranosyl-6-chloro-9H- purine) (1.0 g, 3.5 mmol) in DMF (40 mL) at 110°C for 2 h with diisopropylethylamine (1.80 g, 14 mmol) present.
  • the reaction mixture was evaporated and to the resultant residue was added saturated sodium bicarbonate solution (20 mL) and water (20 mL). Methanol was gradually added until the residue dissolved, and the solid which gradually precipitated was removed by filtration.
  • N-Hydroxyphthalimide (15.0 g, 92 mmol) and sodium acetate (7.5 g, 92 mmol) were stirred in dimethylsulfoxide (70 mL) at ambient temperature for 3h.
  • 2-Chloroethylbenzene (12.5 g, 89 mmol) was added and the reaction mixture was heated at reflux for 2 h. After cooling and standing overnight the reaction mixture was filtered and the filtrate was poured onto ice/water (300 mL). The mixture was extracted with dichloromethane (4 x 100 mL), the combined extracts were dried (MgSO 4 ) and evaporated in vacuo to a residue.
  • N-(2-Phenylethoxy)phthalimide (11.3 g, 42 mmol) was dissolved in hot 96% ethanol (100 mL). Hydrazine hydrate (2.5 g, 50 mmol) was introduced and the reaction mixture was heated at reflux with mechanical stirring for 1.5h. The reaction mixture was stored at 4°C for 72 h, filtered and the filtrate was evaporated in vacuo. The crude white residue was suspended in toluene and stored at 4°C for 16h and filtered. The filtrate was treated with a solution of chlorotrimethyl- silane (4.34 g) in toluene (200 mL) with methanol (1.05 g) present and the title compound precipitated.
  • Ci8H 2 oClN 5 O 5 . 0.75 H 2 O requires C, 49.7; H, 5.0; N, 16.1. Found C, 49.9; H, 4.9; N, 15.8%.
  • the title compound was prepared according to the method described in Example 6 by reacting O-cyclopentylhydroxylamine (prepared by the overall procedure described in example 5) (0.78 g, 5.67 mmol) with 9-(2',3',5'-tri-O-benzoyl- ⁇ -D-ribofi ⁇ ranosyl)-2,6-dichloro-9H-purine (3.0 g, 4.74 mmol), followed by debenzoylation of the purified product using methanolic ammonia to provide the title 2-chloro-N-cyclopentoxyadenosine (0.11 g) (after column chromatography) as a solid, mp 116-119°C.
  • the title compound was prepared according to the method descnbed in Example 4 by reacting O-methylhydroxylamine (0 20 g, 2 0 mmol) with 9-(2',3',5'-tri-O-benzoyl- ⁇ -D-ribofuranosyI)- -2,6-dichloro-9H-purine (1 27 g, 20 mmol) and debenzoylating the purified product using methanolic ammonia to provide the title 2-chloro-N-methoxyadenosine (040 g, 45%) (after column chromatography) as a colorless foam which became crystalline on t ⁇ turation with dichloromethane, providing 020 g of a white solid, mp 123 - 125°C l H NMR (DMSO-de) d
  • the title compound was prepared according the method described in example 6 by reacting O- ethylhydroxylamine hydrochloride (0305 g, 3 1 mmol) with 9-(2 , ,3 , ,5'-tri-O-acetyl- ⁇ -D-ribo- fi ⁇ ranosyl)-2,6-dichloro-9H-purine (1 79 g, 4 0 mmol), followed by deacylation of the purified product using sodium methoxide in methanol to provide the title 2-chloro-N-ethoxyadenosine (0 161 g, 21%) (after column chromatography) as a foam, l H NMR (DMSO-ds) d 1 25 (3H, t, - CH 2 CH3), 3.52 - 3 58 (Hi m, H-5'.), 3 63 - 3 70 (IH, m, H-5' b ), 3 94 (IH, q, H-4'), 4 00 (2H,
  • the title compound was prepared according to the method descnbed in Example 6 by reacting O-(l-propyl)hydroxylam ⁇ ne hydrochloride with 9-(2 , ,3',5 l -t ⁇ -0-acetyl- ⁇ -D-ribofuranosyl)- -2,6-dichloro-9H-purine, followed by deacylation of the purified product using sodium methoxide in methanol to provide the title 2-chloro-N-(l-propyloxy)adenosine (after column chromatography) as a foam
  • the title compound was prepared according to the method descnbed in Example 6 by reacting isobutoxyamine hydrochloride (0603 g, 4 8 mmol) with 9-(2',3',5'-tri-O-acetyl- ⁇ -D-ribo- furanosyl)-2,6-dichloro-9H-pu ⁇ ne (1 79 g, 4 0 mmol), followed by deacylation of the purified product using sodium methoxide m methanol to provide the title 2-chloro-N-ethoxyadenosine (0 31 g, 42%) (after column chromatography) as a foam, ⁇ NMR (DMSO-d*) d 0 96 (6H, 2t, - CH(CH 3 2 ), 20 (IH, h, -CH.C ⁇ CHa ⁇ ), 3 52 - 3 58 (Hi m, H-5' a ), 3 63 - 3 70 (IH, m, H-5' b ), 3
  • the title compound was prepared according to the method described in Examples 4 and 5 by reacting 0-[l,2,3,4-tetrahydronaphth-l-yl)hydroxylamine (prepared by the procedure described in example 6) (0.35 g, 2.0 mmol) with 9-(2',3',5'-tri-O-benzoyl- ⁇ -D-ribofuranosyl)-2,6-dichloro- -9H-purine (1.0 g, 1.58 mmol) and debenzoylating the purified product using methanolic ammonia to provide the title 2-chloro-iV-(l,2,3,4-tetrahydronaphth-l-yloxy)adenosine (0.10 g, 15%) (after column chromatography) as a colorless foam (a mixture of diastereoisomers), *H NMR (DMS ⁇ -d «) d 1.65 - 2.85 (6H, m, -CH 2 CH 2 CH 2 -),
  • the title compound was prepared by reacting 1 -methyl- l-(2-phenoxyethyl)hydrazine (prepared by the general method described in Example 1) (0.80 g, 4 mmol) and 9-(2,3,5-tri-O-benzoyl- ⁇ - D-ribofuranosyl)-2,6dichloro-9H-purine (2.53 g, 4 mmol) and triethylamine (1.11 mL, 8 mmol) in dioxan (25 mL), followed by debenzoylation of the purified product using methanolic ammonia to provide the title 2-cUoro-N-(N-methyl-/V-(2-phenoxyethyl)amino)adenosine (0.84 g, 47%) (after column chromatography) obtained as a solid, mp 166-8°C, *H NMR (DMSO-d*) d 2.70 (3ti s, -CH 3 ), 3.22 (2H, br t,
  • O-Cyclopentylhydroxylamine hydrochloride (0.52 g, 3.75 mmol) was reacted with 9-(2',3',5'-tri- O-acetyl- ⁇ -D-ribofuranosyl)-6-chloro-2-methyl-9H-purine (1.07 g, 2.5 mmol) [prepared from 2-methylinosine (Journal of Organic Chemistry, 1967, 32, 3258 - 3260) by standard acylation and chlorination steps] in dioxan (40 mL) in the presence of triethylamine (0.63 g, 6.25 mmol).
  • O-Methylhydroxylamine hydrochloride (0.20 g, 2.4 mmol) was reacted with 9-(2',3',5'-tri- O-acetyl- ⁇ -D-ribofuranosyl)-6-chloro-2-methyl-9H-purine (0.85 g, 2.0 mmol) (see Example 20) in dioxan (40 mL) in the presence of triethylamine (0.52 g, 5.0 mmol). The reaction mixture was heated at 90°C in a sealed vessel for 70h, before being filtered and evaporated.
  • This compound was prepared by the method described in Example 24.
  • 2-Chloro-N-(4-phenyl- thio-l-piperidinyl)adenosine [WO 93/08206 (Novo Nordisk A/S)] (0.5 g, 1 mmol) was subjected to the reaction conditions described above, providing the title 5'-deoxy-2,5'-dichloro-N-(3-phenyl- thio-l-piperidinyl)adenosine (mixture of diastereoisomers) as a foam (0.48 g, 94%) following flash chromatography on silica gel.
  • reaction mixture was evaporated to a residue and purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (9:1) to provide 5 , -deoxy-2,5'-dichloro-N-(4-phenylsulfinyl-l-piperidinyl)adenosine (0.1 g, 53%) as a foam.
  • This compound was prepared by the method described in Example 24.
  • 2-Chloro-N-- (dimethylamino)adenosine [WO 93/23417 (Novo Nordisk A/S)] (0.62 g, 1.8 mmol) was subjected to the chlorination conditions described above (Example 24), providing the title 5'- deoxy-2,5'-dicMoro-N-(dimethylamino)adenosine as a solid (0.23 g, 41%) after column chromatography, .p.
  • N-Cyclo- pentoxy-2-chloroadenosine [WO 93/23417 ( ⁇ ovo Nordisk A S)] (1.0 g, 2.6 mmol) was subjected to the chlorination conditions described in Example 24, providing the title N-cyclopentoxy-5'-deoxy-2,5'-dichloroadenosine as a foam (0.82 g, 78%), 1H-NMR (400MHz, DMSO-d «) d 1.49 - 1.92 (8H, 3m, cyclopentyl C-H), 3.86, 3.94 (2H, ABX, H-5' a and H-5' b ), 4.11 (Hi q, H-4'), 4.20 (Hi q, H-3'), 4.59 (Hi m, -OC-H), 4.67 (IH, q, H-2'), 5.51, 5.64 (Hi 2d, 2'-and 3'-OH), 5.90 (IH
  • Methyl 2,3-O-(l-methylethylidene)-5-O-(p-toluenesulfonyl)-D-ribofuranoside (28.7 g, 80 mmol) was dissolved in dry acetonitrile (100 mL). Tetra-w-butylammonium fluoride (100 mL, 1.0M in THF) was added dropwise and the reaction mixture was heated at 80°C for 72 h. After cooling to room temperature, the mixture was diluted with dichloromethane (200 mL), washed with water (3 x 50 mL) and dried (MgSO 4 ).
  • Methyl 5-deoxy-5-fluoro-2,3-O-(l-methylethylidene)-D-ribofuranoside (5.0 g, 24 mmol) was treated with sulfuric acid (0.02M, 40 mL) and heated at reflux for 4 h. The reaction mixture was cooled, neutralized with barium carbonate to pH 7, filtered and evaporated to an oil. The oil was dried by coevaporation with ethanol, and the residue was dissolved in dichloromethane (50 mL). Acetic anhydride (25 mL) and pyridine (25 mL) were introduced, and the reaction mixture was stirred for 16 h before being poured onto ice (100 mL).
  • This compound was prepared by general method A, described in more detail in Example 39 by reacting O-benzylhydroxylamine hydrochloride (0.80 g, 5.0 mmol) with 9-[(2',3'-di-O-acetyl-5'- deoxy-5'-fluoro-D-ribofuranosyl)]-2,6-dichloro-9H-purine (1.0 g, 2.5 mmol) as described above.
  • Methyl 2,3-O-(l-methylethylidene)-D-ribofuranoside (13.3 g, 60 mmol), 2,6-di-t-butyl-4-methyl- pyridine (20.0 g, 100 mmol) and methyl trifluoromethylsulfonate (16.0 g, 100 mmol) were dis ⁇ solved in dry dichloromethane (150 mL) placed in a closed reactor and heated to 80°C. After cooling, the reaction mixture was poured onto ice (150 mL). After standing, the product was extracted into dichloromethane (2 x 100 mL) and the combined extracts were dried (MgS ⁇ ) and evaporated in vacuo.
  • 5-O-Methyl-2,3-O-(l-methylethylidene)-D-ribofuranoside (3.0 g, 14 mmol) was dissolved in a mixture of sulfuric acid (0.02M, 100 mL) and ethanol (50 mL) and heated at 80°C for 6 h and stirred for 20 h at 20°C.
  • the reaction mixture was neutralised with aqueous sodium bicarbonate and concentrated in vacuo.
  • the residual oil was dried and acetylated in a mixture of dichloromethane (100 mL), acetic anhydride (8.5 g, 83 mmol) and triethylamine (16.7 g, 165 mmol) at 20°C for 20 h.
  • reaction mixture was washed with hydrochloric acid (IM, 50 mL) and water (50 mL).
  • IM hydrochloric acid
  • organic phase was dried (MgSO ) and concentrated to an oil before being purified by flash chromatography. Elution with a mixture of cyclohexane and ethyl acetate (6:4) provided l,2,3-tri-O-acetyl-5-O-methyl- ⁇ -D-ribofuranose (2.5g, 62%) as an oil.
  • the crude product was purified by flash chromatography eluting with a mbcture of dichloromethane and 10% ammonia in ethanol (95:5) to give 2-chloro-5'-deoxy-5'-methylthio-2',3'-O-( 1 -methylethylidene)-JV-( 1 -piperidinyl)adenosine (0.12 g, 31%) as a foam.
  • Methyl 2,3-O-(l-methylethylidene)-5-O-(4-nitrobenzenesulfonyl)- ⁇ -D-ribofuranoside (45.3 g, 120 m mol) was added over 1.5 h to a suspension of sodium cyanide (6.8 g, 140 mmol) in dry dimethylformamide (1000 mL). The reaction mixture was heated to 50°C for 3 h before being poured onto ice (500 mL). This mixture was extracted with dichloromethane (3 x 500 mL), the combined extracts were dried (MgSO 4 ) and concentrated in vacuo.
  • Ci ⁇ HzoClN- requires C, 48.8; H, 5.1; N, 24.9. Found C, 48.9; H 5.3; N, 24.6%.
  • Methyl 5-deoxy-2,3-O-(l-methylethylidene)-D-ribofuranoside (prepared by reduction of methyl 2,3-O-(l-methyiethylidene)-5'-O-(p-toluenesulphonyl)-D-ribofuranoside using lithium aluminium hydride) (4.36 g, 23.2 mmol) was dissolved in methanol (120 mL) and Amberlyst resin (FT form, 19 g) was introduced. The mixture was stirred at 80°C for 60 h and filtered. The filter pad was washed with methanol and the filtrate was evaporated to an oily residue.
  • Amberlyst resin FT form
  • Triphenylmethylphosphonium bromide (26.79 g, 75 mmol) was suspended in THF (200 mL) and n-butyllithium (1.7M in hexanes) (42 mL, 71.2 mmol) was introduced.
  • Methyl 5-deoxy-2,3-O-(l-methylethylidene)-5-methylene-D-ribofuranoside (5.65 g, 28.2 mmol) was dissolved in methanol (250 mL) and Amberlyst resin (Ff form, 30 g) was introduced. The mixture was stirred at ambient temperature for 40 h and was filtered. The filter pad was washed with methanol and the filtrate was evaporated to an oily residue.
  • 2,3-Di-O-benzoyl-2-chloro-5'-deoxy-5'-methylene-N-cyclopentyladenosine prepared by reaction of 9-(5'-deoxy-2',3 , -di-O-benzoyl-5'-methylene- ⁇ -D-ribofuranosyl)-2,6-dichloro-9H-purine (see Example 48) with cyclopentylamine) (0.30 g, 0.52 mmol) was dissolved in methanolic ammonia (10 mL) and stirred at ambient temperature for 18 h.

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Abstract

Procédé de traitement d'affections associées aux cytokines telles que le facteur de nécrose des tumeurs α (TNFα) chez les mammifères. Cette affection peut être une affection auto-immune, une inflammation, l'arthrite, le diabète de type I ou II, la sclérose en plaques, une attaque, l'ostéoporose, un choc septique ou des complications menstruelles.
PCT/DK1997/000108 1996-03-13 1997-03-12 Procede de traitement d'affections associees aux cytokines chez les mammiferes WO1997033591A1 (fr)

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WO1999024451A3 (fr) * 1997-11-08 1999-08-19 Glaxo Group Ltd Composes chimiques
WO1999024449A3 (fr) * 1997-11-08 1999-08-19 Glaxo Group Ltd Composes chimiques
WO1999024450A3 (fr) * 1997-11-08 1999-08-19 Glaxo Group Ltd Composes chimiques
US5998388A (en) * 1996-05-14 1999-12-07 Glaxo Wellcome Inc. Adenosine derivatives
WO2002070532A3 (fr) * 2001-03-03 2002-11-28 Univ Leiden Nouveaux derives c2,5'disubstitues et n6',c2,5'-trisubstitues de l'adenosine et leurs differentes utilisations
EP1375508A1 (fr) * 2002-06-27 2004-01-02 Aventis Pharma Deutschland GmbH Dérivés de l'adénosine N6-substitués et leur utilisation comme médicament
WO2004016635A3 (fr) * 2002-08-15 2004-04-08 Cv Therapeutics Inc Agonistes partiels et totaux des recepteurs d'adenosine a1
WO2005033121A3 (fr) * 2003-10-03 2005-07-28 King Pharmaceuticals Res & Dev Synthese de 2-aralkyloxyadenosines, 2-alkoxyadenosines, et leurs analogues
US7265111B2 (en) 2002-06-27 2007-09-04 Sanofi-Aventis Deutschland Gmbh Adenosine analogues and their use as pharmaceutical agents
US7342003B2 (en) 2001-10-25 2008-03-11 King Pharmaceuticals Research And Development, Inc. Synthesis of 2-aralkyloxyadenosines, 2-alkoxyadenosines, and their analogs

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Cited By (22)

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US5998388A (en) * 1996-05-14 1999-12-07 Glaxo Wellcome Inc. Adenosine derivatives
US6455510B1 (en) 1997-11-08 2002-09-24 Smithkline Beecham Corporation Chemical Compounds
WO1999024450A3 (fr) * 1997-11-08 1999-08-19 Glaxo Group Ltd Composes chimiques
WO1999024449A3 (fr) * 1997-11-08 1999-08-19 Glaxo Group Ltd Composes chimiques
JP2001522859A (ja) * 1997-11-08 2001-11-20 グラクソ グループ リミテッド 化合物
US6407076B1 (en) 1997-11-08 2002-06-18 Smithkline Beecham Corporation Adenosine analogues and related method of treatment
US6544960B1 (en) 1997-11-08 2003-04-08 Smithkline Beecham Corporation Chemical compounds
WO1999024451A3 (fr) * 1997-11-08 1999-08-19 Glaxo Group Ltd Composes chimiques
US6740644B2 (en) 1997-11-08 2004-05-25 Smithkline Beecham Corporation Chemical compounds
EP1457495A1 (fr) * 1997-11-08 2004-09-15 Glaxo Group Limited Agonistes des récepteurs d'adénosine A1
US7084127B2 (en) 2001-03-03 2006-08-01 Universiteit Leiden C2,5′-disubstituted and N6, C2,5′-trisubstituted adenosine derivatives and their different uses
WO2002070532A3 (fr) * 2001-03-03 2002-11-28 Univ Leiden Nouveaux derives c2,5'disubstitues et n6',c2,5'-trisubstitues de l'adenosine et leurs differentes utilisations
US7189706B2 (en) 2001-03-03 2007-03-13 Universiteit Leiden C2,5′-disubstituted and N6,C2,5′-trisubstituted adenosine derivatives and pharmaceutical compositions containing them
US7342003B2 (en) 2001-10-25 2008-03-11 King Pharmaceuticals Research And Development, Inc. Synthesis of 2-aralkyloxyadenosines, 2-alkoxyadenosines, and their analogs
WO2004003002A1 (fr) * 2002-06-27 2004-01-08 Aventis Pharma Deutschland Gmbh Nouveaux analogues de l'adenosine et leur utilisation comme agents pharmaceutiques
US7265111B2 (en) 2002-06-27 2007-09-04 Sanofi-Aventis Deutschland Gmbh Adenosine analogues and their use as pharmaceutical agents
EP1375508A1 (fr) * 2002-06-27 2004-01-02 Aventis Pharma Deutschland GmbH Dérivés de l'adénosine N6-substitués et leur utilisation comme médicament
JP2006505525A (ja) * 2002-08-15 2006-02-16 シーブイ・セラピューティクス・インコーポレイテッド Ａ１アデノシン受容体の部分および完全アゴニスト
US7022681B2 (en) 2002-08-15 2006-04-04 Cv Therapeutics, Inc. Partial and full agonists of A1 adenosine receptors
WO2004016635A3 (fr) * 2002-08-15 2004-04-08 Cv Therapeutics Inc Agonistes partiels et totaux des recepteurs d'adenosine a1
RU2340623C2 (ru) * 2002-08-15 2008-12-10 Си Ви Терапьютикс, Инк. Частичные и полные агонисты аденозиновых рецепторов a1
WO2005033121A3 (fr) * 2003-10-03 2005-07-28 King Pharmaceuticals Res & Dev Synthese de 2-aralkyloxyadenosines, 2-alkoxyadenosines, et leurs analogues

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