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WO1997033590A1 - 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
WO1997033590A1
WO1997033590A1 PCT/DK1997/000107 DK9700107W WO9733590A1 WO 1997033590 A1 WO1997033590 A1 WO 1997033590A1 DK 9700107 W DK9700107 W DK 9700107W WO 9733590 A1 WO9733590 A1 WO 9733590A1
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Prior art keywords
alkyl
adenosine
phenyl
mmol
deoxy
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PCT/DK1997/000107
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English (en)
Inventor
Lars Knutsen
Uffe Bang Olsen
Andrew Neil Bowler
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Novo Nordisk A/S
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Priority to AU20224/97A priority Critical patent/AU2022497A/en
Publication of WO1997033590A1 publication Critical patent/WO1997033590A1/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 type I or type LI diabetes, multiple schlerosis, stroke, osteoporosis, septic shock and menstrual complications.
  • the invention furthermore relates to new purine derivatives having affinity for i.a. the A 3 subtype 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 A t , A ⁇ , Aa, and A 3 .
  • Adenosine A3 receptors Pharmacological Properties, Species Differences and Receptor Functions. ⁇ PS 1994, 75, 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 Prope ⁇ s. 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-PLA, 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- ⁇ levels are increased in obese rodents (Yamakawa, T , Tanaka, S-I , Yamakawa, Y , Kiuchi, Y , Isoda, F , Kawamoto, S, Okuda, K and Sekihara, H Augmented Production of Tumor Necrosis Factor- ⁇ Production in Obese Mice Clin.
  • adenosine and adenosine agonists, acting via A 2 receptors can be of benefit in for example sepdc shock or ischaemia-reperfusion injury, where cytokine production by mononuclear phagocytes can be inhibited by tiiese agents (Bouma, M G , Stad, R.K., van den Wildenberg, A.J.M. and Buurman, W Differential Regulatory Effects of Adenosine on Cytokine Release by Activated Human Monocytes J.
  • 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 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, N-methoxyadenosine and N-benzyloxyadenosine (Kusachi, S., Thompson, R.D. Bugni, .J., Yamada, N. and Olsson, R.A. Dog Coronary Artery Adenosine Receptor: Structure of the //-Alkyl Subregion. J.
  • N-ethoxyadenosine (Fujii, TRON 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. Bull., 1973, 21, 1676 - 1682); (Fuji, T., W, C.C. and Itaya, T. Purines.
  • Examples of adenosine derivatives with oxygen or nitrogen atoms bonded to the 6-amino substituent, containing an additional purine 2-substituent are 2-amino-Jv ' -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. Med Chem., 1972, 15, 387 - 390); 2-amino-iV-aminoadenosine (Saneyoshi, M. and Terashima, K.
  • (lR,4S)-9-[4-(DimethylthexylsUyloxymethyl)cyclopent-2-enyl]-6-methoxyamino-9H-purine-2- amine is featured as an intermediate in the synthesis of (-)-carbovir (Exall A.M., Jones, M.F., Mo, C-L., Myer, P.L., Paternoster, I.L., Singh, H, Storer, R, Weingarten, G.G., Williamson, C, Brodie, A.C., Cook, J., Lake, D.E., Meerholz, C.A., Tumbull, P.J. and Highcock, KM.
  • (-)-carbovir Exall A.M., Jones, M.F., Mo, C-L., Myer, P.L., Paternoster, I.L., Singh, H, Storer, R, Weingarten, G.G., Williamson, C, Brodie, A.C.
  • 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, KF. Hef ⁇ ier, 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, H.A.; 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.
  • compounds acting as A3 ligands are found to be potent inhibitors of cytokine production, especially TNF- ⁇ production, and to be useful in the treatment of type I and type U diabetes, multiple schlerosis, stroke, osteoporosis, septic shock and menstrual complications.
  • present invention relates to a method of treating a mammal suffering from type I or type U diabetes, multiple schlerosis, stroke, osteoporosis, septic shock or menstrual complications, preferably type I or type II diabetes, more preferably type II diabetes, which method comprises administering to a mammal in need of such treatment an effective amount of an adenosine A 3 ligand.
  • the present invention is furthermore concerned with 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: -R,
  • 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 groups, Cw-alkenyl, C -6-alkynyl, phenoxy, phenylsulphonyl, phenylthio, hydroxy, phenyl, C w -alkoxy or d-e-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 -alkyI, C 2- 6-alkenyl, C 2 -6-alkynyl, phenoxy, phenyl, C ⁇ -alkoxy or
  • R 1 is -NR 2 R 3 or -YR 4 , wherein Y is oxygen;
  • R 2 is C,-s-alkyl;
  • X represents phenyl
  • A is hydroxymethyl, methyl, chloromethyl, bromomethyl, fluoromethyl, cyanomethyl, aminomethyl, vinyl, methylthiomethyl or methoxymethyl; 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 M -alkenyl, C 2-6 -alkynyl, phenoxy, phenylsulphonyl, phenylthio, hydroxy, phenyl, Ci- ⁇ -alkoxy or phenylthioalkyl or
  • R' is -NR 2 R 3 or -YR 4 , wherein Y is oxygen; R 2 is Ci- ⁇ -alkyi;
  • R 3 is phenyl or Cw-alkyl which may be substituted by phenyl or phenoxy;
  • R 4 is straight-chain d-e-alkyl, branched C 3 - 8 -alkyl, C 2-g -alkenyl or C3-g-cycloalkyl, which may be substituted 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 hydrogen, halogen, amino, perhalomethyi, cyano, Ci- ⁇ -alkyl, C ⁇ -alkoxy, C «- 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 2 ⁇ -alkenyl, C 2 -s-alkynyl, phenoxy, phenylsulphonyl, phenylthio, hydroxy, phenyl, Cw-alkoxy or C ⁇ -6-alkoxy- Ci- ⁇ -alkyl, phenylthioalkyl or
  • Y is O, S or NZ, where Z is H C ⁇ -alkyl or phenyl, and where the group (b) may be optionally substituted with C ⁇ -alkyl, C 2-6 -alkenyl, C M -alkynyl, phenoxy, phenyl, d- ⁇ -aikoxy or C ⁇ -6-alkoxy-Cw-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 which may be substituted by phenyl or phenoxy;
  • R 4 is branched C 3-g -alkyl or C 2 .g-alkenyl, which may be substituted by phenyl or phenoxy which in turn may be substituted with nitro, halogen or amine.
  • the compounds of formula (I) have affinity for the A 3 subtype 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- ⁇ release, indicated by lowering of plasma TNF- ⁇ following LPS challenge in rats.
  • the adenosine receptor subtype A3 has been expressed in a human embryonic kidney cell line (HEK 293) and shown to be negatively coupled to adenylate cyclase via a pertussis toxin sensitive G-protein.
  • HEK 293 human embryonic kidney cell line
  • Test procedure & data analysis 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 lE/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/ ⁇ L 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.
  • 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, polyhyroxyethoxylated 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.
  • 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 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 dryness 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
  • mp melting point. Where melting points are given, these are uncon n ected.
  • 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. Examples
  • the title compound was prepared according to the method described in Example 1 by reacting 1- methyl- 1-phenylhydrazine (1.29 g, 11 mmol) with 9-(2 , ,3 , ,5 , -tri-O-benzoyl-b-D-ribofuranosyl)- -2,6-dichloro-9H-purine (1.58 g, 2.5 mmol) and debenzoylating the purified product using potassium carbonate in methanol to provide the title 2-Chloro-N-[(N-methyl-N- phenyl)amino]adenosine (0.70 g, 69%) (after column chromatography) as a colorless foam, TLC r f 0.50 [SiO 2 , THF], l H NMR (DMSO-d*) d 3.23 (3H, 2s, CH 3 ), 3.50 - 3.72 (2H, br, -CH r ), 5.06 (IH, br, 5'-OH),
  • 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- henylmethyl)hydroxylamine hydrochloride (0.77 g, 4.8 mmol) and N,N-diisopropylamine (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.
  • 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.
  • the title compound was prepared according to the method described in Example 4 by reacting 0-methylhydroxylamine (0.20 g, 2.0 mmol) with 9-(2',3',5'-tri-O-benzoyl- ⁇ -D-riboft ⁇ ranosyl)- -2,6-dichloro-9H-purine (1.27 g, 2.0 mmol) and debenzoylating the purified product using methanolic ammonia to provide the title 2-chloro-N-methoxyadenosine (0.40 g, 45%) (after column chromatography) as a colorless foam which became crystalline on trituration with dichloromethane, providing 0.20 g of a white solid, mp 123 - 125°C.
  • the title compound was prepared according the method described in example 6 by reacting 0- ethylhydroxylamine hydrochloride (0.305 g, 3.1 mmol) with 9-(2 , ,3 , ,5'-tri-O-acetyl- ⁇ -D-ribo- furanosyl)-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
  • the title compound was prepared according to the method described in Example 6 by reacting O-tert-butylhydroxylamine hydrochloride (0.603 g, 4.8 mmol) with 9-(2',3',5 , -tri-O-acetyl- ⁇ -D- ribofuranosyl)-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-chIoro-N-ethoxyadenosine
  • the title compound was prepared according to the method described in Example 4 by reacting 1,1-dimethylhydrazine (0.79 g, 13.1 mmol) with 9-(2,3,5-tri-0-acetyl- ⁇ -D-ribofuranosyi)-2- amino-6-chloro-9H-purine (4.0 g, 9.35 mmol) and debenzoylating the purified product using methanolic ammonia to provide the title 2-ammo-N-(dimethylamino)adenosine (after column chromatography) as an amorphous foam (0.56 g, 45%), 1H NMR (DMSO-ds) d 2.54 (6H, s, 2 x -CH 3 ), 3.50 - 3.57 (IH, m, H-5' a ), 3.61 - 3.68 (Hi m, H-5' b ), 3.93 (Hi q, H-4'), 4.12 (IH, q, H-3'), 4.51 (IH q
  • 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-chloro-N-(N-methyl-N-(2-phenoxyethyl)amino)adenosine (0.84 g, 47%) (after column chromatography) obtained as a solid, mp 166-8°C, ⁇ NMR (DMSO-ds) d 2.70 (3H, s, -CH 3 ), 3.22 (2H, br t, -
  • 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 mbcture was heated at 90°C in a sealed vessel for 70h, before being filtered and evaporated.
  • N-methoxy-2-phenyladenosine O-Methylhydroxylamine hydrochloride (10.2 g, 12.2 mmol) was reacted with 9-(2',3',5'-tri- O-acetyl- ⁇ -D-ribofuranosyl)-6-chloro-2-phenyl-9H-purine (0.60 g, 1.2 mmol) in dioxan (30 mL) in the presence of d ⁇ sopropylethylamine (1.70 g, 13.1 mmol). The reaction mixture was heated at 100°C in a sealed vessel for 18h, and at 60°C for 50h before being filtered and evaporated.
  • reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography eluting with dichloromethane and 10% ammonia in ethanol (95:5) to give 5'-deoxy-2,5'-dichloro-2',3 , -O-(l-methyl- ethylidene)-N-(l-piperidinyl)adenosine (0.10 g, 48%) as a foam.
  • This compound was prepared by the general method described in Example 24.
  • 2-Chloro-N-(4-phenoxy-l-piperidinyl)adenosine [WO 93/08206 (Novo Nordisk A/S)] (0.5 g, 1.05 mmol) was subjected to the chlorination conditions described above, providing the title 5'- deoxy-2,5'-dichloro-N-(4-phenoxy-l-piperidinyl)adenosine which precipitated on treatment with dichloromethane following trituration with ether. Drying in vacuo provided a solid (0.28 g, 56%), m.p.
  • 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 reartion 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'-dicWoro-N-(4-phenylsulfinyl-l-piperidinyl)adenosine (0.1 g, 53%) as a foam.
  • EtOH requires C, 42.1; H, 4.9; N, 19.6. Found: C, 41.6; H, 5.2; N, 19.0%.
  • Methyl 2,3-O-(l-mrthylethyUdene)-5-O-(p-toluenesulfonyl)-D-ribofuranoside (28 7 g, 80 mmol) was dissolved in dry acetonitrile (100 mL).
  • Tetra- «-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 mbcture was diluted with dichloromethane (200 mL), washed with water (3 x 50 mL) and dried (MgSO 4 ) Evaporation provided a residue which was purified by flash chromatography eluting with a mixture of ethyl acetate/w-heptane (1/3) to give methyl 5-deoxy-5-fluoro-2,3-O-(l-methylethylidene)- ⁇ -D-ribofuranoside (13 6 g, 82%) as a clear oil, 'H NMR (CDC1 3 ) d 1 34 (3H, s, CH 3 ), 1 50 (3H, s, CH 3 ), 3 35 (3H, s, -OCH 3 ), 4 29 - 448 (3H,
  • 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).
  • 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.
  • the product was purified by flash chromatography eluting with a mixture of dichloromethane and 10% ammonia in ethanol (98:2) giving the intermediate 2',3'-di-0-acetyI-2-chloro- 5'-deoxy-5'-fluoro-N-benzyloxyadenosine (0.2 g, 16%).
  • Deacetylation was performed in methanolic ammonia to afford 2-chloro-5'-deoxy-5'-fluoro-iV-benzyloxyadenosine as a foam (0.11 g, 89%) after flash chromatography eluting with dichloromethane and 10% ammonia in ethanol (95:5).
  • 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 mbcture 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.
  • the reartion mixture was washed with hydrochloric acid (1M, 50 mL) and water (50 mL).
  • the organic phase was dried (MgSO ) and concentrated to an oil before being purified by flash chromatography.
  • Acetic acid (74.5 mL, 1.3 mol), acetic anhydride (173.8 mL, 1840 mmol) and sulfuric acid (1.7 mL, 32 mmol) were mixed together and methyl 2,3-O-dibenzoyl-5-cyano-5-deoxy- ⁇ -D- ribofuranoside (13.01 g, 35 mmol) was added.
  • the reartion mixture was stirred for 20 h at ambient temperature before sodium acetate (37 g, 450 mmol) was introduced. After 30 min.
  • Methyl 5-deoxy-2,3-O-(l-methylethylidene)-D-ribofuranoside (prepared by reduction of methyl 2,3-O-(l-methylethylidene)-5'-O-(p-toluenesulphonyl)-D-ribofi ⁇ ranoside using lithium aluminium hydride) (4.36 g, 23.2 mmol) was dissolved in methanol (120 mL) and Amberlyst resin (Ff form, 19 g) was introduced. The mbcture 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.
  • 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. After stirring for 2 h, methyl 5-deoxy-5-oxo-2,3-O-(l-methylethylidene)-D-ribofi ⁇ ranoside (prepared by oxidation of 1- O-methyl-2,3-O-(l-methylethylidene)-D-ribofuranoside using the method described in Ranganathan, R.S., Jones, G.H.
  • 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 (H * 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 reartion of 9-(5'-deoxy-2',3'-di-O-benzoyl-5'-methylene- ⁇ -D-ribofi ⁇ ranosyl)-2,6-dichloro-9H-purine (see Example 48) with cyciopentylamine) (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 autoimmune, 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/DK1997/000107 1996-03-13 1997-03-12 Procede de traitement d'affections associees aux cytokines chez les mammiferes WO1997033590A1 (fr)

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Cited By (9)

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US6544960B1 (en) * 1997-11-08 2003-04-08 Smithkline Beecham Corporation Chemical compounds
US7423144B2 (en) 2004-05-26 2008-09-09 Inotek Pharmaceuticals Corporation Purine Derivatives as adenosine A1 receptor agonists and methods of use thereof
US7732424B2 (en) 2005-11-30 2010-06-08 Inotek Pharmaceuticals Corporation Purine derivatives and methods of use thereof
US7863253B2 (en) 2004-09-20 2011-01-04 Inotek Pharmaceuticals Corporation Purine Derivatives and methods of use thereof
US9278991B2 (en) 2012-01-26 2016-03-08 Inotek Pharmaceuticals Corporation Anhydrous polymorphs of [(2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)} methyl nitrate and processes of preparation thereof
US9289383B2 (en) 2010-03-26 2016-03-22 Inotek Pharmaceuticals Corporation Method of reducing intraocular pressure in humans
US9370530B2 (en) 2010-01-11 2016-06-21 Inotek Pharmaceuticals Corporation Combination, kit and method of reducing intraocular pressure
US9522160B2 (en) 2013-03-15 2016-12-20 Inotek Pharmaceuticals Corporation Ophthalmic formulations
US12441744B2 (en) 2025-01-27 2025-10-14 Astrazeneca Ab 2,6,9-trisubstituted purines

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Cited By (14)

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Publication number Priority date Publication date Assignee Title
US6740644B2 (en) * 1997-11-08 2004-05-25 Smithkline Beecham Corporation Chemical compounds
US6544960B1 (en) * 1997-11-08 2003-04-08 Smithkline Beecham Corporation Chemical compounds
US8609833B2 (en) 2004-05-26 2013-12-17 Inotek Pharmaceuticals Corporation Purine derivatives as adenosine A1 receptor agonists and methods of use thereof
US7423144B2 (en) 2004-05-26 2008-09-09 Inotek Pharmaceuticals Corporation Purine Derivatives as adenosine A1 receptor agonists and methods of use thereof
US8183224B2 (en) 2004-05-26 2012-05-22 Inotek Pharmaceuticals Corporation Purine derivatives as adenosine A1 receptor agonists and methods of use thereof
US7863253B2 (en) 2004-09-20 2011-01-04 Inotek Pharmaceuticals Corporation Purine Derivatives and methods of use thereof
US8133880B2 (en) 2004-09-20 2012-03-13 Inotek Pharmaceuticals Corporation Purine derivatives and methods of use thereof
US7732424B2 (en) 2005-11-30 2010-06-08 Inotek Pharmaceuticals Corporation Purine derivatives and methods of use thereof
US9370530B2 (en) 2010-01-11 2016-06-21 Inotek Pharmaceuticals Corporation Combination, kit and method of reducing intraocular pressure
US9289383B2 (en) 2010-03-26 2016-03-22 Inotek Pharmaceuticals Corporation Method of reducing intraocular pressure in humans
US9278991B2 (en) 2012-01-26 2016-03-08 Inotek Pharmaceuticals Corporation Anhydrous polymorphs of [(2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)} methyl nitrate and processes of preparation thereof
US9718853B2 (en) 2012-01-26 2017-08-01 Inotek Pharmaceuticals Corporation Anhydrous polymorphs of [(2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-YL)-3,4-dihydroxytetrahydrofuran-2-YL)] methyl nitrate and processes of preparation thereof
US9522160B2 (en) 2013-03-15 2016-12-20 Inotek Pharmaceuticals Corporation Ophthalmic formulations
US12441744B2 (en) 2025-01-27 2025-10-14 Astrazeneca Ab 2,6,9-trisubstituted purines

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