WO1998001459A1 - Nouveaux derives de n-alcoxyadenine inhibant la cytokine - Google Patents

Nouveaux derives de n-alcoxyadenine inhibant la cytokine Download PDF

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Publication number
WO1998001459A1
WO1998001459A1 PCT/DK1997/000293 DK9700293W WO9801459A1 WO 1998001459 A1 WO1998001459 A1 WO 1998001459A1 DK 9700293 W DK9700293 W DK 9700293W WO 9801459 A1 WO9801459 A1 WO 9801459A1
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chloro
alkyl
adenosine
acetyl
branched
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PCT/DK1997/000293
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English (en)
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Lars Knutsen
Uffe Bang Olsen
Stanley M. Roberts
David R. Varley
Andrew Neil Bowler
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Novo Nordisk A/S
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Priority to AU32550/97A priority Critical patent/AU3255097A/en
Publication of WO1998001459A1 publication Critical patent/WO1998001459A1/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
    • C07H19/16—Purine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Definitions

  • Novel ⁇ /-alkoxyadenine derivatives acting as cytokine inhibitors are novel ⁇ /-alkoxyadenine derivatives acting as cytokine inhibitors.
  • the present invention relates to novel ⁇ /,9-disubstituted adenine derivatives and novel aristeromycin analogues which are further substituted at the adenine 2-position, and which have a hydroxymethyl group, or an ester or ester isostere at a position corresponding to the ribose 4-position, and pharmaceutically acceptable addition salts thereof.
  • the compounds act as cytokine inhibitors. Also covered are processes for preparation of the above derivatives and their pharmaceutical compositions as well as methods for using the compounds and compositions as drugs for the treatment of disorders involving cytokines in humans.
  • Adenosine receptors represent a subclass (P.) 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 ⁇ A ⁇ , A 2B and A 3 .
  • Adenosine A 3 receptors Pharmacological Properties, Species Differences and Receptor Functions. TIPS, 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.; A 3 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, TIPS, 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, NECA, 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, 779, 79 -101).
  • Endogenous adenosine has been shown to inhibit lipopolysaccharide-stimulated tumor necrosis factor synthesis (Eigler, A.; Greten, T.F.; Sinha, B.; Haslberger, C; Sullivan, G.W.; Endres, S. Endogenous adenosine curtails lipopolysaccharide-stimulated tumor-necrosis-factor synthesis. Scand. J. Immunol. 1997, 45, 132 -139.
  • Adenosine agonists or adenosine regulating agents have potential therapeutic uses in acute and chronic inflammatory diseases.
  • 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 II 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., Arner, P. Caro, J.F., Atkinson, R.L.
  • adenosine and adenosine agonists acting via A 2 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 Wildenberg, A.J.M. and Buurman, W.A. Differential Regulatory Effects of Adenosine on Cytokine Release by Activated Human Monocytes. J. Immunol., 1994, 153, 4159 - 4168). These effects by A 2 receptor agonists have also been demonstrated on human polymorphonuclear leukocytes (Thiel, M.
  • 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).
  • Adenosine derivatives have potential in the treatment of Rheumatoid Arthritis (Firestein, G.S. Antiinflammatory effects of adenosine kinase inhibitors in acute and chronic inflammation. Drug Dev. Res., 1996, 39, 371-376).
  • 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., Carper, H.T. and Mandell, G.L. 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 of adenosine derivatives in the chemical literature with the heteroatoms, oxygen or nitrogen bonded directly to the 6-amino substituent are summarised below.
  • Examples with hydrogen at the purine 2-position include /V-aminoadenosine, N-[(N- methyl-/V-phenyl)amino]adenosine, ⁇ /-hydroxyadenosine, /V-methoxyadenosine and ⁇ /-benzyloxyadenosine (Kusachi, S., Thompson, R.D. Bugni, W.J., Yamada, N. and Olsson, R.A.
  • Dog Coronary Artery Adenosine Receptor Structure of the ⁇ / 6 -Alkyl Subregion. J. Med. Chem., 1985, 28, 1636 - 1643); /V-ethoxyadenosine (Fujii, T., Wu, C.C., itaya, T., Moro, S. and Saito, T. Purines. XI. The Synthesis of N- Alkoxyadenosines and Their 2',3'-O-lsopropylidene Derivatives. Chem. Pharm. Bull., 1973, 21, 1676 - 1682); (Fuji, T., W, C.C. and Itaya, T. Purines. XII.
  • Examples of adenosine derivatives with oxygen or nitrogen atoms bonded to the 6- amino substituent, containing an additional purine 2-substituent are 2-amino- ⁇ /- hydroxyadenosine (Kikugawa, K., lizuka, K., Higuchi, Y., Hirayama, H. and lchino, 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-/V- aminoadenosine (Saneyoshi, M. and Terashima, K.
  • Pfizer Inc. claim a range of heterocycles, including some purine derivatives, as CRF antagonists.
  • adenosine analogues with hydrazone derivatives on the 6-amino function are disclosed as hypotensive agents.
  • adenosine and 2-aminoadenosine derivatives having a -NH-R 2 group joined to the 6-amino function are disclosed as coronary dilators and platelet aggregation inhibitors.
  • EP A 152,944 a series of 2-, 6- and 8-substituted adenosine derivatives are described having activity as anti-allergy agents.
  • EP 402.752A derivatives of adenosine unsubstituted in the 2-position are described which have a substituted heteroaromatic 1-pyrrolyl moiety attached to the 6-amino group.
  • 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. Heffner, T.G. Mertz, T.E. Ribose-Modified Adenosine Analogues as Adenosine Receptor Agonists. J. Med. Chem., 1986, 29, 346-353).
  • a 3 receptor agonists are 5'-modif ⁇ ed 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 ⁇ '-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 ⁇ /-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 A1 describes a new use of 2-O-methyl adenosine derivatives for a range of ailments including neurodegenerative disorders.
  • X represents hydrogen, halogen, C ⁇ -alky!, C ⁇ -alkoxy, C ⁇ -alkylthio, C ⁇ -alkyl- amino;
  • A is hydroxy, C -alkanoyloxy, C -aikanoyloxymethyl, hydroxymethyl, 1 ,2- dihydroxy-C -alkyl, oxazolyl or isoxazolyl;
  • B is oxygen or methylene
  • W is hydrogen, hydroxy or O-C -alkyl or O-C -alkanoyl
  • Y is hydrogen, hydroxy, O-C -alkyl or O-C -alkanoyl or halogen;
  • R ⁇ is linear C ⁇ _6-alkyl. branched C 3-8 -alkyl, C 2-8 -alkenyl or C 3-8 -cydoalkyl, ail o which may be substituted by carboxyl, branched or linear C -alkoxycarbonyl, phenyl, phenoxy or halophenyl, or
  • R- is -OR2, wherein: R «? ⁇ is linear C ⁇ _g -alkyl, branched C 3-8 -alkyl, C Z-o -alkenyl or C 3-B -cydoalkyl, all of which may be substituted by carboxyl, branched or linear C -alkoxycarbonyl, aminocarbonyl, phenyl, phenoxy or halophenyl;
  • solid/dotted lines both represent single bonds or one of the solid/dotted lines represent a single bond and the other a double bond;
  • R 2 is OR 2 wherein R 2 is linear C 1 6 -alkyl, branched C -alkyl or C -cydoalkyl, all substituted with carboxyl or branched or linear C 1 6 -alkoxycarbonyl or aminocarbonyl; and provided that when A is C ⁇ _6-alkanoyloxymethyl, B is oxygen and W is hydroxy and Y is hydroxy, then R, is OR 2 wherein R 2 is linear C 1 -alkyl, branched C -alkyl, C 2-8 -alkenyl or C 3-8 -cydoalkyl, all of which may be substituted with carboxyl or branched or linear C -alkoxycarbonyl or aminocarbonyl.
  • the compounds of the invention show potent binding to adenosine receptors and 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 II diabetes, autoimmune disorders, multiple schlerosis, stroke, osteoporosis, septic shock and menstrual complications.
  • 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 nudeosides or the acid addition salts can be isolated and these solvates may, for example, be hydrates or alcoholates. In a preferred embodiment, the compounds of the invention are selected from compounds of formula I wherein A is alkanoyloxymethyl.
  • the compounds of the invention are selected from compounds of formula I wherein A is isoxazolyl.
  • the compounds of the invention are selected from compounds of formula I wherein A is hydroxymethyl and B is methylene and/or W is hydrogen.
  • the compounds of the invention are selected from compounds of formula I wherein A is hydroxymethyl and R. is OR 2 wherein R 2 is linear C 1-6 -alkyl, branched C 3-8 -alkyl or C 3-9 -cydoalkyl, all substituted with carboxyl or branched or linear C -alkoxycarbonyl.
  • the compounds of the invention are selected from:
  • the present invention is furthermore concerned with a pharmaceutical composition
  • a pharmaceutical composition comprising as active component a compound of formula I and a pharmaceutically acceptable carrier or diluent.
  • the present invention relates to a method of treating disorders related to cytokines in mammals, preferably autoimmune disorders, inflammation, arthritis, type I or type II diabetes, multiple schlerosis, stroke, osteoporosis, septic shock, ocular ailments or menstrual complications, more preferably type I type II diabetes, even more preferably type II diabetes, comprising administering to a mammal in need thereof an effective amount of a compound of formula I, and to the use of these compounds for manufacturing a medicament for treating one or more of said disorders.
  • disorders related to cytokines in mammals preferably autoimmune disorders, inflammation, arthritis, type I or type II diabetes, multiple schlerosis, stroke, osteoporosis, septic shock, ocular ailments or menstrual complications, more preferably type I type II diabetes, even more preferably type II diabetes, comprising administering to a mammal in need thereof an effective amount of a compound of formula I, and to the use of these compounds for manufacturing a medicament for treating one or more of said disorders.
  • 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- ⁇ release, indicated by lowering of plasma TNF- ⁇ following LPS challenge in rats.
  • the affinity of the compounds of this invention for the adenosine A, receptor was determined essentially as described in the literature using [ 3 H]-R-PIA as a radioligand (Naunyn-Schmiedeberg's Archives of Pharmacology, 1980, 313, 179- 187). Affinity for the A ⁇ receptor was measured using the radioligand [ 3 H]-CGS 21680 (European Journal of Pharmacology, 1989, 168, 243-246).
  • An assay for the human adenosine A 3 receptor is described in Jacobson, M. Cloning and Expression of Human Adenosine Receptor Subtypes. In Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology, Belardinelli, L. and Pelleg, A., Eds.; Kluwer: Boston, MA; 1995, pp 5-13.
  • test compound is dissolved in dimethyl sulphoxide (DMSO) at 8 mg/mL and is diluted with Cremophor/5% saline to 160, 16 and 1.6 mg/mL. 25 mL is added to each tube, and 350 mL heparinised (50 iE/mL) rat blood, 25 mL LPS and finally 1.6 mg/mL saline are introduced, i.e the concentrations of the test compound is 10, 1 and 0.1 mg/mL respectively.
  • the samples are shaken carefully and and are placed in a water bath for 5 h at 37°C.
  • the samples are centrifuged for 10 min. at 3000 r.p.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 dele- teriously 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, hydroxymethylcellulose 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 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
  • DMF is ⁇ /, ⁇ /-dimethylformamide
  • THF is tetra- hydrofuran
  • TFA is trifluoroacetic acid
  • m.p. is 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 mass spectroscopy MS and/or microanalysis where appropriate.
  • Compounds used as starting materials are either known compounds or compounds which can be prepared by methods known per se. Flash chromatography was carried out using the technique described by Still et al M on Merck silica gel 60 (Art 9385).
  • HPLC was carried out on a Merck Hitachi model L6200A Intelligent chromatograph interfaced to a Merck Hitachi L4000A UV detector to a LiChrospher 100 reversed phase C 18 column (5 mm, 250 x 4 mm, 5mm, 100A; eluent flow rate 1 mUmin). Retention times are given in minutes.
  • reaction mixture was left at ambient temperature for 5 h, and at 4°C for 72 h, after which time the starting material was not present by TLC.
  • the reaction mixture was neutralized by addition of a solution of citric acid in CH 3 OH, evaporated in vacuo, and the residue was purified by flash chromatography, eluting with a mixture of CH 2 CI 2 and EtOH (10/1) initially, then with a 5/1 mixture of these solvents, to provide 5'-O-acetyl- 2-chloro-/V-(2-methyl-1-propyloxy)adenosine (0.26 g, 32%) as a foam, ⁇ NMR (400 MHz, DMSO-d 6 ) ⁇ 0.95, 0.97 (6H, 2s, CH Oby,), 2.00 (1 H, h, CjH(CH 3 ) 2 ), 2.02 (3H, s, OCOCH 3 ), 3.53 (2H, d, CH 2 CH(CH 3 ) 2 ), 4.09 (1H, m
  • This compound was prepared using the procedure described in Example 1. ⁇ '.S'.S'-Tri-O-acetyl- ⁇ -D-ribofuranosyl ⁇ -dichloro- ⁇ H-purine (1.35 g, 3.02 mmol) was dissolved in dry dioxane (25 mL). N-Ethyldiisopropylamine (0.57 mL, 3.32 mmol) and aminooxy-acetic acid terf-butyl ester (0.49 g, 3.32 mmol) were introduced and the reaction mixture was heated at 50°C for 3 days. Since TLC was showing only slow progress, the temperature was increased to 80°C and the reaction left for a further week.
  • Example 5 The chromatography elution in Example 5 was continued to provide 2-chloro- ⁇ /-(tert- butyloxycarbonylmethoxy)adenosine (0.325 g, 63%).
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 1.45 (9H, s, C(CH 3 ) 3 ), 3.62 (2H, ABX, H-5' a and H-5V), 3.96 (1H, dd, H-4'), 4.15 (1H, dd, H-3'), 4.52 (1H, dd, H-2'), 4.54 (1H, s, OCH 2 ), 5.07 (1H, t, 5'-OH) 5.41 (1H, d, 3'- OH), 5.23 (1 H, d, 2'-OH), 5.51 (1 H, d, 1'-OH), 5.88 (1 H, d, H-1'), 8.53 (1H, s, H-8), 11.58 (1 H, s, NH), MS (+FAB)
  • Aminooxyacetic acid hemihydrochloride (4.0 g, 37 mmol) was partially dissolved in methanol (70 mL) and cooled to 0°C.
  • Thionyl chloride (5.30 mL, 73 mmol) was added dropwise at such a rate as to maintain the temperature below 10°C. Addition was complete after 20 min and the reaction kept around 0°C for a further 30 min. The reaction was then stirred at room temperature for 30 min, then heated to 60°C for 2 h. After this time the solvent was carefully evaporated to leave an oily residue (4.70 g, 90%).
  • Example 7 The chromatography elution in Example 7 was continued using CH 2 CI 2 /EtOH (12:1), to provide 2-chloro- ⁇ /-(methoxycarbonylmethoxy)adenosine (0.13 g, 48%).
  • 1 H NMR 400 MHz, DMSO-d ⁇ ) ⁇ 3.62 (2H, ABX, H-5' a and H-5' b ), 3.70 (3H, s, OCH 3 ), 3.96 (1H, dd, H-4'), 4.13 (1H, dd, H-3'), 4.51 (1H, dd, H-2'), 4.67 (1H, s, OCH 2 ), 5.07 (1H, t, 5'-OH), 5.23 (1H, d, 3'-OH), 5.52 (1H, d, 2'-OH), 5.86 (1H, d, H-1'), 8.53 (1 H, s, H-8), 11.67 (1H, s, NH), C 13 H 16 N 5 0
  • 2,6-Dichloro-9H-purine (0.95 g, 5.0 mmol) was heated at reflux in 1,1,1 ,3,3,3- hexamethyldislazane (15 mL) for 2 h.
  • the reaction mixture was evaporated in vacuo, and co-evaporated with xylene ((25 mL).
  • the resultant white solid was dissolved in dry CH 3 CN (20 mL), 1-0-methyl-3,5-di-0-p-toluoyl-D-ribofuranose (1.92 g, 5 mmol) was introduced, and the mixture was cooled to -20°C.
  • Trimethylsilyl trifluorornethanesulphonate (1.06 mL) in 1 ,2-dichloroethane (10 mL) was then added, and the temperature was maintained at -20°C for 16 h.
  • the reaction mixture was diluted with CH 2 CI 2 (100 mL), treated with cold saturated NaHC0 3 solution, and the organic phase was separated and dried (MgS0 4 ).
  • This example was prepared from 9-(2'-deoxy-3',5'-di-0-p-toluoyl- ⁇ -D-ribofuranosyl)- 2,6-dichloro-9H-purine (0.10 g) (see experimental procedure for Example 10, method B) using O-methylhydroxylamine hydrochloride (0.035 g, 0.42 mmol) in 1,4-dioxan (10 mL) in the presence of ⁇ /-ethyldisopropylamine (0.14 mL, 0.11 g, 0.84 mmol), giving 2- chloro-9-(2'-deoxy-3',5'-di-0-p-toluoyl- ⁇ -D-ribofuranosyl)- ⁇ /-methoxyadenine (0.08 g, 88%).
  • O-Methyl hydroxylamine hydrochloride (0.17 mg, 0.2 mmol) and TEA (40 mg, 0.4 mmol) were added to a solution of 2,6-dichloro-9-(2,3-di-0-benzoyl-4-isoxazol-3-yl- ⁇ -D-eryf/7rofuranos-1-yl)-9H-purine (0.056 g, 0.1 mmol) in 1 ,4 dioxane (5 mL). The reaction mixture was refluxed for 20 h and concentrated in vacuo.
  • 3-lodobenzylamine hydrochloride (26.9 mg, 0.1 mmol) and Et 3 N (40 mg, 0.4 mmol) were introduced to a solution of 2,6-dichloro-9-(2,3-di-0-benzoyl-4-isoxazol-3-yl- ⁇ - D-ety /?ro-furanos-1-yl)-9H-purine (see Example 21) (0.056 g, 0.1 mmol) in 1 ,4- dioxane (5 mL). The solution was heated at reflux for 10 h and concentrated in vacuo.
  • the mixture was ex- tracted with petroleum ether (4 x 100 mL) to remove unreacted cydopentadiene.
  • the aqueous layer was saturated with sodium chloride and extracted with EtOAc (15 x 200 mL).
  • the combined organic layers were concentrated to 500 mL, cooled to 0°C and washed with cold saturated sodium bicarbonate solution (2 x 100 mL) to remove unreacted glyoxylic acid.
  • the organic layer was dried (MgS0 4 ), filtered and the solvent evaporated in vacuo to give the crude material as an yellow mobile oil.
  • Tetrakis(triphenylphosphine)palladium (0.128 g, 0.111 mmol) and ( ⁇ )-(1S,3'R,4'R)-(3'-acetoxycyclopenten-4 , -yl)-1,2-diacetoxyethane were suspended in THF (10 mL) and added to the warm solution of 2-amino-6- chloro-(9H)-purine using a cannula and rinsing with DMF (3 x 1 mL). After 3 h stirring at 50°C, the reaction mixture was cooled to room temperature and water (20 mL) was added.
  • Acetic acid, (1 S, 4S)-4-(2,6-dichloro-9H-purin-9-yl)cyclopent-2-enyl ester (0.72 g, 2.3 mmol) was dissolved in 1,4-dioxan (50 mL).
  • O-Methylhydroxylamine hydrochloride (1.54 g, 18.39 mmol) and N.N-diisopropylethylamine (4.0 mL, 2.97 g, 23.0 mmol) were introduced and the reaction mixture was stirred at 50°C for 20h, and evaporated to a residue which was purified by flash chromatography.

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Abstract

L'invention concerne des nouveaux dérivés d'adénine N,9-disubstitués et de nouveaux analogues d'aristéromycine substitués en outre à la position 2 de l'adénine, et ayant un groupe hydroxyméthyle ou un ester ou un ester isostère à une position qui correspond à la position 4 de la ribose, et les sels d'addition pharmaceutiquement acceptable de ces substances. De tels composés inhibent la cytokine. On décrit des procédés relatifs à l'élaboration des dérivés et de leurs compositions pharmaceutiques ainsi que des procédés relatifs à l'utilisation des composés et des compositions comme médicaments pour traiter les affections impliquant la cytokine chez l'homme.
PCT/DK1997/000293 1996-07-05 1997-07-03 Nouveaux derives de n-alcoxyadenine inhibant la cytokine WO1998001459A1 (fr)

Priority Applications (1)

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AU32550/97A AU3255097A (en) 1996-07-05 1997-07-03 Novel (n)-alkoxyadenine derivatives acting as cytokine inhibitors

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DK74596 1996-07-05
DK0745/96 1996-07-05

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WO1998001459A1 true WO1998001459A1 (fr) 1998-01-15

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WO1999038877A2 (fr) * 1998-01-31 1999-08-05 Glaxo Group Limited Derives de 2-(purine-9-yl)-tetrahydrofurane-3,4-diol
WO1999067262A1 (fr) * 1998-06-23 1999-12-29 Glaxo Group Limited Derives d'adenosine
WO1999067263A1 (fr) * 1998-06-23 1999-12-29 Glaxo Group Limited Derives du 2-(purin-9-yl)-tetrahydrofuran-3,4 diol
WO1999067265A1 (fr) * 1998-06-23 1999-12-29 Glaxo Group Limited Derives du 2-(purin-9-yl)-tetrahydrofuran-3,4 diol
WO1999067266A1 (fr) * 1998-06-23 1999-12-29 Glaxo Group Limited Derives du 2-(purin-9-yl)-tetrahydrofuran-3,4 diol
WO1999067264A1 (fr) * 1998-06-23 1999-12-29 Glaxo Group Limited Derives du 2-(purin-9-yl)-tetrahydrofuran-3,4 diol
WO2002074781A1 (fr) * 2001-03-20 2002-09-26 Glaxo Group Limited Procede de preparation de nucleosides de ribofuranose aminopurine substitues en n6
US6624158B2 (en) 2000-09-15 2003-09-23 Pfizer Inc Purine derivatives
WO2004069185A2 (fr) * 2003-02-03 2004-08-19 Cv Therapeutics Inc. Agonistes partiels et pleins des recepteurs a1 de l'adenosine
US6841549B1 (en) 1999-07-02 2005-01-11 Eisai Co., Ltd. Condensed imidazole compounds and a therapeutic agent for diabetes mellitus
EP1546167A1 (fr) * 2002-09-06 2005-06-29 Alchemia Limited Composes qui interagissent avec des kinases
AU2002323990B2 (en) * 1998-06-23 2006-03-30 Glaxo Group Limited Adenosine derivatives
US7737126B2 (en) 2004-05-24 2010-06-15 Glaxo Group Limited Purine derivative
US7985740B2 (en) 2005-07-19 2011-07-26 Glaxo Group Limited Purine derivatives as agonists of the adenosine A2A receptor
WO2013120078A1 (fr) * 2012-02-11 2013-08-15 Academia Sinica Méthodes et compositions de traitement de la douleur
CN108676048A (zh) * 2018-06-04 2018-10-19 上海兆维科技发展有限公司 一种虫草素的制备方法

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WO1994017803A1 (fr) * 1993-02-03 1994-08-18 Gensia, Inc. Inhibiteurs de l'adenosine kinase

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WO1999038877A3 (fr) * 1998-01-31 1999-09-30 Glaxo Group Ltd Derives de 2-(purine-9-yl)-tetrahydrofurane-3,4-diol
WO1999038877A2 (fr) * 1998-01-31 1999-08-05 Glaxo Group Limited Derives de 2-(purine-9-yl)-tetrahydrofurane-3,4-diol
US6492348B1 (en) 1998-06-23 2002-12-10 Smithkline Beecham Corporation Adenosine derivatives
AU758018B2 (en) * 1998-06-23 2003-03-13 Glaxo Group Limited Adenosine derivatives
WO1999067266A1 (fr) * 1998-06-23 1999-12-29 Glaxo Group Limited Derives du 2-(purin-9-yl)-tetrahydrofuran-3,4 diol
WO1999067264A1 (fr) * 1998-06-23 1999-12-29 Glaxo Group Limited Derives du 2-(purin-9-yl)-tetrahydrofuran-3,4 diol
KR100612797B1 (ko) * 1998-06-23 2006-08-17 글락소 그룹 리미티드 아데노신 유도체
BG65064B1 (bg) * 1998-06-23 2007-01-31 Glaxo Group Limited Аденозинови производни
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WO1999067265A1 (fr) * 1998-06-23 1999-12-29 Glaxo Group Limited Derives du 2-(purin-9-yl)-tetrahydrofuran-3,4 diol
US6534486B1 (en) 1998-06-23 2003-03-18 Smithkline Beecham Corporation 2-(purin-9-yl)-Tetrahydrofuran-3,4-diol derivatives
AU2002323990B2 (en) * 1998-06-23 2006-03-30 Glaxo Group Limited Adenosine derivatives
US6677316B2 (en) 1998-06-23 2004-01-13 Smithkline Beecham Corporation Adenosine derivatives and methods of administration
WO1999067263A1 (fr) * 1998-06-23 1999-12-29 Glaxo Group Limited Derives du 2-(purin-9-yl)-tetrahydrofuran-3,4 diol
EP1447407A1 (fr) * 1998-06-23 2004-08-18 Glaxo Group Limited Dérivés d'adénosine
WO1999067262A1 (fr) * 1998-06-23 1999-12-29 Glaxo Group Limited Derives d'adenosine
US6841549B1 (en) 1999-07-02 2005-01-11 Eisai Co., Ltd. Condensed imidazole compounds and a therapeutic agent for diabetes mellitus
US6624158B2 (en) 2000-09-15 2003-09-23 Pfizer Inc Purine derivatives
WO2002074781A1 (fr) * 2001-03-20 2002-09-26 Glaxo Group Limited Procede de preparation de nucleosides de ribofuranose aminopurine substitues en n6
US7297787B2 (en) 2001-03-20 2007-11-20 Glaxo Group Limited Process for preparing N6 substituted aminopurine ribofuranose nucleosides
EP2471803A1 (fr) 2002-09-06 2012-07-04 Alchemia Limited Composés interagissant avec des kinases
EP1546167A1 (fr) * 2002-09-06 2005-06-29 Alchemia Limited Composes qui interagissent avec des kinases
JP2006503020A (ja) * 2002-09-06 2006-01-26 アルケミア リミティッド キナーゼと相互作用する化合物
EP1546167A4 (fr) * 2002-09-06 2008-05-21 Alchemia Ltd Composes qui interagissent avec des kinases
WO2004069185A2 (fr) * 2003-02-03 2004-08-19 Cv Therapeutics Inc. Agonistes partiels et pleins des recepteurs a1 de l'adenosine
US7163928B2 (en) 2003-02-03 2007-01-16 Cv Therapeutics, Inc. Partial and full agonists of A1 adenosine receptors
JP2006516641A (ja) * 2003-02-03 2006-07-06 シーブイ・セラピューティクス・インコーポレイテッド アデノシン受容体の完全アゴニストおよび部分アゴニスト
WO2004069185A3 (fr) * 2003-02-03 2004-09-23 Cv Therapeutics Inc Agonistes partiels et pleins des recepteurs a1 de l'adenosine
US7737126B2 (en) 2004-05-24 2010-06-15 Glaxo Group Limited Purine derivative
US7985740B2 (en) 2005-07-19 2011-07-26 Glaxo Group Limited Purine derivatives as agonists of the adenosine A2A receptor
WO2013120078A1 (fr) * 2012-02-11 2013-08-15 Academia Sinica Méthodes et compositions de traitement de la douleur
US10117890B2 (en) 2012-02-11 2018-11-06 Academia Sinica Methods and compositions for treating pain
CN108676048A (zh) * 2018-06-04 2018-10-19 上海兆维科技发展有限公司 一种虫草素的制备方法
CN108676048B (zh) * 2018-06-04 2021-04-27 上海兆维科技发展有限公司 一种虫草素的制备方法

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AU3255097A (en) 1998-02-02
ZA975986B (en) 1998-03-23

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