- Purines. LXI. An attempted synthesis of 2'-deoxy-7-methyladenosine: Glycosidic hydrolyses of the N6-methoxy derivative and 2'-deoxy-N(x)- methyladenosines
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In an attempt to synthesize 2'-deoxy-7-methyladenosine (5b), 2'-deoxy- N6-methoxyadenosine (13b) was treated with MeI in AcNMe2 at 0°C for 7h to give the 2'-deoxy-N6-methoxy-7-methyladenosine salt (14b), which was unstable and easily underwent glycosidic hydrolysis in H2O at 16-18°C to form N6-methoxy-7-methyladenine (15). On account of such instability, hydrogenolysis of 14b in H2O using hydrogen and Raney Ni catalyst failed to afford the desired nucleoside (5b). 2'-Deoxy-N6-methyladenosine (2b), 2'- deoxy-1-methyladenosine (3b), and 14b were found to undergo glycosidic hydrolysis in 0.1 N aqueous HCl at 25°C at rates of 7.92 x 10-2 min-1 (half-life 87.5 min), 5.02 x 10-3min-1 (half-life 138 min), and 2.31 x 10-2 min-1 (half-life 30.0 min), respectively, while the rate in the case of 5h was roughly estimated to be ca. 2 min-1 (half-life 0.35 min).
- Fujii,Saito,Iguchi
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Read Online
- Method for treating disease or condition susceptible to amelioration by AMPK activators and compounds of formula which are useful to activate AMP-activated protein kinase (AMPK)
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The present invention relates to a method for treating disease or condition susceptible to amelioration by AMPK activators and compounds of formula which are useful to activate AMP-activated protein kinase (AMPK) and the use of the compounds in the prevention or treatment of disease, including pre-diabetes, type 2 diabetes, syndrome X, metabolic syndrome and obesity.
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Paragraph 0051-0052
(2014/10/16)
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- HETEROARYLPHENYLUREA DERIVATIVE
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The present invention provides a compound represented by the formula (1): wherein R 1 , R 2 and R 5 are each independently selected from a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl is substituted with a halogen atom and the like; R 3 and R 4 are each independently selected from a hydrogen atom, a halogen atom, a substituted C 1 -C 6 alkyl group and the like; R 6 and R 7 are each independently selected from a hydrogen atom and a halogen atom; Z 1 and Z 2 are each independently selected from a hydrogen atom, a hydroxyl group and -O(CHR 11 )OC(=O)R 12 ; Q is a group of the formula: (wherein G 1 is C-Y 2 or N; a ring A is a benzene ring or a 5- to 6-membered unsaturated heterocycle) a pharmaceutically acceptable salt thereof or a prodrug thereof.
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Page/Page column 138
(2010/11/24)
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- PHOSPHODIESTERASE INHIBITORS
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The present invention relates to purine derivatives, which can be used as selective phosphodiesterase (PDE) type IV inhibitors. Compounds disclosed herein can be useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases especially in humans. Also provided are processes for the preparation of disclosed compounds, pharmaceutical composition containing the disclosed compounds and their use as selective phosphodiesterase (PDE) type IV inhibitors.
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Page/Page column 33
(2008/06/13)
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- Design, synthesis and structure-activity relationships of a series of 9-substituted adenine derivatives as selective phosphodiesterase type-4 inhibitors
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Adenine derivatives substituted in position 9 have been demonstrated to have potent cyclic nucleotide phosphodiesterase (PDE) inhibition properties with high selectivity toward PDE-4. Starting from our initial lead compound 9-(2-fluorobenzyl)-N6-methyl-2-trifluoromethyladenine (4, NCS613), we designed and synthesized a new series of 9-substituted derivatives for developing structure-activity relationship studies. This new series of derivatives showed increased potencies and better selectivity profiles. Structural modifications were achieved in parallel on three different positions of the adenine ring, and led to the following observations: (i) introduction of a lipophilic substituent such as trifluoromethyl, n-propyl group or iodine in the C-2 position is favourable for both the PDE-4 inhibitory activity and the selectivity towards other isoenzymes; (ii) functionalization of the N9 benzyl group with a 2-methoxy substituent led to remarkably more active compounds; (iii) replacement of the N6-methylamino moiety by other amino groups is detrimental to the activity. Among all derivatives prepared, the 9-(2-methoxybenzyl)-N6-methyl-2-trifluoromethyladenine (9r), 9-(2-methoxybenzyl)-N6-methyl-2-n-propyladenine (9s), and the 2-iodo-9-(2-methoxybenzyl)-N6-methyladenine (13b) were found to be the most potent inhibitors within this series (PDE-4-IC50=1.4, 7.0, and 0.096 nM, respectively). Compared to our reference compound 4, which showed an IC50 of 42 nM, the derivative 13b was found 450-fold more potent. Moreover, 2-iodo-9-(2-methoxybenzyl)-N6-methyladenine (13b) and 9-(2-methoxybenzyl)-N6-methyl-2-trifluoromethyladenine (9r), were at least 50 000-150 000 times more selective for the PDE-4 than for the other PDE families. Additionally, these new derivatives showed improved efficiency in inhibiting the TNFα release from mononuclear cells from healthy subjects (e.g. adenines 7l, 9s and 13b). Thus, compounds 7l, 9r, 9s and 13b are among the most potent and selective PDE-4 inhibitors reported so far and represent very promising pharmacological tools for a better understanding of the signal transduction involving cyclic AMP within the cell: this pathway is implicated in the physiology and the pathophysiology of inflammation, asthma and autoimmune disorders.
- Raboisson, Pierre,Lugnier, Claire,Muller, Christian,Reimund, Jean-Marie,Schultz, Dominique,Pinna, Guillaume,Le Bec, Alain,Basaran, Helene,Desaubry, Laurent,Gaudiot, Francois,Seloum, Mohamed,Bourguignon, Jean-Jacques
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p. 199 - 214
(2007/10/03)
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- Purines. LXXII. Oxidation of N6-alkyladenines with m-chloroperoxybenzoic acid leading to N6-alkyladenine 1-oxides
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Oxidations of N6-methyladenine (8a) and N6-benzyladenine (8b) with m- chloroperoxybenzoic acid (mcpba) in methanol have been found to afford the N(1)-oxides 7a,b in 36% and 35% yields, respectively. The structure of 7b has been established by leading it to N6-methoxyadenine (10) through O- methylation, Dimroth rearrangement, and nonreductive debenzylation. On the other hand, N6,N6-dimethyladenine (16) afforded the N(3)-oxide 17 in 40% yield on treatment with Mcpba in methanol. On the basis of these findings, together with data accumulated for N-oxidations of adenine, N(x)- monosubstituted adenines, and 6-substituted purines, the formation of hydrogen bonding between the 6-amino Nh and the carbonyl oxygen of a peroxycarboxylic acid may account for regioselective N(1)and N(7)-oxidations of adenine and N(x)-monosubstituted adenines.
- Itaya, Taisuke,Ogawa, Kazuo,Takada, Yasutaka,Fujii, Tozo
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p. 967 - 971
(2007/10/03)
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- Process for preparing N6,9-disubstituted adenine
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A process for preparing N6, 9-disubstituted adenines which comprises reacting a metal salt of N6 -substituted adenine with a benzyl halide compound, preferably in the presence of a phase transfer catalyst. According to the process, the N6,9-disubstuted adenines can be obtained in high yields and good selectivity.
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- A 15N-STUDY ON THE DEAMINATION OF 1-AMINOPURINIUM SALTS WITH AMINES
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Reaction of 1-aminoadenosinium mesitylenesulphonate, 1a, with methanolic ammonia for 10 h at 80 deg C yields adenosine, 7a, and nebularine, 6a.With methanolic methylamine 1a gives 6-methylamino-9-β-D-ribofuranosylpurine, 8a, and adenosine, 7a, respectively.Similar results are obtained with the salt of 1-amino-2',3'-O-isopropylideneadenosine, 1b. 1-Aminoadeninium mesitylenesulphonate, 1c, with methanolic methylamine only yields 6-(methylamino)purine, 8c.In contrast, the mesitylenesulphonate salt of 1,2-diaminopurine, 11, with methanolic methylamine gives only deamination at N1, affording 2-aminopurine, 12.Studies with 15N-labelled methanolic ammonia or 15N-labelled purinium compounds show that in all these reactions, except that of 11, a ring-opening mechanism (ANRORC-mechanism) is involved.
- Kos, Nico J.,Jongejan, Hugo,Plas, Henk C. van der
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p. 369 - 374
(2007/10/02)
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- The Chemistry of N-Substituted Benzotriazoles. Part 4. A Novel and Versatile Method for the Mono-N-alkylation of Aromatic and Heteroaromatic Amines
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Mono-N-alkylation of aromatic and heteroaromatic amines is achieved in high yield by NaBH4 reduction of the adducts formed from benzotriazole, aliphatic aldehydes and the amines.Reaction of the same adducts with Grignard reagents gives N-(secondary alkyl)arylamines.Carboxy groups need no protection and nitro groups are unaffected.Adenine is mono-N-alkylated in high yield.
- Katritzky, Alan R.,Rachwal, Stanislaw,Rachwal, Bogumila
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p. 805 - 810
(2007/10/02)
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- Production of purine derivatives and intermediates therefor
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Improved processes for producing purine derivatives, such as 9-(2-chloro-6-fluorobenzyl)-6-methylaminopurine, which are useful as anticoccidial agents, and new arylazopyrimidine compounds of the formula: STR1 wherein R1 and R2 each is hydrogen, C1-3 alkyl, allyl or dihalobenzyl, and when either one of R1 and R2 is hydrogen, the other is other than hydrogen, and R3 is aryl, and acid addition salts thereof, which are useful as intermediates for production of the purine derivatives.
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- METHYLATION OF ADENINE AND THERMAL TRANSFORMATIONS OF ITS N-METHYL DERIVATIVES
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The methylation of adenine with methyl iodide in DMFA at 20-30 deg C gives the products from kinetically controlled reactions, i.e., 3-methyl- and 1-methyl-adeninium salts, and the reaction at 100 deg C gives 3-methyl- and 1,9-dimethyladeninium salts.The reaction mixture formed under more drastic conditions (150 deg C) consists mainly of thermodynamically stable 3,7- and 1,9-dimethyladeninium iodides.The transformation from the 1- and 3-methyladeninium iodides to the thermodynamically stable 9-methyladenine is only observed during fusion.
- Muravich-Aleksandr, Kh. L.,Pernikoza, V. G.,Girshovich, M. Z.,Ragozina, T. N.
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p. 2094 - 2099
(2007/10/02)
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- SYNTHESIS AND GLYCOSIDIC BOND CLEAVAGE OF 7-METHYL- AND 7-ETHYL-ADENOSINES: AN ALTERNATIVE SYNTHESIS OF 7-ALKYLADENINES
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7-Methyladenosine perchlorate (VIIa: X = ClO4) was prepared in pure and crystalline form from N6-methoxyadenosine (I) by methylation with MeI at the 7-position followed by catalytic hydrogenolysis of the N6-methoxy group. 7-Ethyladenosine perchlorate (VIIb: X = ClO4) was also synthesized from N6-benzyloxyadenosine (II) in an analogous manner.On treatment with H2O at 98-100 deg C for 40 min, VIIa (X = ClO4) and VIIb (X = ClO4) produced 7-methyladenine (VIIIa) and 7-ethyladenine (VIIIb) in 84percent and 55percent yields.In 0.1 N aqueous HCl at 25 deg C, VIIa (X = ClO4) and VIIb (X = ClO4) were hydrolyzed in similar manners at rates of 2.22E-3 min-1 and 1.69E-3 min-1, respectively.Comparison of these rate conctants with those of other three N-methyladenosine isomers X, XI, and XII has revealed that the relative ease of the hydrolysis of the glycosidic bond is in the order of 3- (XI) > 7- (VIIa) >> N6- (X) >/= 1-methyladenosine (XII).
- Fujii, Tozo,Saito, Tohru
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p. 117 - 123
(2007/10/02)
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