- 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 0049-0050
(2014/10/16)
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- Synthesis and cytostatic activity of N-[2-(phosphonomethoxy)alkyl] derivatives of N6-substituted adenines, 2,6-diaminopurines and related compounds
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N6-Substituted adenine and 2,6-diaminopurine derivatives of 9-[2-(phosphonomethoxy)ethyl] (PME), 9-[(R)-2-(phosphonomethoxy)propyl] [(R)-PMP] and enantiomeric (S)-PMP series were synthesized by reactions of primary or secondary amines with 6-chloro-9-{[2-(diisopropoxyphosphoryl)methoxy]alkyl}purines (26-28) or 2-amino-6-chloro-9-{[2-(diisopropoxyphosphoryl)methoxy]alkyl}purines (29-31) followed by treatment of the diester intermediates 32 with bromo(trimethyl)silane and hydrolysis. Diesters 32 were also obtained by reaction of N6-substituted purines with synthons 23-25 bearing diisopropoxyphosphoryl group. Alkylation of 2-amino-6-chloropurine (9) with diethyl [2-(2-chloroethoxy)ethyl]phosphonate (148) gave the diester 149 which was analogously converted to N6-substituted 2,6-diamino-9-[2-(2-phosphonoethoxy)ethyl]purines 151-153. Alkylation of N6-substituted 2,6-diaminopurines with (R)-[(trityloxy)methyl]oxirane (155) followed by reaction of thus-obtained intermediates 156 with dimethylformamide dimethylacetal and condensation with diisopropyl [(tosyloxy)methyl]phosphonate (158) followed by deprotection of the intermediates 159 gave N6-substituted 2,6-diamino-9-[(S)-3-hydroxy-2-(phosphononiethoxy)propyl]purines 160-163. The highest cytostatic activity in vitro was exhibited by the following N6-derivatives of 2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine (PMEDAP): 2,2,2-trifluoroethyl (53), allyl (54), [(2-dimethylamino)ethyl] (68), cyclopropyl (75) and dimethyl (91). In CCRF-CEM cells, the cyclopropyl derivative 75 is deaminated to the guanine derivative PMEG (3) which is then converted to its diphosphate.
- Holy, Antonin,Votruba, Ivan,Tloustova, Eva,Masojidkova, Milena
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p. 1545 - 1592
(2007/10/03)
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- An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy
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A general and efficient synthesis of carbocyclic and hexenopyranosyl nucleosides has been developed. The strategy combines three key transformations: an asymmetric aldol addition to establish the relative and absolute configuration of the pseudosugar, a ring-closing metathesis to construct the pseudosugar ring, and a Trost-type palladium(0)-mediated substitution to assemble the pseudosugar and the aromatic base. Carbovir, abacavir, and their 2'-methyl derivatives as well as hexenopyranosyl nucleoside analogues have been prepared by this sequence.
- Crimmins,King,Zuercher,Choy
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p. 8499 - 8509
(2007/10/03)
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