31-05-2012, 04:08 PM
pyrimidine compounds
[attachment=23733]
Substituted fused pyrimidine compounds
Fused pyrimidine derivs., such as I [R1 = alkyl, alkenyl, hydroxyalkyl, etc.; R2 = H, CN, halogen, alkyl, haloalkyl, aryl, arylalkyl,etc.; R7 =
H, alkyl, alkenyl, aryl, etc.; R8 = X-A-B, where X = arylene or heteroarylene, A = bond, alkylene, alkenylene, alkynylene, heteroalkylene,
etc. and B = H, heterocyclyl, cycloalkyl, heteroaryl, acyl, amino, acylamino, etc.; Y = N, CR9 where R9 = H, OH, alkoxy, alkyl, aryl, etc.]
, were prepd. for therapeutic use in pharmaceutical compns. contg. them and methods of treating conditions and diseases that are
mediated by adenosine receptor activity. This invention also provided tautomers, polymorphs, stereoisomers, prodrugs, solvates, and
pharmaceutically acceptable salts of these fused pyrimidines. These compds. were claimed for use in the treatment, prevention or
suppression of diseases and disorders that may be susceptible to improvement by antagonism of the adenosine receptor, such as
asthma, chronic obstructive pulmonary disorder, angiogenesis, pulmonary fibrosis, emphysema, allergic diseases, inflammation,
reperfusion injury, myocardial ischemia, atherosclerosis, hypertension, congestive heart failure, retinopathy, diabetes mellitus, obesity,
inflammatory gastrointestinal tract disorders, autoimmune diseases, Parkinson's disease, Alzheimer's disease, restless leg syndrome,
nocturnal myoclonus, cerebral ischemia, Huntington's disease, Wilson's disease, multiple system atrophy and/or corticobasal
degeneration.
The Fate of C5' Radicals of Purine Nucleosides under Oxidative Conditions
The factors that influence the reactivity of C5' radicals in purine moieties under aerobic conditions are unknown not only in DNA, but
also in simple nucleosides. 5',8-Cyclopurine lesions are the result of a rapid C5' radical attack to the purine moieties before the reaction
with oxygen. These well-known lesions among the DNA modifications were suppressed by the presence of mol. oxygen in soln. Here
we elucidate the chem. of three purine-substituted C5' radicals (i.e., 2'-deoxyadenosin-5'-yl, 2'-deoxyinosin-5'-yl, and 2'-deoxyguanosin-
5'-yl) under oxidative conditions using g-radiolysis coupled with product studies. 2'-Deoxyadenosin-5'-yl and 2'-deoxyinosin-5'-yl radicals
were selectively generated by the reaction of hydrated electrons (eaq-) with 8-bromo-2'-deoxyadenosine and 8-bromo-2'-deoxyinosine
followed by a rapid radical translocation from the C8 to the C5' position. Trapping these two C5' radicals with Fe(CN)63- gave
corresponding hydrated 5'-aldehydes in good yields that were isolated and fully characterized. When an oxygen concn. in the range of
13-266 mM (typical oxygenated tissues) is used, the hydrated 5'-aldehyde is accompanied by the 5',8-cyclopurine nucleoside. The
formation of 5',8-cyclopurines is relevant in all expts., and the yields increased with decreasing O2 concn. The reaction of HO.bul.
radicals with 2'-deoxyadenosine and 2'-deoxyguanosine under normoxic conditions was also investigated. The minor path of C5'
radicals formation was found to be ca.
Process for the preparation of nucleic acid base having perfluoroalkyl group
Process for producing a nucleic acid base having a perfluoroalkyl group, characterized by reacting a halogenated perfluoroalkane
represented by Rf-X [Rf = perfluoroalkyl; X = halo] with a nucleic acid base in the presence of a sulfoxide represented by R1a-SO-R1b
[R1a, R1b = alkyl, (un)substituted phenyl], a peroxide and an iron compd., was provided. For example, a mixt. of uracil (0.11 g), 1N
H2SO4 in DMSO (2.0 mL), trifluoromethyl iodide/DMSO (2.1 mol/L, 1.0 mL), aq. hydrogen peroxide (30%, 0.2 mL), and aq. FeSO4 (1.0
mol/L, 0.3 mL) was stirred at 40-50° for 20 min afforded 5-trifluoromethyluracil (0.17 g).
Preparation of bicyclic imidazolyl pyrimidinones as cannabinoid receptor ligands
disclosed as ligands of the cannabinoid receptor. Thus, e.g., II was prepd. by cyclization of 2-chloro-N-[4-chloro-6-(4-
chlorophenylamino)-pyrimidin-5-yl]benzamide (prepn. given) under acidic conditions followed by alkylation with 2-iodopropane. The
activity of I was evaluated in binding assays and it was revealed that selected compds. of the invention displayed binding activities from
0.5 to 5000 nM. I as cannabinoid receptor ligand should prove useful in the treatment of eating disorders and obesity. Pharmaceutical
compns. comprising I are disclosed.
[attachment=23733]
Substituted fused pyrimidine compounds
Fused pyrimidine derivs., such as I [R1 = alkyl, alkenyl, hydroxyalkyl, etc.; R2 = H, CN, halogen, alkyl, haloalkyl, aryl, arylalkyl,etc.; R7 =
H, alkyl, alkenyl, aryl, etc.; R8 = X-A-B, where X = arylene or heteroarylene, A = bond, alkylene, alkenylene, alkynylene, heteroalkylene,
etc. and B = H, heterocyclyl, cycloalkyl, heteroaryl, acyl, amino, acylamino, etc.; Y = N, CR9 where R9 = H, OH, alkoxy, alkyl, aryl, etc.]
, were prepd. for therapeutic use in pharmaceutical compns. contg. them and methods of treating conditions and diseases that are
mediated by adenosine receptor activity. This invention also provided tautomers, polymorphs, stereoisomers, prodrugs, solvates, and
pharmaceutically acceptable salts of these fused pyrimidines. These compds. were claimed for use in the treatment, prevention or
suppression of diseases and disorders that may be susceptible to improvement by antagonism of the adenosine receptor, such as
asthma, chronic obstructive pulmonary disorder, angiogenesis, pulmonary fibrosis, emphysema, allergic diseases, inflammation,
reperfusion injury, myocardial ischemia, atherosclerosis, hypertension, congestive heart failure, retinopathy, diabetes mellitus, obesity,
inflammatory gastrointestinal tract disorders, autoimmune diseases, Parkinson's disease, Alzheimer's disease, restless leg syndrome,
nocturnal myoclonus, cerebral ischemia, Huntington's disease, Wilson's disease, multiple system atrophy and/or corticobasal
degeneration.
The Fate of C5' Radicals of Purine Nucleosides under Oxidative Conditions
The factors that influence the reactivity of C5' radicals in purine moieties under aerobic conditions are unknown not only in DNA, but
also in simple nucleosides. 5',8-Cyclopurine lesions are the result of a rapid C5' radical attack to the purine moieties before the reaction
with oxygen. These well-known lesions among the DNA modifications were suppressed by the presence of mol. oxygen in soln. Here
we elucidate the chem. of three purine-substituted C5' radicals (i.e., 2'-deoxyadenosin-5'-yl, 2'-deoxyinosin-5'-yl, and 2'-deoxyguanosin-
5'-yl) under oxidative conditions using g-radiolysis coupled with product studies. 2'-Deoxyadenosin-5'-yl and 2'-deoxyinosin-5'-yl radicals
were selectively generated by the reaction of hydrated electrons (eaq-) with 8-bromo-2'-deoxyadenosine and 8-bromo-2'-deoxyinosine
followed by a rapid radical translocation from the C8 to the C5' position. Trapping these two C5' radicals with Fe(CN)63- gave
corresponding hydrated 5'-aldehydes in good yields that were isolated and fully characterized. When an oxygen concn. in the range of
13-266 mM (typical oxygenated tissues) is used, the hydrated 5'-aldehyde is accompanied by the 5',8-cyclopurine nucleoside. The
formation of 5',8-cyclopurines is relevant in all expts., and the yields increased with decreasing O2 concn. The reaction of HO.bul.
radicals with 2'-deoxyadenosine and 2'-deoxyguanosine under normoxic conditions was also investigated. The minor path of C5'
radicals formation was found to be ca.
Process for the preparation of nucleic acid base having perfluoroalkyl group
Process for producing a nucleic acid base having a perfluoroalkyl group, characterized by reacting a halogenated perfluoroalkane
represented by Rf-X [Rf = perfluoroalkyl; X = halo] with a nucleic acid base in the presence of a sulfoxide represented by R1a-SO-R1b
[R1a, R1b = alkyl, (un)substituted phenyl], a peroxide and an iron compd., was provided. For example, a mixt. of uracil (0.11 g), 1N
H2SO4 in DMSO (2.0 mL), trifluoromethyl iodide/DMSO (2.1 mol/L, 1.0 mL), aq. hydrogen peroxide (30%, 0.2 mL), and aq. FeSO4 (1.0
mol/L, 0.3 mL) was stirred at 40-50° for 20 min afforded 5-trifluoromethyluracil (0.17 g).
Preparation of bicyclic imidazolyl pyrimidinones as cannabinoid receptor ligands
disclosed as ligands of the cannabinoid receptor. Thus, e.g., II was prepd. by cyclization of 2-chloro-N-[4-chloro-6-(4-
chlorophenylamino)-pyrimidin-5-yl]benzamide (prepn. given) under acidic conditions followed by alkylation with 2-iodopropane. The
activity of I was evaluated in binding assays and it was revealed that selected compds. of the invention displayed binding activities from
0.5 to 5000 nM. I as cannabinoid receptor ligand should prove useful in the treatment of eating disorders and obesity. Pharmaceutical
compns. comprising I are disclosed.