Antiinflammatory activity of substituted 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-triones. Atypical nonsteroidal antiinflammatory agents

A novel class of antiinflammatory drugs, which are substituted derivatives of the fused tricyclic system 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione, is described. Synthetic procedures and structure determination with the assistance of X-ray crystallography are discussed. Semiempirical molecular orbital calculations are used to investigate the relative stability of the possible isomers and tautomers of the title compounds. A biological profile of the class, and of several of the more potent analogues, in several antiinflammatory models, including the adjuvant-induced arthritis and the collagen II models, is defined. Several members of the class are shown to possess extremely low ulcerogenic effects in spite of exhibiting cyclooxygenase inhibition. A preliminary bioavailability study of two of the lead structures is presented. The compounds 6-72 appear to constitute a class of drugs that shows interesting potential antiarthritic activity and also exhibits an activity profile different from that of the standard classical NSAI drugs, as determined by a comparison of the profile of this class of drug with that of several standard agents. Certain findings from toxicological studies have precluded the further development of compounds within this group, although related structural types are being investigated.     

3-Hydroxy-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-ones as new HIV-1 integrase inhibitors WO2011046873 A1

Since the discovery of raltegravir, the first FDA-approved integrase inhibitor, Merck and other pharmaceutical companies have continued their research programs in order to introduce novel molecules as second generation integrase inhibitors. Elvitegravir (Japan Tobacco/Gilead) and dolutegravir (Shionogi/GlaxoSmithKline) are in advanced stages of clinical development. Bristol-Myers Squibb has developed molecules leading to BMS-707035, which was stopped at the Phase II clinical trial stage. Herein is presented the last patent from this company where, in particular, new 3-hydroxy-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-ones are synthesized and their biological properties given.     

3-Hydroxy-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-ones as new HIV-1 integrase inhibitors WO2011046873 A1

Since the discovery of raltegravir, the first FDA-approved integrase inhibitor, Merck and other pharmaceutical companies have continued their research programs in order to introduce novel molecules as second generation integrase inhibitors. Elvitegravir (Japan Tobacco/Gilead) and dolutegravir (Shionogi/GlaxoSmithKline) are in advanced stages of clinical development. Bristol-Myers Squibb has developed molecules leading to BMS-707035, which was stopped at the Phase II clinical trial stage. Herein is presented the last patent from this company where, in particular, new 3-hydroxy-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-ones are synthesized and their biological properties given.     

Antiinflammatory activity of a series of substituted 2,3-dihydro-6-hydroxypyrimido[2,1-f]purine-4,8(1H,9H)-diones

A series of substituted analogues based on the novel 2,3-dihydro-6-hydroxypyrimido[2,1-f]purine-4,8(1H,9H)-dione ring system have been synthesized and shown to exhibit antiinflammatory activity in the adjuvant-induced arthritis rat model (AAR). The activity exhibited by the pyrimidopurinediones in this model of chronic inflammation is comparable to that of their previously studied 2-oxo congeners, the 6-hydroxypyrimido[2,1-f]purine-2,4,8-(1H,3H,9H)-triones, the best of which show potency levels approximately equal to that of naproxen. On the basis of its potency in the AAR assay, 9-benzyl-2,3-dihydro-1,3-dimethyl-6-hydroxy-7-(3-methyl-2-butenyl) pyrimido-[2,1-f]purine-4,8(1H,9H)-dione was selected for further evaluation and found to exhibit cyclooxygenase inhibitory activity in the in vitro rat neutrophil model. With respect to side-effect liability, this prenylated derivative has been shown to be devoid of gastric ulcer inducing potential, as well as the ocular toxicity observed previously with the 2-oxo series.     

Substituted 6,7-dihydroimidazo[1,2-a]purin-9(4H)-ones

The synthesis of a series of substituted 6,7-dihydroimidazo[1,2-a]purin-9(4H)-ones is described. Several members of the series exhibit enhanced antiallergic and bronchodilator activity and reduced side effects as compared to theophylline. Structure-activity relationships and metabolic considerations are discussed for the series. Analogues substituted with a 4-(4-chlorobenzyl) moiety, such as 33 and 40, shown an optimal balance of antiallergic and bronchodilator activity and are of particular interest. Compound 33 is significantly more potent than theophylline against both metacholine- and antigen-induced bronchospasms, does not affect spontaneous motor activity, and shows minimal cardiovascular effects in the rat.     

Imidazo[4,5-f]quinolines III: Antibacterial 7-methyl-9-(substituted arylamino)imidazo[4,5-f]quinolines.

A series of 7-methyl-9-(substituted arylamino)imidazo[4,5-f]quinolines was prepared and screened against four varieties of bacteria. The compounds possessed antibacterial activity against both Gram-positive and Gram-negative organisms.     

Cardiovascular effect of a novel substance, 3-[2-[4-(o-methoxyphenyl)-1-piperazinyl] ethyl]-2,4 (1H, 3H)-quinazolinedione monohydrochloride (SGB 1534)

During the search for a new antihypertensive substance, the author and his co-workers found that SGB 1534 has a potent vasodepressor action. However, its pharmacological properties are not well-known. Therefore, we examined the cardiovascular effect and the site of action of this substance. In anesthetized beagle dogs, SGB 1534 (0.01 micrograms/kg, i.v.) caused a 8% fall in mean systemic blood pressure. It caused a transient increase in aortic blood flow. Heart rate was increased transiently and was decreased thereafter. Systemic vascular resistance was reduced, but Vpm and time constant "T" were little influenced by this substance. The phenylephrine-induced vasopressor effect was eliminated by SGB 1534. In dogs pretreated with propranolol and prazosin, the norepinephrine-induced vasopressor effect was suppressed by yohimbine, but not by SGB 1534. In dogs pretreated with prazosin and yohimbine, isoproterenol-induced increase in heart rate was not influenced by this substance. The results indicate that SGB 1534 is a potent alpha 1-adrenoreceptor blocking substance.     

Synthesis and Biochemical Testing of 3-(Carboxyphenylethyl)imidazo[2,1-f][1,2,4]triazines as Inhibitors of AMP Deaminase

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New pyrrolo[2,1-f]purine-2,4-dione and imidazo[2,1-f]purine-2,4-dione derivatives as potent and selective human A3 adenosine receptor antagonists

Compounds presenting an additional fused ring on the xanthine nucleus have been reported to exhibit antagonistic activity with various levels of affinity and selectivity toward the four adenosine receptors subtypes A(1), A(2A), A(2B), and A(3). This paper reports synthesis and biological evaluation of new 1-benzyl-3-propyl-1H,6H-pyrrolo[2,1-f]purine-2,4-diones and 1-benzyl-3-propyl-1H,8H-imidazo[2,1-f]purine-2,4-diones, among which we identified potent and selective A(3) adenosine receptors antagonists. In particular, 1-benzyl-7-methyl-3-propyl-1H,8H-imidazo[2,1-f]purine-2,4-dione (11e) shows a K(i) (hA(3)) value from binding assay of 0.8 nM.     

3H]N-[4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl]-2-methoxy-5-methylbenzamide: a novel sigma-2 receptor probe

N-[4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl]-2-methoxy-5-methyl-benzamide (RHM-1) and N-[2-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)ethyl]-2-methoxy-5-methylbenzamide (RHM-2), two conformationally flexible benzamide analogues, were radiolabeled with tritium (specific activity=80 Ci/mmol) and the binding of [3H]RHM-1 and [3H]RHM-2 to sigma-2 (sigma2) receptors was evaluated in vitro. [3H]RHM-1 was found to have a higher affinity for sigma2 receptors compared to [3H]RHM-2 and [3H]1,3-di-o-tolylguanidine ([3H]DTG). [3H]RHM-1 had a dissociation constant (Kd) of 0.66+/-0.12 nM in rat liver membrane homogenates, which was 30-fold higher than that of [3H]RHM-2 (Kd=19.48+/-0.51 nM). The lower affinity of [3H]RHM-2 can be attributed to its faster K(off) rate since both radioligands have similar K(on) rates. Competitive binding assays were also conducted using a panel of compounds with known affinity for sigma2 receptors. The pharmacologic profile of [3H]RHM-1 was in agreement with that of [3H]DTG. The results of this study indicate that [3H]RHM-1 is a useful ligand for studying sigma2 receptors in vitro.     

The pharmacokinetics of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) in Sprague-Dawley rats

Using adult male Sprague-Dawley rats, we examined the blood protein binding and pharmacokinetics of the potent phencyclidine (PCP) receptor ligand 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP). The average percentage of unbound [3H]TCP in rat serum was 42 +/- 6% and the [3H]TCP blood to plasma ratio was 0.98 +/- 0.03 (mean +/- SD, n = 5 in both studies). For the pharmacokinetic studies, [3H]TCP and 1 mg/kg unlabeled TCP were administered as an iv bolus dose. The average [3H]TCP elimination half-life was 2.1 hr. In contrast, total radioactivity in the plasma had a much longer half-life, suggesting much slower metabolite elimination. The average distribution volumes were 27 +/- 17, 15.6 +/- 6.2, and 5.6 +/- 3.0 liters/kg for V beta, Vss, and Vc, respectively. Total body and renal clearance values were 132 +/- 45 and 1.1 +/- 0.4 ml/min/kg, respectively. When TCP pharmacokinetic parameters were compared to PCP pharmacokinetic data in rats from a previous study, a strikingly similar pharmacokinetic profile was found. These data indicated that TCP and PCP are equivalent, from a pharmacokinetic point of view, and that the higher pharmacological potency of TCP over PCP is probably due to receptor-mediated differences.     

Synthesis and preliminary pharmacological assessment of novel 9-substituted pyrimidino-[2,1-f]-purines.

Synthesis, chemical properties and results of preliminary pharmacological evaluation of several new 9-substituted pyrimidino-[2,1-f]-purines are described. The most interesting was 1,3-dimethyl-2,4,8-trioxo-9-[gamma-N1-(N4-C6H5)-piperazynopropy l]-1,3,6,7-tetrahydro-9H-pyrimidino-[2,1-f]-purine (compound 4a), which exerted strong sedative, hypothermizing and cataleptogenic action and possessed some anti-amphetamine and anti-apomorphine properties.     

Imidazo[2,1-b]-1,3,4-thiadiazolo[3,2-a]pyrimidone-(6) aus 2-Acetoacetylamino-imidazo[2,1-b]-1,3,4-thiadiazolen

Imidazo[2,1-b]-1,3,4-thiadiazolo[3,2-α]pyrimidin-6-ones by Cyclisation of 2-(Acetoacetylamino)-imidazo[2,1-b]-1,3,4-thiadiazoles The 2-acetoacetylamino-6-methyl- (or -aryl) imidazo[2,1-b]-1,3,4-thiadiazoles 1, 2a–f cyclise on heating in polyphosphoric acid (PPA) to yield the tricyclic 2,8-dimethyl- or 2-aryl-8-methyl-imidazo[2,1-b]-1,3,4-thiadiazolo[3,2-α]pyrimidin-6-ones 3, 4a–f . Only 4c inhibits the growth of vaccinia viruses. The other compounds have no antiviral activity.     

1,3-二甲基-6-[2-(对甲苯磺酰氧基)乙基氨基]尿嘧啶的合成

目的:合成盐酸尼非卡兰中间体1,3-二甲基-6-[2-(对甲苯磺酰氧基)乙基氨基]尿嘧啶.方法:以二甲基脲和氰乙酸为原料经3步反应合成目标产物.结果:以氰乙酸计,总收率44.4%.目标产物的光谱数据与文献报道一致.结论:新的合成方法所用原料价廉易得,适合生产.     

Regioselective synthesis of [1]benzopyrano[4,3-c]pyrazol-4-(1H)-one and [1]benzopyrano[3,4-c]pyrazol-4(3H)-one derivatives

The cycloaddition reaction of N-phenyl-C-cinnamonitrilimine4 to coumarin leads to the formation of 3-styrylbenzopyrano[4,3-c]pyrazole derivative6, whereas 3-phenylsulfonylcoumarin 0163 0181 V 39 or 3-bromocoumarin10 or 3-cyanocoumarin11 gives 1-styrylbenzopyrano[3,4-c]pyrazole derivative7. Also, the cycloaddition of4 to 3-acetylcoumarin15 and 3-benzoylcoumarin16 gives the corresponding dihydropyrano[3,4-c]pyrazole adducts17 and18 respectively. Oxidation of17 and18 gives7.