Synthesis and evaluation of substituted 5-(3-chloro-2-oxo-4-phenylazetidin-1-ylamino)pyrimidine-2,4,6(1H,3H,5H)-triones against pentylenetetrazole-induced convulsant in mice

This study was designed to synthesis of substituted 5-(3-chloro-2-oxo-4-phenylazetidin-1-ylamino)pyrimidine-2,4,6(1H,3H,5H)-triones followed by evaluation against pentylenetetrazole-(PTZ) induced convulsant in mice. The titled compounds were confirmed by IR and ¹H-NMR spectral techniques. Pre-treatment of compound 4c showed significant anticonvulsant activity at 40?mg/kg which was comparable to that of PTZ and sodium valproate pre-treated groups. The results show the importance of barbituric acid derivative (i.e., compound 4c (R?=?p-OH, m-OCH₃) for this anti-convulsant activity. It may be due to its anti-oxidative and neuroprotective potential. Therefore, compound 4c emerged as the most active molecules in the management of convulsive disorder.     

Effect of 5-(Arylmethylidene)-2,4,6-Pyrimidine-2,4,6(1H,3H,5H)-Triones on the Course of Experimental Leprosy Infection

Pharmaceutical Chemistry Journal - The anti-leprosy activity of 5-(phenylmethylidene)- and 5-[(4-chlorophenyl)methylidene]-2,4,6-pyrimidine-2,4,6(1H,3H,5H)-triones was confirmed in in vivo...     

5-Fluoro (3H) pyrimidine-4-ones: synthesis, reactivity and pharmacological properties]

Fourteen fluoro pyrimidine-4-ones, four fluoro bispyrimidine-4-ones and two fluoro pyrimidine-4-ones with fused ring have been prepared. The reactivity of the carbonyl group of two pyrimidine-4-ones phosphorus oxychloride was studied. The 4-chloro pyrimidines reacted with ammonia or morpholine giving 4-substituted pyrimidines. Eight compounds are evaluated for their anti-inflammatory and anti-convulsivant properties: they were found to be weakly active against oedema and three of them protected rats form tonic convulsions.     

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.     

Synthesis and Biological Screening of 5-{[(4,6-Disubstituted pyrimidine-2-yl)thio]methyl}-N-phenyl-1,3,4-thiadiazol-2-amines

A number of substituted-α,β-unsaturated carbonyl compounds (1a-i) were prepared by Claisen-Schmidt condensation of substituted acetophenone with selected araldehydes, which on cycloaddition with thiourea furnished 4,6-disubstituted pyrimidine-2-thiols (2a-i). Reaction of (2a-i) with ethyl chloroacetate followed by condensation with hydrazine hydrate yielded 2-[(4,6-disubstituted pyrimidine-2-yl) thio] acetohydrazides (4a-c). Condensation of compounds (4a-c) with phenyl isothiocyanate gave 2-{[(4,6-disubstituted pyrimidine-2-yl) thio] acetyl}-N-phenylhydrazinecarbothioamides (5a-c) which on treatment with concentrated sulphuric acid afforded titled compounds 5-{(4,6-disubstituted pyrimidine-2-yl) thio] methyl}-N-phenyl-1,3,4-thiadiazole-2-amines (6a-c). These compounds have been characterized on the basis of elemental analysis, IR, (1)H NMR and MS. Compounds have been evaluated for their anticancer and antioxidant activities. Compounds 2b, 2c and 6b exhibited significant antitumor activity against human breast cancer MCF 7 cell line. However, moderate antioxidant activity was observed with compounds 2c, 2d, 2g and 6b.     

Synthesis and antiulcer activity of (E)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo [1,5-a]pyrimidine-7-ones

A series of (E)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo-[1,5-a]pyrimidine-7-ones were synthesized and evaluated for the inhibition of stress-induced gastric ulcers in the rat after oral administration. Several molecules were found to be very active. The particularly interesting compound (E)-1-(3-chlorophenyl)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo[1,5-a]- pyrimidine-7-one was chosen for wider pharmacological investigation.     

Synthesis and antimicrobial activity of coumarin pyrazole pyrimidine 2,4,6(1H,3H,5H)triones and thioxopyrimidine4,6(1H,5H)diones

A series of 5-((3-(2-oxo-2H-chromen-3-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-trione (4a–f) and dihydro-5-((3-(2-oxo-2H-chromen-3-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)-2-thioxopyrimidine-4,6(1H,5H)-dione (5a–f) derivatives were synthesized by the condensation of 3-(2-oxo2H-chromen-3-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde (3a–f) with barbituric acid and thiobarbituric acid in acetic acid under microwave irradiation method. The newly synthesized compounds were evaluated for their antibacterial activity against Bcillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeoginosa, and Klebsiella pneumoniae. All the compounds were found to be moderately active against used microorganisms, whereas compounds (4d) and (4e) exhibited good antifungal activity against Aspergillus niger.     

Conversion of 3-arylazo-5-phenyl-2(3H)-furanones into other heterocycles of anticipated biological activity

3-arylazo-5-phenyl-2(3H)-furanones 3 were prepared and converted into a variety of heterocyclic systems of synthetic and biological importance. Hydrazine hydrate reacted with furanones as nucleophiles and gave the corresponding acid hydrazides 4. The latter products were used as starting materials for the synthesis of 1,3,4-oxadiazoles 6, 9, and the 1,2,4-triazoles 8. Evaluation of the antiviral activity of selected compounds obtained was performed using two viruses: HAV and HSV-1. Some of the tested compounds showed promising activities.     

Synthesis and Antioxidant Activity of 7-Thio Derivatives of 6,7-Dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione

New 7-thio derivatives of 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione have been synthesized by the reaction of 3-cyclohexyl-7-thio-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione with alkylhalogenides. The synthesized compounds were tested for antioxidant activity on the model of Fe²⁺-dependent oxidation of adrenaline in vitro. It was found that the antiradical activity of 7-thio derivatives of 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione significantly depends on the structure of the substituent which is part of the thioether fragment of the base molecule.     

(6R,7R)-7-[2-呋喃基(甲氧亚氨基)乙酰氨基]-3-羟甲基-8-氧代-5-硫杂-1-氮杂二环[420]辛-2-烯-2-甲酸的合成研究

目的　制备(6R,7R) - 7-[2 -呋喃基(甲氧亚氨基)乙酰氨基] - 3-羟甲基- 8-氧代- 5 -硫杂- 1-氮杂二环[4 2 0]辛- 2 -烯- 2 -甲酸。方法　通过7-氨基头孢烷酸的水解,生成去乙酰基7-氨基头孢烷酸,再与2 - (2 -呋喃基)- 2 -甲氧亚胺基乙酸氯反应进行7位氨基的酰化制备上述医药中间体。结果及结论　适宜的反应条件为:7-氨基头孢烷酸在- 2 5℃水解,与2 - (2 -呋喃基) - 2 -甲氧亚胺基乙酰氯在- 10℃反应,二者的摩尔比为1 0∶1. 15,收率可达80 %。     

Pharmacological properties of the orally active leukotriene antagonist [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl]thio]-1,3,4- thiadiazol-2-yl]thio]acetic acid

The anti-leukotriene effect of [[5-[[3-(4-acetyl-3-hydroxy -2- propylphenoxy)propyl] thio]-1,3,4-thiadiazol-2-yl] thio] acetic acid (YM-16638) was examined. In isolated guinea-pig ileum, YM-16638 antagonized the contractions induced by slow reacting substance of anaphylaxis (SRS-A) and leukotriene D4 (LTD4) with IC50 values of 6.0 x 10(-8) and 1.1 x 10(-7) mol/l, respectively. However, the compound at 10(-5) mol/l did not affect the contractions induced by histamine, acetylcholine, 5-hydroxytryptamine, prostaglandin (PG)E2 and PGF2 alpha. In isolated guinea-pig trachea, YM-16638 inhibited the contractions elicited by LTC4, LTD4 and LTE4 and its IC50 values were 5.7 x 10(-8), 1.6 x 10(-7) and 9.6 x 10(-8) mol/l, respectively. In isolated human bronchi, YM-16638 also antagonized the contractions induced by LTC4, LTD4 and LTE4 and its IC50 values were 6.0 x 10(-8), 1.2 x 10(-7) and 2.1 x 10(-8) mol/l, respectively. YM-16638 at the doses of 3 to 100 mg/kg p.o. inhibited the skin reaction induced by LTD4 in conscious guinea-pigs and its ED50 value was 17.9 mg/kg p.o. Successive oral administration of YM-16638 (50 mg/kg/d) for 10 days did not develop tolerance in its inhibitory effect against LTD4-induced skin reaction. Furthermore, the compound at the doses of 10 and 30 mg/kg p.o. significantly inhibited the antigen-induced bronchoconstriction in conscious guinea-pigs pretreated with mepyramine, propranolol and indomethacin. These results indicate that YM-16638 is a selective, potent and orally active leukotriene antagonist.     

Antiallergic properties of an orally effective agent, [[3-(1H-tetrazol-5-yl)-phenyl] amino] oxoacetic acid n-butyl ester

A newly synthesized compound, [[3-(1H-tetrazol-5-yl)-phenyl] amino]oxoacetic acid n-butyl ester (MTB) has been demonstrated to be an orally active antiallergic agent. This compound inhibited the 48-hr passive cutaneous anaphylaxis (48-hr PCA) induced by IgE in rats. In guinea pigs, MTB also inhibited the 8-day passive cutaneous anaphylaxis (8-day PCA) and the 8-day passive systemic anaphylaxis induced by IgE. The compound partially inhibited the IgG-mediated 3-hr PCA in rats and guinea pigs, but failed to have any effect on the rabbit IgG-mediated 3-hr PCA in these animals. In the rat, MTB was not an antagonist of histamine or serotonin. The antiallergic effect of MTB was not mediated via any adrenergic mechanisms. MTB significantly inhibited histamine release from rat peritoneal cells induced by rat IgE in vitro.     

Determinants of 1-piperidinecarboxamide, N-[2-[[5-amino-l-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS) affinity for calcitonin gene-related peptide and amylin receptors--the role of receptor activity modifying protein 1

1-Piperidinecarboxamide, N-[2-[[5-amino-l-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS), a calcitonin gene-related peptide (CGRP) receptor antagonist, can alleviate the symptoms of migraine and is highly selective for CGRP over adrenomedullin (AM) receptors. These receptors are heterodimers of the calcitonin receptor-like receptor (CL) and receptor activity modifying proteins (RAMPs), with the pharmacological properties determined by the RAMP subunit. BIBN4096BS-sensitive CGRP(1) receptors are CL/RAMP1, whereas BIBN4096BS-insensitive AM receptors are CL/RAMP2 or CL/RAMP3 (AM(1) and AM(2), respectively), implicating RAMP1 in conferring BIB-N4096BS sensitivity. Because calcitonin receptors [CT((a))] also interact with RAMP1 [AMY(1(a)) receptors], BIBN4096BS could also have affinity for these receptors. To test this, receptors were transfected into COS-7 cells and agonist-stimulated cAMP levels measured in the presence and absence of antagonists. We found that AMY(1(a)) receptors were approximately 150-fold less sensitive to BIBN4096BS antagonism than CGRP(1) receptors. In contrast, AMY(3(a)) [CT((a))/RAMP3] or AM(2) receptors were not sensitive to BIBN4096BS antagonism. We investigated Trp74 in RAMP1, a residue implicated in the species selectivity of BIBN4096BS. BIBN4096BS affinity was reduced at AMY(1(a)) and CGRP(1) receptors when this residue was mutated to lysine or alanine. The equivalent residue in RAMP3, Glu74, when mutated to tryptophan (E74W), induced BIBN4096BS sensitivity at AM(2) and AMY(3(a)) receptors. It is interesting that a selective reduction in AM potency was observed at E74W AM(2) receptors, implicating this residue in AM interactions with this receptor. These data support the importance of Trp74 in RAMP1 in the interaction of BIBN4096BS with CGRP(1) and AMY(1(a)) receptors and identified Glu74 in RAMP3 as the first amino acid in RAMP important for agonist interactions with calcitonin-family receptors.     

Novel, potent aldose reductase inhibitors: 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl] methyl]-1-phthalazineacetic acid (zopolrestat) and congeners

A new working hypothesis that there is a hitherto unrecognized binding site on the aldose reductase (AR) enzyme with strong affinity for benzothiazoles was pursued for the design of novel, potent aldose reductase inhibitors (ARIs). The first application of this hypothesis led to a novel series of 3,4-dihydro-4-oxo-3-(benzothiazolylmethyl)-1-phthalazineacetic+ + + acids. The parent of this series (207) was a potent inhibitor of AR from human placenta (IC50 = 1.9 x 10(-8) M) and was orally active in preventing sorbitol accumulation in rat sciatic nerve, in an acute test of diabetic complications (ED50 = 18.5 mg/kg). Optimization of this lead through medicinal chemical rationale, including analogy from other drug series, led to more potent congeners of 207 and culminated in the design of 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl] methyl]-1-phthalazineacetic acid (216, CP-73,850, zopolrestat). Zopolrestat was found to be more potent than 207, both in vitro and in vivo. Its IC50 against AR and ED50 in the acute test were 3.1 x 10(-9)M and 3.6 mg/kg, respectively. Its ED50s in reversing already elevated sorbitol accumulation in rat sciatic nerve, retina, and lens in a chronic test were 1.9, 17.6, and 18.4 mg/kg, respectively. It was well absorbed in diabetic patients, resulting in high blood level, showed a highly favorable plasma half-life (27.5 h), and is undergoing further clinical evaluation. An assortment of synthetic methods used for the construction of benzothiazoles, including an efficient synthesis of zopolrestat, is described. Structure-activity relationships in the new series are discussed.     

4-[[1-[(4-氟苯基)甲基]-1H-2-苯并咪唑基]氨基]-1-哌啶甲酸乙酯的合成

以邻苯二胺为起始原料，经过缩合、氯代、烷基化和取代反应来合成4-[[1-[（4-氟苯基）甲基]-1H-2-苯并咪唑基]氨基]-1-哌啶甲酸乙酯。该合成方法操作简单，总收率达到30．7％。     

3-(Nitrobenzylidene)-2,4(3H,5H)-furandione in the Hantzsch-pyridine synthesis 2. 6,7-Dihydrophthalide

Melting the 3-(o- and p-nitrobenzylidene)tetronic acids 2a and 2c with the enaminocarbonyl compounds 1 at 70-90 degrees C yields the hexahydro-7a-hydroxyfuro[3,4-b]-pyridines 3, while with the m-nitro compound 2b at 100 degrees C the 6,7-dihydrophthalides 4 are obtained. Dehydrogenation of the dihydro derivatives 4 with activated manganese dioxide affords the phthalides 5.     

3,4-dihydro-2(1H)-quinolinone as a novel antidepressant drug: synthesis and pharmacology of 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3,4- dihydro-5-methoxy-2(1H)-quinolinone and its derivatives

To develop a novel antidepressant drug with central nervous system-stimulating activity, we prepared a series of 1-[omega-(4-substituted phenyl-1-piperazinyl)alkyl]-3, 4-dihydro-2(1H)-quinolinone derivatives and examined their activities by their effects at 30 and 100 mg/kg po on the sleeping time of mice anesthetized with halothane and on the time required for recovery from coma induced in mice by cerebral concussion. We examined their binding affinities for sigma receptors by evaluating their ability to inhibit [(3)H]-1,3-di(o-tolyl)guanidine ([(3)H]DTG) binding to the rat whole brain membrane in comparison with three putative sigma receptor agonists: 1,3-di(o-tolyl)guanidine (DTG, 66), (+)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2, 6-methano-3-benzazecin-8-ol (SKF10,047, 67), and (+)-1,2,3,4,5, 6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2, 6-methano-3-benzazecin-8-ol (pentazocine, 68). Among the series of derivatives, 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3, 4-dihydro-5-methoxy-2(1H)-quinolinone hydrochloride (34b) and its mesylate (34c), at a dose of 30 mg/kg po, reduced the sleeping time and the time for recovery from coma and they inhibited [(3)H]DTG binding for sigma receptors. The putative sigma receptor agonists reduced the sleeping time and the time for recovery from coma whereas two sigma receptor antagonists, alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol hydrochloride (BMY14802, 69) and cis-9-[3-(3, 5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride (rimcazole, 70), were inactive in the two tests. Preadministration of the putative sigma receptor antagonists 69 (3 mg/kg po) and 70 (30 mg/kg po) completely antagonized the actions of 34b and the sigma receptor agonists in the test for recovery from coma. These results suggested that 34b and 34c are sigma receptor agonists. Furthermore, a single administration of 1 and 10 mg/kg po 34b and 34c showed antidepressant-like activity by reducing the immobility time in the forced-swimming test with mice, while a tricyclic antidepressant, 10, 11-dihydro-N,N-dimethyl-5H-dibenz[b,f]azepine-5-propanamine hydrochloride (imipramine, 1) (10 and 30 mg/kg po), did not reduce the time after a single administration. 1 reduced the time after repeated administration of 30 mg/kg po once a day for 4 days. The structure-activity relationship of the series of compounds is also discussed.     

Characterization of 2-[[4-[[2-(1H-tetrazol-5-ylmethyl)phenyl]methoxy]methyl]quinoline N-glucuronidation by in vitro and in vivo approaches.

RG 12525 is a new chemical entity recently evaluated for the treatment of type II diabetes. Clinical studies have previously identified the tetrazole N2-glucuronide conjugate of RG 12525 as the predominant metabolite in plasma following oral administration of RG 12525. Species differences in RG 12525 glucuronidation were first investigated with incubations of RG 12525 with rat, monkey, and human hepatocytes. The results showed the N2-glucuronide to be the major metabolite in human and monkey samples, with only low levels observed for the rat. The formation of this glucuronide by human liver microsomes was subsequently characterized. RG 12525 N2-glucuronidation was found to have a pH optimum of 7.0 to 7.5 and demonstrated a high affinity with a K(m) range of 16.6 to 21.1 microM RG 12525 (n = 3). The rate of N2-glucuronide formation ranged from 2.5 to 15.4 nmol of RG 12525 N2-glucuronide formed/min/mg of protein ( approximately 6-fold) in the 21 samples assayed. The reaction was inhibited by known substrates for glucuronidation, with imipramine (62%), naringenin (44%), and scopoletin (38%) producing the largest degree of inhibition at equimolar concentrations of substrate and inhibitor. Of the eight expressed UDP-glucuronosyltransferase (UGT) forms assayed, UGT1A1 and 1A3 displayed the highest rate of RG 12525 N2-glucuronidation (0.109 and 0.125 nmol/min/mg, respectively). Finally, low levels of N2-glucuronidation of RG 12525 by human jejunum microsomes were demonstrated, suggesting that presystemic clearance via glucuronidation may constitute a barrier to bioavailability.