Reactions with heterocyclic amidines (VI): Synthesis of some new sym. and assym. pyrazolotriazines and pyrazolo[4,5-e]pyrimidine derivatives

Several new pyrazolo[1,5-a]-S-triazine, pyrazolo[4,5-e]pyrimidine, pyrazolo [1,5-a]pyrimidine derivatives were synthesizedvia condensation of 3-antipyrinyl-5-aminopyrazole (2) with β-bifunctional reagents. The azo analogues of pyrazolo[1,5-a] pyrimidines;i.e pyrazolo[5,1-c]-as-triazine and pyrazolo[5,1-c]-as-benzotriazine were synthesized by coupling of diazotized 2 with agents containing active hydrogen.     

Synthesis and pharmacological evaluation of newer thiazolo [3,2-a] pyrimidines for anti-inflammatory and antinociceptive activity

A new series of thiazolo [3,2-a] pyrimidine derivatives was designed and synthesized using 4-fluoroaniline and ethylacetoacetate as starting material. Anti-inflammatory activity was assessed by the rat paw edema method and antinociceptive activity was evaluated by thermal stimulus technique. The compounds 5-(4-chlorophenyl)-2-(4-fluorobenzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid (4-fluorophenyl)amide (3l) and 2-(4-chlorobenzylidene)-5-(4-fluorophenyl)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid (4-fluorophenyl)amide (3q) were found to possess significant anti-inflammatory and antinociceptive activities. These compounds also showed lower ulcerogenic activity and higher ALD₅₀ values. Compounds with an aryl ring substituted with a smaller electron withdrawing group at the fourth position displayed better activity than the other derivatives.     

Preparation and bioevaluation of <Superscript>99m</Superscript>Tc nitrido radiopharmaceuticals with pyrazolo[1,5-a]pyrimidine as tumor imaging agents

The 7-(2-aminoethylamino)-5-methyl-3-cyanopyrazolo[1,5-a]pyrimidine (AMCPP) was synthesized and conjugated with N-mercaptoacetylglycine (MAG), N-mercaptoacetylphenylalanine (MAF), and N-mercaptoacetylvaline (MAA), respectively. These three compounds were labeled successfully with [^99mTcN]²⁺ intermediate in high radiochemical purities. Biodistribution in tumor-bearing mice demonstrated that the three new complexes showed high tumor-to-muscle (T/M) ratios and rapid clearance from the blood, muscle, liver, kidney, and lung. Among them, the ^99mTcN-MAG-AMCPP showed the most favorable characteristics. The tumor/blood and tumor/muscle ratios reached 1.50 and 1.15 at 30 min post-injection, 2.20 and 1.83 at 60 min post-injection.     

Patent Evaluation : EP-544445-A: ICI Plc: Novel nucleosides and pterdines as adenosine antagonists

Novelty: In these two patents furyl-substituted, oxazolopyrimidines and pteridines, and 2-heteroaryl-triazolo[1,5-a][1,3,5]triazines and pyrazolo[2,3-a][1,3,5]triazines are disclosed. All are useful as adenosine antagonists. The compounds have application for the treatment of diseases affecting the mammalian cardiac peripheral and cerebral vascular systems such as ischaemic heart disease and cerebral ischaemia, as well as migraine.

Biology: The antagonist ability of the compounds was assayed according to a method described by Williams et al. (J. Neurochem. (1987) 48(2): 498). Compounds exhibited pIC₅₀ values of 6 or more; one showed a 78% displacement of control binding at 10^-5M and 59% displacement at 10^-7M, indicating a pIC₅₀7 (CV9846). In the second application (CV9848), one compound exhibited a 97.3% displacement of control binding at a concentration of 10^-5M and 77.7% displacement at 10^-7M, indicating a pIC₅₀ of greater than 7, compared to the known compound 1,3-dimethylxanthine having a pIC₅₀ of about 5.

Chemistry: In CV9846 examples of twenty-nine syntheses are given. Twenty-six examples include 7-amino-2-(2-furyl)-5-[2-(4-methoxyphenyl)ethyl]amino-oxazolo[5,4-d]pyrimidine. Three examples of synthesise are given in CV9848; 7-amino-2-(2-furyl)-5-[2-[(4-dimethylaminoethyl-N-methylsulfonamido)-phenyl]ethyl]amino[1, 2,4]triazolo[1,5-a][1,3,5]triazine is one of three specifically claimed compounds.     

Inhibition of indoleamine-N-methyltransferase by 2,3,4,6,7,8-hexahydropyrrololo[1,2-a]pyrimidine.

2,3,4,6,7,8-Hexahydropyrrolo[l,2-a]pyrimidine is a potent inhibitor in vitro of indoleamine-N-methyltransferase, an enzyme present in animal and human lung catalyzing the conversion of N-methyltryptamine to N,N-dimethyltryptamine. It is a reversible inhibitor, non-competitive with respect to N-methyltryptamine. The compound does not block the activity of phenethanolamine- or imidazole-N-methyltransferases in vitro. When administered orally to rabbits, 2,3,4,6,7,8-hexahydropyrrolo[1.2-a]pyrimidine markedly reduces the specific activity of the lung indoleamine-N-methyltransferase. This inhibition of enzyme activity is accompanied by a block in the conversion of intravenously administered ¹⁴C-labeled N-methyltryptamine to [¹⁴C]dimethyltryptamine in lung and brain.     

Synthesis of several new isoxazole,imidazo[1,2-a]pyridine,imidazo[1,2-a]pyrimidine,benzoxadiazine and benzothiazine derivatives from hydroximoyl halides

Furoylhydroximoyl chloride3 reacted with 2-aminopyridine, 2-aminopyrimidine,O-aminophenol,O-phenylenediamine and aminothiophenol to afford imidazo[1,2-a]pyridine6, imidazo[1,2-a]pyrimidine8, benzoxadiazine10, nitrosobenzopyrazine13a and nitrosobenzothiazine13b, respectively. Isoxazoline18 and pyrrolidino[3,4-d]isoxazolin-4,6-dione derivatives19a and19b obtained by the reaction of3 with acrylonitrile and N-arylmaleimide. Hydroximoyl chloride3 reacted with thiophenol and sodium benzenesulfinate to yield furylglyoxaloxime16a and16b, respectively. Hydroximoyl chloride3 reacted also with some active methylene compound to give isoxazole derivatives20–23, respectively.     

Synthesis and biological evaluation of some pyrimidine, pyrimido[2,1-b][1,3]thiazine and thiazolo[3,2-a]pyrimidine derivatives

4,6-Diamino-1H-pyrimidine-2-thione (1) was used for the preparation of pyrimidine derivatives 2-5. Compound 5 was cyclized to produce pyrimido[2,1-b][1,3]thiazine derivative 6 which was condensed with p-chlorobenzaldehyde to give compound 7. The latter compound was reacted with hydroxylamine to give isoxazolo[4,5-d]thiazino[2,3-a]pyrimidine 8. Compound 8b was treated with 2-chloroethyl methyl ether to afford compound 9. Similarly, compound 3 reacted with chloroacetic acid to give thiazolo[3,2-a]pyrimidine 10, which was condensed with p-chlorobenzaldehyde to give compound 11. Compound 11 was condensed with hydroxylamine to give isoxazolo[4,5-d]thiazolo[2,3-a]pyrimidine 12. Compound 12b was treated with 2-chloroethyl methyl ether to afford compound 13. Biological evaluation of some prepared products showed that many of them revealed promising antimicrobial activity.     

Reactions with hydrazidoyl halides (V)1): synthesis of some amidrazones,hydrazides, pyrazoles and pyrazolo[3,4-d]pyridazine derivatives

2-Bromo (2′-benzofuryl)glyoxal-2-arylhydrazonesI reacted with nucleophiles displacing the bromide. Treatment ofI with active methylene compounds yield the pyrazole derivativesVIII–XI. CompoundsXII–XIV reacted with hydrazine to give pyrazolo[3,4-d]pyridazine derivativeXIV–XVI. The structures of the products were assigned and confirmed on the basis of their elemental analysis and spectral data.     

Synthesis of certain heteroaryl-fused pyrimidines and pyridines and selena- and thia-diazoles with naphthyl substituent as potential antifungal agents

A convenient route is reported for the synthesis of 1,2,3-selenadiazole, 1,2,3-thiadiazole, 1,2,4-triazolo[4,3-a]pyrimidine, tetrazolo[4,5-a]pyrimidine, benzimidazolo[1,2-a]pyrimidine and pyrazolo[3,4-b]pyridine derivatives in which the naphthyl nucleus is incorporated. The preliminary results of antifungal testing are reported.     

作用于神经系统药物:吡啶并[1,2-a]嘧啶酮系列化合物的合成

加锡果宁(Ⅰ)是中药野花椒的成分之一,具有较强的镇痛作用和中枢抑制作用。为寻找低毒高效的类似物,我们曾对其进行结构改造,设计合成了系列化合物并进行了药理试验。前文报道的是在母核芳环上引入不同取代基而不改变母核结构,本文进一步对不同母核的类似物进行了合成及药理研究。     

Synthesis and antiproliferative activity in vitro of new derivatives of 3-aminopyrazolo[3,4-b]pyridine. Part 1. Reaction of 3-aminopyrazolo[3,4-b]pyridine with 1,3-, 1,4-diketones and alpha,beta-unsaturated ketones

The synthesis of several new pyrazolo[3,4-b]pyridine, pyrido[2',3':3,4]-pyrazolo[1,5-a]pyrimidine and imidazo[1',2':1,5]pyrazolo[3,4-b]pyridine derivatives is described. The obtained compounds were tested for their antiproliferative activity in vitro. One of them, 4-phenyl-2-(3,4,5-trimethoxy-beta-styrylo)pyrido- [2',3':3,4]pyrazolo[1,5-a]pyrimidine (9), revealed cytotoxic properties against the cells of all three human cancer cell lines applied. Another one, 2,4-dimethyl-pyrido[2',3':3,4]pyrazolo[1,5-a]-pyrimidine (2), revealed weak cytotoxic activity only against the cells of human bladder cancer cell line HCV29T. All other compounds tested did not reveal any cytotoxic activity.     

Synthesis and antiallergy activity of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines and 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines

Synthesis and antiallergy activity of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines (2 and 3) and 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines (4 and 5) are described. The activity, shown by these compounds in the rat passive cutaneous anaphylaxis (PCA) test, is compared to the PCA data previously reported for a series of 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidines. 10-Oxo-N-1H-tetrazol-5-yl-10H-pyrido[1,2-a]thieno[3,4-d]pyri midine (2b), 10-oxo-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno[3,4-d]py rimidine (4e), and 3,10-dihydro-10-oxo-7-(1H-tetrazol-5-yl)-1H-pyrido[1,2-a]thieno[3, 4-d] pyrimidine (7e) gave a 100% inhibition in the rat PCA test at a dose of 5 mg/kg. The activity displayed by these compounds is comparable to that of the most active compounds in the 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine series.     

新型乙酰胆碱酯酶抑制剂5H-噻唑并[3,2-a]嘧啶类化合物的设计、合成与生物活性研究

目的 寻找作为乙酰胆碱酯酶抑制剂的具有新化学结构类型的化合物。方法 采用分子对接的虚拟筛选方法寻找新型乙酰胆碱酯酶抑制剂，设计了10个5H-噻唑并[3,2-a]嘧啶类化合物。以芳醛、硫脲等为起始原料，通过Biginelli反应生成二氢嘧啶类化合物，再与氯代苯乙酮作用经Hantzsch环合反应制得目标化合物，其结构经红外光谱、质谱、核磁共振氢谱和碳谱确证。采用Ellman方法进行体外抑制乙酰胆碱酯酶活性测试。 结果 合成了10个5H-噻唑并[3,2-a]嘧啶类化合物，体外抑制乙酰胆碱酯酶活性测试结果显示，所有目标化合物均具有乙酰胆碱酯酶抑制活性，其中3个目标化合物在10 μmol.L^-1时抑制活性均超过50%。结论5H-噻唑并[3,2-a]嘧啶类化合物是潜在的乙酰胆碱酯酶抑制剂。将计算机辅助药物分子设计、有机合成和生物活性测试相结合是发现和设计新型乙酰胆碱酯酶抑制剂的有效途径。     

Synthesis and biological activity of pyrimido[2,1-b][1,3]thiazine, [1,3]thiazino[3,2-a]purine and [1,2,3]triazolo[4,5-d][1,3]thiazino[3,2-a]pyrimidine derivatives and thiazole analogues.

Some series of thiazolo[3,2-a]pyrimidine, pyrimido[2,1-b] [1,3]thiazine, thiazolo[3,2-a]purine, [1,3]thiazino[3,2-a]purine, thiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidine and [1,2,3]triazolo[4,5-d][1,3]thiazino[3,2-a]pyrimidine derivatives, variously functionalized, were prepared. The compounds were tested for antimicrobial and antimycotic activity on a number of strains, namely: E. coli, Proteus vulgaris, P. mirabilis, Pseudomonas aeruginosa, Salmonella sp., Staphylococcus aureus, S. faecalis, Bacillus subtilis, Sarcina lutea, Candida albicans, C. tropicalis, Aspergillus sp., and for antiviral activity on Herpes simplex virus Type 1, Vesicular stomatitis virus and Coxsackievirus B5. The compounds proved to be devoid of activity against viruses and gram-negative bacteria, while some of them exhibited modest activity against gram-positive bacterial strains.     

Studies on synthesis and heterocyclisation reactions of michael products and formation of new 1,4-thiazine quinoxaline derivatives

Synthesis of α-piperidino and α-morphelino styryl’quinoxalinone2f, 2g respectively by facile one step method is reported. The Michael adducts (3a-d) obtained by the interaction of 2-styryl-2 (1H) quinoxalinone (2) and ethylacetoacetate have been treated with resorcinol and hydroxylamine separatly. With resorcinol the chromones (4) are obtained whereas with hydroxylamine isoxazolones (6) are the products. Michael addition of acetylacetone to2 leads to 3-[1′-aryl-2′-(2′-hydroxy-3′-quinoxalinyl)ethyl]-2,4-pentanediones (5) which undergo cyclisation with hydroxylamine to give isoxazoles (7). Addition of thiophenol and thioglycolic acid to2 gives3-α-[β-(phenyl)-β-(plenylthio)]ethyl-2(1H)-quinoxalinone (8) and 3-α-[β-phenyl)-β-(hydroxycarbonylmethylthio)]-ethyl-2(1H)-quinox-alinone (9) respectively. 2-Bromomethyl-2(1H)-quinoxalinone (1b) reacts with thioglycolic acid to gives S-[2 (1H)-oxoquinoxalin-3-yl-methyl]mercaptoacetic acid (10) which on cyclisation with acetic anhydride/pyridine affords 1,2,5,6-tetrahydro[1,4]thiazino[4,3-a] quinoxaline-1,6-dione (11).     

Biotransformation of the trapidil (rocornal) derivative AR 12463 in the rat

After p.o. administration of 5-piperidino-7-[N-pentyl-N-(beta- hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine (1; AR 12463) more than 15 metabolites were isolated from urine and feces of male Wistar rats. Only small amounts of unchanged 1 were observed. The structure of 12 metabolites was elucidated or proposed on the basis of UV-, 13C NMR- and mass spectra. Main metabolites are 5-piperidin-4'-olyl-7-[N-pentyl-N-(beta- hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine and 5-piperidin-4'-olyl-7-[N-pent-4-olyl-N-(beta-hydroxyet hyl)]amino-s- triazolo[1,5-a]pyrimidine. The other metabolites are mainly hydroxy- or ketopentyl derivatives and piperidinoles or piperidinones, respectively. Conjugates of most of the metabolites were identified, but the ratio phase-I/II metabolites was about 3:1. In contrast to trapidil, 5-methyl-7-diethylamino-s- triazolo[1,5-a]pyrimidine, no hydroxy derivatives of the bicyclic system were observed. The major part of unchanged 1 and metabolites is excreted via kidneys.     

2-Amino-5,7-dipropyl-s-triazolo[1,5-a]pyrimidin Mitt. Kondensationen mit Hydrazin-N,N′-dicarbonsäure-diamidin

2-Amino-5,7-dipropyl-s-triazolo[1,5-a]pyrimidine In contrast to the formation of 2,2′-hydrazopyrimidines occurring predominantly at room temperature, s-triazolo[1,5-a]pyrimidines prevail in the reaction of hydrazine-N,N′-dicarboxylic acid diamidine (I) and β-diketones at elevated reaction temperatures. Thus, 2-amino-5,7-dipropyl-s-triazolo[1,5-a]pyrimidine (VIII) results from the reaction of I with 4,6-nonanedione (II). Structure proof of VIII has been adduced by independent synthesis from II and 3,5-diamino-s-triazole (IX). Furthermore, VIII was characterized as acetyl (X), monobenzoyl (XI), and dibenzoyl derivative (XII).     

Synthesis and <Emphasis Type="Italic">In Vitro</Emphasis> antiproliferative activity of 2-methyl-3-(2-piperazin-1-yl-ethyl)-pyrido[1,2-a]pyrimidin-4-one derivatives against human cancer cell lines

A series of new 2-methyl-3-(2-piperazin-1-yl-ethyl)-pyrido[1,2-a]pyrimidin-4-one derivatives 6a-j were synthesized by a nucleophilic substitution reaction of 2-methyl-3-(2-piperazin-1-ylethyl)-pyrido[1,2-a]pyrimidin-4-one with various sulfonyl chlorides. The compounds were characterized by different spectral studies. All the compounds were evaluated for their antiproliferative effect using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay method against four human cancer cell lines (K562, Colo-205, MDA-MB 231, IMR-32) for the time period of 24 h. Among the series, compounds 6d, 6e and 6i showed good activity on all cell lines except K562, whereas the other compounds in the series exhibited moderate activity. Compound 6d could be a potential anticancer agent and therefore deserves further research.     

Adenosine cyclic 3',5',-monophosphate phosphodiesterasr inhibitors. 2.3-Substituted 5,7-dialkylpyrazolo [1,5-a]pyrimidines.

A number of 3-bromo-, 3-nitro-, and 3-ethoxycarbonyl-5,7-dialkylpyrazolo[1,5-a]pyrimidines were synthesized and screened as in vitro cAMP phosphodiesterase inhibitors. The condensation of 3-aminopyrazole with symmetrical beta-diketones (acetylacetone, heptane-3,5-dione, etc.) afforded symmetrical dialkylpyrazolo[1,5-a]pyrimidines (5). The reaction of 3-aminopyrazole with unsymmetrical beta-diketones (hexane-2,4-dione, heptane-3,5-dione, etc.) gave a mixture of 5-methyl-7-alkylpyrazolo[1,5-a]pyrimidine (3) and 5-alkyl-7-methylpyrazolo[1,5-a]pyrimidines (4). The technique for the separation of 3 from 4 is described. The inhibition constants, alpha (the ratio of the molar I50 of theophylline to the molar I50 of the test compounds), were subjected to a Hansch correlation analysis. The results indicated that PDE isolated from beef heart tissue was most sensitive to changes in the length of the alkyl group in the 5 position of the pyrazolo[1,5-a]pyrimidine ring, whereas the PDE isolated from rabbit lung tissue was more sensitive to changes in the length of the 7-alkyl group. Experimentally and theoretically, the n-propyl group was found to approximate the ideal size for the alkyl group in both the 5 and 7 positions;5,7-di-n-propyl-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine (5e) was the most potent inhibitor of both lung and heart PDE.     

Reactions of thioamides and alkali metal salts of dithiocarbamates with 2-bromo-7-methyl-5-oxo-5H-1,3,4-thiazolo[3,2-a]pyrimidine and antimicrobial activity of products

A series of thiuronium salts have been synthesized via reactions of various thioamides with 2-bromo-7-methyl-5-oxo-5H-1,3,4-thiazolo[3,2-a]pyrimidine. The products have been characterized with respect to antimicrobial activity. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 8, pp. 15–17, August, 2006.