α-Oxoketene-S,S-, N,S- and N,N-acetals: Versatile intermediates in organic synthesis

Compounds of formula (1) are described and the salts, solvates, hydrates and N-oxides thereof, in which R?1, R2, R3, R4, R5, R6 and R7? have the meanings given in Claim 1. The compounds are selective inhibitors of protein kinases, especially src-family protein kinases and are of use in the prophylaxis and treatment of immune diseases, hyperproliferative disorders and other diseases in which inappropriate protein kinase action is believed to have a role.

Substituted 2-anilinopyrimidines useful as protein kinase inhibitors

C-vinylpyrroles as pyrrole building blocks.

Pyrimidines of formula (1) are described wherein Ar is an optionally substituted aromatic or heteroaromatic group; R1 is a hydrogen atom or a straight or branched chain alkyl group; R2 is a -X1-R3 group where X1 is a direct bond or a linker atom or group, and R3 is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group; and the salts, solvates, hydrates and N-oxides thereof. The compounds are selective KDR Kinase and/or FGFr Kinase inhibitors and are of use in the prophylaxis and treatment of disease states associated with angiogenesis.

5-Cyano-2-aminopyrimidine derivatives

Compounds are described in formula (1), wherein Y is a halogen atom or a group -OR1, where R1 is an optionally substituted alkyl group; R2 is an optionally substituted cycloalkyl or cycloalkenyl group; R3 is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, nitrogen or sulphur atoms or a group -N(R4)- where R4 is a hydrogen atom or an alkyl group; X is -O-, -S-, or -N(R5)-, where R5 is a hydrogen atom or an alkyl group; with the proviso that when X is -O- the R3 is not a 3-cyanamino-6-pyridazinyl or a 3-chloro-6-pyridazinyl group; and the salts, solvates, hydrates and N- oxides thereof. The compounds are selective phosphodiesterase IV inhibitors and are useful for the prophylaxis or treatment of inflammatory diseases.

Tri-substituted phenyl derivatives and processes for their preparation

Polarized ethylenes. IV. Synthesis of polarized ethylenes using thioamides and methyl dithiocarboxylates and their application to syntheses of pyrazoles, pyrimidines, pyrazolo[3,4‐d]pyrimidines, and 5‐aza[2.2.3]cyclazines

The benzannalated cycl [3 2 2] azine, benzo [g] cycl [3 2 2] azine (2), was synthesized from 2-methylthiopyrrolo [2, 1-a] isoquinoline (5) and dimethyl acetylenedicarboxylate The key intermediate (5) for the synthesis of 2 was prepared using the reaction of isoquinolinium ketene dithioacetal (8) with nitromethane in good yields Compound 8 was obtained using the reaction of 2-ethoxycarbonylmethylisoquinolinium bromide (6) with carbon disulfide and dimethyl sulfate in the presence of sodium hydroxide followed by methylation with methyl iodide

SYNTHESIS OF BENZANNELATED CYCL [3. 2. 2] AZINE : BENZO [g] CYCL [3. 2. 2] AZINE

Synthese du compose du titre et de son derive methylthio-2, a partir de l'iodure de [dimethylthio-2',2' ethoxycarbonyl-1' vinyl]-2 isoquinoleinium et de mesitylenesulfonate d'amino-1 pyridinium, via la cycloaddition du butynedioate de dimethyle sur la methylthio-2 imidazo [2,1-a] isoquinoleine

Synthesis of Benzannelated 1‐Azacycl‐[3.2.2]azine: 1‐Azabenzo[h]cycl‐[3.2.2]azine.

In the present study, we aimed to investigate the association between urate‐lowering drugs and cardiovascular events, primarily focusing on the risk of febuxostat and topiroxostat when compared with allopurinol in Japan. We conducted an observational study with a cohort design using the National Database of Health Insurance Claims and Specific Health Checkups of Japan, including new urate‐lowering drugs users between August 1, 2010, and March 31, 2018. Exposure and control groups were defined based on the first prescription of urate‐lowering drugs as follows: febuxostat or topiroxostat for exposure groups, allopurinol for the control group, and benzbromarone for the secondary control group. The primary outcome was cardiovascular events, defined as a composite of acute coronary syndrome, cerebral infarction, and cerebral hemorrhage. Hazard ratios were estimated using a Cox proportional hazards model. The number of patients in each exposure and control group was 1,357,671 in the febuxostat group, 83,683 in the topiroxostat group, 1,273,211 in the allopurinol group, and 258,786 in the benzbromarone group. The adjusted hazard ratios for the cardiovascular risk were 0.97 (95% confidence interval [CI]: 0.95–0.98) for febuxostat and 0.84 (95% CI: 0.78–0.90) for topiroxostat groups. The benzbromarone group exhibited similar results. No increased cardiovascular risk was observed with febuxostat or topiroxostat when compared with allopurinol in patients with hyperuricemia in Japan. These results provide real‐world evidence regarding the cardiovascular risk associated with urate‐lowering drugs, indicating that no additional safety‐related regulatory actions are warranted in Japan.

Cardiovascular risk of urate‐lowering drugs: A study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan

By the reaction of 6-methyl-4-imino-4H-quinolizine derivatives (5, 8) with the mixed anhydrides (6a-h), 2-phenyl-1-azacycl [3.3.3] azines (7a-p, 9a-g) were obtained.2-Pheny1-1, 3, 6-triazacycl [3.3.3] azine derivatives (15ah, 17a-h, 18a-g) were prepared by the reaction of 2-(2-cyanovinyl) amino-6-aminopyridines (13, 16) with mixed anhydrides (6a-h).The proton nuclear magnetic resonance spectral data of the 2-phenylazacycl [3.3.3] azines (12, 18a) may be interprited in terms of a paramagnetic ring current.

Yukio Oniyama

Papers

Polarized ethylenes. IV. Synthesis of polarized ethylenes using thioamides and methyl dithiocarboxylates and their application to syntheses of pyrazoles, pyrimidines, pyrazolo[3,4‐d]pyrimidines, and 5‐aza[2.2.3]cyclazines

SYNTHESIS OF BENZANNELATED CYCL [3. 2. 2] AZINE : BENZO [g] CYCL [3. 2. 2] AZINE

Synthesis of Benzannelated 1‐Azacycl‐[3.2.2]azine: 1‐Azabenzo[h]cycl‐[3.2.2]azine.

Cardiovascular risk of urate‐lowering drugs: A study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan

Studies on quinolizine derivatives. XXII. Syntheses and properties of 2-phenylazacycl[3.3.3]azine derivatives.