From Quinoxaline, Pyrido[2,3-b]pyrazine and Pyrido[3,4-b]pyrazine to Pyrazino-Fused Carbazoles and Carbolines.

2,3-Diphenylated quinoxaline, pyrido[2,3-b]pyrazine and 8-bromopyrido[3,4-b]pyrazine were halogenated in deprotometalation-trapping reactions using mixed 2,2,6,6-tetramethyl piperidino-based lithium-zinc combinations in tetrahydrofuran. The 2,3-diphenylated 5-iodo- quinoxaline, 8-iodopyrido[2,3-b]pyrazine and 8-bromo-7-iodopyrido[3,4-b]pyrazine thus obtained were subjected to palladium-catalyzed couplings with arylboronic acids or anilines, and possible subsequent cyclizations to afford the corresponding pyrazino[2,3-a]carbazole, pyrazino[2',3':5,6] pyrido[4,3-b]indole and pyrazino[2',3':4,5]pyrido[2,3-d]indole, respectively. 8-Iodopyrido[2,3-b] pyrazine was subjected either to a copper-catalyzed C-N bond formation with azoles, or to direct substitution to introduce alkylamino, benzylamino, hydrazine and aryloxy groups at the 8 position. The 8-hydrazino product was converted into aryl hydrazones. Most of the compounds were evaluated for their biological properties (antiproliferative activity in A2058 melanoma cells and disease-relevant kinase inhibition).

Continuity of care in general practice at cancer diagnosis (COOC-GP study): a national cohort study of 2853 patients.

BACKGROUND: At cancer diagnosis, it is unclear whether continuity of care (COC) between the patient and GP is safeguarded. AIM: To identify patient-GP loss of COC around the time of, and in the year after, a cancer diagnosis, together with its determinants. DESIGN AND SETTING: A post-hoc analysis of data from a prospective cohort of GPs in France, taken from a survey by the Observatoire de la Médecine Générale. METHOD: A prospective GP cohort (n = 96) filed data on patients who were diagnosed with incident cancer between 1 January 2000 and 31 December 2010. COC was assessed by ascertaining the frequency of consultations and the maximal interval between them. (In France, patients see their referring/named GP in most cases.) A loss of COC was measured during the trimester before and the year after the cancer diagnosis, and the results compared with those from a 1-year baseline period before cancer had been diagnosed. A loss of COC was defined as a longer interval (that is, the maximum number of days) between consultations in the measurement periods than at baseline. Determinants of the loss in COC were assessed with univariate and multivariate logistic regression models. RESULTS: In total, 2853 patients were included; the mean age was 66.1 years. Of these, 1440 (50.5%) were women, 389 (13.6%) had metastatic cancer, and 769 (27.0%) had a comorbidity. The mean number of consultations increased up to, and including, the first trimester after diagnosis. Overall, 26.9% (95% confidence interval [CI] = 25.3 to 28.6) of patients had a loss of COC in the trimester before the diagnosis, and 22.3% (95% CI = 20.7 to 23.9) in the year after. Increasing comorbidity score was independently associated with a reduction in the loss of COC during the year after diagnosis (adjusted odds ratio [OR] comorbidity versus no comorbidity 0.61, 95% CI = 0.48 to 0.79); the same was true for metastatic status (adjusted OR metastasis versus no metastasis 0.49, 95% CI = 0.35 to 0.70). CONCLUSION: As COC is a core value for GPs and for most patients, special care should be taken to prevent a loss of COC around the time of a cancer diagnosis, and in the year after.