RESUMEN
A visible-light-mediated late-stage aminocarbonylation of unactivated alkyl iodides with stoichiometric amounts of carbon monoxide is presented. The method provides a mild, one-step route to [carbonyl-13/14C] alkyl amides, thereby reducing radioactive waste, and handling of radioactive materials. Easily accessible and low-cost equipment and a palladium catalyst were successfully used for the synthesis of a wide range of alkyl amides.
RESUMEN
A medicinal chemistry program to develop potent and selective LABA compounds required the synthesis of both carbon-14 and stable-isotope labelled materials. Carbon-14 labelled AZD7307 was successfully synthesised in 6 steps from [14C]chloroacetyl chloride in an overall radiochemical yield of 10%. In addition, the synthetic route of a stable labelled isotopomer of AZD7307 is also described and synthesised in four linear steps from [13C6]cyclohexylamine hydrochloride in an overall yield of 12%.
Asunto(s)
Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/síntesis química , Radioisótopos de Carbono/química , Receptores Adrenérgicos beta 2/metabolismo , Técnicas de Química Sintética , Marcaje Isotópico , RadioquímicaRESUMEN
As part of a medicinal chemistry program aimed at developing a highly potent and selective cathepsin C inhibitor, tritium, carbon-14, and stable isotope-labeled materials were required. The synthesis of tritium-labeled methanesulfonate 5 was achieved via catalytic tritiolysis of a chloro precursor, albeit at a low radiochemical purity of 67%. Tritium-labeled AZD5248 was prepared via a 3-stage synthesis, utilizing amide-directed hydrogen isotope exchange. Carbon-14 and stable isotope-labeled AZD5248 were successfully prepared through modifications of the medicinal chemistry synthetic route, enabling the use of available labeled intermediates.
Asunto(s)
Compuestos de Bifenilo/química , Catepsina C/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Radiofármacos/síntesis química , Tritio/química , Radioisótopos de Carbono/química , Inhibidores de Cisteína Proteinasa/química , Mesilatos/química , Radiofármacos/químicaRESUMEN
As part of a Medicinal Chemistry program aimed at developing an orally bioavailable selective estrogen receptor degrader, a number of tritium, carbon-14, and stable isotope labelled (E)-3-[4-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl]prop-2-enoic acids were required. This paper discusses 5 synthetic approaches to this compound class.
Asunto(s)
Radioisótopos de Carbono/química , Indoles/química , Indoles/síntesis química , Receptores de Estrógenos/metabolismo , Tritio/química , Disponibilidad Biológica , Técnicas de Química Sintética , Indoles/farmacocinética , Indoles/farmacología , Marcaje IsotópicoRESUMEN
The CXCR2 antagonist AZD5069 has been synthesized in tritium and carbon-14-labelled forms. [(3) H]AZD5069 was prepared via reductive dehalogenation of an iodinated precursor with tritium gas to provide material with a specific activity of 25.1 Ci/mmol. [(14) C]AZD5069 was labelled in the pyrimidine ring from [(14) C]thiourea in an overall radiochemical yield of 18%. In addition, a synthetic route to the major metabolite of AZD5069 was developed. The synthesis of this metabolite was achieved from AZD5069 using a chemoselective Lindgren-Pinnick reaction in order to minimize oxidation of the sulphide group.
Asunto(s)
Pirimidinas/síntesis química , Pirimidinas/metabolismo , Receptores de Interleucina-8B/antagonistas & inhibidores , Sulfonamidas/síntesis química , Sulfonamidas/metabolismo , Radioisótopos de Carbono/química , Técnicas de Química Sintética , Humanos , Marcaje Isotópico , Pirimidinas/química , Pirimidinas/farmacología , Radioquímica , Sulfonamidas/química , Sulfonamidas/farmacología , Tritio/químicaRESUMEN
AZD5122, N-(2-(2,3-difluorobenzylthio)-6-((2R,3R)-3,4-dihydroxybutan-2-ylamino)pyrimidin-4-yl)azetidine-1-sulfonamide was under investigation as a potential chemokine receptor CXCR2 antagonist for the treatment for inflammatory diseases. To gain a better understanding of the human pharmacokinetic profile, an exploratory phase I IV microtracer study was conducted using carbon-14 radiolabelled AZD5122. [(14) C]AZD5122 was carbon-14 labelled in the pyrimidine ring in five steps in an overall radiochemical yield of 19% from [(14) C]thiourea. The absolute oral bioavailability of AZD5122 was assessed in healthy subjects by an oral administration of AZD5122, followed by a concomitant intravenous [(14) C]AZD5122 microdose.
Asunto(s)
Azetidinas/síntesis química , Azetidinas/farmacocinética , Radioisótopos de Carbono/química , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinética , Administración Oral , Azetidinas/administración & dosificación , Azetidinas/química , Disponibilidad Biológica , Técnicas de Química Sintética , Semivida , Humanos , Inyecciones Intravenosas , Trazadores Radiactivos , Sulfonamidas/administración & dosificación , Sulfonamidas/químicaRESUMEN
To support the development of a reactive metabolite strategy, the preparation of several radiolabelled compounds such as [(14)C] Ticlopidine was required. In this report, we describe a facile and rapid synthesis of [(14)C] Ticlopidine starting from [(14)C] carbon dioxide. The compound was radiolabelled in the 2-chloromethyl portion of the molecule with a specific activity of 53.4 mCi/mmol and with a radiochemical purity of 98.5%. Storage stability was best as the hydrochloride salt in an ethanol solution.
Asunto(s)
Radiofármacos/síntesis química , Ticlopidina/síntesis química , Radioisótopos de Carbono , Técnicas de Química Sintética , Cinética , Radioquímica , Radiofármacos/química , Ticlopidina/químicaRESUMEN
Current immunosuppressive therapies act on T lymphocytes by modulation of cytokine production, modulation of signaling pathways or by inhibition of the enzymes of nucleotide biosynthesis. We have identified a previously unknown series of immunomodulatory compounds that potently inhibit human and rat T lymphocyte proliferation in vitro and in vivo in immune-mediated animal models of disease, acting by a novel mechanism. Here we identify the target of these compounds, the monocarboxylate transporter MCT1 (SLC16A1), using a strategy of photoaffinity labeling and proteomic characterization. We show that inhibition of MCT1 during T lymphocyte activation results in selective and profound inhibition of the extremely rapid phase of T cell division essential for an effective immune response. MCT1 activity, however, is not required for many stages of lymphocyte activation, such as cytokine production, or for most normal physiological functions. By pursuing a chemistry-led target identification strategy, we have discovered that MCT1 is a previously unknown target for immunosuppressive therapy and have uncovered an unsuspected role for MCT1 in immune biology.