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J Org Chem ; 82(19): 10376-10387, 2017 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-28877441


An efficient large-scale synthesis of acid 1, a penultimate precursor to the HCV NS5A inhibitor BMS-986097, along with the final API step are described. Three routes were devised for the synthesis of 1 at the various stages of the program. The third generation route, the one that proved scalable and is the main subject of this paper, features a one-step Michael addition of t-butyl 2-((diphenylmethylene)amino)acetate (24) to (E)-benzyl 4-(1-hydroxycyclopropyl)but-2-enoate (28) followed by cyclization and chiral separation to form 27c, the core skeleton of cap piece 1. The epimerization and chiral resolution of 27c followed by further synthetic manipulations involving the carbamate formation, lactone reduction and cyclization, afforded cyclopropyl pyran 1. A detailed study of diphenylmethane deprotection via acid hydrolysis as well as a key lactone to tetrahydropyran conversion, in order to avoid a side reaction that afforded an alternative cyclization product, are discussed. This synthesis was applied to the preparation of more than 100 g of the final API BMS-986097 for toxicology studies.

Antivirais/síntese química , Glicina/análogos & derivados , Imidazóis/síntese química , Piranos/farmacologia , Pirrolidinas/síntese química , Compostos de Espiro/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Antivirais/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Estrutura Molecular , Piranos/síntese química , Piranos/química , Pirrolidinas/química , Pirrolidinas/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Proteínas não Estruturais Virais/metabolismo
J Org Chem ; 81(4): 1520-6, 2016 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-26795884


An efficient regioselective synthesis of substituted 4-alkylamino and 4-arylaminophthalazin-1(1H)-ones 5 is described. This new method features the formation of substituted phthalazin-1(1H)-ones 3 by the reaction of 2-formylbenzoic acids 1 or 3-hydroxyisobenzofuran-1(3H)-ones 2 with hydrazine to generate phthalazin-1(2H)-ones 3. Subsequent regioselective bromination of phthalazin-1(2H)-ones 3 with benzyltrimethylammonium tribromide (BTMA-Br3) followed by mixed copper-copper oxide-catalyzed amination of 4-bromophthalazin-1(2H)-ones 4 with primary amines generates aminophthalazin-1(2H)-ones in good overall yields.

J Med Chem ; 52(23): 7653-68, 2009 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-19954247


Detailed metabolic characterization of 8, an earlier lead pyrazinone-based corticotropin-releasing factor-1 (CRF(1)) receptor antagonist, revealed that this compound formed significant levels of reactive metabolites, as measured by in vivo and in vitro biotransformation studies. This was of particular concern due to the body of evidence suggesting that reactive metabolites may be involved in idiosyncratic drug reactions. Further optimization of the structure-activity relationships and in vivo properties of pyrazinone-based CRF(1) receptor antagonists and studies to assess the formation of reactive metabolites led to the discovery of 19e, a high affinity CRF(1) receptor antagonist (IC(50) = 0.86 nM) wherein GSH adducts were estimated to be only 0.1% of the total amount of drug-related material excreted through bile and urine, indicating low levels of reactive metabolite formation in vivo. A novel 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine group in 19e contributed to the potency and improved in vivo properties of this compound and related analogues. 19e had excellent pharmacokinetic properties in rats and dogs and showed efficacy in the defensive withdrawal model of anxiety in rats. The lowest efficacious dose was 1.8 mg/kg. The results of a two-week rat safety study with 19e indicated that this compound was well-tolerated.

Pirazinas/metabolismo , Pirazinas/farmacologia , Piridinas/metabolismo , Piridinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Cães , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Masculino , Pirazinas/administração & dosagem , Pirazinas/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Ratos
J Med Chem ; 48(18): 5639-43, 2005 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-16134929
J Med Chem ; 45(17): 3660-8, 2002 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-12166939


A highly convergent synthesis was developed for the novel dopamine agonist dinapsoline (12) (Ghosh, D.; Snyder, S. E.; Watts, V. J.; Mailman, R. B.; Nichols, D. E. 8,9-Dihydroxy-2,3,7, 11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline: A Potent Full Dopamine D(1) Agonist Containing a Rigid beta-Phenyldopamine Pharmacophore. J. Med. Chem. 1996, 39 (2), 549-555). The crucial step in the new synthesis was a free radical-initiated cyclization to give the complete dinapsoline framework. The improved synthesis required half as many steps as the original procedure (Nichols, D. E.; Mailman, R.; Ghosh, D. Preparation of novel naphtho[1,2,3-de]isoquinolines as dopamine receptor ligands. PCT Int. Appl. WO 9706799 A1, Feb 27, 1997). One of the late-stage intermediates (11) was resolved into a pair of enantiomers. From there, the (R)-(+)-12 (absolute configuration by X-ray) of dinapsoline was identified as the active enantiomer. In unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats, (+)-dinapsoline showed robust rotational behavior comparable to that of an external benchmark, trans-4,5,5a,6,7,11b-hexahydro-2-propyl-benzo[f]thieno[2,3-c]quinoline-9,10-diol, hydrochloride 18 (Michaelides, M. R.; Hong, Y. Preparation of heterotetracyclic compounds as dopamine agonists. PCT Int. Appl. WO 9422858 A1, Oct 13, 1994).

Agonistas de Dopamina/síntese química , Isoquinolinas/síntese química , Naftóis/síntese química , Animais , Linhagem Celular , Corpo Estriado/metabolismo , Cristalografia por Raios X , AMP Cíclico/biossíntese , Agonistas de Dopamina/farmacologia , Técnicas In Vitro , Isoquinolinas/farmacologia , Conformação Molecular , Naftóis/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Estereoisomerismo