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1.
J Med Chem ; 62(21): 9931-9946, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31638797

RESUMO

RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.

2.
J Chromatogr A ; 1586: 106-115, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30578026

RESUMO

Bruton's tyrosine kinase (BTK) plays an essential role in multiple cell types responsible for numerous autoimmune diseases, thus inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases. Preparative-scale super/subcritical fluid chromatography (SFC) separation methods for four groups of highly potent and selective BTK inhibitor atropisomers were successfully developed. Depending on the rotation barrier around the chiral axis, the compounds were prepared as a single stereochemically stable atropisomer or as an atropisomeric mixture. Among the four, compound 2 with one rotationally stable atropisomeric center (carbazole/quinazolinedione based) was resolved as a mixture of two atropisomers, while compound 3 (carbazole-chlorine/quinazolinedione based) and 4 (tetrahydrocarbazole-fluorine/quinazolinedione based) with two rotationally stable atropisomeric centers were resolved into a single stable atropisomer. This article discusses the challenges and strategies in preparing large quantities of these atropisomeric active pharmaceutical ingredients (APIs) in support of the BTK program discovery efforts.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Cromatografia com Fluido Supercrítico/métodos , Descoberta de Drogas/métodos , Inibidores de Proteínas Quinases/análise , Inibidores de Proteínas Quinases/isolamento & purificação , Descoberta de Drogas/instrumentação , Humanos , Estereoisomerismo
3.
J Org Chem ; 82(19): 10376-10387, 2017 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-28877441

RESUMO

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.


Assuntos
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
4.
J Med Chem ; 59(19): 9173-9200, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27583770

RESUMO

Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.


Assuntos
Carbazóis/química , Carbazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Animais , Carbazóis/farmacocinética , Cristalografia por Raios X , Feminino , Humanos , Isomerismo , Macaca fascicularis , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/metabolismo , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Relação Estrutura-Atividade
5.
J Pharm Biomed Anal ; 131: 54-63, 2016 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-27522108

RESUMO

A series of racemic 2,2-dimethyl-3-aryl-propanoic acids were resolved by chiral supercritical fluid chromatography (SFC) without the use of an acidic additive, trifluoroacetic acid (TFA). The use of additive-free protic methanol as co-solvent in CO2 was expanded to successfully resolve other series of carboxylic acid containing racemates. Large-scale SFC of racemic acid 4, 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid, in methanol without TFA as additive on both Chiralpak AD-H and Chiralcel OJ-H will be discussed, along with impact on throughput and solvent consumption. Investigation of co-solvent effect on peak sharpening of acid racemate 20, 2-(2-chloro-9-fluoro-5H-chromeno[2,3-b]pyridin-5-yl)-2-methylpropanoic acid, without TFA further indicated that methanol in CO2 provided improved peak shape compared with isopropanol (IPA) and acetonitrile. Finally, we discuss the resolution of basic aromatic chiral amines without the addition of basic additives such as diethylamine (DEA) and application of this protocol for the large-scale SFC separation of weakly basic indazole-containing racemate 14, methyl 3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate, in methanol without DEA.


Assuntos
Cromatografia com Fluido Supercrítico/métodos , Ácidos Pentanoicos/análise , Ácidos Pentanoicos/química
6.
J Org Chem ; 81(4): 1520-6, 2016 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-26795884

RESUMO

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.

7.
J Chromatogr A ; 1432: 122-31, 2016 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-26768405

RESUMO

While traditional non-chlorinated Cellulose- and Amylose-derivatized phases have been used successfully in supercritical fluid chromatography (SFC) to resolve a broad variety of chiral compounds, some chiral pharmaceutical compounds are not well resolved on these traditional chiral stationary phases (CSP) due to the lack of chiral selectivity. Since there are no universal CSP to resolve all chiral compounds, chlorinated CSP can be complementary to the non-chlorinated CSP. Chlorinated CSP such as 4-Chloro-3-methylphenyl-carbamatecellulose (Lux-Cellulose-4), 3-Chloro-4-methylphenyl-carbamatecellulose (Lux-Cellulose-2), 5-Chloro-2-methylphenyl-carbamateamylose (Lux-Amylose-2) and immobilized 3,5-dichlorophenyl-carbamatecellulose (Chiralpak IC) have provided a range of chiral recognition mechanisms which have allowed the authors to successfully achieve chiral SFC resolution on several structurally diverse compounds, which are not well resolved in the non-chlorinated CSP. In addition, chlorinated Lux-Cellulose-4, Chiralpak IC and Lux-Amylose-2 have enabled us to utilize non-alcohol solvents as sample diluents and as co-solvents to significantly improve compound solubility and selectivity. This article will discuss the challenges associated with several SFC applications on both coated and immobilized chlorinated CSP to deliver high-quality drug candidates in large quantity. The use of dichloromethane in both sample preparation and as co-solvent in CO2 to increase sample solubility will be presented in preparative example #2 and #3.


Assuntos
Amilose/química , Celulose/análogos & derivados , Celulose/química , Preparações Farmacêuticas/isolamento & purificação , Cromatografia com Fluido Supercrítico/métodos , Halogenação , Cloreto de Metileno , Solubilidade , Solventes , Estereoisomerismo
8.
J Sep Sci ; 31(8): 1290-8, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18366026

RESUMO

The phosphatidylcholine (PC)-enriched fraction from soybean lecithin is of interest due to its critical role in both the pharmaceutical and industrial field. In this work, enhancement of the purity of the PC fraction along with other individual polar lipid fractions was achieved from crude soybean lecithin by using supercritical fluid extraction (SFE) with methanol-modified SC-CO(2). Neutral lipids were first removed from the crude sample using pure CO(2). Then, the effect of CO(2 )pressure, temperature, and modifier percentage on phospholipid (PL) fractionation from deoiled lecithin was compared with and without silica gel mixed with the lecithin. Pure fractions of phosphatidylethanolamine (PE) and PC were obtained by varying the modifier concentration of the extraction fluid at 460 atm and 40 degrees C with silica gel added to the deoiled lecithin. Without silica gel, coextraction of PE and PC was observed. A total of six components were isolated and tentatively identified in the extract of deoiled crude soybean lecithin.


Assuntos
Cromatografia com Fluido Supercrítico/métodos , Lecitinas/análise , Lecitinas/isolamento & purificação , Lipídeos/química , Lipídeos/isolamento & purificação , Adsorção , Dióxido de Carbono/química , Glicolipídeos/química , Lecitinas/química , Espectrometria de Massas/métodos , Metanol/química , Modelos Químicos , Fosfatidiletanolaminas/química , Pressão , Sílica Gel , Dióxido de Silício/química , Soja , Temperatura Ambiente , Fatores de Tempo
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