13 research outputs found
Regioselective Synthesis of Substituted 4‑Alkylamino and 4‑Arylaminophthalazin-1(2<i>H</i>)‑ones
An
efficient regioselective synthesis of substituted 4-alkylamino
and 4-arylaminophthalazin-1Â(1<i>H</i>)-ones <b>5</b> is described. This new method features the formation of substituted
phthalazin-1Â(1<i>H</i>)-ones <b>3</b> by the reaction
of 2-formylbenzoic acids <b>1</b> or 3-hydroxyisobenzofuran-1Â(3<i>H</i>)-ones <b>2</b> with hydrazine to generate phthalazin-1Â(2<i>H</i>)-ones <b>3</b>. Subsequent regioselective bromination
of phthalazin-1Â(2<i>H</i>)-ones <b>3</b> with benzyltrimethylammonium
tribromide (BTMA-Br<sub>3</sub>) followed by mixed copper–copper
oxide-catalyzed amination of 4-bromophthalazin-1Â(2<i>H</i>)-ones <b>4</b> with primary amines generates aminophthalazin-1Â(2<i>H</i>)-ones in good overall yields
Evolution of a Scale-Up Synthesis to a Potent GluN2B Inhibitor and Its Prodrug
This paper describes the efficient
scale-up synthesis of the potent
negative allosteric glutamate N2B (GluN2B) inhibitor <b>1</b> (BMS-986169), which relies upon a stereospecific S<sub>N</sub>2
alkylation strategy and a robust process for the preparation of its
phosphate prodrug <b>28</b> (BMS-986163) from parent <b>1</b> using POCl<sub>3</sub>. A deoxyfluorination reaction employing bisÂ(2-methoxyethyl)Âaminosulfur
trifluoride (Deoxo-Fluor) is also used to stereospecifically introduce
a fluorine substituent. The optimized routes have been demonstrated
to provide APIs suitable for toxicological studies in vivo
Development of the Large-Scale Synthesis of Tetrahydropyran Glycine, a Precursor to the HCV NS5A Inhibitor <b>BMS-986097</b>
An efficient large-scale
synthesis of acid <b>1</b>, a penultimate
precursor to the HCV NS5A inhibitor <b>BMS-986097</b>, along
with the final API step are described. Three routes were devised for
the synthesis of <b>1</b> 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 <i>t</i>-butyl 2-((diphenylmethylene)Âamino)Âacetate (<b>24</b>) to (<i>E</i>)-benzyl 4-(1-hydroxycyclopropyl)Âbut-2-enoate
(<b>28</b>) followed by cyclization and chiral separation to
form <b>27c</b>, the core skeleton of cap piece <b>1</b>. The epimerization and chiral resolution of <b>27c</b> followed
by further synthetic manipulations involving the carbamate formation,
lactone reduction and cyclization, afforded cyclopropyl pyran <b>1</b>. 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 <b>BMS-986097</b> for toxicology
studies
Synthesis of Biologically Active Piperidine Metabolites of Clopidogrel: Determination of Structure and Analyte Development
Clopidogrel
is a prodrug anticoagulant with active metabolites
that irreversibly inhibit the platelet surface GPCR P2Y<sub>12</sub> and thus inhibit platelet activation. However, gaining an understanding
of patient response has been limited due to imprecise understanding
of metabolite activity and stereochemistry, and a lack of acceptable
analytes for quantifying in vivo metabolite formation. Methods for
the production of all bioactive metabolites of clopidogrel, their
stereochemical assignment, and the development of stable analytes
via three conceptually orthogonal routes are disclosed
The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV‑1 Maturation
GSK3640254 is an HIV-1 maturation inhibitor (MI) that
exhibits
significantly improved antiviral activity toward a range of clinically
relevant polymorphic variants with reduced sensitivity toward the
second-generation MI GSK3532795 (BMS-955176). The key structural difference
between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3
position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic
acid substituted with a CH2F moiety at the carbon atom
α- to the pharmacophoric carboxylic acid. This structural element
provided a new vector with which to explore structure–activity
relationships (SARs) and led to compounds with improved polymorphic
coverage while preserving pharmacokinetic (PK) properties. The approach
to the design of GSK3640254, the development of a synthetic route
and its preclinical profile are discussed. GSK3640254 is currently
in phase IIb clinical trials after demonstrating a dose-related reduction
in HIV-1 viral load over 7–10 days of dosing to HIV-1-infected
subjects
The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV‑1 Maturation
GSK3640254 is an HIV-1 maturation inhibitor (MI) that
exhibits
significantly improved antiviral activity toward a range of clinically
relevant polymorphic variants with reduced sensitivity toward the
second-generation MI GSK3532795 (BMS-955176). The key structural difference
between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3
position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic
acid substituted with a CH2F moiety at the carbon atom
α- to the pharmacophoric carboxylic acid. This structural element
provided a new vector with which to explore structure–activity
relationships (SARs) and led to compounds with improved polymorphic
coverage while preserving pharmacokinetic (PK) properties. The approach
to the design of GSK3640254, the development of a synthetic route
and its preclinical profile are discussed. GSK3640254 is currently
in phase IIb clinical trials after demonstrating a dose-related reduction
in HIV-1 viral load over 7–10 days of dosing to HIV-1-infected
subjects
Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P<sub>1</sub> Receptor Modulator in Clinical Trials
Clinical
validation of S1P receptor modulation therapy was achieved
with the approval of fingolimod (Gilenya, <b>1</b>) as the first
oral therapy for relapsing remitting multiple sclerosis. However, <b>1</b> causes a dose-dependent reduction in the heart rate (bradycardia),
which occurs within hours after first dose. We disclose the identification
of clinical compound BMS-986104 (<b>3d</b>), a novel S1P<sub>1</sub> receptor modulator, which demonstrates ligand-biased signaling
and differentiates from <b>1</b> in terms of cardiovascular
and pulmonary safety based on preclinical pharmacology while showing
equivalent efficacy in a T-cell transfer colitis model
Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms
JAK2 kinase inhibitors are a promising
new class of agents for
the treatment of myeloproliferative neoplasms and have potential for
the treatment of other diseases possessing a deregulated JAK2-STAT
pathway. X-ray structure and ADME guided refinement of C-4 heterocycles
to address metabolic liability present in dialkylthiazole <b>1</b> led to the discovery of a clinical candidate, BMS-911543 (<b>11</b>), with excellent kinome selectivity, <i>in vivo</i> PD activity, and safety profile
Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of <i>N</i>‑[(1<i>R</i>)‑1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)Âphenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)Âbenzamide (BMS-795311)
Cholesteryl ester transfer protein
(CETP) inhibitors raise HDL-C
in animals and humans and may be antiatherosclerotic by enhancing
reverse cholesterol transport (RCT). In this article, we describe
the lead optimization efforts resulting in the discovery of a series
of triphenylethanamine (TPE) ureas and amides as potent and orally
available CETP inhibitors. Compound <b>10g</b> is a potent CETP
inhibitor that maximally inhibited cholesteryl ester (CE) transfer
activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic
mice and increased HDL cholesterol content and size comparable to
torcetrapib (<b>1</b>) in moderately-fat fed hamsters. In contrast
to the off-target liabilities with <b>1</b>, no blood pressure
increase was observed with <b>10g</b> in rat telemetry studies
and no increase of aldosterone synthase (CYP11B2) was detected in
H295R cells. On the basis of its preclinical profile, compound <b>10g</b> was advanced into preclinical safety studies
Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of <i>N</i>‑[(1<i>R</i>)‑1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)Âphenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)Âbenzamide (BMS-795311)
Cholesteryl ester transfer protein
(CETP) inhibitors raise HDL-C
in animals and humans and may be antiatherosclerotic by enhancing
reverse cholesterol transport (RCT). In this article, we describe
the lead optimization efforts resulting in the discovery of a series
of triphenylethanamine (TPE) ureas and amides as potent and orally
available CETP inhibitors. Compound <b>10g</b> is a potent CETP
inhibitor that maximally inhibited cholesteryl ester (CE) transfer
activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic
mice and increased HDL cholesterol content and size comparable to
torcetrapib (<b>1</b>) in moderately-fat fed hamsters. In contrast
to the off-target liabilities with <b>1</b>, no blood pressure
increase was observed with <b>10g</b> in rat telemetry studies
and no increase of aldosterone synthase (CYP11B2) was detected in
H295R cells. On the basis of its preclinical profile, compound <b>10g</b> was advanced into preclinical safety studies