Abstract N-Diphenylthiophosphinyl-N-methyl carboxamide (laab) undergoes an uncatalyzed “[O,S]-transposition” in CCl4 to form a 75:25 equilibrium mixture of laab and N-diphenylphosphinyl-N-methyl thiocarboxamide (2aab). This equilib-rium mixture then slowly undergoes a disproportionation to initially form the unsymmetrical diphenylthiophosphinic diphenylphosphinic anhydride (9) and the corresponding N-benz(methylimino)-N-methyl thiobenzamide (8). Parallel or sub sequent processes result in the formation of N-methyl thiobenzamide (6), N-methyl benzamide (7), bis-diphenylphosphinic anhydride (10), and bis-diphenylthio phosphinic anhydride (11). Pathways for these transformation are suggested.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
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Starting from the micromolar 8-quinoline carboxamide high-throughput screening hit 1a, a systematic exploration of the structure-activity relationships (SAR) of the 4-, 6-, and 8-substituents of the quinoline ring resulted in the identification of approximately 10-100-fold more potent human CD38 inhibitors. Several of these molecules also exhibited pharmacokinetic parameters suitable for in vivo animal studies, including low clearances and decent oral bioavailability. Two of these CD38 inhibitors, 1ah and 1ai, were shown to elevate NAD tissue levels in liver and muscle in a diet-induced obese (DIO) C57BL/6 mouse model. These inhibitor tool compounds will enable further biological studies of the CD38 enzyme as well as the investigation of the therapeutic implications of NAD enhancement in disease models of abnormally low NAD.
A series of thiazoloquin(az)olinones were synthesized and found to have potent inhibitory activity against CD38. Several of these compounds were also shown to have good pharmacokinetic properties and demonstrated the ability to elevate NAD levels in plasma, liver, and muscle tissue. In particular, compound 78c was given to diet induced obese (DIO) C57Bl6 mice, elevating NAD > 5-fold in liver and >1.2-fold in muscle versus control animals at a 2 h time point. The compounds described herein possess the most potent CD38 inhibitory activity of any small molecules described in the literature to date. The inhibitors should allow for a more detailed assessment of how NAD elevation via CD38 inhibition affects physiology in NAD deficient states.
Abstract Five unique fluorinated analogs, 8a‐c and 15a,b , of the monoamine oxidase‐A inhibitor 3‐iso‐propoxyphenoxathiin 10,10‐dioxide ( II ) were prepared via oxidation of the corresponding phenoxathiins 7 and 14 . 3‐Fluoro‐7‐isopropoxy‐ 7a , 2‐fluoro‐3‐isopropoxy‐ 7b , and 2,7‐difluoro‐3‐isopropoxyphenoxathiin ( 7c ) were prepared by a modification of the Mauthner synthesis which involved cyclization of the corresponding 2‐hydroxy‐4‐isopropoxythiophenols 4 with the appropriate 2‐halonitrobenzenes 5 in the presence of potassium tert ‐butoxide. Preparation of 2,8‐difluoro‐3‐isopropoxyphenoxathiin ( 14b ) from 4b and 2,4‐difluoronitrobenzene ( 5c ) employing similar methods failed, leading instead to a novel macrocycle 9 . Attempts to obtain 2‐fluoro‐7‐isopropoxyphenoxathün ( 14a ) and the 2,8‐difluoro analog 14b via trifluoroacetic acid deprotection of intermediate thio‐protected 2‐nitrophenyl 2‐thiophenyl ethers 11a and c followed by cyclization of the resulting thiols were also unsuccessful. Deprotection of 11a with trifluoroacetic acid produced only complex product mixtures, while similar deprotection of 11c and treatment of the resulting crude product with potassium tert ‐butoxide in refluxing dimethylformamide produced the 2,7‐difluorophenoxathiin analog 7c , a result consistent with a Smiles rearrangement of the intermediate thiol 12 prior to ring closure. The phenoxathiins 14 were ultimately prepared by a modification of a relatively unexploited phenoxathiin synthesis involving the intramolecular radical substitution at sulfur of 2‐aminophenyl 2‐thiophenyl ethers 13 containing para ‐methoxybenzyl and methoxymethylthio‐protecting groups.
A scale-up of diazaindoline 1 was achieved in four stages and 32% overall yield. The key step involved rapid reductive amination of aldehyde 8 with aniline 5 by sodium triacetoxyborohydride (STAB-H) and TFA followed by ring closure of intermediate amine 9 to compound 1 in the same pot. These reaction conditions were also applied to facile reductive aminations with anilines known to have little reactivity under STAB-H/AcOH conditions. Spectral data supported the tris(trifluoroacetoxy)borohydride anion (16) as the active reducing agent.
A synthesis of the benzothiazepine phosphonic acid 3, employing both enzymatic and transition metal catalysis, is described. The quaternary chiral center of 3 was obtained by resolution of ethyl (2-ethyl)norleucinate (4) with porcine liver esterase (PLE) immobilized on Sepabeads. The resulting (R)-amino acid (5) was converted in two steps to aminosulfate 7, which was used for construction of the benzothiazepine ring. Benzophenone 15, prepared in four steps from trimethylhydroquinone 11, enabled sequential incorporation of phosphorus (Arbuzov chemistry) and sulfur (Pd(0)-catalyzed thiol coupling) leading to mercaptan intermediate 18. S-Alkylation of 18 with aminosulfate 7 followed by cyclodehydration afforded dihydrobenzothiazepine 20. Iridium-catalyzed asymmetric hydrogenation of 20 with the complex of [Ir(COD)2BArF] (26) and Taniaphos ligand P afforded the (3R,5R)-tetrahydrobenzothiazepine 30 following flash chromatography. Oxidation of 30 to sulfone 31 and phosphonate hydrolysis completed the synthesis of 3 in 12 steps and 13% overall yield.
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