113778-66-8

The assembly of (Z)-chloro-exo-methylenetetrahydrofurans by an original and connective anionic cascade sequence is reported. Base-catalysed condensation of β-hydroxyketones with 1,1-dichloroethylene generates, in moderate to good yields, the corresponding

Provided herein are pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, pharmaceutical composition comprising such compounds, and their use as menin/MLL protein/protein interaction inhibitors, useful for treating diseases such as cancer, including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN); and diabetes.

This invention relates to novel compounds of the Formula (I), (Ia1-10), (Ib1-10), (Ic1-10), (Id1-7), (Ie1-5) pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11β-HSD1 in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of cortisol in a cell or the inhibition of the conversion of cortisone to cortisol in a cell.

This invention relates to novel compounds of the Formula Ik, Im1, Im2, Im5, In1, In2, In5, Io1, Io2, Io5, Ip1, Ip3, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11β-HSD1 in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of cortisol in a cell or the inhibition of the conversion of cortisone to cortisol in a cell.

This invention relates to novel compounds of the Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih); (Ii); (Ij), (Ik), (II) pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11 β-HSD1 in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of cortisol in a cell or the inhibition of the conversion of cortisone to cortisol in a cell.

Two series of 1,2-disubstituted imidazolylmethylcyclopentanol derivatives (5a-d, 10a-d) were prepared by using easily available methyl 2- oxocyclopentanecarboxylate as the starting material. Evaluation of the aromatase inhibitory activities in vitro was p

The first synthesis of antibiotic A25822 B, a 15-aza-D-homosterol that displays powerful antifungal activity, was achieved from epiandrosterone.

β-Hydroxy ketones can be doubly deprotonated with >2 equiv of an amide base at low temperature providing both proximal or distal aldolate dianions in good to excellent yield. A variety of substitutionally biased β-hydroxy ketones give exclusively distal dianions. If the distal site is blocked, proximal dianions are formed in good yield; however, Chromatographic separation of the silylated products leads to decreased yields. Comparative enolization studies of 4-hydroxy-2-butanone, l-hydroxy-3-pentanone, and hydroxyl-substituted derivatives reveal a kinetic factor favoring proximal deprotonation of β-OTMS and β-alkoxy ketones. However, there is a thermodynamic factor favoring distal dianions that becomes significant as solutions of the dianions are warmed. Thermal stability studies indicate good room temperature stability of the dianions toward elimination and retroaldolization processes; control studies in this area also support the presence of a dianionic species. Precedent suggests that the dianions exist as internally chelated species, and we speculate that ion triplets containing bridging lithiums are good candidates for the structure of both proximal and distal dianion species. The distal dianions undergo clean reaction with aldehydes and acyl cyanides leading to β,β′-dihydroxy ketones and β-hydroxy-β′-oxo ketones, respectively.

An efficient synthesis of α-(hydroxymethyl) ketones from β-keto esters has been developed, which is experimentally simple, amenable to large scale production and provides products of high purity without resort to chromatography in most cases. The method is a useful alternative and complement to condensation processes.

3β-Acetoxyandrost-5-en-17-one has been converted into 15β-hydroxy-24-oxocholesterol.Reaction of (17E)-3-β-(dimethyl-t-butylsilyloxy)-15β,16β-epoxypregna-5,17(20)-diene with the magnesium cyanocuprate derivative of 3-(1,3-dioxolan-2-yl)-4-methylpentyl bromide gave (20R)-3β-(dimethyl-t-butylsilyloxy)-15β-hydroxy-24-oxocholesta-5,16-diene 24-ethylene acetal in 80percent yield, and this was converted into the target compound in high yield by catalytic hydrogenation followed by removal of the protecting groups.Reaction of 3β,15β-diacetoxycholest-5-en-24-one with the anion of diethyl cyanomethylphosphonate and reduction of the resulting nitrile with DIBAL-H, gave 15β,29-dihydroxyfucosterol.This was converted into the 3,29-diacetate 15-formate and oxidized with chromium trioxide-3,5-dimethylpyrazole.Removal of the acetate and formate groups with aqueous potassium carbonate afforded 15β,29-dihydroxy-7-oxofucosterol.