- MTA-Cooperative PRMT5 Inhibitors
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The present invention relates to compounds that inhibit Protein Arginine N-Methyl Transferase 5 (PRMT5) activity. In particular, the present invention relates to compounds, pharmaceutical compositions and methods of use, such as methods of treating cancer using the compounds and pharmaceutical compositions of the present invention.
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Paragraph 0235; 0237
(2021/03/19)
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- Phototransposition chemistry of phenylisothiazoles and phenylthiazoles. 1. Interconversions in benzene solution
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Phenylthiazoles 1-3 and phenylisothiazoles 4-6 undergo phototransposition in benzene solvent mainly by P5, P6, and P7 permutation pathways. Phenylisothiazoles 5 and 6 also transpose via a P4 permutation process to yield phenylthiazoles 2 and 3 in less than 1% yield. In benzene saturated with D2O, 2-phenylthiazole (1) and 5-phenylisothiazole (6) each phototranspose to yield 4-deuterio-3-phenylisothiazole (4-D-4) and 4-phenylthiazole (2) without deuterium incorporation. Irradiation of 4-phenylthiazole (2) under these conditions results in rapid photodeuteration to yield 2-deuterio-4-phenylthiazole (2-D-2), which subsequently phototransposes to 5-deuterio-3-phenylisothiazole (5-D-3). These experimental results can be rationalized by a mechanism involving initial electrocyclic ring closure and sigmatropic shift of sulfur around the four sides of the azetine ring. Rearomatization of each bicyclic intermediate thus allows sulfur to insert into each position in the carbon-nitrogen sequence. As a consequence, these compounds divide into a tetrad in which isomers 1, 2,4, and 6 interconvert mainly via P5, P6, and P7 pathways and a dyad of two compounds in which 3 phototransposes to 5 via P5 and P7 pathways. Within the tetrad, BC-6, the bicyclic intermediate derived from 5-phenylisothiazoles (6), is postulated to undergo deuteration with simultaneous sigmatropic shift of sulfur when the reaction is carried out in benzene-D2O. This mechanistic view provides one coherent interpretation for the observed phototransposition and photodeuteration reactions.
- Pavlik, James W.,Tongcharoensirikul, Pakamas,Bird, Nigel P.,Day, A. Colin,Barltrop, John A.
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p. 2292 - 2300
(2007/10/02)
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- ADDITION REACTION OF SULFUR DICHLORIDE TO FUNCTIONALIZED IMINES DIRECTED TOWARD HETEROCYCLIC SYNTHESIS
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Although it was shown that the reactions of sulfur dichloride (SCl2) with imines 1a-c or with the azine 14 gave rise to very unstable 1:1 adducts, 1-aza- and 2-azabutadienes, 5 and 10, reacted with SCl2 to afford the isothiazoles 6 and the thiazoles 11, respectively, in high yields.Addition of SCl2 to heterocumulenes was also studied and the ketenimines 16 and diphenylketene 27 gave 1:1 adducts which were applied to heterocyclic synthesis as bifunctional reagents.Addition of SCl2 to these compounds was investigated by monitoring the reactions by 13C nmr spectroscopy.
- Komatsu, Mitsuo,Harada, Nobuyuki,Kashiwagi, Hiroshi,Ohshiro, Yoshiki,Agawa, Toshio
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p. 119 - 134
(2007/10/02)
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- THERMOLYSIS OF 1,3-DITHIOL-2-YL AZIDES AND THERMAL PROPERTIES OF THE RESULTING 1,4,2-DITHIAZINES
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2-Substituted 1,3-dithiol-2-yl azides, on thermolysis in refluxing toluene, give 3-substituted 1,4,2-dithiazines wich thermally extrude sulfur atom of the 4-position selectively to yield 3-substituted isothiazoles, while 2-unsubstituted 1,3-dithiol-2-yl azides undergo both ring expansion yielding 1,4,2-dithiazines and peculiar thermal dissociation into 1,3-dithiol-2-ylidene carbenes and hydrogen azide.
- Nakayama, Juzo,Sakai, Atsuhiro,Tokiyama, Akira,Hoshino, Masamatsu
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p. 3729 - 3732
(2007/10/02)
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- New Synthesis of Isoxazoles and Isothiazoles. A Convenient Synthesis of Thioenaminones from Enaminones
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The reaction of 1-aryl-3-(dimethylamino)-2-propene-1-ones (enaminones) and 1-aryl-3-(dimethylamino)-2-propene-1-thiones (thioenaminones) with hydroxylamine-O-sulfonic acid gave, respectively, isoxazoles in 76-84 percent yields and isothiazoles in 60-65 pe
- Lin, Yang-i,Lang, Stanley, A.
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p. 4857 - 4860
(2007/10/02)
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