US2021171555A1PendingUtilityA1
Chiral reagents for preparation of homogeneous oligomers
Est. expiryAug 5, 2035(~9 yrs left)· nominal 20-yr term from priority
A61K 31/713A61K 31/7088C07H 21/00C07H 21/02C07H 1/00C07F 9/65616C07F 9/65583C07B 2200/07A61K 31/7125
67
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Claims
Abstract
We provide diastereomerically pure or substantially diastereomerically pure activated phosphoramidochloridate morpholino nucleosides, methods of their preparation, and methods of their use in stereospecific coupling for stereospecific synthesis of diastereomerically pure phosphorodiamidate morpholino oligomers (PMOs).
Claims
exact text as granted — not AI-modified1 - 3 . (canceled)
4 . A method for preparing a stereochemically pure oligonucleotide, comprising reacting substantially diastereomerically pure compounds selected from the group consisting of the compound of Formula 20, the compound of Formula 21, the compound of Formula 22, the compound of Formula 23, the compound of Formula 24, the compound of Formula 25, the compound of Formula 26, the compound of Formula 27, the compound of Formula 28, the compound of Formula 29, the compound of Formula 30, and the compound of Formula 31,
Compound
Formula #
20
21
22
23
24
25
26
27
28
29
30
31
wherein R 1 and R 2 may be the same or different, and are selected from the group consisting of —H, optionally substituted C 1 -C 3 alkyl, optionally substituted phenyl, optionally substituted naphthyl, or, with the nitrogen to which they are attached, form an optionally substituted heterocycle, which may be, for example, pyrrolidine, piperazine, and morpholine;
wherein R 3 is selected from the group consisting of trityl (Tr), which may be substituted trityl, including but not limited to such as MMTr (p-methoxyphenyldiphenylmethyl); optionally substituted benzyl, 4-methoxybenzyl (PMB, MPM), 3,4-dimethoxybenzyl, diphenylmethyl (Dpm), 4-methoxybenzyl, and sulfonyl;
R 4 , R 5 , and R 6 are selected from the group consisting of —H, —C(O)R 7 , and —C(O)OR 7 , where R 7 is C1-C6 alkyl, benzyl, 2,2,2-trichloroethyl, and aryl;
R 9 is selected from the group consisting of optionally substituted alkyl, cyanoethyl, acyl, carbonate, carbamate, optionally substituted benzyl, 4-pivaloyloxy benzyl, and silyl, and enantiomers thereof.
5 . A method for preparing a substantially diastereomerically pure oligomer, comprising:
selecting a substantially stereochemically pure activated monomer; and synthesizing a substantially diastereomerically pure oligomer from the selected substantially stereochemically pure activated monomer.
6 . The method of claim 5 , wherein the oligomer is an oligonucleotide comprising chiral phosphorous linkages.
7 . The method of claim 5 , further comprising:
separating a diastereomeric mixture of activated monomers into two substantially stereochemically pure monomers prior to the step of selecting a substantially stereochemically pure activated monomer.
8 . The method of claim 5 , wherein said substantially diastereomerically pure oligomer is at least 90% diastereomerically pure.
9 . The method of claim 8 , wherein said substantially diastereomerically pure oligomer is at least 95% diastereomerically pure.
10 . The method of claim 9 , wherein said substantially diastereomerically pure oligomer is at least 99% diastereomerically pure.
11 . The method of claim 10 , wherein said substantially diastereomerically pure oligomer is 100% diastereomerically pure.
12 . A method for preparing a substantially diastereomerically pure phosphorodiamidate oligomer, comprising:
selecting a substantially stereochemically pure phosphoramidochloridate monomers; and synthesizing a substantially diastereomerically pure phosphorodiamidate oligomer from the selected substantially stereochemically pure phosphoramidochloridate monomer.
13 . The method of claim 12 , further comprising separating a diastereomeric mixture of phosphoramidochloridates into two substantially stereochemically pure phosphoramidochloridate monomers prior to the step of selecting a substantially stereochemically pure phosphoramidochloridate monomer.
14 . The method of claim 13 , wherein the separation of the diastereomeric mixture occurs by at least one member of the group consisting of chromatography and crystallization.
15 . The method of claim 12 , wherein the phorphorodiamidate oligomer is a phosphorodiamidate morpholino oligomer.
16 - 18 . (canceled)
19 . A substantially diastereomerically pure oligomer made by the method of claim 4 .
20 . A substantially diastereomerically pure oligomer made by the method of claim 5 .
21 . A substantially diastereomerically pure oligomer made by the method of claim 6 .
22 . A substantially diastereomerically pure oligomer made by the method of claim 7 .
23 . A substantially diastereomerically pure oligomer made by the method of claim 8 .
24 . A substantially diastereomerically pure oligomer made by the method of claim 9 .
25 . A substantially diastereomerically pure oligomer made by the method of claim 10 .
26 . A substantially diastereomerically pure oligomer made by the method of claim 11 .
27 . A pharmaceutical composition comprising a substantially diastereomerically pure oligomer of claim 19 , or a pharmaceutically acceptable salt thereof.Join the waitlist — get patent alerts
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