Chiral auxiliaries

• US 10,428,019 B2
• Filed: 09/22/2011
• Issued: 10/01/2019
• Est. Priority Date: 09/24/2010
• Status: Active Grant

• Current Assignee: WAVE Life Sciences Ltd.
• Original Assignee: WAVE Life Sciences Ltd.
• Inventors: Wada, Takeshi, Shimizu, Mamoru
• Primary Examiner(s): Crane, Lawrence E
• Application Number:
  US13/825,627
• Publication Number:
  US 20130178612A1
• Time in Patent Office: 2,931 Days
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/62 Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
• CPC Class Codes: C07D 211/42 attached in position 3 or 5
• CPC Class Codes: C07D 211/44 attached in position 4
• CPC Class Codes: C07D 211/62 attached in position 4
• CPC Class Codes: C07D 217/24 Oxygen atoms
• CPC Class Codes: C07D 221/10 Aza-phenanthrenes
• CPC Class Codes: C07D 221/18 Ring systems of four or more rings
• CPC Class Codes: C07H 1/00 Processes for the preparation of sugar derivatives
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical

Abstract

The disclosed and claimed compounds are chiral auxiliaries useful for efficiently producing a phosphorus atom-modified nucleic acid derivative with high stereoregularity. The disclosed and claimed compounds include those represented by the following formula (I) or formula (XI) for introducing the chiral auxiliaries.

Claims

1. A nucleic acid derivative comprising a chiral auxiliary, wherein the chiral auxiliary is represented by formula (II) and binds to a phosphorus atom of a phosphite moiety of the nucleic acid derivative through the oxygen atom of the chiral auxiliary, wherein the squiggly line represents the point of attachment to a phosphorus atom of a phosphite moiety of the nucleic acid derivative:

2. The nucleic acid derivative of claim 1, wherein R³ represents an unsubstituted or substituted aryl group.

3. The nucleic acid derivative of claim 2, wherein Y² represents a single bond.

4. The nucleic acid derivative of claim 1, wherein Y¹ represents an unsubstituted or substituted o-aryldiyl group.

5. A nucleoside-3′

-phosphoramidite reagent represented by formula (IV);

6. The reagent of claim 5, wherein R³ represents an unsubstituted or substituted aryl group.

7. The reagent of claim 5, wherein Y¹ represents an unsubstituted or substituted o-aryldiyl group.

8. The reagent of claim 7, wherein Y² represents a single bond.

9. A compound represented by formula (XI), or a salt thereof:

10. The compound or a salt thereof according to claim 9, wherein R¹⁰¹ and R¹⁰² are independently a hydrogen atom or an unsubstituted or substituted alkyl group, R¹⁰³ is a cyano group, and Z is —

C(R¹⁰⁴)(R¹⁰⁵)—

wherein R¹⁰⁴ and R¹⁰⁵ are independently a hydrogen atom or an unsubstituted or substituted alkyl group.

11. The compound or a salt thereof of claim 9, wherein R¹⁰¹ and R¹⁰² are hydrogen atoms, R¹⁰³ is a cyano group, and Z is —

C(R¹⁰⁶)(R¹⁰⁵)—

wherein R¹⁰⁴ and R¹⁰⁵ are hydrogen atoms.

12. The compound or a salt thereof of claim 9, wherein R¹⁰³ is a cyano group.

13. A nucleic acid derivative, wherein a chiral auxiliary represented by the following general formula (XII) binds to a phosphorus atom of a phosphite moiety of the nucleic acid derivative through the oxygen of the chiral auxiliary, wherein the squiggly line represents the point of attachment to a phosphorus atom of a phosphite moiety of the nucleic acid derivative:

14. The nucleic acid derivative of claim 13, wherein R¹⁰³ is a cyano group.

15. The nucleic acid derivative of claim 14, wherein R¹⁰¹ and R¹⁰² are independently a hydrogen atom or an unsubstituted or substituted alkyl group, and Z is —

C(R¹⁰⁴)(R¹⁰⁵)—

wherein R¹⁰⁴ and R¹⁰⁵ are independently a hydrogen atom or an unsubstituted or substituted alkyl group.

16. The nucleic acid derivative of claim 14, wherein R¹⁰¹ and R¹⁰² are hydrogen atoms, and Z is —

C(R¹⁰⁴)(R¹⁰⁵)—

wherein R¹⁰⁴ and R¹⁰⁵ are hydrogen atoms.

17. A nucleoside-3′

-phosphoramidite reagent represented by formula (XIV);

18. The nucleoside of claim 17, wherein R¹⁰³ is a cyano group.

19. The nucleoside of claim 18, wherein R¹⁰¹ and R¹⁰² are independently a hydrogen atom or an unsubstituted or substituted alkyl group, and Z is —

C(R¹⁰⁴)(R¹⁰⁵)—

wherein R¹⁰⁴ and R¹⁰⁵ are independently a hydrogen atom or an unsubstituted or substituted alkyl group.

20. The nucleoside of claim 18, wherein R¹⁰¹ and R¹⁰² are hydrogen atoms, and Z is —

C(R¹⁰⁴)(R¹⁰⁵)—

wherein R¹⁰⁴ and R¹⁰⁵ are hydrogen atoms.