Morpholino Nucleic Acid Derivatives

• US 20130197220A1
• Filed: 09/29/2011
• Published: 08/01/2013
• Est. Priority Date: 09/30/2010
• Status: Active Grant

• Current Assignee: Nippon Shinyaku Company Limited
• Original Assignee: Nippon Shinyaku Company Limited
• Inventors: Ueda, Toshihiro
• Granted Patent: US 8,969,551 B2
• Time in Patent Office: Days
• US Class Current: 544/118
• CPC Class Codes: C07D 473/18 one oxygen and one nitrogen atom, e.g. guanine
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention provides a useful morpholino nucleic acid derivative for synthesizing a morpholino nucleic acid oligomer. The present invention provides a compound represented by the following general formula (1) or a salt thereof.

Here, R¹ represents hydrogen, trityl and so on.
R² represents an amide or an imine.
R³ represents a hydroxy group which may be protected by trialkylsilyl and so on, or a group represented by the following general formula (5):

(wherein X represents O or S, Y represents dialkylamino or alkoxy, and Z represents chlorine).

Claims

1. :

A compound represented by the following general formula (1) or a salt thereof;

2. :

The compound or salt thereof according to claim 1, wherein X is O, Y is dialkylamino, and Z is chlorine.

3. :

The compound or salt thereof according to claim 1, wherein R³ is hydroxy group which may be protected by t-butyldimethylsilyl or t-butyldiphenylsilyl.

4. :

The compound or salt thereof according to claim 1, wherein R⁴ is phenoxymethyl.

5. :

The compound or salt thereof according to claim 1, wherein R¹ is trityl, 4-methoxytrityl, 4-methyltrityl, 4,4′

-dimethytrityl, 4,4′

-dimethoxytrityl, or 4,4′

,4″

-trimethyltrityl.

6. A compound selected from the group consisting of the following compounds:

N⁹-[(2R,6S)-6-{(tert-butyldimethylsilyloxy)methyl}-4-tritylmorpholin-2-yl]-N²-(phenoxyacetyl)-O⁶-(2-cyanoethyl)guanine,

N⁹-{(2R,6)-6-hydroxymethyl-4-tritylmorpholin-2-yl}-N²-(phenoxyacetyl) -O⁶-(2-cyanoethyl)guanine, and

[(2S,6R)-6-{N²-(phenoxyacetyl)-O⁶-(2-cyanoethyl)guanin-9-yl}-4-tritylmorpholin-2-yl]methyl dimethylphosphoramidochloridate;

or a salt thereof.

7. :

A method of increasing the chain length of a morpholino nucleic acid oligomer, the method comprising the steps of;

providing a compound represented by the following general formula (1) or a salt thereof;

8. :

The method according to claim 7, wherein the reaction step is performed with the morpholino nucleic acid oligomer attached to a solid support.

9. :

The method according to claim 7, wherein X is O, Y is dialkylamino, and Z is chlorine.

10. :

The method according to claim 9, wherein the reaction step is performed with the morpholino nucleic acid oligomer attached to a solid support.

11. :

The method according to claim 7, wherein R² is the group represented by the general formula (3), and R⁴ is phenoxymethyl.

12. :

The method according to claim 11, wherein the reaction step is performed with the morpholino nucleic acid oligomer attached to a solid support.

13. :

The method according to claim 7, wherein R¹ is trityl, 4-methoxytrityl, 4-methyltrityl, 4,4′

-dimethyltrityl, 4,4′

-dimethoxytrityl, or 4,4′

,4″

-trimethyltrityl.

14. :

The method according to claim 13, wherein, the reaction step is performed with the morpholino nucleic acid oligomer attached to a solid support.

15. :

The method according to claim 7, wherein the compound or salt thereof is [(2S,6R)-6-{N²-(phenoxyacetyl)-O⁶-(2-cyanoethyl)guanin-9-yl}-4-tritylmorpholin-2-yl]methyl dimethylphosphoramidochloridate or a salt thereof.

16. :

The method according to claim 15, wherein the reaction step is performed with the morpholino nucleic acid oligomer attached to a solid support.