Conformationally-preorganized, miniPEG-containing gamma-peptide nucleic acids

Patent metadata

Field	Value
Publication number	US-10364272-B2
Application number	US-201816145075-A
Country	US
Kind code	B2
Filing date	Sep 27, 2018
Priority date	Apr 8, 2011
Publication date	Jul 30, 2019
Grant date	Jul 30, 2019

Abstract

The present invention relates to γ-PNA monomers according to Formula I where substituent groups R1, R2, R3, R4, R5, R6, B and P are defined as set forth in the specification. The invention also provides methodology for synthesizing compounds according to Formula I and methodology for synthesizing PNA oligomers that incorporate one or more Formula I monomers.

First claim

What is claimed is:

1. A compound according to Formula VIII

wherein,
P is selected from the group consisting of hydrogen (H), 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), tosylate (Tos), allyloxycarbonyl (alloc), benzhydryloxycarbonyl (Bhoc), O-nitroveratryloxycarbonyl (Nvoc), 1-(4,4-dimethyl-2,6-dioxacyclohexylidene)ethyl (Dde), diathiasuccinoyl (Dts), benzothiazole-2-sulfonyl (Bts), trityl (Trt), monomethoxytrityl (MMT), and dimethoxytrityl (DMT);
each of R 1 and R 2 is independently selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )hydroxylalkyl, (C 3 -C 8 )aryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aryl(C 1 -C 6 )alkylene, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylene,

provided that at least one of R 1 and R 2 is selected from the group consisting of

each of R 3 and R 4 is independently selected from the group consisting of hydrogen (H),

R 5 is selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )hydroxylalkyl, (C 3 -C 8 )aryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aryl(C 1 -C 6 )alkylene, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylene;
R 7 is selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 )aryl, and (C 1 -C 6 )alkylene;
P 2 is selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), tosylate (Tos), allyloxycarbonyl (alloc), trityl (Trt), monomethoxytrityl (MMT), and dimethoxytrityl (DMT);
P 3 is selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )aryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aryl(C 1 -C 6 )alkylene, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylene;
x is an integer from 1 to 10, inclusive; and
y is an integer from 1 to 9, inclusive.

2. The compound of claim 1 , wherein
R 1 is —CH 2 —O[(CH 2 ) 2 —O—] X R 8 ; each of R 2 , R 3 and R 4 is hydrogen (H); wherein x is an integer from 1 to 4 inclusive;
R 5 is selected from the group consisting of hydrogen (H) and methyl;
R 7 is selected from the group consisting of hydrogen (H), methyl, ethyl, and t-butyl; and
R 8 is selected from the group consisting of hydrogen (H), methyl, ethyl, and t-butyl.

3. The compound of claim 2 , wherein R 5 is hydrogen (H); R 7 is methyl, ethyl or t-butyl; R 8 is methyl, ethyl, or t-butyl and P is 9-fluorenylmethyloxycarbonyl (Fmoc) or t-butyloxycarbonyl (Boc).

4. The compound of claim 3 having the formula VIIIa-1:

wherein, x is 1, 2 or 3; R 7 is methyl, ethyl or t-butyl, and R 8 is methyl, ethyl or t-butyl.

5. The compound of claim 4 having the formula VIIIa-2 or VIIIa-3:

wherein R 7 is methyl, ethyl or t-butyl.

6. The compound of claim 5 , having an optical purity of at least 99% enantomeric excess (ee).

7. The compound of claim 3 having the formula VIIIa-1T:

wherein, x is 1, 2 or 3; R 7 is methyl or ethyl and R 8 is methyl or ethyl.

8. The compound of claim 7 having the formula VIIIa-2T or VIIIa-3T:

wherein R 7 is methyl or ethyl.

9. The compound of claim 8 , having an optical purity of at least 99% enantomeric excess (ee).

10. The compound of claim 1 , wherein
R 2 is —CH 2 —O[(CH 2 ) 2 —O—] X R 8 ; each of R 1 , R 3 and R 4 is H, wherein x is an integer from 1 to 4 inclusive;
R 5 is selected from the group consisting of hydrogen (H) and methyl;
R 7 is selected from the group consisting of hydrogen (H), methyl, ethyl, and t-butyl; and
R 8 is selected from the group consisting of hydrogen (H), methyl, ethyl, and t-butyl.

11. The compound of claim 10 , wherein R 5 is hydrogen (H); R 7 is methyl, ethyl or t-butyl; R 8 is methyl, ethyl or t-butyl, and P is 9-fluorenylmethyloxycarbonyl (Fmoc) or t-butyloxycarbonyl (Boc).

12. The compound of claim 11 , having the formula VIIIa-4:

wherein, x is 1, 2 or 3; R 7 is methyl, ethyl or t-butyl, and R 8 is selected from methyl, ethyl or t-butyl.

13. The compound of claim 12 , having the formula VIIIa-5 or VIIIa-6:

wherein R 7 is methyl, ethyl or t-butyl.

14. The compound of claim 13 , having an optical purity of at least 99% enantomeric excess (ee).

15. The compound of claim 11 having the formula VIIIa-4T:

wherein, x is 1, 2 or 3; R 7 is methyl or ethyl and R 8 is selected from methyl or ethyl.

16. The compound of claim 15 having the formula VIIIa-5T or VIIIa-6T:

wherein R 7 is methyl or ethyl.

17. The compound of claim 16 , having an optical purity of at least 99% enantomeric excess (ee).

Assignees

• Univ Carnegie Mellon

Inventors

• Ly Danith H
• Rapireddy Srinivas
• Sahu Bichismita

Classifications

• C07C229/12

  to carbon atoms of acyclic carbon skeletons · CPC title

• C07K14/003 Primary

  Peptide-nucleic acids (PNAs) · CPC title

• C07D239/47

  One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine · CPC title

• C07K1/08

  using activating agents {(C07K1/003, C07K1/006 take precedence)} · CPC title

• C07D473/18

  one oxygen and one nitrogen atom, e.g. guanine · CPC title