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

Patent metadata

Field	Value
Publication number	US-10793605-B2
Application number	US-201916362579-A
Country	US
Kind code	B2
Filing date	Mar 22, 2019
Priority date	Apr 8, 2011
Publication date	Oct 6, 2020
Grant date	Oct 6, 2020

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 peptide nucleic acid (PNA) monomer having the following formula:

wherein
B is adenine, guanine, cytosine, thymine, or uracil;
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), 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, and

provided that at least one of R 1 and R 2 is

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

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 6 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 3 -C 8 )aryl(C 1 -C 6 )alkylene;
P 1 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);
n is an integer from 0 to 10, inclusive; and
q is an integer from 1 to 10, inclusive.

2. The PNA monomer of claim 1 , wherein one of R 1 and R 2 is independently

and the other of R 1 and R 2 is independently hydrogen (H).

3. The PNA monomer of claim 2 , wherein R 1 is

and R 2 is hydrogen (H).

4. The PNA monomer of claim 2 , wherein R 2 is

and R 1 is hydrogen (H).

5. The PNA monomer of claim 1 , wherein
R 1 is —CH 2 (OCH 2 CH 2 ) q OH; —CH 2 (OCH 2 CH 2 ) q OCH 3 ; —CH 2 (OCH 2 CH 2 ) q OCH 2 CH 3 ; or —CH 2 (OCH 2 CH 2 ) q OC(CH 3 ) 3 ;
R 2 is H;
R 3 , R 4 , R 5 , and R 6 each independently are H;
P is selected from the group consisting of H, 9-fluorenylmethyloxy carbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), tosylate (Ts), benzyl (Bn), allyloxycarbonyl (alloc), trityl (Trt), dimethoxytrityl (DMT), and monomethoxytrityl (MMT);
n is 0, 1, or 2; and
q is 1, 2, 3, 4, or 5.

6. The PNA monomer of claim 5 , wherein P is H; n is 1; and q is 1, 2, or 3.

7. The PNA monomer of claim 1 , wherein R 3 and R 4 are H; R 5 is H or —CH 3 ; R 6 is H or —CH 3 ; n is 1; and q is 1, 2 or 3.

8. The PNA monomer of claim 7 , wherein P is 9-fluorenylmethyloxy carbonyl (Fmoc) or tert-butyloxycarbonyl (Boc).

9. The PNA monomer of claim 1 , selected from the following compounds:

wherein P 1 is hydrogen (H), tert-butyloxycarbonyl (Boc) or 9-fluorenylmethyloxy carbonyl (Fmoc); and R is —(OCH 2 CH 2 ) q OH; —(OCH 2 CH 2 ) q OCH 3 ; —(OCH 2 CH 2 ) q OCH 2 CH 3 ; or —(OCH 2 CH 2 ) q OC(CH 3 ) 3 .

10. The PNA monomer of claim 1 having the following formula:

wherein y is 1, 2, 3, or 4 (inclusive).

11. A PNA oligomer comprising the PNA monomer of claim 1 .

12. The PNA oligomer of claim 11 , wherein one of R 1 and R 2 is independently

and the other of R 1 and R 2 is independently hydrogen (H).

13. The PNA oligomer of claim 12 , wherein R 1 is

and R 2 is hydrogen (H).

14. The PNA oligomer of claim 12 , wherein R 2 is

and R 1 is hydrogen (H).

15. The PNA oligomer of claim 11 , wherein
R 1 is —CH 2 (OCH 2 CH 2 ) q OH; —CH 2 (OCH 2 CH 2 ) q OCH 3 ; —CH 2 (OCH 2 CH 2 ) q OCH 2 CH 3 ; or —CH 2 (OCH 2 CH 2 ) q OC(CH 3 ) 3 ;
R 2 is H;
R 3 , R 4 , R 5 , and R 6 each independently are H;
P is selected from the group consisting of H, 9-fluorenylmethyloxy carbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), tosylate (Ts), benzyl (Bn), allyloxycarbonyl (alloc), trityl (Trt), dimethoxytrityl (DMT), and monomethoxytrityl (MMT);
n is 0, 1, or 2; and
q is 1, 2, 3, 4, or 5.

16. The PNA oligomer of claim 11 , wherein P is H; n is 1; and q is 1, 2, or 3.

17. The PNA oligomer of claim 11 , wherein R 3 and R 4 are H; R 5 is H or —CH 3 ; R 6 is H or —CH 3 ; n is 1; and q is 1, 2 or 3.

18. The PNA oligomer of claim 17 , wherein P is 9-fluorenylmethyloxy carbonyl (Fmoc) or tert-butyloxycarbonyl (Boc).

19. The PNA oligomer of claim 11 , comprising a PNA monomer selected from the following compounds:

wherein P 1 is hydrogen (H), tert-butyloxycarbonyl (Boc) or 9-fluorenylmethyloxy carbonyl (Fmoc); and R is —(OCH 2 CH 2 ) q OH; —(OCH 2 CH 2 ) q OCH 3 ; —(OCH 2 CH 2 ) q OCH 2 CH 3 ; or —(OCH 2 CH 2 ) q OC(CH 3 ) 3 .

Assignees

• Univ Carnegie Mellon

Inventors

• Ly Danith H
• Rapireddy Srinivas
• Sahu Bichismita

Classifications

• C07D239/47

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

• C07K1/04

  on carriers {(C07K1/003, C07K1/006 take precedence)} · CPC title

• C07K14/003 Primary

  Peptide-nucleic acids (PNAs) · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• C07D473/34

  attached in position 6, e.g. adenine · CPC title