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

Patent metadata

Field	Value
Publication number	US-10160787-B2
Application number	US-201815972494-A
Country	US
Kind code	B2
Filing date	May 7, 2018
Priority date	Apr 8, 2011
Publication date	Dec 25, 2018
Grant date	Dec 25, 2018

Abstract

Described are γ-PNA monomers, methodology for synthesizing them, and methodology for synthesizing PNA oligomers that incorporate them.

First claim

What is claimed is:

1. A compound according to Formula IIIa

wherein,
Z is selected from the group consisting of hydroxyl (OH), iodine (I), 4-toluenesulfonate and methanesulfonate;
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;
P is selected from the group consisting of: 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 11 and R 12 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 11 and R 12 is selected from the group consisting of

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 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
Z is selected from the group consisting of iodine and hydroxyl;
R 11 is —CH 2 —[O(CH 2 ) 2 ] x —OR 8 and R 12 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; and
R 8 is selected from the group consisting of hydrogen, methyl, ethyl, and t-butyl.

3. The compound of claim 2 , wherein Z is hydroxyl, R 5 is hydrogen, R 12 is hydrogen and P is 9-fluorenylmethyloxycarbonyl (Fmoc) or t-butyloxycarbonyl (Boc).

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

wherein, P 3 is selected from methyl, ethyl and t-butyl.

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

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

7. The compound of claim 1 , wherein
Z is selected from the group consisting of iodine and hydroxyl;
R 11 is H and R 12 is —CH 2 —[O(CH 2 ) 2 ] x —OR 8 , wherein x is an integer from 1 to 4 inclusive;
R 5 is selected from the group consisting of hydrogen (H) and methyl; and
R 8 is selected from the group consisting of hydrogen, methyl, ethyl, and t-butyl.

8. The compound of claim 7 , wherein Z is hydroxyl, R 5 is hydrogen, R 11 is hydrogen and P is 9-fluorenylmethyloxycarbonyl (Fmoc) or t-butyloxycarbonyl (Boc).

9. The compound of claim 8 , having the formula IIIa-4:

wherein, P 3 is selected from methyl, ethyl and t-butyl.

10. The compound of claim 9 , having the formula IIIa-5 or IIIa-6:

11. The compound of claim 10 , having an optical purity of at least 99% enantiomeric excess (ee).

12. The compound of claim 1 , wherein Z is hydroxyl (—OH).

13. The compound of claim 1 , wherein Z is iodine (I), 4-toluenesulfonate or methanesulfonate.

14. A method comprising: a) contacting a compound of formula X:

wherein, P is selected from the group consisting of: 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), tosylate (Tos), allyloxycarbonyl (alloc), trityl (Trt), monomethoxytrityl (MMT) and dimethoxytrityl (DMT); 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;
one of R 1 and R 2 is —CH 2 —OH and the other of R 1 and R 2 is H with a compound of formula: P 3 —(O—CH 2 —CH 2 —) x OX, wherein X is CH 3 S(O) 2 —, P 3 is methyl, ethyl, or t-butyl; and x is a number from 1 to 10, inclusive, to thereby obtain a compound of formula XI:

wherein one of R 11 and R 12 is —CH 2 —O—(CH 2 —CH 2 —O)x-P 3 and the other of R 11 and R 12 is H; and
b) reducing the carboxylic acid of formula XI to an alcohol to thereby produce a compound of formula

15. The method of claim 14 , further comprising:
c) contacting said compound of formula with a reagent selected from the group consisting of: methanesulfonyl chloride, 4-toluenesulfonyl chloride and sodium iodide.

16. The method of claim 14 , wherein the compound of formula IIIa-7 has the formula IIIa-1:

wherein, P 3 is selected from methyl, ethyl and t-butyl.

17. The method of claim 16 , wherein the compound of formula IIIa-1 has the formula IIIa-2 or IIIa-3:

18. The method of claim 14 , wherein the compound of formula IIIa-7 has the formula IIIa-4:

wherein, P 3 is selected from methyl, ethyl and t-butyl.

19. The method of claim 18 , wherein the compound of formula IIIa-4 has the formula IIIa-5 or IIIa-6:

Assignees

• Univ Carnegie Mellon

Inventors

• Ly Danith H
• Rapireddy Srinivas
• Sahu Bichismita

Classifications

• 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

• C07C229/12

  to carbon atoms of acyclic carbon skeletons · CPC title

• C07D239/54

  as doubly bound oxygen atoms or as unsubstituted hydroxy radicals · CPC title

• C07C271/20

  to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups · CPC title