Thiophene-based lipids

Patent metadata

Field	Value
Publication number	US-2024300972-A1
Application number	US-202418617043-A
Country	US
Kind code	A1
Filing date	Mar 26, 2024
Priority date	Sep 27, 2021
Publication date	Sep 12, 2024
Grant date	—

Abstract

Disclosed herein are compounds according to Formula A

wherein the compound comprises at least one C 6-30 aliphatic moiety. Also disclosed are compositions comprising the compounds that may be useful for delivering agents such as therapeutic and/or prophylactic agents, for example, nucleic acids such as, but not limited to, DNA or RNA, small molecules, proteins, polypeptides or peptides. In some embodiments, the composition is a lipid nanoparticle. Also disclosed herein are lipid nanoparticles comprising the compounds and methods for making and using the nanoparticles.

First claim

We claim:

1 . A compound according to Formula A

wherein:
X is a bond, —C(O)O—, —OC(O)—, —NH—, —N(R 1 )—, —C(O)N(R 1 )—, —N(R 1 )C(O)—, —C(O)NH—, —NHC(O)—, —C≡C—, —CH═CH—, —O—, —S—, —NHC(O)NH—, —OC(O)O—, —OC(O)NH—, —NHC(O)O—, —O(CH 2 ) m or —(CH 2 ) m O—;
m is from 0 to 6;
each R 1 is H, halogen, CN, or aliphatic;
R 2 is H, halogen, aromatic, or aliphatic;
or X is a bond and R 1 and R 2 , together with the atoms to which there are attached, form a 4- to 7-membered nitrogen-containing non-aromatic heterocyclyl;
R A3 is halogen, R 3 , —C(O)N(R 6 )(R 7 ), —C(O)R 3 , —CN, —(CH 2 ) r N(R 6 )(R 7 ), —N(R 6 )(R 7 ), —S(O)R d , —S(O)R 3 , —CH 2 SR d , —CH 2 R 3 , —S(O)N(R 6 )(R 7 ), or —X 1 (CH 2 ) r N(R a ) 2 ;
X 1 is O, S or NH;
r is from 1 to 8;
each R a independently is H, C 1-6 alkyl, C 3-6 cycloalkyl, or both R a s together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclyl;
R 3 is aliphatic, —O-aliphatic or N(R 6 )(R 7 );
R A4 is halogen, boronic acid, —N(R 4 )(R 5 ), NHC(O)N(R 4 )(R 5 ), —N═CHR d , —NHC(S)N(R 4 )(R 5 ), —NHC(O)(CH 2 ) z —N(R 4 )(R 5 ), —NHSO 2 R d , —NHS(O)R d , —NHC(O)C(O)NH(CH 2 ) z —N(R 4 )(R 5 ), or —OR 4 , where z is an integer from 1 to 6;
each R d is aliphatic;
R 4 is aliphatic or —C(O)aliphatic;
R 5 is H, aliphatic, or —C(O)aliphatic;
R 6 is H or aliphatic;
R 7 is aliphatic or C(O)aliphatic;
or R 6 and R 7 , together with the atom to which there are attached, form a 4- to 7-membered nitrogen-containing heterocyclyl; and
wherein the compound comprises at least one C 6-30 aliphatic moiety.

2 . The compound of claim 1 , wherein:
R 6 is H or aliphatic; and R 7 is aliphatic or C(O)aliphatic.

3 . The compound of claim 1 , having a Formula I:

wherein X is a bond, —NH—, —N(R 1 )—, or —OC(O)—.

4 . The compound of claim 1 , having a Formula I-A:

5 . The compound of claim 4 , wherein
R 1 is aliphatic; R 2 is H or aliphatic; or R 1 and R 2 , together with the atoms to which there are attached, form a 5- to 7-membered nitrogen-containing non-aromatic heterocyclyl; R 3 is aliphatic, —O-aliphatic or N(R 6 )(R 7 ); R 4 is aliphatic or —C(O)aliphatic; R 5 is H, aliphatic or —C(O)aliphatic; R 6 is H or aliphatic; R 7 is aliphatic or C(O)aliphatic; and wherein the compound comprises at least one C 6-30 aliphatic moiety.

6 . The compound of claim 1 , wherein R 1 is C 6-30 aliphatic.

7 . The compound of claim 1 , wherein R 1 is C 6-10 aliphatic.

8 . The compound of claim 1 , wherein R 1 is C 1-6 alkyl and is substituted with N(R a ) 2 , where each R a independently is H or C 1-6 alkyl, or both R a s together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered heterocyclyl.

9 . The compound of claim 8 , wherein R 1 is —(CH 2 ) 14 N(R a ) 2 .

10 . The compound of claim 9 , wherein R 1 is —CH 2 NH 2 .

11 . The compound of claim 1 , wherein R 2 is H.

12 . The compound of claim 1 , wherein R 2 is C 6-30 aliphatic.

13 . The compound of claim 1 , wherein R 1 and R 2 are both C 6-30 aliphatic, and R 1 and R 2 are different.

14 . The compound of claim 1 , wherein the compound has a formula

wherein each of R 1 and R 2 independently is C 6-30 aliphatic.

15 . The compound of claim 1 , wherein the compound has a formula

wherein:
each of R 1 and R 2 independently is C 6-30 aliphatic;
each R a independently is H or C 1-6 alkyl, or both R a s together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered heterocyclyl; and
s is an integer from 1 to 8.

16 . The compound of claim 1 , wherein the compound has a formula

wherein:
each of R 1 and R 2 independently is C 6-30 aliphatic;
each R a independently is H or C 1-6 alkyl, or both R a s together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered heterocyclyl; and
s is an integer from 1 to 8.

17 . The compound of claim 1 , wherein the compound has a formula

wherein:
each of R 1 and R 2 independently is C 6-30 aliphatic; and
each R a independently is H or C 1-6 alkyl, or both R a s together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered heterocyclyl.

18 . The compound of claim 17 , wherein the compound has a formula

19 . The compound of claim 1 , wherein the compound has a formula

wherein:
each R a independently is H or C 1-6 alkyl, or both R a s together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered heterocyclyl; and
s is an integer from 1 to 8.

20 . The compound of claim 19 , wherein the compound has a formula

21 . The compound of claim 15 , wherein s is an integer from 1, 2, 3 or 4.

22 . The compound of claim 8 , wherein each R a independently is C 1-6 alkyl.

23 . The compound of claim 16 , wherein:
s is 2 or 3; each of R 1 and R 2 independently is C 6-10 alkyl; R 3 is O-methyl or O-ethyl; each R a independently is C 14 alkyl; or a combination thereof.

24 . The compound of claim 1 , wherein X is a bond and R 1 and R 2 , together with the atoms to which there are attached, form a 4- to 7-membered nitrogen-containing non-aromatic heterocyclyl; provided that the compound is not of the formula:

or a salt thereof.

25 . The compound of claim 24 , wherein the compound has a formula II′:

wherein:
R 8 is H or R c ; and
R c is -aliphatic, -aliphatic-amino, —C(O)-aliphatic, or —C(O)-aliphatic-amino.

26 . The compound of claim 24 , wherein the compound has a formula II:

wherein:
R 8 is H or Re; and
R c is -aliphatic, -aliphatic-amino, —C(O)-aliphatic, or —C(O)-aliphatic-amino.

27 . The compound of claim 26 , wherein the compound has a formula II-a:

28 . The compound of claim 25 , wherein R

Assignees

• Univ Oregon State

Inventors

• Sahay Gaurav
• Gupta Mohit
• Kim Jeonghwan
• Eygeris Yulia V
• Gautam Milan
• Renner Jonas

Classifications

• C07D333/26 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/4365

  the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine · CPC title

• A61K31/381

  having five-membered rings · CPC title

• A61K9/5146

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides · CPC title