IP Library › Granted Patent US 11,981,618

Granted Patent B2

US 11,981,618 · App. 17/262,129 · Granted May 14, 2024

P62 ligand compound, and composition for preventing, ameliorating or treating proteinopathies comprising the same

Inventors: Yong Tae Kwon (Seoul, KR); Chang Hoon Ji (Seoul, KR); Srinivasrao Ganipisetti (Seoul, KR); Hee Yeon Kim (Seoul, KR); Su Ran Mun (Seoul, KR); Chan Hoon Jung (Seoul, KR); Eui Jung Jung (Seoul, KR); Ki Woon Sung (Seoul, KR)

Assignee: AUTOTAC INC.

C07C217/58 A23L33/10 A61K31/05 A61K31/12 A61K31/138 A61K31/166 A61K31/192 A61K31/277 A61K31/336 A61K31/355 A61K31/4015 A61K31/4155 A61K31/4184 A61K31/421 A61K31/428 A61K31/4535 A61K31/4709 A61K31/4745 A61K31/496 A61K31/50 A61K31/5025 A61K31/506 A61K31/517 A61K31/5377 A61K31/5415 A61K31/551 A61K31/565 A61K39/3955 A61K47/54 A61K47/55 A61K47/6803 A61K47/6849 A61P25/28 C07C43/23 C07C47/575 C07C235/06 C07C237/06 C07C275/24 C07C279/12 C07D303/18 C07B2200/07

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Quick Facts

Patent No.: US 11,981,618
App. No.: 17/262,129
Granted: May 14, 2024
Kind: B2

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Abstract

The present invention relates to a novel p62 ligand compound, a stereoisomer, hydrate, solvate or prodrug thereof, and a pharmaceutical or food composition for preventing or treating proteinopathies comprising the same as an active ingredient. The p62 ligand compound according to the present invention can be usefully used as a pharmaceutical composition for the prevention, amelioration or treatment of various proteinopathies by activating autophagy in cells and thus selectively eliminating in vivo proteins, organelles and aggregates.

Claims (69)

1. A p62 ligand compound of the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof:

in Chemical Formula 1,

W is C6-C10 aryl;

n1 is an integer of 1 to 4;

m is an integer of 0 to 2;

R a is R 1 or —OR 1 ,

where R 1 is (CH 2 ) n2 —R′ 1 ,

R′ 1 is phenyl which is unsubstituted or substituted by hydroxy, halogen, C 1-4 alkyl′, C 1-4 alkoxy, nitro, amino, (C 1-4 alkyl)amino, or di(C 1-4 alkyl)amino,

n2 is an integer of 1 to 6;

R b is —OR 2 ,

where R 2 is hydrogen or —(CH 2 ) n3 —R′ 2 ,

R′ 2 is phenyl which is unsubstituted or substituted by hydroxy, halogen, C 1-4 alkyl, C 1-4 alkoxy, nitro, amino, (C 1-4 alkyl)amino, or di(C 1-4 alkyl)amino,

n3 is an integer of 1 to 6;

R c is —(CH 2 ) n4 —OH, —(CH 2 ) n4 —NH—C(═NH)NH 2 , —C(═NH)NH 2 , C 1-6 alkyl, —CH(R 3 )—COO—R 4 , or —CH(COO—R 4 )—CH 2 CH 2 CH 2 —NH—C(═NH)NH 2 , —(CH 2 ) n4 —O—(CH 2 ) n4 —OR 4 , —CONH(CH 2 ) n4 —OR 4 , —CO(CH 2 ) n5 —OR 4 , —(CH 2 ) n5 —CH(NH 2 )—COOR 4 , —(CH 2 ) n5 —CONHR 4 ,

n4 is an integer of 2 to 4,

n5 is an integer of 1 to 4,

R 3 is hydrogen or C 1-4 alkyl,

R 4 is hydrogen, or C 1-4 alkyl, and

wherein the p62 ligand compound is optically pure (R) form, and

wherein the compound of Chemical Formula 1 is not a compound selected from the group consisting of the following compounds:

1) (R)-1-(3,4-(bis(benzyloxy)phenoxy)-3-((2-hydroxyethyl)amino)propan-2-ol (YOK-1106);

2) (R)-1-(3,4-(bis((4-chlorobenzyl)oxy)phenoxy)-3-((2-hydroxyethyl)amino)propan-2-ol (YT-6-1);

3) (R)-1-(3-((4-chlorobenzyl)oxy)phenoxy)-3-((2-hydroxyethyl)amino)propan-2-ol (YT-6-2);

4) (R)-1-(3-((4-chlorobenzyl)oxy)phenoxy)-3-((2-hydroxyethyl)amino)propan-2-ol (YT-6-7);

5) (R)-1-(3-((4-fluorobenzyl)oxy)phenoxy)-3-((2-hydroxyethyl)amino)propan-2-ol (YT-6-8);

6) (R)-1-(2-((3-(3,4-bis(benzyloxy)phenoxy)-2-hydroxypropyl)amino)ethyl)guanidine (YOK-1109);

7) (R)-1-(2-((3-(3,4-diphenethoxyphenoxy)-2-hydroxypropyl)amino)ethyl)guanidine (YOK-2209);

8) (R)-1-(2-((3-(3,4-bis(4-chlorobenzyl)oxy)phenoxy)-2-hydroxypropyl)amino)ethyl)guanidine (YT-9-1);

9) (R)-1-(2-((3-(3,4-bis(4-fluorobenzyl)oxy)phenoxy)-2-hydroxypropyl)amino)ethyl)guanidine (YT-9-2);

10) (R)-1-(3-(3,4-bis(benzyloxy)phenoxy)-2-hydroxypropyl)guanidine (YOK-1107);

11) (R)-1-(3-(3,4-diphenethoxyphenoxy)-2-hydroxypropyl)guanidine (YOK-2207);

12) (R)-1-(3,4-bis(benzyloxy)phenoxy)-3-(isopropylamino)propan-2-ol (YOK-1104);

13) (R)-1-(3,4-diphenethoxyphenoxy)-3-(isopropylamino)propan-2-ol (YOK-2204);

14) (R)-1-(3,4-bis(3-phenylpropoxy)phenoxy)-3-(isopropylamino)propan-2-ol (YOK-3304);

15) (R)-1-(3,4-bis(4-phenylbutoxy)phenoxy)-3-(isopropylamino)propan-2-ol (YOK-4404);

16) (R)-1-(4-(benzyloxy)-3-phenethoxyphenoxy)-3-(isopropylamino)propan-2-ol (YOK-1204);

17) (R)-1-(4-(benzyloxy)-3-(3-phenylpropoxy)phenoxy)-3-(isopropylamino)propan-2-ol (YOK-1304);

18) (R)-1-(3,4-bis((4-chlorobenzyl)oxy)phenoxy)-3-(isopropylamino)propan-2-ol (YT-4-1); and

19) (R)-1-(3,4-bis((4-fluorobenzyl)oxy)phenoxy)-3-(isopropylamino)propan-2-ol (YT-4-2).

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the W is phenyl, and n1 is 1 or 2.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the R a is hydrogen or —O—(CH 2 ) n2 —R′ 1 , R′ 1 is phenyl that is unsubstituted or substituted by hydroxy, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, nitro, amino or dimethylamino, and n2 is an integer of 1 to 4.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the R b is hydroxy, or —O—(CH 2 ) n3 —R′ 2 , R′ 2 is phenyl which is unsubstituted or substituted by hydroxy, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, nitro, amino or dimethylamino, and n3 is an integer of 1 to 4.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the R c is is —(CH 2 ) n4 —OH, —(CH 2 ) n4 —NH—C(═NH)NH 2 , —C(═NH)NH 2 , methyl, ethyl or isopropyl, and n4 is an integer of 2 to 3.

6. A p62 ligand compound or a pharmaceutically acceptable salt, wherein the compound is selected from the group consisting of the following compounds 1) to 19: