Methods of preventing or treating atherosclerosis with inhibitors of specific isoenzymes of human neuraminidase

Patent metadata

Field	Value
Publication number	US-11773129-B2
Application number	US-201816616426-A
Country	US
Kind code	B2
Filing date	May 25, 2018
Priority date	May 25, 2017
Publication date	Oct 3, 2023
Grant date	Oct 3, 2023

Abstract

The present invention provides a method of preventing or treating atherosclerosis or a symptom thereof comprising administering to a subject in need thereof a specific inhibitor of neuraminidase 1 (neu1); neuraminidase 3 (neu3); or a bispecific inhibitor of neu1 or neu3 of formula I; (I) and a compound of formula I.

First claim

The invention claimed is:

1. A compound of formula I

wherein R 1 is H, a C1-C10 alkyl, C2-C10 heteroalkyl; C3-C7 cycloalkyl; C3-C7 heterocycloalkyl; C6-C8 aryl; or C3-C8 heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyl, a C3-C8 cycloalkyl, C6-C7 aryl, a halogen, an amide or a hydroxyl;
R 2 is H; —OH; —NHC(═NH)NH 2 ; azide; or —NHC(O)R;
wherein R is —NH(CH 2 ) m COOH, wherein m is 1, 2 or 3;
R 3 is —NHC(O)(CH 2 )nR 5 ,
wherein R 5 is H; —OH; C1-C10 alkyl; C2-C10 heteroalkyl; C3-C7 cycloalkyl; C3-C7 heterocycloalkyl; C6-C8 aryl; C3-C8 heteroaryl; or

wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyl; a C3-C8 cycloalkyl; C6-C7 aryl; a halogen; a —C(O)OH; an amide; or a hydroxyl;
R a is a trifluoromethyl, a C1-C10 alkyl, a —C(O)OH, a —O—C1-C10 alkyl, a halogen, an amine, or —NH-acetamido; and
r is 0, 1, 2 or 3; and
n is 0 to 7;
R 4 is H; —OH; —O-alkyl; —C(O)-alkyl-NHC(O)-aryl; —NHC(O)R 6 ; or

wherein the alkyl and aryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyl, a C3-C8 cycloalkyl, C6-C7 aryl, a halogen, an amine, an amide or a hydroxyl,
and wherein:
R 6 is H, C1-C10 alkyl; or C6-C7 aryl,
wherein the C1-C10 alkyl and C6-C7 aryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyl, a C3-C8 cycloalkyl, a C6-C7 aryl, a halogen, an amide, an amine or a hydroxyl;
R 7 is H; halogen; —O-alkyl; —C(O)OH; amine; amide; —C1-C10 alkyl; O—C6-C7 aryl; or —(CH 2 )qNH(CO)aryl,
wherein q is 0 or 1; and
p is 0, 1, 2 or 3; and
X is O or CH 2 ,
or an ester, solvate, hydrate or pharmaceutical salt thereof,
with the proviso that:
when R 2 and R 4 are —OH, R 3 is not —NHC(═O)CH 3 , —NHC(═O)CH 2 CH 3 , —NHC(═O)(CH 2 ) 2 CH 3 , —NHC(═O)CH(CH 3 ) 2 , —NHC(═O)CH 2 CH(CH 3 ) 2 , —NHC(═O)cyclopropyl, —NHC(═O)cyclobutyl, or —NHC(═O)phenyl;
when R 2 is —OH and R 3 is —NHC(═O)CH 3 , R 4 is not -1,2,3-triazolyl-CH 2 OH, —NHC(═O)(CH 2 ) 2 CH 3 , —NHC(═O)(CH 2 ) 3 CH 3 , —NHC(═O)CH(CH 3 ) 2 , —NHC(═O)CH 2 CH(CH 3 ) 2 , or —NHC(═O)phenyl;
when R 3 is —NHC(═O)CH 3 and R 4 is OH, R 2 is not —NHC(═NH)NH 2 or azide;
when R 2 is —NHC(═NH)NH 2 and R 3 is —NHC(O)(CH 2 ) n R 5 , where n=1 and R 5 ═C1-C10 alkyl or n=0 and R 5 ═C6-C8 aryl, R 4 is not OH;
and when R 3 is —NHC(═O)CF 3 and R 4 is OH, R 2 is not —NHC(═NH)NH 2 .

2. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim 1 , with the further proviso that:
when R 3 is —NHC(═O)CH 3 , R 2 is —OH, and R 4 is

R 7 is not —N(CH 3 ) 2 , —NHC(═O)CH 3 , —NH 2 , —CH 3 , —OCH 3 , F, —CF 3 , or —C(═O)OH.

3. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim 1 , wherein R 3 is —NHC(O)(CH 2 )nR 5 .

4. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim 3 , wherein R 5 is cycloalkyl, aryl, C1-C10 alkyl, or C1-C10 alkyl substituted with a C1-C10 alkyl.

5. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim 1 , wherein n is 1 and wherein R 5 is H, straight or branched C1-C5 alkyl, heteroaryl, or

wherein R 8 is —CF 3 , —CH 3 , —C(═O)OH, —OCH 3 , F, —NH 2 , —N(CH 3 ) 2 , or —NHC(═O)CH 3 .

6. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim 5 , wherein r is 1.

7. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim 1 , wherein R 2 is OH, —NHC(═NH)NH 2 , azido, —NHC(O)R or —NH(CH 2 ) m C(O)OH, wherein m is 1, 2 or 3.

8. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim 1 , wherein R 4 is —OH or —NHC(O)R 6 .

9. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim 8 , wherein R 6 is straight or branched C1-C10 alkyl or, C6-C7 aryl, wherein the C6-C7 aryl is optionally substituted with an amine or an amide.

10. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim 1 , wherein R 4 is

11. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim 10 , wherein p is 0 and R 7 is —(CH 2 )qNH(CO)aryl or C1-C10 alkyl.

12. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim 10 , wherein p is 1 and R 7 is halogen, O-alkyl, —C(O)OH, amine, acetamide, C1-C10 alkyl, CH 2 NH(CO)aryl, or —O—C6-C7 aryl.

13. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim 10 , wherein p is 2 and R 7 is H.

14. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim 1 , wherein R 4 is —C(O)-alkyl-NHC(O)-aryl.

15. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim 14 , wherein the alkyl is C1-C10 alkyl and the aryl is C6-C7 aryl, which is optionally substituted with an amide.

16. The compound of claim 1 , wherein:
(i) R 3 is —NHC(O)(CH 2 ) n R 5 , wherein n is 0 to 7 and wherein R 5 is C1-C10 alkyl, C3-C7 cycloalkyl, C6-C8 aryl, wherein the alkyl, cycloalkyl, and aryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyl, a C3-C8 cycloalkyl, C6-C7 aryl, a halogen, an amide or a hydroxyl;
(ii) R 2 is —OH, —NHC(═NH)NH 2 or azide; and
(iii) R 4 is —OH; —NHC(O)R 6 , wherein R 6 is C1-C10 alkyl; —(CH 2 )qNH(CO)aryl, wherein q is 0 or 1; or

wherein p is 0, 1, 2 or 3, and R 7 is H, —C(═O)OH, phenyl, or phenyloxy, with the proviso that:
when R 2 and R 4 is —OH, R 3 is not —NHC(═O)CH 3 , —NHC(═O)CH 2 CH 3 , —NHC(═O)(CH 2 ) 2 CH 3 , —NHC(═O)CH(CH 3 ) 2 , —NHC(═O)CH 2 CH(CH 3 ) 2 , —NHC(═O)cyclopropyl, —NHC(═O)cyclobutyl, or —NHC(═O)phenyl;
when R 2 is —OH and R 3 is —NHC(═O)CH 3 , R 4 is not —NHC(═O)(CH 2 ) 2 CH 3 , —NHC(═O)(CH 2 ) 3 CH 3 , —NHC(═O)CH(CH 3 ) 2 , —NHC(═O)CH 2 CH(CH 3 ) 2 , or —NHC(═O)phenyl; and
when R 3 is —NHC(═O)CH 3 and R 4 is OH, R 2 is not —NHC(═NH)NH 2 , or wherein:
(i) R 3 is —NHC(O)(CH 2 )nCH 3 , wherein n is 0 to 7;
(ii) R 2 is —OH or —NHC(═NH)NH 2 ; and
(iii) R 4 is —OH; —NHC(O)R 6 , wherein R 6 is C6-C7 aryl or C1-C10 alkyl; or

wherein p is 1, 2 or 3, and R 7 is H, —C(═O)OH, phenyl, or phenyloxy.

17. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of

Assignees

• Univ Alberta
• Valorisation Hsj Lp

Inventors

• Cairo Christopher
• Pchejetski Alexey
• Guo Tianlin

Classifications

• C07H15/26 Primary

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title

• A61P9/10 Primary

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• C07H15/02

  Acyclic radicals, not substituted by cyclic structures · CPC title

• C07H15/18

  Acyclic radicals, substituted by carbocyclic rings · CPC title

• A61K31/351

  not condensed with another ring · CPC title