Compounds for the treatment of acute brain injury

Patent metadata

Field	Value
Publication number	US-12077495-B2
Application number	US-201916965343-A
Country	US
Kind code	B2
Filing date	Feb 1, 2019
Priority date	Feb 2, 2018
Publication date	Sep 3, 2024
Grant date	Sep 3, 2024

Abstract

The invention relates to a compound according to formula I wherein when R 5 is H, and R 1 and R 2 form a ring system, then said compound is selected from the following compounds of formula II or formula IV or when R 2 is H, and R 1 and R 5 form a ring system, then said compound has formula III.

First claim

The invention claimed is:

1. A compound according to formula I

or a pharmaceutically acceptance salt thereof, wherein:
i) R 5 is H, R 1 and R 2 form a ring system, and said compound is selected from:

 or a compound of formula IV:

wherein:
n is 1;
X is selected from O and NH
Y is selected from NH, O, and CH 2
R 3 is selected from H, linear or branched C 1 -C 6 alkyl, benzyl, polyethylenglycolyl,

R 9 is selected from linear and branched C 1 -C 6 alkyl;
R 10 is selected from H, -Me, -Et, —Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl;
R 4 is selected from H, —C(═O)—C 1 -C 6 -alkyl; —C(═O)-benzyl, polyethylenglycolyl,

R 11 is selected from linear and branched C 1 -C 6 alkyl;
each instance of is a bond;
R 12 is selected from H, -Me, -Et, —Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl;
R 6 and R 7 are each independently selected from H, F, Cl, Br, I, aryl, straight linear or branched C 1-8 alkyl, —CH 2 (CH 2 ) p -aryl, —CH═CH-aryl, NH 2 , NO 2 , OH, SH, linear or branched —O—C 1-8 alkyl, linear or branched —S—C 1-8 alkyl, linear or branched —NH—C 1-8 alkyl, —O-aryl, —S-aryl, and —NH-aryl;
wherein aryl optionally includes one or more heteroatoms selected from O, N and S; and
wherein p is 0 or 1; or
ii) R 2 is H, R 1 and R 5 form a ring system, and said compound is a compound of formula IIIb, formula IIIc, or formula IIId:

wherein:
n is 0 or 1;
X is selected from O and NH;
m is 0 or 1;
R 3 is selected from H, linear or branched C 1 -C 6 -alkyl; -benzyl, polyethylenglycolyl,

R 9 is selected from linear and branched C 1 -C 6 alkyl;
R 10 is selected from H, -Me, -Et, —Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl;
R 4 is selected from H, —C(═O)—C 1 -C 6 -alkyl; —C(═O)-benzyl, polyethylenglycolyl,

each instance of is a bond;
R 1 is selected from linear and branched C 1 -C 6 alkyl; R 12 is selected from H, -Me, -Et, —Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl;
R 13 , is selected from H, F, Br, aryl, linear or branched C 1-8 alkyl, —CH 2 (CH 2 ) p -aryl, —CH═CH-aryl, NH 2 , NO 2 , OH, SH, linear or branched —O—C 2-8 alkyl, linear or branched —S—C 1-8 alkyl, linear or branched —NH—C 1-8 alkyl, —O-aryl, —S-aryl, and —NH-aryl,
R 14 is selected from H, F, Cl, Br, aryl, linear or branched C 1-8 alkyl, —CH 2 (CH 2 ) p -aryl, —CH═CH-aryl, NH 2 , OH, SH, linear or branched —O—C 1-8 alkyl, linear or branched —S—C 1-8 alkyl, linear or branched —NH—C 1-8 alkyl, —O-aryl, —S-aryl, and —NH-aryl,
each aryl optionally includes one or more heteroatoms selected from O, N and S, and wherein each instance of p is independently 0 or 1;

with the proviso that the compounds of formula IV, when R 4 is H or H 3 or CH 3 , then:
i) R 6 and R 7 are not both Cl,
ii) R 6 and R 7 are not both methyl,
iii) when R 6 is Cl then R 7 is not F, and
iv) when R 6 is F then R 7 is not Cl . . .

2. The compound according to claim 1 , wherein:
said compound is the compound of formula IIIb, the compound of formula IIIc or the compound of formula IIId, and wherein n is 0.

3. The compound according to claim 1 , wherein said compound is the compound of formula IV, wherein R 3 is selected from H, -Me, -Et, —Pr, -iPr, -Bu, -tBu, -iBu, pentyl, neopentyl, hexyl; -benzyl, polyethylenglycolyl

4. The compound according to claim 1 , wherein said compound is the compound of formula IV, and wherein R 4 is selected from H, —C(═O)-Me, —C(═O)-Et, —C(═O)—Pr, —C(═O)-iPr, —C(═O)—Bu, —C(═O)-tBu; —C(═O)-benzyl, polyethylenglycolyl

5. The compound according to claim 1 , wherein said compound is the compound of formula IIIb, the compound of formula IIIc, or the compound of formula IIId, and wherein R 3 is selected from H, -Me, -Et, —Pr, -iPr, -Bu, -tBu, -iBu, pentyl, isopentyl, hexyl, -benzyl, polyethylenglycolyl,

6. The compound according to claim 1 , wherein said compound is the compound of formula IIIb, the compound of formula IIIc, or the compound of formula IIId, and wherein R 4 is selected from H, —C(═O)-Me, —C(═O)-Et, —C(═O)—Pr, —C(═O)-iPr, —C(═O)—Bu, —C(═O)-tBu; —C(═O)-benzyl, polyethylenglycolyl, r

7. The compound according to claim 1 , wherein said compound is the compound of formula IIIb, the compound of formula IIIc, or the compound of formula IIId, wherein:
i) R 13 is H and R 14 is selected from H, F, Cl, Br, aryl, linear or branched C 1-8 alkyl, —CH 2 (CH 2 ) p -aryl, and —CH═CH-aryl, or
ii) wherein R 14 is H and R 13 is selected from H, F, Br, aryl, linear or branched C 1-8 alkyl, —CH 2 (CH 2 ) p -aryl, and —CH═CH-aryl.

8. The compound according to claim 1 , wherein said compound is the compound of formula IIIb, the compound of formula IIIc, or the compound of formula IIId, wherein:
i) R 13 is H and R 14 is selected from H, F, Cl, Br, Ph, and —CH═CH-phenyl, or
ii) R 14 is H and R 13 is selected from H, F, Br, Ph, and —CH═CH-phenyl.

9. The compound according to claim 1 , wherein said compound is the compound of formula IIIb, the compound of formula IIIc, or the compound of formula IIId, wherein:
i) n=0, R 3 is H, X is O, R 4 is H, R 13 is selected from H, F, Br, phenyl, and methyl, and R 14 is H, or
ii) n=0, R 3 is H, X is O, R 4 is H, R 14 is selected from H, F, Cl, Br, phenyl, and methyl, and R 13 is H.

10. The compound according to claim 1 , wherein said compound is the compound of formula IIIb, the compound of formula IIIc, or the compound of formula IIId, wherein:
i) n=0, R 3 is selected from H, -Me, -Et, —Pr, -iPr, -Bu, and -tBu; X is O, R 4 is H, R 13 is selected from H, F, Br, phenyl, and methyl, and R 14 is H, or
ii) n=0, R 3 is H, X is O, R 4 is H, R 14 is selected from H, F, Cl, Br, phenyl, and methyl, and R 13 is H.

11. A method of treating acute brain injury, said method comprising administering a compound according to claim 1 to a subject in need thereof, thereby treating the acute brain injury in the subject.

12. The method according to claim 11 , wherein the compound is the compound of formula IIIb, the compound of formula IIIc, or the compound of formula IIId.

13. The method according to claim 11 , wherein:
i) said compound is

Assignees

• Univ Copenhagen
• Otago Innovation Ltd

Inventors

• Klein Anders Bue
• Clarkson Andrew Neil
• Houlton Joshua Macdonald
• Leurs Ulrike
• Clausen Rasmus Prætorius
• Frølund Bente
• Wellendorph Petrine

Classifications

• C07C69/757 Primary

  having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] in the acid moiety · CPC title

• A61K31/192 Primary

  having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid  {(cannabinoids A61K31/658)} · CPC title

• C07C69/732

  of unsaturated hydroxy carboxylic acids · CPC title

• C07C59/56

  containing halogen · CPC title

• C07C59/54

  containing six-membered aromatic rings and other rings · CPC title