US 12,077,495 B2
Compounds for the treatment of acute brain injury
Anders Bue Klein, Søborg (DK); Andrew Neil Clarkson, Dunedin (NZ); Joshua Macdonald Houlton, Dunedin (NZ); Ulrike Leurs, Copenhagen (DK); Rasmus Prætorius Clausen, København S (DK); Bente Frølund, Charlottenlund (DK); and Petrine Wellendorph, Kgs. Lyngby (DK)
Assigned to Københavns Universitet, Copenhagen K (DK); and Otago Innovation Ltd., Dunedin (NZ)
Appl. No. 16/965,343
Filed by Københavns Universitet, Copenhagen K (DK); and Otago Innovation Ltd, Dunedin (NZ)
PCT Filed Feb. 1, 2019, PCT No. PCT/DK2019/050041
§ 371(c)(1), (2) Date Jul. 28, 2020,
PCT Pub. No. WO2019/149329, PCT Pub. Date Aug. 8, 2019.
Claims priority of application No. PA 2018 70067 (DK), filed on Feb. 2, 2018.
Prior Publication US 2021/0122700 A1, Apr. 29, 2021
Int. Cl. C07C 69/757 (2006.01); A61P 25/00 (2006.01); C07C 59/54 (2006.01); C07C 59/56 (2006.01); C07C 69/732 (2006.01)
CPC C07C 69/757 (2013.01) [A61P 25/00 (2018.01); C07C 59/54 (2013.01); C07C 59/56 (2013.01); C07C 69/732 (2013.01)] 19 Claims
OG exemplary drawing
 
1. A compound according to formula I

OG Complex Work Unit Chemistry
or a pharmaceutically acceptance salt thereof, wherein:
i) R5 is H, R1 and R2 form a ring system, and said compound is selected from:

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 or a compound of formula IV:

OG Complex Work Unit Chemistry
wherein:
n is 1;
X is selected from O and NH
Y is selected from NH, O, and CH2
R3 is selected from H, linear or branched C1-C6 alkyl, benzyl, polyethylenglycolyl,

OG Complex Work Unit Chemistry
R9 is selected from linear and branched C1-C6 alkyl;
R10 is selected from H, -Me, -Et, —Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl;
R4 is selected from H, —C(═O)—C1-C6-alkyl; —C(═O)-benzyl, polyethylenglycolyl,

OG Complex Work Unit Chemistry
R11 is selected from linear and branched C1-C6 alkyl;
each instance of custom character is a bond;
R12 is selected from H, -Me, -Et, —Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl;
R6 and R7 are each independently selected from H, F, Cl, Br, I, aryl, straight linear or branched C1-8 alkyl, —CH2(CH2)p-aryl, —CH═CH-aryl, NH2, NO2, OH, SH, linear or branched —O—C1-8 alkyl, linear or branched —S—C1-8 alkyl, linear or branched —NH—C1-8 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) R2 is H, R1 and R5 form a ring system, and said compound is a compound of formula IIIb, formula IIIc, or formula IIId:

OG Complex Work Unit Chemistry
wherein:
n is 0 or 1;
X is selected from O and NH;
m is 0 or 1;
R3 is selected from H, linear or branched C1-C6-alkyl; -benzyl, polyethylenglycolyl,

OG Complex Work Unit Chemistry
R9 is selected from linear and branched C1-C6 alkyl;
R10 is selected from H, -Me, -Et, —Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl;
R4 is selected from H, —C(═O)—C1-C6-alkyl; —C(═O)-benzyl, polyethylenglycolyl,

OG Complex Work Unit Chemistry
each instance of custom character is a bond;
R1 is selected from linear and branched C1-C6 alkyl; R12 is selected from H, -Me, -Et, —Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl;
R13, is selected from H, F, Br, aryl, linear or branched C1-8 alkyl, —CH2(CH2)p-aryl, —CH═CH-aryl, NH2, NO2, OH, SH, linear or branched —O—C2-8 alkyl, linear or branched —S—C1-8 alkyl, linear or branched —NH—C1-8 alkyl, —O-aryl, —S-aryl, and —NH-aryl,
R14 is selected from H, F, Cl, Br, aryl, linear or branched C1-8 alkyl, —CH2(CH2)p-aryl, —CH═CH-aryl, NH2, OH, SH, linear or branched —O—C1-8 alkyl, linear or branched —S—C1-8 alkyl, linear or branched —NH—C1-8 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 R4 is H or H3 or CH3, then:
i) R6 and R7 are not both Cl,
ii) R6 and R7 are not both methyl,
iii) when R6 is Cl then R7 is not F, and
iv) when R6 is F then R7 is not Cl . . .

OG Complex Work Unit Chemistry