US2021317070A1PendingUtilityA1
Cannabidiol derivatives as inhibitors of the hif prolyl hydroxylases activity
Assignee: EMERALD HEALTH PHARMACEUTICALS INCPriority: Mar 29, 2017Filed: Feb 16, 2021Published: Oct 14, 2021
Est. expiryMar 29, 2037(~10.7 yrs left)· nominal 20-yr term from priority
Inventors:Eduardo Muñoz BlancoCarmen María Navarrete RuedaCristina Cruz TenoMaría Luz Bellido Cabello De Alba
C07C 225/28A61K 31/135A61K 31/133
50
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Claims
Abstract
Cannabidiol quinol derivatives of Formula (I) and compositions comprising the same for use in the treatment of conditions that benefit from the inhibition of the HIF prolyl hydroxylases (PHDs) activity are described. Said cannabidiol quinol derivatives of Formula (I), and compositions comprising the same, show thus capacity to inhibit PHD activities and, as a result, stabilize the HIF-1α and HIF-2α levels, activate the HIF pathway in different cell types, induce angiogenesis in human endothelial vascular cell, regulate HIF-dependent gene expression in different cell types and induce collagen contraction. Said cannabidiol quinol derivatives of Formula (I) are useful in the treatment of conditions that benefit from the inhibition of the HIF prolyl hydroxylases (PHDs) activity such as stroke, traumatic injuries anemia, myocardial ischaemia-reperfusion injury, acute lung injury, infectious diseases, diabetic and chronic wounds, organ transplantation, acute kidney injury or arterial diseases.
Claims
exact text as granted — not AI-modified1 . A method for treating or preventing a neurological and cognitive disease or disorder, the method comprising administering a composition comprising an inhibitor of ACSS2 to a subject in need thereof.
2 . The method of claim 1 , wherein neurological and cognitive disease or disorder is selected from the group consisting of post-traumatic stress disorder (PTSD), bipolar disorder, depression, Tourette's Syndrome, schizophrenia, obsessive-compulsive disorder, anxiety disorder, panic disorders, and phobias.
3 . The method of claim 1 , wherein the neurological and cognitive disease or disorder is PTSD.
4 . The method of claim 1 , wherein the inhibitor of ACSS2 is at least one of the group consisting of a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, an antisense nucleic acid molecule.
5 . The method of claim 1 , wherein the inhibitor of ACSS2 is a small molecule.
6 . The method of claim 5 , wherein the small molecule is a compound according to one of Formula (1) to Formula (4):
wherein, X 11 is selected from the group consisting of C(R 14 )(R 15 ), O, S and NR 15 ;
each occurrence of X 12 is selected from the group consisting of C(R 14 )(R 15 ), O, S and NR 15 ;
R 11 is selected from the group consisting of hydrogen, —OR 15 , alkyl, cycloalkyl, —C 4 -C 6 heterocyclyl, aryl, and —C 4 -C 6 heteroaryl, wherein R 11 is optionally substituted;
R 12 and R 13 are each independently selected from the group consisting of hydrogen, alkyl, aryl, and —C 4 -C 6 heteroaryl, wherein R 12 and R 13 are optionally substituted;
each occurrence of R 14 and R 15 are independently selected from the group consisting of hydrogen, halogen, —OH, and C 1 -C 6 alkyl; and
n is an integer from 0-8;
wherein,
R 21 is selected from the group consisting of —C(R 23 ) m , cycloalkyl, heterocycyl, cycloalkyl-one, and heterocycyl-one;
R 22 is selected from the group consisting of alkyl, aryl, heteroaryl, —C 1 -C 3 alkyl-(C 3 -C 6 aryl), and —C 1 -C 3 alkyl-(C 3 -C 6 heteroaryl);
each occurrence of R 23 is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycyl, —OH, and —CN; and
m is an integer from 1 to 3;
wherein R 31 is selected from the group consisting of —C(R 35 ) p , cycloalkyl, heterocycyl, cycloalkyl-one, heterocycyl-one;
R 32 is selected from the group consisting of alkyl, aryl, heteroaryl, —C 1 -C 3 alkyl-(C 3 -C 6 aryl), and —C 1 -C 3 alkyl-(C 3 -C 6 heteroaryl);
R 33 and R 34 are each independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, heteroaryl;
each occurrence of R 35 is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycyl, —OH, and —CN; and
p is an integer from 1 to 3;
wherein,
X 41 is selected from the group consisting of O and S;
R 41 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and combinations thereof, wherein R 41 may be optionally substituted; and
R 42 and R 43 are each independently selected from the group consisting of phenyl, thiophenyl and furanyl.
7 . The method of claim 6 , wherein the compound of Formula (1) is selected from the group consisting of
8 . The method of claim 6 , wherein the compound of Formula (2) is selected from the group consisting of
9 . The method of claim 6 , wherein the compound of Formula (3) is selected from the group consisting of
10 . The method of claim 6 , wherein the compound of Formula (4) is selected from the group consisting of
11 . A method for treating or preventing an addiction or addiction-related disease or disorder the method comprising administering a composition comprising an inhibitor of ACSS2 to a subject in need thereof.
12 . The method of claim 11 , wherein addiction is alcoholism.
13 . The method of claim 11 , wherein the addiction-related disease or disorder is acute and/or chronic alcohol induced memory deficit.
14 . The method of claim 11 , wherein the inhibitor of ACSS2 is at least one of the group consisting of a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, an antisense nucleic acid molecule.
15 . The method of claim 14 , wherein the small molecule is a compound according to one of Formula (1) to Formula (4):
wherein, X 11 is selected from the group consisting of C(R 14 )(R 15 ), O, S and NR 15 ;
each occurrence of X 12 is selected from the group consisting of C(R 14 )(R 15 ), O, S and NR 15 ;
R 11 is selected from the group consisting of hydrogen, —OR 15 , alkyl, cycloalkyl, —C 4 -C 6 heterocyclyl, aryl, and —C 4 -C 6 heteroaryl, wherein R 11 is optionally substituted;
R 12 and R 13 are each independently selected from the group consisting of hydrogen, alkyl, aryl, and —C 4 -C 6 heteroaryl, wherein R 12 and R 13 are optionally substituted;
each occurrence of R 14 and R 15 are independently selected from the group consisting of hydrogen, halogen, —OH, and C 1 -C 6 alkyl; and
n is an integer from 0-8;
wherein,
R 21 is selected from the group consisting of —C(R 23 ) m , cycloalkyl, heterocycyl, cycloalkyl-one, and heterocycyl-one;
R 22 is selected from the group consisting of alkyl, aryl, heteroaryl, —C 1 -C 3 alkyl-(C 3 -C 6 aryl), and —C 1 -C 3 alkyl-(C 3 -C 6 heteroaryl);
each occurrence of R 23 is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycyl, —OH, and —CN; and
m is an integer from 1 to 3;
wherein R 31 is selected from the group consisting of —C(R 35 ) p , cycloalkyl, heterocycyl, cycloalkyl-one, heterocycyl-one;
R 32 is selected from the group consisting of alkyl, aryl, heteroaryl, —C 1 -C 3 alkyl-(C 3 -C 6 aryl), and —C 1 -C 3 alkyl-(C 3 -C 6 heteroaryl);
R 33 and R 34 are each independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, heteroaryl;
each occurrence of R 35 is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycyl, —OH, and —CN; and
p is an integer from 1 to 3;
wherein,
X 41 is selected from the group consisting of O and S;
R 41 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and combinations thereof, wherein R 41 may be optionally substituted; and
R 42 and R 43 are each independently selected from the group consisting of phenyl, thiophenyl and furanyl.
16 . The method of claim 15 , wherein the compound of Formula (1) is selected from the group consisting of
17 . The method of claim 15 , wherein the compound of Formula (2) is selected from the group consisting of
18 . The method of claim 15 , wherein the compound of Formula (3) is selected from the group consisting of
19 . The method of claim 15 , wherein the compound of Formula (4) is selected from the group consisting of
20 . A compound according to one of Formula (1) to Formula (4):
wherein, X 11 is selected from the group consisting of C(R 14 )(R 15 ), O, S and NR 15 ;
each occurrence of X 12 is selected from the group consisting of C(R 14 )(R 15 ), O, S and NR 15 ;
R 11 is selected from the group consisting of hydrogen, —OR 15 , alkyl, cycloalkyl, —C 4 -C 6 heterocyclyl, aryl, and —C 4 -C 6 heteroaryl, wherein R 11 is optionally substituted;
R 12 and R 13 are each independently selected from the group consisting of hydrogen, alkyl, aryl, and —C 4 -C 6 heteroaryl, wherein R 12 and R 13 are optionally substituted;
each occurrence of R 14 and R 15 are independently selected from the group consisting of hydrogen, halogen, —OH, and C 1 -C 6 alkyl; and
n is an integer from 0-8;
wherein,
R 21 is selected from the group consisting of —C(R 23 ) m , cycloalkyl, heterocycyl, cycloalkyl-one, and heterocycyl-one;
R 22 is selected from the group consisting of alkyl, aryl, heteroaryl, —C 1 -C 3 alkyl-(C 3 -C 6 aryl), and —C 1 -C 3 alkyl-(C 3 -C 6 heteroaryl);
each occurrence of R 23 is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycyl, —OH, and —CN; and
m is an integer from 1 to 3;
wherein R 31 is selected from the group consisting of —C(R 35 ) p , cycloalkyl, heterocycyl, cycloalkyl-one, heterocycyl-one;
R 32 is selected from the group consisting of alkyl, aryl, heteroaryl, —C 1 -C 3 alkyl-(C 3 -C 6 aryl), and —C 1 -C 3 alkyl-(C 3 -C 6 heteroaryl);
R 33 and R 34 are each independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, heteroaryl;
each occurrence of R 35 is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycyl, —OH, and —CN; and
p is an integer from 1 to 3;
wherein,
X 41 is selected from the group consisting of O and S;
R 41 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and combinations thereof, wherein R 41 may be optionally substituted; and
R 42 and R 43 are each independently selected from the group consisting of phenyl, thiophenyl and furanyl.
21 . The method of claim 20 , wherein the compound of Formula (1) is selected from the group consisting of
22 . The method of claim 20 , wherein the compound of Formula (2) is selected from the group consisting of
23 . The method of claim 20 , wherein the compound of Formula (3) is selected from the group consisting of
24 . The method of claim 20 , wherein the compound of Formula (4) is selected from the group consisting ofJoin the waitlist — get patent alerts
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