AU2015204609B2

AU2015204609B2 - Novel functionalized 1,3-benzene diols and their method of use for the treatment of hepatic encephalopathy

Info

Publication number: AU2015204609B2
Application number: AU2015204609A
Authority: AU
Inventors: Douglas E. Brenneman; William Alvin Kinney; Mark Mcdonnell; Dean PETKANAS
Original assignee: KANNALIFE Inc
Current assignee: Kannalife Sciences Inc
Priority date: 2014-01-13
Filing date: 2015-01-09
Publication date: 2019-11-07
Anticipated expiration: 2035-01-09
Also published as: RU2676475C2; WO2015106108A2; US10004722B2; AU2015204609A1; RU2016133213A; JP2017507119A; CA2936506A1; CN106456573A; US20170157097A1; RU2016133213A3; US20160311769A1; CN106456573B; WO2015106108A3; EP3094318A2; EP3094318B1; US9611213B2; EP3094318A4; JP6486950B2

Abstract

Pharmaceutical compositions of the invention include novel functionalized 1,3-benzenediols having a disease-modifying action in the treatment of hepatic encephalopathy and related conditions. Pharmaceutical compositions of the invention further include novel neuroprotective agents.

Description

(57) Abstract: Pharmaceutical compositions of the invention include novel functionalized 1,3-benzenediols having a disease-modifying action in the treatment of hepatic encephalopathy and related conditions. Pharmaceutical compositions of the invention further include novel neuroprotective agents.

-H—IV-2 mg/kg —·—PO-10 mg/kg

20 24 wo 2015/106108 A3 lllllllllllllllllllllllllllllllll (88) Date of publication of the international search report:

November 2015

2015204609 24 Sep 2019

NOVEL FUNCTIONALIZED 1,3-BENZENE DIOLS AND THEIR METHOD OF USE FOR THE TREATMENT OF HEPATIC ENCEPHALOPATHY

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 61926869 filed January 13^th, 2014, which is herein incorporated by reference in its entirety.

FIELD OF INVENTION

Claims

Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs, enantiomers, and complexes thereof, wherein:

z is 0, 1, or 2;

Y-N , R¹ is selected from the group consisting of

When A is R¹

R , and R

When A is R¹

and z is 0, R¹ is

When A is R¹

Y-N

R³;

and z is 1, R¹ is

and z is 2, R¹ is selected from the group consisting of

When A is R¹

When R¹ is

, n is not 0;

2015204609 24 Sep 2019 □4a Tn,

X.N

When R¹ is R^{4b N} , n is not 0;

Y-N'

R² is R³;

W is (CH₂)_m;

m is 1 or 2;

Y is (CH₂)_q;

q is 1 or 2;

n is 0, 1, 2, or 3;

b is 0, 1, 2, or 3;

d is 0, 1, 2, or 3;

R³ is selected from the group consisting of COR⁵, CO2R⁶, CONR^7aR^7b, SO2NR^7aR^7b, SO₂R⁸, and optionally substituted heteroaryl;

R^4a and R^4b are each independently selected from the group consisting of hydrogen and Ci-6 alkyl;

R^4c is selected from the group consisting of hydrogen and OH;

R⁵ is selected from the group consisting of hydrogen, Ci-6 alkyl, optional substituted heteroaryl, -C(R^9aR^9b)NR^7aR^7b, and -C(R^9aR^9b)OR¹⁰;

R⁵ is also selected from optional substituted Ci-6 alkyl;

R⁶ is Ci-6 alkyl;

R⁶ is also selected from optional substituted Ci-6 alkyl;

R^7a and R^7b are each independently selected from the group consisting of hydrogen and Ci-6 alkyl;

R^7a and R^7b are also each independently selected from optional substituted Ci-6 alkyl;

R⁸ is selected from the group consisting of hydrogen, Ci-6 alkyl and optional substituted heteroaryl;

R⁸ is also selected from optional substituted Ci-6 alkyl;

R^9a and R^9b are each independently selected from the group consisting of hydrogen, Ci-6 alkyl, C3-7 branched alkyl, CH₂OH, CH(OH)CH3, CH₂Ph, CH₂(4OH-Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂;

100

2015204609 24 Sep 2019

R¹⁰ is selected from the group consisting of hydrogen and Ci-6 alkyl.
2. The compound according to claim 1 having formula (II):

including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof
3. The compound according to claim 1 having formula (III):

_R4c

including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof
4. The compound according to claim 1 having formula (IV):

including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof
5. The compound according to claim 1 having formula (V):

including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof
6. The compound according to claim 1 having formula (VI):

101 including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and

2015204609 24 Sep 2019 complexes thereof.
7. The compound according to claim 1 having formula (VII):

(VII) including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof.
8. The compound according to claim 1 having formula (VIII):

OH (VIII) ' including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof.
9. The compound according to claim 1 having formula (IX):

including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof.
10. The compound according to claim 1 having formula (X):

102 including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof.
11. The compound according to claim 1 that is:

5-(2-( 1 Η-1,2,3-triazol-1 -yl)ethyl)-2-(( 1 R,6R)-3-methyl-6-(prop-1 -en-2yl)cyclohex-2-enyl)benzene-1,3 -diol;

2015204609 24 Sep 2019

1-(3-(3,5-dihydro xy-4-((lR, 6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2enyl)benzyl)azetidin-1 -yl)ethanone;

ethyl 3-(3,5-dihydro xy-4-((lR, 6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2enyl)benzyl) azetidine-1 -carboxylate;

or a pharmaceutically acceptable salt thereof.
12. A compound of the formula (I) according to claim 1 that is isotopically labeled with 1 to 10 deuterium atoms.
13. A composition comprising an effective amount of at least one compound according to any one of claims 1 to 12.
14. The composition according to claim 13, further comprising at least one excipient.
15. A neuroprotection method comprising administering to a subject at least one compound according to any one of claims 1-12 in an amount effective to protect neurons.
16. The neuroprotection method of claim 15, wherein the neurons are protected from oxidative stress.
17. The neuroprotection method of claim 15, wherein the neurons are protected from death or damage caused by oxidative stress or excess glutamate.
18. The neuroprotection method of claim 15, wherein the neurons are protected from death or damage caused by oxidative stress associated with a disease or condition selected from the group consisting of epilepsy, neuropathic pain, traumatic head injury, stroke, Chronic Traumatic Encephalopathy (CTE), Post Cardiac Arrest Hypoxic Ischemic Encephalopathy, Epileptic Encephalopathy, and neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s, Huntington’s disease, and amyotrophic lateral sclerosis (ALS).

103

WO 2015/106108

PCT/US2015/010827

1/1

Figure 1

Mean plasma concentration-time profiles of KLS-13019 after single IV and PO administrations in CD1 mice (N=3/time point)

Mean plasma concentration (ng/mL) Mean plasma cot (centration (ng/mL)

10000 _Ί

1000 ¾ -b—IV-2 mg/kg

Ji

1 0.1 -I........-.............: ..................,-----------------------------------;----------------_s

0 4 8 12 16 20 24

Time (hr)

Figure 2

Mean plasma concentration-time profiles of KLS-13019 after single 10 mg.kg PO administrations in CD1 mice (N=3/time point)