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

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

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AU2015204609B2
AU2015204609B2 AU2015204609A AU2015204609A AU2015204609B2 AU 2015204609 B2 AU2015204609 B2 AU 2015204609B2 AU 2015204609 A AU2015204609 A AU 2015204609A AU 2015204609 A AU2015204609 A AU 2015204609A AU 2015204609 B2 AU2015204609 B2 AU 2015204609B2
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ch
alkyl
compound according
selected
pharmaceutically acceptable
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AU2015204609A1 (en
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Douglas E. Brenneman
William Alvin Kinney
Mark Mcdonnell
Dean PETKANAS
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Kannalife Sciences Inc
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KANNALIFE Inc
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Assigned to Kannalife Science, Inc. reassignment Kannalife Science, Inc. Amend patent request/document other than specification (104) Assignors: KANNALIFE, INC.
Assigned to KANNALIFE SCIENCES, INC. reassignment KANNALIFE SCIENCES, INC. Amend patent request/document other than specification (104) Assignors: Kannalife Science, Inc.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41921,2,3-Triazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02Muscle relaxants, e.g. for tetanus or cramps
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002Heterocyclic compounds
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D205/00Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D205/00Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/041,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05Isotopically modified compounds, e.g. labelled

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 13th, 2014, which is herein incorporated by reference in its entirety.

FIELD OF INVENTION

Claims (18)

  1. 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 R4b 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, CONR7aR7b, SO2NR7aR7b, SO2R8, and optionally substituted heteroaryl;
    R4a and R4b are each independently selected from the group consisting of hydrogen and Ci-6 alkyl;
    R4c 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(R9aR9b)NR7aR7b, and -C(R9aR9b)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;
    R7a and R7b are each independently selected from the group consisting of hydrogen and Ci-6 alkyl;
    R7a and R7b 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;
    R9a and R9b 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. 2. The compound according to claim 1 having formula (II):
    including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof
  3. 3. The compound according to claim 1 having formula (III):
    R4c
    including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof
  4. 4. The compound according to claim 1 having formula (IV):
    including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof
  5. 5. The compound according to claim 1 having formula (V):
    including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof
  6. 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. 7. The compound according to claim 1 having formula (VII):
    (VII) including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof.
  8. 8. The compound according to claim 1 having formula (VIII):
    OH (VIII) ' including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof.
  9. 9. The compound according to claim 1 having formula (IX):
    including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof.
  10. 10. The compound according to claim 1 having formula (X):
    102 including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof.
  11. 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. 12. A compound of the formula (I) according to claim 1 that is isotopically labeled with 1 to 10 deuterium atoms.
  13. 13. A composition comprising an effective amount of at least one compound according to any one of claims 1 to 12.
  14. 14. The composition according to claim 13, further comprising at least one excipient.
  15. 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. 16. The neuroprotection method of claim 15, wherein the neurons are protected from oxidative stress.
  17. 17. The neuroprotection method of claim 15, wherein the neurons are protected from death or damage caused by oxidative stress or excess glutamate.
  18. 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)
AU2015204609A 2014-01-13 2015-01-09 Novel functionalized 1,3-benzene diols and their method of use for the treatment of hepatic encephalopathy Active AU2015204609B2 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US201461926869P true 2014-01-13 2014-01-13
US61/926,869 2014-01-13
PCT/US2015/010827 WO2015106108A2 (en) 2014-01-13 2015-01-09 Novel functionalized 1,3-benzene diols and their method of use for the treatment of hepatic encephalopathy

Publications (2)

Publication Number Publication Date
AU2015204609A1 AU2015204609A1 (en) 2016-09-01
AU2015204609B2 true AU2015204609B2 (en) 2019-11-07

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US (2) US9611213B2 (en)
EP (1) EP3094318B1 (en)
JP (1) JP6486950B2 (en)
CN (1) CN106456573B (en)
AU (1) AU2015204609B2 (en)
CA (1) CA2936506A1 (en)
RU (1) RU2676475C2 (en)
WO (1) WO2015106108A2 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100022631A1 (en) * 2006-10-25 2010-01-28 Yissum Research Development Company Of The Hebrew University Of Jerusalem Treatment of hepatic encephalopathy and liver cirrhosis
US20120172339A1 (en) * 2009-07-10 2012-07-05 Northeastern University Angiogenic resorcinol derivatives
EA016813B1 (en) * 2005-06-16 2012-07-30 Еуро-Селтик С.А. Cannabinoid pharmaceutical composition and methods for preparing and administration thereof
CN103113340A (en) * 2013-01-21 2013-05-22 四川大学 Genistein alkylamine compound, preparation method and use of genistein alkylamine compound

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA016813B1 (en) * 2005-06-16 2012-07-30 Еуро-Селтик С.А. Cannabinoid pharmaceutical composition and methods for preparing and administration thereof
US20100022631A1 (en) * 2006-10-25 2010-01-28 Yissum Research Development Company Of The Hebrew University Of Jerusalem Treatment of hepatic encephalopathy and liver cirrhosis
US20120172339A1 (en) * 2009-07-10 2012-07-05 Northeastern University Angiogenic resorcinol derivatives
CN103113340A (en) * 2013-01-21 2013-05-22 四川大学 Genistein alkylamine compound, preparation method and use of genistein alkylamine compound

Also Published As

Publication number Publication date
RU2676475C2 (en) 2018-12-29
WO2015106108A2 (en) 2015-07-16
US10004722B2 (en) 2018-06-26
AU2015204609A1 (en) 2016-09-01
RU2016133213A (en) 2018-02-20
JP2017507119A (en) 2017-03-16
CA2936506A1 (en) 2015-07-16
CN106456573A (en) 2017-02-22
US20170157097A1 (en) 2017-06-08
RU2016133213A3 (en) 2018-06-14
US20160311769A1 (en) 2016-10-27
CN106456573B (en) 2019-12-03
WO2015106108A3 (en) 2015-11-12
EP3094318A2 (en) 2016-11-23
EP3094318B1 (en) 2020-02-19
US9611213B2 (en) 2017-04-04
EP3094318A4 (en) 2016-11-23
JP6486950B2 (en) 2019-03-20

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