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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Douglas E. Brenneman
William Alvin Kinney
Mark Mcdonnell
Dean PETKANAS
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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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/08Antiepileptics; Anticonvulsants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs
    • AHUMAN NECESSITIES
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    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/18Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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

Figure AU2015204609B2_D0001

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. Figure AU2015204609B2_C0001
    Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs, enantiomers, and complexes thereof, wherein:
    Figure AU2015204609B2_C0002
    z is 0, 1, or 2;
    Figure AU2015204609B2_C0003
    Figure AU2015204609B2_C0004
    Y-N , R1 is selected from the group consisting of
    When A is R1
    Figure AU2015204609B2_C0005
    Figure AU2015204609B2_C0006
    R , and R
    Figure AU2015204609B2_C0007
    When A is R1
    Figure AU2015204609B2_C0008
    and z is 0, R1 is
    Figure AU2015204609B2_C0009
    When A is R1
    Figure AU2015204609B2_C0010
    Figure AU2015204609B2_C0011
    Y-N
    R3;
    and z is 1, R1 is
    Figure AU2015204609B2_C0012
    and z is 2, R1 is selected from the group consisting of
    When A is R1
    Figure AU2015204609B2_C0013
    When R1 is
    Figure AU2015204609B2_C0014
    , 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):
    Figure AU2015204609B2_C0015
    including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof
  3. 3. The compound according to claim 1 having formula (III):
    R4c
    Figure AU2015204609B2_C0016
    including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof
  4. 4. The compound according to claim 1 having formula (IV):
    Figure AU2015204609B2_C0017
    including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof
  5. 5. The compound according to claim 1 having formula (V):
    Figure AU2015204609B2_C0018
    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.
    Figure AU2015204609B2_C0019
  7. 7. The compound according to claim 1 having formula (VII):
    Figure AU2015204609B2_C0020
    (VII) including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof.
  8. 8. The compound according to claim 1 having formula (VIII):
    Figure AU2015204609B2_C0021
    OH (VIII) ' including hydrates, solvates, pharmaceutically acceptable salts, enantiomers, and complexes thereof.
  9. 9. The compound according to claim 1 having formula (IX):
    Figure AU2015204609B2_C0022
    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
    Figure AU2015204609B2_C0023
    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
    Figure AU2015204609B2_C0024
    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)
    Figure AU2015204609B2_C0025
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)

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CN111943813A (en) * 2019-05-17 2020-11-17 上海特化医药科技有限公司 Preparation method of cannabidiol compound

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

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EP3094318B1 (en) 2020-02-19
WO2015106108A3 (en) 2015-11-12
RU2676475C2 (en) 2018-12-29
DK3094318T3 (en) 2020-05-04
CN106456573B (en) 2019-12-03
US20160311769A1 (en) 2016-10-27
EP3094318A4 (en) 2016-11-23
AU2015204609A1 (en) 2016-09-01
JP6486950B2 (en) 2019-03-20
CA2936506A1 (en) 2015-07-16
EP3094318A2 (en) 2016-11-23
RU2016133213A3 (en) 2018-06-14
WO2015106108A2 (en) 2015-07-16
US10004722B2 (en) 2018-06-26
US20170157097A1 (en) 2017-06-08
RU2016133213A (en) 2018-02-20

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