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WO2024250904A1 - Liaisons imidazolyles avec des dérivés de dinitrophényle et leur utilisation - Google Patents

Liaisons imidazolyles avec des dérivés de dinitrophényle et leur utilisation Download PDF

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Publication number
WO2024250904A1
WO2024250904A1 PCT/CN2024/092306 CN2024092306W WO2024250904A1 WO 2024250904 A1 WO2024250904 A1 WO 2024250904A1 CN 2024092306 W CN2024092306 W CN 2024092306W WO 2024250904 A1 WO2024250904 A1 WO 2024250904A1
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Prior art keywords
pharmaceutically acceptable
acceptable salt
alkyl
stereoisomer
deuterated derivative
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Inventor
Xiaobing Deng
Yaning SU
Wenjia TIAN
Bo Li
Huiling Chen
Weiyi Cui
Yanhong Wang
Shuo CAO
Jingying DONG
Xiaobo Zhang
Yisui ZHOU
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Beijing Double Crane Runchuang Technology Co Ltd
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Beijing Double Crane Runchuang Technology Co Ltd
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Priority to CN202480021353.1A priority Critical patent/CN121013841A/zh
Publication of WO2024250904A1 publication Critical patent/WO2024250904A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to compounds that are useful for regulating mitochondria activity, reducing adiposity, treating diseases including diabetes and diabetes-associated complications, compositions comprising the same, and the methods of using the same.
  • Mitochondrial uncouplers are compounds that dissipate the proton gradient across the mitochondrial inner membrane, which leads to the inefficient production of ATP. This uncoupling can lead to an increase in mitochondrial respiration, which may reduce the amount of energy stored as fat, resulting in weight loss. The mechanism of action of mitochondrial uncouplers on energy expenditure has made them attractive targets for the development of therapies for obesity.
  • mitochondrial uncouplers have been identified and studied for their potential efficacy in treating obesity.
  • One of the most well-known uncoupling agents is 2, 4-dinitrophenol (DNP) , which has been used in the past for weight loss but was later banned due to its toxicity.
  • DNP 2-dinitrophenol
  • newer mitochondrial uncoupling agents have been developed, including carbonyl cyanide 4- (trifluoromethoxy) phenylhydrazone (FCCP) and 2, 3, 5-triiodo-L-thyronine (T3) , which have shown promising results in preclinical studies.
  • FCCP carbonyl cyanide 4- (trifluoromethoxy) phenylhydrazone
  • T3 2, 3, 5-triiodo-L-thyronine
  • the present application aims to provide safe and effective mitochondrial uncouplers.
  • a compound of formula (I) a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof:
  • R 1 at each occurrence is independently selected from hydrogen, deuterium, -C 1-6 alkyl, haloC 1-6 alkyl and -C 1-6 alkoxyalkyl; said -C 1-6 alkyl, haloC 1-6 alkyl or -C 1-6 alkoxyalkyl is optionally substituted with one or more R 11 ;
  • R 2 and R 3 together with the atom to which they are both attached form a 3-14 membered carbocyclic ring, a 3-14 membered heterocyclic ring, a 6-12 membered aryl ring or a 5-14 membered heteroaryl ring; each said ring is independent optionally substituted with n 1 R S1 ;
  • n 1 is selected from 0, 1, 2, 3, 4, 5 and 6;
  • Each of heteroaryl at each occurrence is independently contains 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O and S.
  • R 1 at each occurrence is independently selected from hydrogen, deuterium, -C 1-3 alkyl and -C 2-3 alkoxyalkyl;
  • R 1 is optionally substituted with one or more R 11 ;
  • R 1 at each occurrence is independently selected from -C 1-3 alkyl and -C 2-3 alkoxyalkyl;
  • said -C 1-3 alkyl or -C 2-3 alkoxyalkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 R 11 ;
  • R 1 at each occurrence is independently selected from -C 1-3 alkyl and -C 2-3 alkoxyalkyl;
  • R 1 is optionally substituted with 1, 2, 3, 4, 5, 6 or 7 R 11 ;
  • said R 11 is selected from deuterium, -C 2-3 alkoxyalkyl and -O (C 1-3 alkyl) ; said R 11 is optionally substituted with one or more -D.
  • R 1 at each occurrence is independently selected from -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CD 3 , -CH 2 CD 2 CD 3 , -CD 2 CD 2 CD 3 , -CH (CH 3 ) 2 , -CD (CH 3 ) 2 , -CD (CD 3 ) (CH3) , -CH (CD 3 ) 2 , -CD (CD 3 ) 2 ,
  • R 1 at each occurrence is independently selected from -CD 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CD 3 , -CH 2 CD 2 CD 3 , -CD 2 CD 2 CD 3 , -CH (CH 3 ) 2 , -CD (CH 3 ) 2 , -CD (CD 3 ) 2 ,
  • R 1 at each occurrence is independently selected from -CD 3 ,
  • R 1 at each occurrence is independently selected from -C 1-3 alkyl; said R 1 is optionally substituted with 1, 2, 3, 4, 5, 6 or 7 deuterium.
  • R 1 at each occurrence is independently selected from -CH 3 , said -CH 3 is substituted with 1, 2 or 3 deuterium.
  • R 1 at each occurrence is independently selected from -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CD 3 , -CH 2 CD 2 CD 3 , -CD 2 CD 2 CD 3 , -CH (CH 3 ) 2 , -CD (CH 3 ) 2 , -CD (CD 3 ) (CH3) , -CH (CD 3 ) 2 and -CD (CD 3 ) 2 .
  • R 1 at each occurrence is independently selected from -CD 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CD 3 , -CH 2 CD 2 CD 3 , -CD 2 CD 2 CD 3 , -CH (CH 3 ) 2 , -CD (CH 3 ) 2 and -CD (CD 3 ) 2 .
  • R 1 at each occurrence is independently selected from -CD 3 .
  • R 3 , R 2 or R 4 have the same definitions as in [1] .
  • R 1 at each occurrence is independently selected from -C 1-3 alkyl, said R 1 is substituted with R 11 ; said R 11 is selected from -C 2-3 alkoxyalkyl, said R 11 is optionally substituted with one or more deuterium.
  • R 1 at each occurrence is independently selected from -CH 3 ; said R 1 is substituted with -CH 2 -O-CH 3 .
  • R 3 , R 2 or R 4 have the same definitions as in [1] .
  • R 1 at each occurrence is independently selected from -C 2-3 alkoxyalkyl, said R 1 is substituted with R 11 ; said R 11 is selected from -C 2-3 alkoxyalkyl and -O (C 1-3 alkyl) , said R 11 is optionally substituted with one or more deuterium.
  • R 1 at each occurrence is independently selected from -CH 2 -O-CH 3 , -CH 2 -O-CH 2 -CH 3 , -CH 2 -CH 2 -O-CH 3 and -CH (CH 3 ) -O-CH 3 , said R 1 is substituted with R 11 ; said R 11 is selected from -CH 2 -O-CH 3 , -CH 2 -O-CH 2 -CH 3 , -CH 2 -CH 2 -O-CH 3 , -CH (CH 3 ) -O-CH 3 , -O-CH 3 , -O-CH 2 -CH 3 , -O-CH 2 -CH 2 -CH 3 and -O-CH (CH 3 ) 2 ; said R 11 is optionally substituted with 1, 2, 3, 4, 5, 6 or 7 deuterium.
  • R 1 at each occurrence is independently selected from -CH 2 -CH 2 -O-CH 3 ; said R 1 is substituted with -CH 2 -O-CH 3 .
  • R 1 at each occurrence is independently selected from
  • R 1 at each occurrence is independently selected from
  • a compound of formula (I-3) a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof:
  • R 3 , R 2 or R 4 have the same definitions as in [1] .
  • R 3 or R 2 have the same definitions as in [1] .
  • R 3 or R 2 have the same definitions as in [1] .
  • a compound of formula (II-3) a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof:
  • R 3 or R 2 have the same definitions as in [1] .
  • R 2 and R 3 are each independently selected from -H, -D, -CD 3 and -CH 3 .
  • a compound of formula (I) a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof:
  • R 1 at each occurrence is independently selected from -C 1-3 alkyl and -C 2-3 alkoxyalkyl;
  • R 1 is optionally substituted with 1, 2 or 3 R 11 ;
  • said R 11 is selected from deuterium, -C 2-3 alkoxyalkyl and -O (C 1-3 alkyl) ; when R 11 is -C 2-3 alkoxyalkyl or -O (C 1-3 alkyl) , said R 11 is optionally substituted with one or more deuterium;
  • a compound of formula (I) a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof:
  • R 1 at each occurrence is independently selected from -C 1-3 alkyl and -C 2-3 alkoxyalkyl;
  • R 1 is optionally substituted with 1, 2 or 3 R 11 ;
  • said R 11 is selected from deuterium, -C 2-3 alkoxyalkyl and -O (C 1-3 alkyl) ; when R 11 is -C 2-3 alkoxyalkyl or -O (C 1-3 alkyl) , said R 11 is optionally substituted with one or more deuterium;
  • R 4 is each independent selected from -H, -D and -C 1-3 alkyl; wherein when R 4 is -C 1-3 alkyl, said R 4 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium;
  • R 2 and R 3 are each independently selected from -H, -D and -C 1-3 alkyl; wherein when R 2 or R 3 is -C 1-3 alkyl, said R 2 or R 3 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium.
  • a compound of formula (I) a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof:
  • R 1 at each occurrence is independently selected from -C 1-3 alkyl; said R 1 is optionally substituted with 1, 2, 3, 4, 5, 6 or 7 deuterium;
  • R 4 is each independent selected from -H, -D and -C 1-3 alkyl; wherein when R 4 is -C 1-3 alkyl, said R 4 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium;
  • R 2 and R 3 are each independently selected from -H, -D, -C 1-3 alkyl; wherein when R 2 or R 3 is -C 1-3 alkyl, said R 2 or R 3 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium.
  • a compound of formula (I) a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof:
  • R 1 at each occurrence is independently selected from -C 1-3 alkyl, said R 1 is substituted with R 11 ; said R 11 is selected from -C 2-3 alkoxyalkyl, said R 11 is optionally substituted with one or more deuterium;
  • R 4 is each independent selected from -H, -D and -C 1-3 alkyl; wherein when R 4 is -C 1-3 alkyl, said R 4 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium;
  • R 2 and R 3 are each independently selected from -H, -D, -C 1-3 alkyl; wherein when R 2 or R 3 is -C 1-3 alkyl, said R 2 or R 3 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium.
  • a compound of formula (I) a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof:
  • R 1 at each occurrence is independently selected from -C 2-3 alkoxyalkyl, said R 1 is substituted with R 11 ; said R 11 is selected from -C 2-3 alkoxyalkyl or -O (C 1-3 alkyl) , said R 11 is optionally substituted with one or more deuterium;
  • R 4 is each independent selected from -H, -D and -C 1-3 alkyl; wherein when R 4 is -C 1-3 alkyl, said R 4 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium;
  • R 2 and R 3 are each independently selected from -H, -D and -C 1-3 alkyl; wherein when R 2 or R 3 is -C 1-3 alkyl, said R 2 or R 3 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium.
  • R 4 is each independent selected from -H, -D and -C 1-3 alkyl; wherein when R 4 is -C 1-3 alkyl, said R 4 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium;
  • R 2 and R 3 are each independently selected from -H, -D and -C 1-3 alkyl; wherein when R 2 or R 3 is -C 1-3 alkyl, said R 2 or R 3 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium.
  • R 4 is each independent selected from -H, -D and -C 1-3 alkyl; wherein when R 4 is -C 1-3 alkyl, said R 4 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium;
  • R 2 and R 3 are each independently selected from -H, -D and -C 1-3 alkyl; wherein when R 2 or R 3 is -C 1-3 alkyl, said R 2 or R 3 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium.
  • a compound of formula (I-3) a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof:
  • R 4 is each independent selected from -H, -D and -C 1-3 alkyl; wherein when R 4 is -C 1-3 alkyl, said R 4 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium;
  • R 2 and R 3 are each independently selected from -H, -D and -C 1-3 alkyl; wherein when R 2 or R 3 is -C 1-3 alkyl, said R 2 or R 3 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium.
  • a pharmaceutical composition comprising the compound, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof of any one of [1] to [52] , and at least one pharmaceutically acceptable excipient.
  • a method of treating a subject having mitochondria-related disorders or conditions comprising administering to the subject a therapeutically effective amount of a compound, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof of any one of [1] to [52] ; or the pharmaceutical composition of [53] .
  • the disorder is obesity, excess body fat, diabetes, insulin resistance or intolerance, non-alcoholic fatty liver disease (NAFLD) , non-alcoholic steatohepatitis (NASH) , hepatic steatosis, type 2 diabetes (T2DM) , dyslipidemia, cardiovascular disease, heart disease or atherosclerosis.
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • T2DM type 2 diabetes
  • the disorder is obesity, excess body fat, diabetes, insulin resistance or intolerance, non-alcoholic fatty liver disease (NAFLD) , non-alcoholic steatohepatitis (NASH) , hepatic steatosis, type 2 diabetes (T2DM) , dyslipidemia, cardiovascular disease or heart disease or atherosclerosis.
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • T2DM type 2 diabetes
  • dyslipidemia cardiovascular disease or heart disease or atherosclerosis.
  • the disorder is obesity, excess body fat, diabetes, insulin resistance or intolerance, non-alcoholic fatty liver disease (NAFLD) , non-alcoholic steatohepatitis (NASH) , hepatic steatosis, type 2 diabetes (T2DM) , dyslipidemia, cardiovascular disease or heart disease or atherosclerosis.
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • T2DM type 2 diabetes
  • dyslipidemia cardiovascular disease or heart disease or atherosclerosis.
  • the compound of formula (I) a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof of the present application provides higher solubility, less toxicity and good clinical safety.
  • Figure 1 The 1 H-NMR spectrum for Compound 1-1A.
  • FIG. 1 The 1 H-NMR spectrum for Compound 1-1B.
  • Figure 4 The Cmax of plasma DNP after dosing of Compound 1, Compound HU6 and DNP in Male ICR Mice.
  • halogen or “halo” , as used interchangeably herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include -F, -Cl and -Br.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl.
  • C 1-6 in -C 1-6 alkyl is defined to identify the group having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
  • haloalkyl as used herein, unless otherwise indicated, means the aboven-mentioned alkyl substituted with one or more (for 1, 2, 3, 4, 5, or 6) halogen (-F, -Cl or -Br) .
  • the haloalkyl is interchangeable -C 1-6 haloalkyl or haloC 1-6 alkyl, wherein, C 1-6 in the -C 1-6 haloaklyl or haloC 1-6 alkyl indicates that the total carbon atoms of the alkyl is 1 to 6.
  • the -C 1-6 haloalkyl is the -C 1-3 haloalkyl.
  • the -C 1-3 haloalkyl is (methyl, ethyl, propyl or isopropyl) substituted with 1, 2, 3, 4, 5, or 6 -F; preferably, the -C 1-3 haloalkyl is -CF 3 .
  • alkylene means a difunctional group obtained by removal of an additional hydrogen atom from an alkyl group defined above.
  • methylene i.e., -CH 2 -
  • ethylene i.e., -CH 2 -CH 2 -or -CH (CH 3 ) -
  • propylene i.e., -CH 2 -CH 2 -CH 2 -, -CH (-CH 2 -CH 3 ) -or -CH 2 -CH (CH 3 ) -
  • alkenyl means a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length.
  • alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
  • alkynyl contains a straight or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length.
  • C 2-6 alkynyl contains from 2 to 6 carbon atoms.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • alkoxyalkyl radicals are oxygen ethers formed from the previously described alkyl groups, in which the total number of carbon atoms is as indicated.
  • Alkoxyalkyl referring to alkyl substituted with -O-alkyl includes, but is not limited to -CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 (CH 3 ) -O-CH 3 and -CH 2 CH 2 -O-CH 2 CH 2 .
  • haloalkoxyalkyl as used herein, unless otherwise indicated, means the aboven-mentioned alkoxyalkyl substituted with one or more (for 1, 2, 3, 4, 5, or 6) halogen (-F, -Cl or -Br) .
  • the haloalkoxyalkyl is interchangeable -C 1-6 haloalkoxyalkyl or haloC 1-6 alkoxyalkyl, wherein, C 1-6 in the -C 1-6 haloakloxyalkyl or haloC 1-6 alkoxyalkyl indicates that the total carbon atoms of the alkoxyalkyl is 1 to 6.
  • the -C 1-6 haloalkoxyalkyl is the -C 1-3 haloalkoxyalkyl.
  • the -C 1-3 haloalkoxyalkyl is (methoxy, ethoxy, propoxy or isopropoxy) substituted with 1, 2, 3, 4, 5, or 6 -F; preferably, the -C 1-3 haloalkoxyalkyl is -OCF 3 .
  • aryl refers to an unsubstituted or substituted mono or polycyclic aromatic ring system containing carbon ring atoms.
  • the preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
  • heterocyclyl or “heterocyclic” , as used herein, unless otherwise indicated, refers to unsubstituted and substituted mono or polycyclic non-aromatic ring system containing one or more heteroatoms, which comprising moncyclic heterocyclyl ring, bicyclic heterocyclyl ring, bridged heterocyclyl ring, fused heterocyclyl ring or sipro heterocyclyl ring.
  • Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to ten membered and is either fully saturated or has one or more degrees of unsaturation.
  • heterocyclyl groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone and oxadiazolyl.
  • heteroaryl represents an aromatic ring system containing carbon (s) and at least one heteroatom.
  • Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
  • a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms.
  • a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclicheteroaryl is a polycyclic heteroaryl.
  • Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
  • Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) .
  • heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl or isoquinolinyl.
  • carbocyclic refers to a substituted or unsubstituted monocyclic ring, bicyclic ring, bridged ring, fused ring, sipiro ring non-aromatic ring system only containing carbon atoms.
  • the ring is three to ten membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition.
  • the carbocyclic includes but not be limited cycloalkly, cycloalkenyl and cycloalkynyl.
  • Examplary “cycloalkyl” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • one or more refers to one or more than one. In some embodiments, “one or more” refers to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, “one or more” refers to 1, 2, 3, 4, 5 or 6. In some embodiments, “one or more” refers to 1, 2, 3 or 4. In some embodiments, “one or more” refers to 1, 2, or 3. In some embodiments, “one or more” refers to 1 or 2. In some embodiments, “one or more” refers to 1. In some embodiments, “one or more” refers to 2. In some embodiments, “one or more” refers to 3. In some embodiments, “one or more” refers to 4. In some embodiments, “one or more” refers to 5. In some embodiments, “one or more” refers to 6.
  • each of substituents may be respectively independently substituted on every ring atom of the ring including but not limited to a ring carbon atom or a ring nitrogen atom.
  • each of substituents may be respectively independently substituted on every ring atom of the ploycyclic ring.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds in the present invention are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75%pure, especially at least 98%pure (%are on a weight for weight basis) .
  • terapéuticaally effective amount means an amount of the compound, which is effective in treating the named disorder or condition.
  • the present invention includes within its scope the prodrugs of the compounds of this invention.
  • such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs” , ed. H. Bundgaard, Elsevier, 1985.
  • the present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • stereoisomer refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and conformational isomers.
  • the configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers.
  • the invention includes all possible stereoisomers of the compound.
  • Certain of the compounds provided herein may exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule.
  • the compounds provided herein include all atropisomers, both as pure individual atropisomer preparations, enriched preparations of each, or a non-specific mixture of each. Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted.
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • the isotopes of hydrogen can be denoted as 1 H (hydrogen) , 2 H (deuterium) and 3 H (tritium) . They are also commonly denoted as D for deuterium and T for tritium.
  • CD 3 denotes a methyl group wherein all of the hydrogen atoms are deuterium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by prcesses analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
  • deuterated derivative refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom ( “D” ) . It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending on the origin of chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation is small and immaterial as compared to the degree of stable isotopic substitution of deuterated derivative described herein.
  • the deuterated derivative of the disclosure have an isotopic enrichment factor for each deuterium atom, of at least 3500 (52.5%deuterium incorporation at each designated deuterium) at least 4500, (67.5 %deuterium incorporation) , at least 5000 (75%deuterium incorporation) at least 5500 (82.5%deuterium incorporation) , at least 6000 (90%deuterium incorporation) , at lease 6333.3 (95%deuterium incorporation, at least 6466.7 (97%deuterium incorporation, or at least 6600 (99%deuterium incorporation) .
  • the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
  • compositions of the present invention comprise a compound in present invention (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds in present invention or a prodrug or a metabolite or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous) .
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compound represented by Formula I or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt.
  • the compounds of Formula I or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 0.05 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about 0.0lmg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, l000mg, 1500mg or 2000mg.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
  • dosage levels on the order of from about 0.001mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions or alternatively about 0.05mg to about 7g per patient per day.
  • inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) may be effectively treated by the administration of from about 0.001 to 50mg of the compound per kilogram of body weight per day or alternatively about 0.05mg to about 3.5g per patient per day.
  • the DNP is a metabolite of Compound 1 and Compound HU6.
  • the pH of the solution of NaCl (2.00 g) in ultrapure water (900 mL) was adjusted to 1.6 with aq. HCl (1 N) , and then diluted to a volume of 1000 mL with ultrapure water to obtain the HCl/NaCl solution.
  • FaSSIF, FeSSIF & FaSSGF (0.06 g) powder was added to the HCl/NaCl solution (500 mL) , stirred until completely dissolved, and then diluted to a volume of 1000 mL with the HCl/NaCl solution.
  • the obtained the FaSSGF solution should be used within 48 hrs at r.t and 24 hrs at 37 °C.
  • Each of (compound designated for testing and the positive compound) was diluted with DMSO to achieve a concentration of 1 mg/ml, and then diluted with 50%acetonitrile (IS, 100ng/ml dexamethasone) to afford standard solution of each compound to be tested and the standard solution of the positive compound (the dilution factor may be changed according to the LC-MS/MS response) .
  • 50%acetonitrile IS, 100ng/ml dexamethasone
  • Each of the compounds to be tested ( ⁇ 1 mg) was dispensed into individual well of a 96-well plate, subsequently, either FaSSIF solution or FaSSGF solution was added to each well to adjust the concentration to 1 mg/mL.
  • the 96-well plate was transferred to the Thermomixer Cand shaken at 37 °C at 1200 rpm for 24 hours, and then filtered.
  • Area Ratio sample means the area ratio (Analyte Peak Area/IS Peak Area) of test solution.
  • Area Ratio Std means the area ratio (Analyte Peak Area/IS Peak Area) of standard solution.
  • DF means the dilution factor
  • [STD] means the concentration of standard solution.
  • thermodynamic solubility assay The results of thermodynamic solubility assay are shown in the following Table 2:
  • the Compound 1 has a higher solubility.
  • FaSSIF solution the solubility of Compound 1 is 2.6 times higher than Compound HU6;
  • FaSSGF solution the solubility of Compound 1 is 3.4 times higher than Compound HU6.
  • group 1 ⁇ 18 Mice were treated with 5 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 50 mg/kg, 100 mg/kg, 600 mg/kg, 1000 mg/kg and 2000 mg/kg dose of compound HU6 and compound 1 (p.o. ) .
  • Mice in group 19 ⁇ 21 were treated with 0.1 mg/kg, 0.5 mg/kg 10 mg/kg dose of compound (p.o. ) .
  • blood samples were collected at the time point of 0.25, 0.5, 1, 2, 4 and 8 h post-dose. Blood samples were placed on ice until centrifugation to obtain plasma samples. The plasma samples were stored at -80°C until analysis. The concentration of compound in plasma samples was determined using a LC-MS/MS method.

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Abstract

L'invention concerne un composé de formule (I), un stéréoisomère de celui-ci, un dérivé deutéré de celui-ci, un sel pharmaceutiquement acceptable de celui-ci, un sel pharmaceutiquement acceptable du stéréoisomère de celui-ci ou un sel pharmaceutiquement acceptable du dérivé deutéré de celui-ci, et des compositions pharmaceutiques de celui-ci, ainsi que son utilisation.
PCT/CN2024/092306 2023-06-07 2024-05-10 Liaisons imidazolyles avec des dérivés de dinitrophényle et leur utilisation Pending WO2024250904A1 (fr)

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WO2025077675A3 (fr) * 2023-10-12 2025-05-22 Shenzhen Hightide Biopharmaceutical Ltd. Promédicaments et conjugués de 2, 4-dinitrophénol, et compositions et procédés associés

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CN102264693A (zh) * 2008-10-27 2011-11-30 康金尼亚有限公司 用作线粒体通透性转变抑制剂的丙烯酰胺衍生物
US20160008298A1 (en) * 2014-07-14 2016-01-14 Oregon State University Xanthohumol-based compounds and compositions thereof, and methods of making and using the same
CN107205971A (zh) * 2014-11-18 2017-09-26 罗格斯，新泽西州立大学 用于治疗代谢疾病和癌症的新的线粒体解偶联剂
CN110167918A (zh) * 2017-01-06 2019-08-23 里维斯制药股份有限公司 新型苯基衍生物
WO2021080189A1 (fr) * 2019-10-25 2021-04-29 서울대학교산학협력단 Composition pour blanchir la peau et son utilisation
WO2021080188A2 (fr) * 2019-10-25 2021-04-29 서울대학교산학협력단 Composition pour la prévention ou le traitement de la dépression comprenant un inhibiteur d'expression de protéines et son utilisation

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Publication number Priority date Publication date Assignee Title
CN102264693A (zh) * 2008-10-27 2011-11-30 康金尼亚有限公司 用作线粒体通透性转变抑制剂的丙烯酰胺衍生物
US20160008298A1 (en) * 2014-07-14 2016-01-14 Oregon State University Xanthohumol-based compounds and compositions thereof, and methods of making and using the same
CN107205971A (zh) * 2014-11-18 2017-09-26 罗格斯，新泽西州立大学 用于治疗代谢疾病和癌症的新的线粒体解偶联剂
CN110167918A (zh) * 2017-01-06 2019-08-23 里维斯制药股份有限公司 新型苯基衍生物
WO2021080189A1 (fr) * 2019-10-25 2021-04-29 서울대학교산학협력단 Composition pour blanchir la peau et son utilisation
WO2021080188A2 (fr) * 2019-10-25 2021-04-29 서울대학교산학협력단 Composition pour la prévention ou le traitement de la dépression comprenant un inhibiteur d'expression de protéines et son utilisation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025077675A3 (fr) * 2023-10-12 2025-05-22 Shenzhen Hightide Biopharmaceutical Ltd. Promédicaments et conjugués de 2, 4-dinitrophénol, et compositions et procédés associés

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