WO2017152570A1 - Nouveau composé gvs et son utilisation - Google Patents

Nouveau composé gvs et son utilisation Download PDF

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WO2017152570A1
WO2017152570A1 PCT/CN2016/092066 CN2016092066W WO2017152570A1 WO 2017152570 A1 WO2017152570 A1 WO 2017152570A1 CN 2016092066 W CN2016092066 W CN 2016092066W WO 2017152570 A1 WO2017152570 A1 WO 2017152570A1
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group
substituted
unsubstituted
gvs
compound
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PCT/CN2016/092066
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English (en)
Chinese (zh)
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段小群
徐华强
易伟
胡增仁
吴啸川
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浙江旭晨医药科技有限公司
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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the field of pharmaceutical applications.
  • the present invention relates to a GVS series of compounds and uses thereof, and the compounds of the present invention can significantly improve non-alcoholic fatty liver and fat accumulation.
  • Non-alcoholic fatty liver disease refers to the clinical pathological syndrome characterized by excessive deposition of intrahepatic fat due to alcohol and other well-defined liver damage factors, and is closely related to insulin resistance and genetic susceptibility. Metabolic stress liver damage, including simple fatty liver (SFL), nonalcoholic steatohepatitis (NASH) and related cirrhosis. With the global trend of obesity and its related metabolic syndrome, nonalcoholic fatty liver disease has become an important cause of chronic liver disease in developed countries such as Europe and the United States and in rich areas of China. The prevalence of NAFLD in ordinary adults is 10%-30%. Among them, 10%-20% are NASH, and the latter has a cirrhosis rate of 25% within 10 years.
  • SFL simple fatty liver
  • NASH nonalcoholic steatohepatitis
  • Non-alcoholic fatty liver disease can directly lead to decompensated cirrhosis, hepatocellular carcinoma and transplanted liver recurrence, and can also affect the progression of other chronic liver diseases, and participate in the onset of type 2 diabetes and atherosclerosis. Therefore, it is extremely important to prevent further damage to the liver by early prevention and treatment of nonalcoholic fatty liver.
  • drugs and health foods for preventing and treating non-alcoholic fatty liver disease, but there are also many problems, such as patients can not tolerate, resulting in weight loss, fluid retention, cardiovascular and other adverse reactions. Therefore, there is an urgent need in the art to develop novel drugs for preventing and treating non-alcoholic fatty liver.
  • a compound of the formula A an optical isomer, a hydrate thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament or a preparation, Said drug or preparation for:
  • ALT alanine aminotransferase
  • MDA malondialdehyde
  • LDL-C low density lipoprotein cholesterol
  • HDL-C high-density lipoprotein cholesterol
  • X is O or N
  • R 1 is -LR a , wherein L is none or a divalent linking group selected from the group consisting of -(CH 2 )m-, -(CR 4 H)m-, m is 1, 2 or 3, R 4 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 4 cycloalkyl;
  • R a is selected from the group consisting of substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted, containing 1-5 selected from N, S and 4-20 membered heterocyclic C 1 -C 10 alkyl group of a hetero atom in O, substituted or unsubstituted C 5 -C 20 aryl group, substituted or unsubstituted C 5 -C 20 aryl C 1 -C a 10 alkyl group, and a substituted or unsubstituted C 5 -C 20 heteroaryl group having 1 to 5 hetero atoms selected from N, S and O;
  • the substituent is selected from the group consisting of C 1 -C 10 alkyl, C 1 -C 6 alkylcarbonyl, carboxyl, nitro and halogen;
  • R 2 is selected from the group consisting of H, halogen, methyl, methoxy, formamide, nitro, trifluoromethyl and cyano;
  • R 3 is one or more groups selected from the group consisting of H, halogen, methyl, methoxy, formamide, nitro, trifluoromethyl, cyano, and 3,4-cyclobutadiene base;
  • the fatty liver is nonalcoholic fatty liver.
  • the superoxide dismutase is a superoxide dismutase in serum.
  • the fatty acid synthase is a fatty acid synthase in serum.
  • the medicament or formulation has one or more characteristics selected from the group consisting of:
  • the "weak activation ability" refers to a ratio (M1/M0) of the test group measurement value M1 to the control reference value M0 of ⁇ 0.75, preferably ⁇ 0.6, more preferably ⁇ 0.5, more preferably Ground ⁇ 0.4, optimally ⁇ 0.3, where The compound of the control group was rosiglitazone.
  • the "strong binding ability" refers to a ratio (C1/C0) of the test group measurement value C1 to the control reference value C0 of >0.9, preferably >1, more preferably >1.15, more preferably > 1.25, optimally > 1.35, wherein the compound of the control group is rosiglitazone.
  • the "the ability of the weak preadipocyte 3T3-L1 to transform into an adipocyte” means that the ratio of the test group measured value T1 to the control reference value T0 (T1/T0) ⁇ 0.5, preferably ⁇ 0.25, more preferably ⁇ 0.1, more preferably ⁇ 0.06, wherein the compound of the control group is rosiglitazone.
  • a compound of the formula A an optical isomer, a hydrate thereof, a solvate thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof,
  • X is O or N
  • R 1 is -LR a , wherein L is none or a divalent linking group selected from the group consisting of -(CH 2 )m-, -(CR 4 H)m-, m is 1, 2 or 3, R 4 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 4 cycloalkyl;
  • R a is selected from the group consisting of substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted, containing 1-5 selected from N, S and 4-20 membered heterocyclic C 1 -C 10 alkyl group of a hetero atom in O, substituted or unsubstituted C 5 -C 20 aryl group, substituted or unsubstituted C 5 -C 20 aryl C 1 -C a 10 alkyl group, and a substituted or unsubstituted C 5 -C 20 heteroaryl group having 1 to 5 hetero atoms selected from N, S and O;
  • the substituent is selected from the group consisting of C 1 -C 10 alkyl, C 1 -C 6 alkylcarbonyl, carboxyl, nitro and halogen;
  • R 2 is selected from the group consisting of H, halogen, methyl, methoxy, formamide, nitro, trifluoromethyl and cyano;
  • R 3 is one or more groups selected from the group consisting of H, halogen, methyl, methoxy, formamide, nitro, trifluoromethyl, cyano, and 3,4-cyclobutadiene base;
  • R 1 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted containing 1-3 4-10 membered heterocyclic C 1 -C 6 alkyl group selected from N, S and O hetero atoms, substituted or unsubstituted C 5 -C 10 aryl group, substituted or unsubstituted C 5 -C 10 aryl C 2 -C 6 alkyl, and substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, S and O.
  • R 1 is selected from the group consisting of benzyl, phenyl, pyridin-4-ylmethyl, pyridin-4-ylethyl, 1-phenylethyl, methoxycarbonylbenzyl, and Carboxybenzyl.
  • the compound of formula A is selected from the group consisting of:
  • a pharmaceutical composition comprising:
  • the pharmaceutical composition contains a therapeutically effective amount or a safe and effective amount of a compound of formula A, an optical isomer, hydrate, solvate, prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 0.0001 to 99% by weight (preferably 0.01 to 90% by weight, more preferably 0.1 to 80% by weight) of the component (i) to the total of the pharmaceutical composition. Weight meter.
  • the pharmaceutical composition is for the preparation of a medicament for the treatment and/or prevention of fatty liver.
  • a method for treating and/or preventing fatty liver comprising: administering a compound of the formula A according to the first aspect and the second aspect of the present invention or the present invention to a subject in need thereof The pharmaceutical composition of the third aspect.
  • the object comprises a person.
  • the subject comprises a non-human mammal.
  • the non-human mammal comprises a rodent such as a mouse or a rat.
  • the fatty liver is non-alcoholic fatty liver.
  • the administration dose is 10-10000 mg/kg/day, preferably 500-10000 mg/kg/day, more preferably 1000-10000 mg/kg/day.
  • the application frequency is 1-5 times/day, preferably 1-2 times/day.
  • the administration comprises one or more cycles, each cycle being from 2 to 30 days, preferably from 3 to 7 days.
  • Figure 1 shows the results of the compound GVS-12 targeting PPAR ⁇ activity test.
  • A The chemical structural formula of GVS-12;
  • C oil red O staining test;
  • D 3T3-L1 preadipocytes, DMSO (1 ⁇ M) to promote fat differentiation ability results;
  • E 3T3-L1 preadipocytes, GVS-12 (1 ⁇ M) results in promoting fat differentiation;
  • F the result of rosiglitazone (1 ⁇ M) promoting fat differentiation ability in 3T3-L1 preadipocytes;
  • Figure 2 shows the GVS-12 Effect of Compound # P ⁇ 0.05vs fatty liver model group on body weight in rats.
  • Figure 3 shows the pathological examination of compound GVS-12 in nonalcoholic fatty liver rats.
  • the term “about” means that the value can vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “consisting essentially of,” or “consisting of.”
  • substituted or unsubstituted means that the group may be unsubstituted or that H in the group is one or more (eg 1-10, preferably 1-5) More preferably 1-3, optimally 1-2) substituents are substituted.
  • substituted or “substituted” means that the group has one or more (preferably 1-6, more preferably 1-3) substituents selected from the group consisting of: C 1 -C 6 alkylcarbonyl, carboxyl, nitro and halogen.
  • C 1 -C 10 alkyl refers to a straight or branched alkyl group having from 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, iso Butyl, sec-butyl, tert-butyl, or the like;
  • C 1 -C 3 alkyl means a straight or branched alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, N-propyl, isopropyl, or the like.
  • C 3 -C 10 cycloalkyl refers to a cyclic alkyl group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or Similar group.
  • C 5 -C 20 aryl refers to a monovalent aromatic carbocyclic group of 5 to 20 (preferably 5 to 14) carbon atoms which has a monocyclic (eg phenyl) or fused ring. (eg naphthyl or anthracenyl), if the point of attachment is on an aromatic carbon source, the fused ring may be non-aromatic (eg 2-benzoxazolone, 2H-1,4-benzoxazine-3 (4H) -keto-7-yl, etc.).
  • Preferred aryl groups include phenyl and naphthyl.
  • the term includes substituted or unsubstituted forms wherein the substituents are as defined above.
  • C 5 -C 20 heteroaryl refers to an aromatic group having 5 to 20 carbon atoms and 1 to 5 (preferably 1 to 3) hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur,
  • Such heteroaryl groups may be monocyclic (such as pyridyl or furyl) or fused (such as indolizinyl or benzothienyl), wherein the fused ring may be non-aromatic and/or Contains a heteroatom as long as the point of attachment is through an aromatic heteroaryl atom.
  • the heteroaryl group includes a pyridyl group, a pyrrolyl group, a fluorenyl group, a thienyl group, and a furyl group.
  • the term includes substituted or unsubstituted heteroaryl.
  • C 4 -C 20 heterocyclyl refers to a saturated, partially saturated or unsaturated group (but not aromatic) having a single ring or a fused ring (including a bridged ring system and a spiro ring). a system having 4 to 20 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen. In a fused ring system, one or more of the rings may be a cycloalkyl, aryl or heteroaryl group, as long as The point of attachment passes through a non-aromatic ring.
  • the term includes substituted or unsubstituted heterocyclic groups.
  • halogen means fluoro, chloro, bromo, or iodo, preferably fluoro, chloro and bromo.
  • halo refers to a group substituted by the same or different one or more of the above halogen atoms, and may be partially or fully halogenated, such as trifluoromethyl, pentafluoroethyl, heptafluoro. Isopropyl, or a similar group.
  • the compounds of the invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers.
  • the asymmetric center that can exist depends on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds are included within the scope of the invention.
  • the invention includes all isomeric forms of the compounds.
  • the invention provides the use of a compound of formula A for the preparation of a medicament or formulation for:
  • ALT alanine aminotransferase
  • MDA malondialdehyde
  • LDL-C low density lipoprotein cholesterol
  • compounds of the invention As used herein, “compounds of the invention”, “compounds of formula A”, “compounds of GVS series” are used interchangeably and refer to a compound of formula A or formula A-1 or formula A-2, optical isomers, hydrates thereof, a solvate, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound represented by Formula A, an optical isomer, a hydrate thereof, a solvate thereof, and the like a prodrug or a pharmaceutically acceptable salt thereof,
  • X is O or N
  • R 1 is -LR a , wherein L is none or a divalent linking group selected from the group consisting of -(CH 2 )m-, -(CR 4 H)m-, m is 1, 2 or 3, R 4 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 4 cycloalkyl;
  • R a is selected from the group consisting of substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted, containing 1-5 selected from N, S and 4-20 membered heterocyclic C 1 -C 10 alkyl group of a hetero atom in O, substituted or unsubstituted C 5 -C 20 aryl group, substituted or unsubstituted C 5 -C 20 aryl C 1 -C a 10 alkyl group, and a substituted or unsubstituted C 5 -C 20 heteroaryl group having 1 to 5 hetero atoms selected from N, S and O;
  • the substituent is selected from the group consisting of C 1 -C 10 alkyl, C 1 -C 6 alkylcarbonyl, carboxyl, nitro and halogen;
  • R 2 is selected from the group consisting of H, halogen, methyl, methoxy, formamide, nitro, trifluoromethyl and cyano;
  • R 3 is one or more groups selected from the group consisting of H, halogen, methyl, methoxy, formamide, nitro, trifluoromethyl, cyano, and 3,4-cyclobutadiene base;
  • R 1 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted containing 1-3 4-10 membered heterocyclic C 1 -C 6 alkyl group selected from N, S and O hetero atoms, substituted or unsubstituted C 5 -C 10 aryl group, substituted or unsubstituted C 5 -C 10 aryl C 2 -C 6 alkyl, and substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, S and O.
  • R 1 is selected from the group consisting of benzyl, phenyl, pyridin-4-ylmethyl, pyridin-4-ylethyl, 1-phenylethyl, methoxycarbonylbenzyl, and Carboxybenzyl.
  • the compound of formula A is a compound prepared in accordance with an embodiment of the invention.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient in a safe and effective amount, together with a pharmaceutically acceptable carrier.
  • the "active ingredient” as used in the present invention means a compound of the formula A, an optical isomer, a hydrate, a solvate thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof according to the present invention.
  • the "active ingredient" and pharmaceutical composition of the present invention are useful for the preparation of a medicament for the treatment and/or prevention of fatty liver.
  • the pharmaceutical compositions contain from 1 to 2000 mg of active ingredient per dose, more preferably from 10 to 200 mg of active ingredient per dose.
  • the "one dose” is a tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • “compatibility” it is meant herein that the components of the composition are capable of intermingling with the active ingredients of the present invention and with respect to each other without significantly reducing the efficacy of the active ingredients.
  • the compounds of the preferred embodiments of the invention may be administered as separate active agents or in combination with one or more other agents useful in the treatment of diabetes.
  • the use of the compounds of the preferred embodiments of the invention in combination with known therapeutic agents is also effective, and combinations of currently known compounds and other therapeutic agents for treating diabetes are within the scope of the preferred embodiments.
  • therapeutic agents for treating diabetes include, but are not limited to, the following: Wendia, Aiketo, and the like.
  • the compounds of the preferred embodiments are also effective when administered simultaneously with a therapeutic agent for treating diabetes.
  • the compounds of the preferred embodiments will be administered in a therapeutically effective amount by any of the accepted modes of administration of agents having similar effects.
  • the actual amount of the compound (i.e., active ingredient) of the preferred embodiment is determined by a number of factors, such as the severity of the condition to be treated, the age and relative health of the patient, the potency of the compound being used, the route and form of administration, and other factors. .
  • the drug can be administered multiple times a day, preferably once or twice a day. All of these factors are within the consideration of the attending physician.
  • the therapeutically effective dose may generally be a total daily dose for one-time administration or divided administration to a patient, for example, from about 0.001 to about 1000 mg/kg body weight per day, preferably from about 1.0 to about daily. 30 mg / kg body weight.
  • a Dosage unit composition can include its dosage factor to form a daily dose. The choice of dosage form will depend on various factors such as the mode of administration and the bioavailability of the drug substance.
  • the compounds of the preferred embodiments can be administered as a pharmaceutical composition by any of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous). Or subcutaneous).
  • the preferred mode of administration is oral, and a convenient daily dose can be adjusted depending on the degree of bitterness.
  • the compositions may take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols or any other suitable compositions.
  • Another preferred mode of administration of the preferred embodiment compounds is inhalation. This is an effective method of delivering a therapeutic agent directly to the respiratory tract (see, e.g., U.S. Patent No. 5,607,915).
  • Suitable pharmaceutically acceptable carriers or excipients include, for example, treatment and drug delivery modifiers and accelerators such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starches, gelatin, cellulose , sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting wax, ion exchange resin, and the like, and combinations of any two or more thereof.
  • treatment and drug delivery modifiers and accelerators such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starches, gelatin, cellulose , sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting wax, ion exchange resin, and the like, and combinations of any two or more thereof.
  • the liquid and semi-solid excipients may be selected from the group consisting of glycerin, propylene glycol, water, ethanol, and various oils, including petroleum, animal, vegetable, or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • Preferred liquid carriers, particularly carriers for injectable solutions include water, saline, aqueous dextrose and ethylene glycol.
  • Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991), incorporated herein by reference.
  • pharmaceutically acceptable salt refers to a non-toxic acid or alkaline earth metal salt of a compound of formula I. These salts can be prepared in situ by final isolation and purification of the compound of formula I, or by separately reacting a suitable organic or inorganic acid or base with a basic or acidic functional group.
  • Representative salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate , camphorate, camphor sulfonate, digluconate, cyclopentane propionate, lauryl sulfate, ethanesulfonate, glucose heptanoate, glycerol phosphate, hemisulfate, heptanoic acid Salt, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate , 2-naphthyl sulfonate, oxalate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, Succinate, sul
  • the nitrogen-containing basic group can be quaternized by the following reagents: alkyl halides such as methyl, ethyl, propyl, butyl chloride, bromide and iodide; dialkyl sulfate Such as dimethyl, diethyl, dibutyl and dipentyl sulfate; long chain halides such as sulfhydryl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl Base halides such as benzyl and phenethyl bromide. A water soluble or oil soluble or dispersible product is thus obtained.
  • alkyl halides such as methyl, ethyl, propyl, butyl chloride, bromide and iodide
  • dialkyl sulfate Such as dimethyl, diethyl, dibutyl and dipentyl sulfate
  • long chain halides
  • Examples of the acid which can be used to form a pharmaceutically acceptable acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and such as oxalic acid, horse An organic acid of acid, methanesulfonic acid, succinic acid or citric acid.
  • the base addition salt can be prepared in situ upon final isolation and purification of the compound of formula I, or by separately reacting the carboxylic acid moiety with a suitable base such as a hydroxide, carbonate or carbonate of a pharmaceutically acceptable metal cation. Hydrogen salt) or ammonia, or organic primary, secondary or tertiary amine reaction.
  • Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including However, it is not limited to: ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.
  • Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.
  • the term "pharmaceutically acceptable prodrug” refers to a prodrug of a compound of those preferred embodiments, which is rapidly converted in vivo to a parent compound of the above formula, for example, hydrolyzed in blood.
  • pharmaceutically acceptable prodrug refers to a prodrug of a compound of those preferred embodiments, which is rapidly converted in vivo to a parent compound of the above formula, for example, hydrolyzed in blood.
  • the compound of the present invention can effectively prevent and/or treat fatty liver, and in particular, has an effect of improving non-alcoholic fatty liver and fat accumulation while maintaining normal body weight.
  • the compound of the present invention is capable of agonizing the PPAR gamma receptor and does not significantly induce fat differentiation.
  • Solvents such as petroleum ether and ethyl acetate were purchased from Shanghai Sinopharm Group.
  • HSGF254TLC board (Yantai Chemical Industry Research Institute).
  • Step 1 p-Hydroxybenzoic acid (1.38 g, 10 mmol) and benzylamine (1.08 g, 10 mmol) were placed in a 25 mL round bottom flask, and a BOP condensing agent (5.3 g, 12 mmol) and DMAP (1.46 g, 12 mmol) were added. After adding 20 mL of dry DMF, stirring at room temperature, the reaction was followed by TLC. After 3 h, the reaction was completely extracted with EA and washed to afford Intermediate 1, MS (EI): m/z 227.1 [M+H] + .
  • Step 2 Intermediate 1 (230 mg, 1 mmol) and 3,4-difluorobenzyl bromide (206 mg, 1 mmol) were placed in a 25 mL round bottom flask, and Cs 2 CO 3 (490 mg, 1.5 mmol) was added to the flask. After adding 8 mL of dry DMF, stirring at room temperature, the reaction was followed by TLC. After 3 h, the reaction was completed and extracted with water/ethyl acetate until the aqueous phase had no compound. The organic phase was washed twice with water and then washed with saturated NaCl.
  • GVS-2 (yield 85%) was prepared by the procedure for preparing GVS-1 by using 3-fluoro-4-chlorobenzyl bromide instead of 3,4-difluorobenzyl bromide.
  • LCMS LCMS (ESI): m/z 354.1 [M+H] + .
  • GVS-3 (yield 81%) was prepared by the method of preparing GVS-1 by using 4-trifluoromethylbenzyl bromide instead of 3,4-difluorobenzyl bromide.
  • 1 H NMR 400 MHz, chloroform-d
  • LCMS LCMS (ESI): m/ z 386.1[M+H] + .
  • Step 1 Preparation of intermediate 2 by 4-methylaminopyridine in place of benzylamine.
  • Intermediate 2 LCMS (ESI): m/z 229.1 [M+H] + .
  • Step 2 Substituting Intermediate 2 for Intermediate 1 GVS-4 was prepared according to the procedure for the preparation of GVS-1 (yield: 79%).
  • LCMS LCMS (ESI): m/z 355.1 [M+H] + .
  • GVS-5 (yield 75%) was prepared by the procedure for the preparation of GVS-2 using Intermediate 2 instead of Intermediate 1.
  • Step 1 Preparation of intermediate 3 by 3-methylaminopyridine in place of benzylamine.
  • Intermediate 3 LCMS (ESI): m/z 229.1 [M+H] + .
  • Step 2 Substituting Intermediate 3 for Intermediate 1 GVS-7 was prepared according to the procedure for the preparation of GVS-1 (yield 81%).
  • 1 H NMR 400MHz, CHLOROFORM -d
  • ⁇ 8.63-8.56 m, 1H)
  • 7.79-7.74 m, 2H
  • 7.30 - 7.27 (m, 1H), 7.23 (dd, J 9.7, 2.0 Hz, 1H), 7.16 - 7.12 (m, 1H), 6.99–6.94 (m, 2H)
  • LCMS LCMS (ESI): m/z 355.1 [ M+H] + .
  • Step 1 substituting furan-3-amino-benzylamine is prepared as an intermediate is prepared from intermediate 4, LCMS (ESI): m / z 218.1 [M + H] +.
  • the desiccant was removed by suction filtration and spun dry to give a crude product.
  • the product was purified by silica gel column chromatography toield of 1-(4-chloro-3-fluorobenzyl)-1H-indole-5-carboxylic acid methyl ester (B-1) (57 mg, 0.18 mmol), yield 90% .
  • GVS-14 (yield 91%) was prepared by the procedure for the preparation of GVS-13 using aniline instead of benzylamine.
  • GVS-15 (yield 93%) was prepared by the procedure for the preparation of GVS-13 using 4-aminomethylpyridine instead of benzylamine.
  • GVS-17 (yield 72%) was prepared by the method of synthesizing GVS-13 using 3-, 4-difluorobenzyl bromide instead of 3-fluoro-4-chlorobenzyl bromide.
  • GVS-18 (yield 76%) was prepared by the method of synthesizing GVS-17 using 4-isopropylbenzylamine instead of benzylamine.
  • GVS-21 (yield 69%) was prepared by the method of synthesizing GVS-13 using 2-bromomethylnaphthalene instead of 3-fluoro-4-chlorobenzyl bromide.
  • LCMS LCMS (ESI): m/z 391.2 [M+H] + .
  • Cos-7 cells were purchased from ATCC and cultured in 10% FBS antibiotic DMEM, 37 ° C, 5% CO 2 incubator. When the cells were inoculated into a 24-well plate in a logarithmic growth phase and the cells were fused about 70%, the plasmid was co-transfected according to the lipofectamine 2000 (Invitrogen) protocol (50 ng full-length hPPAR ⁇ , 100 ng PPAR ⁇ , 5 ng Renilla luciferase plasmid). ). After 24 h, the transfected cells were treated with 1 ⁇ M compound, 1 ⁇ M rosiglitazone as a positive control and DMSO as a negative control. After 24 hours of intervention, the luciferase activity was determined according to the Reporter luciferase assay kits (Promega) protocol, and 3 independent test wells were set for each group.
  • the lipofectamine 2000 Invitrogen
  • the transfected cells were treated with 1 ⁇ M compound, 1
  • Example 24 TR-FRET method for testing the binding ability of a compound to PPAR gamma:
  • the diluted compound (1 to 22, rosiglitazone) was again diluted to 2 ⁇ M with TR-FRETbuffer.
  • TR-FRET buffer as a solvent to prepare Fluormone TM Pan-PPAR Green solution ( 20nM).
  • Binding ability is marked as + in 0.1-0.5, ++ in 0.5-0.8, and +++ in 0.8-1.5
  • 3T3-L1 preadipocytes were purchased from ATCC and cultured in 10% FBS DMEM containing penicillin-streptomycin double antibody in a 37 ° C, 5% CO 2 incubator. Inoculated on the culture plate, the induction solution was added 2 days after confluence (10% FBS DMEM containing 0.5 mmol/L IBMX (3-isobutyl-1-methylxanthine), 1 ⁇ mol/L DEX (dexamethasone), 850 nmol/L insulin). After 72h, it was replaced with 10% FBS high glucose DMEM containing 850nmol/L insulin, which was changed every 2d.
  • Example 26 Role of GVS series compounds in nonalcoholic fatty liver disease
  • Synthetic GVS series compounds (purity >99.5%), alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA) and superoxide dismutase (SOD) kits were purchased from Nanjing Institute of Bioengineering.
  • LDL-C Low-density lipoprotein cholesterol
  • HDL-C high-density lipoprotein cholesterol
  • TG triglyceride
  • Adiponectin ADP
  • FOS fatty acid synthase
  • a rat model of nonalcoholic fatty liver induced by high-fat diet was established.
  • the blank group was given normal feed for 16 weeks.
  • the model group and the drug-administered group were given high-fat diet (feed ratio: 82.5% normal feed + 10% lard + 5) % yolk powder + 2% cholesterol + 0.5% sodium cholate) was fed for 16 weeks, and was administered at the fourth week.
  • GVS-12 was administered subcutaneously for 12 weeks, and the blank control group and the model group were given an equal volume. Distilled water.
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • MDA malondialdehyde
  • SOD superoxide dismutase
  • LDL-C Low-density lipoprotein cholesterol
  • HDL-C high-density lipoprotein cholesterol
  • TC total cholesterol
  • TG triglyceride
  • Adiponectin (ADP) and FAS) kits were purchased from Wuhan Elitet Biotechnology Co., Ltd.
  • liver of each rat was fixed with 10% neutral formalin, dehydrated, embedded, sliced, dewaxed, and stained with oil red O to visually detect the improvement of lipid deposition of GVS-12. .
  • HE staining was used to observe the degree of liver fat accumulation and inflammation in rats, and the pathological changes of liver tissues were observed under microscope.
  • the body weight of the rats in the administration group was not significantly increased as compared with the model group.
  • HE staining results showed that the liver tissue of the model group showed severe inflammatory damage and liver fibrosis, and the inflammatory injury of the drug-administered group gradually decreased, and it was continuously improved in a dose-dependent manner.
  • liver function factors such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), malondialdehyde (MDA) and superoxide dismutase (SOD) in fatty liver rats were detected by biochemical method.
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • MDA malondialdehyde
  • SOD superoxide dismutase
  • GVS-12 can significantly reduce the activity and concentration of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and malondialdehyde (MDA) in serum, and can significantly increase superoxide.
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • MDA malondialdehyde
  • SOD dismutase
  • LDL-C low-density lipoprotein cholesterol
  • HDL-C high-density lipoprotein cholesterol
  • TG triglyceride
  • GVS-12 can reduce low-density lipoprotein cholesterol (LDL-C), compared with the model group.
  • LDL-C low-density lipoprotein cholesterol
  • TG Triglyceride
  • HDL-C high density lipoprotein cholesterol
  • the serum adiponectin (ADP) content and the activity of fatty acid synthase (FAS) were increased as compared with the model group.
  • GVS-12 can improve non-alcoholic liver inflammation and fat accumulation under the condition of maintaining normal body weight, and has a good effect of preventing non-alcoholic fatty liver.
  • the structure of the GVS series compound having the novel mother core structure of the invention is different from that of rosiglitazone, the raw material is simple and easy to obtain, can bind and agonize the PPAR ⁇ receptor, and has the function of not significantly inducing fat differentiation, and has the effect of The glitazone is quite or even better.

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Abstract

La présente invention décrit un nouveau composé GVS et son utilisation. Le nouveau composé GVS peut atténuer de manière significative une stéatose hépatique et une accumulation de graisse. Tout en conservant un poids normal, le composé peut : (a) atténuer l'inflammation non alcoolique du foie et l'accumulation de graisse ; (b) augmenter l'activité de la superoxyde dismutase (SOD) tout en réduisant de manière significative les activités de l'aspartate transaminase (AST), de l'alanine transaminase (ALT), et du malondialdéhyde (MDA) dans le sérum ; (c) réduire les teneurs en cholestérol de lipoprotéine basse densité (LDL-C) et en triglycéride (TG), et accroître la teneur en cholestérol de lipoprotéine haute densité (HDL-C) ; et (d) accroître la teneur en adiponectine (ADP) dans le sérum et réduire l'activité de l'acide gras synthase (FAS).
PCT/CN2016/092066 2016-03-09 2016-07-28 Nouveau composé gvs et son utilisation WO2017152570A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1379774A (zh) * 1999-08-18 2002-11-13 阿斯特拉曾尼卡有限公司 化合物
CN1835914A (zh) * 2003-06-13 2006-09-20 S.A.L.V.A.T.实验室有限公司 作为PPARγ调节剂的新型苯甲酰胺
TW200906400A (en) * 2007-04-05 2009-02-16 Daiichi Sankyo Co Ltd Aryl derivative
WO2012170561A1 (fr) * 2011-06-06 2012-12-13 The Scripps Research Institute (T.S.R.I.) Modulateurs n-benzylindole du pparg
WO2012170554A1 (fr) * 2011-06-06 2012-12-13 Theodore Mark Kamenecka Modulateurs n-biphénylméthylindole de pparg
CN104788358A (zh) * 2014-01-20 2015-07-22 中国科学院上海药物研究所 N-(3-氟-4-氯苄基)吲哚衍生物及其用途
CN105175309A (zh) * 2015-10-29 2015-12-23 中国科学院上海药物研究所 N-苄基-5/6-甲酰氨基吲哚-2-羧酸衍生物及其用途

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1379774A (zh) * 1999-08-18 2002-11-13 阿斯特拉曾尼卡有限公司 化合物
CN1835914A (zh) * 2003-06-13 2006-09-20 S.A.L.V.A.T.实验室有限公司 作为PPARγ调节剂的新型苯甲酰胺
TW200906400A (en) * 2007-04-05 2009-02-16 Daiichi Sankyo Co Ltd Aryl derivative
WO2012170561A1 (fr) * 2011-06-06 2012-12-13 The Scripps Research Institute (T.S.R.I.) Modulateurs n-benzylindole du pparg
WO2012170554A1 (fr) * 2011-06-06 2012-12-13 Theodore Mark Kamenecka Modulateurs n-biphénylméthylindole de pparg
CN104788358A (zh) * 2014-01-20 2015-07-22 中国科学院上海药物研究所 N-(3-氟-4-氯苄基)吲哚衍生物及其用途
CN105175309A (zh) * 2015-10-29 2015-12-23 中国科学院上海药物研究所 N-苄基-5/6-甲酰氨基吲哚-2-羧酸衍生物及其用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE CAS 8 July 2015 (2015-07-08), retrieved from STN Database accession no. 1797055-09-4 *

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