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WO2009123164A1 - Dérivé hétérocyclique ayant une activité inhibitrice sur la lipase endothéliale - Google Patents

Dérivé hétérocyclique ayant une activité inhibitrice sur la lipase endothéliale Download PDF

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Publication number
WO2009123164A1
WO2009123164A1 PCT/JP2009/056598 JP2009056598W WO2009123164A1 WO 2009123164 A1 WO2009123164 A1 WO 2009123164A1 JP 2009056598 W JP2009056598 W JP 2009056598W WO 2009123164 A1 WO2009123164 A1 WO 2009123164A1
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Prior art keywords
substituted
unsubstituted
compound
pharmaceutically acceptable
solvate
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PCT/JP2009/056598
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English (en)
Japanese (ja)
Inventor
泰彦 神田
仁美 荒木
恭平 林
直樹 大森
典一 黒田
士郎 木田
Original Assignee
塩野義製薬株式会社
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Publication of WO2009123164A1 publication Critical patent/WO2009123164A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/10—Drugs 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

Definitions

  • the present invention relates to a compound having a vascular endothelial lipase (Endothelial Lipase, hereinafter referred to as EL) inhibitory activity and useful as a medicine.
  • EL vascular endothelial lipase
  • HDLc coronary artery disease
  • CAD coronary artery disease
  • HDLc is considered to exhibit an anti-arteriosclerosis action through an antioxidant action, an anti-inflammatory action, a reverse cholesterol transfer action, and the like, and hypoHDLcemia is recognized as one of the risk factors of CAD.
  • Endothelial Lipase (EL) is a Triglyceride Lipase family along with Lipoprotein Lipase (LPL) and Hepatic Lipase (HL), and its strong phospholipase activity is involved in the metabolism of HDLc from the analysis of knockout mice and transgenic mice. It becomes clear and has attracted attention as a factor that defines the amount of blood HDLc.
  • Non-Patent Document 1 Therefore, there is a possibility that an EL inhibitor may be a CAD therapeutic agent through an increase in HDLc, and it has been reported that a diseased mouse that actually knocked out EL has an increase in HDLc and a decrease in atherosclerotic lesion sites.
  • Non-Patent Document 2 These findings suggest the possibility of EL selective inhibitors as therapeutic agents for dyslipidemia or arteriosclerosis.
  • Patent Document 1 describes a derivative in which the 2-position of thiazole is substituted with an acetyl group or a secondary alcohol as a compound useful as a therapeutic agent for hyperTGemia, an anti-obesity agent, or a hyperlipidemia. Yes. Examples 57 and 79 of the patent document disclose derivatives in which the 2-position of thiazole is substituted with a trifluoroacetyl group, the 4-position is substituted with a cycloalkyl group, and the 5-position is substituted with an aryl group. .
  • Patent Document 1 discloses the results of a blood triglyceride concentration lowering effect and a body weight gain suppressing effect using rats, but does not describe a vascular endothelial lipase inhibitory action or an HDLc raising action.
  • Patent Document 2 discloses a derivative in which the 2-position of thiazole is substituted with a trifluoroacetyl group as a compound useful for an anticancer agent.
  • Patent Document 3 discloses a derivative in which the 2-position of thiazole is substituted with a trifluoroacetyl group as a compound useful as an Alzheimer's therapeutic agent.
  • Non-Patent Documents 3, 4, 5, and 6 disclose derivatives in which the 2-position of imidazole is substituted with a trifluoroacetyl group or a difluoroacetyl group, but do not describe the vascular endothelial lipase inhibitory action.
  • Patent Documents 4, 5, 6, 7 and 8 disclose derivatives in which the 2-position of imidazole is substituted with a trifluoroacetyl group as compounds useful as anti-inflammatory agents.
  • Patent Documents 9, 10 and 11 disclose compounds useful as hepatic lipase and / or endothelial lipase inhibitors, but do not disclose derivatives having a trifluoroacetyl group such as the compounds of the present invention.
  • Patent Document 12 includes triglyceride lipase, lipoprotein lipase, hepatic lipase, Compounds useful for pancreatic lipase and endothelial lipase inhibitors are disclosed, but derivatives having a trifluoroacetyl group such as the compound of the present invention are not disclosed.
  • Patent Documents 13 to 21 disclose compounds useful as EL inhibitors, but do not disclose derivatives having a trifluoroacetyl group such as the compounds of the present invention.
  • An object of the present invention is to provide an excellent vascular endothelial lipase inhibitor.
  • the present invention (1) Formula (I): (Where Z is a nitrogen-containing heterocycle, R 1 is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl Substituted or unsubstituted heterocycle, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted alkylsilyloxy, substituted or unsubstituted Substituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted al
  • R 1 is substituted or unsubstituted cycloalkyl, D is a single bond, and E is substituted or unsubstituted aryl.
  • thiazolyl R 1 is substituted or unsubstituted aryl, D is a single bond, and E is substituted or unsubstituted cycloalkyl, Z is imidazolyl, and R 1 is substituted or unsubstituted Except for substituted aryl, D is a single bond, and E is substituted or unsubstituted aryl.
  • R 1 is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkenyl Substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted alkylsilyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted Acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alky
  • Formula (I) The compound represented by Formula (III): (Where X is ⁇ N—, ⁇ CH— or ⁇ CR 1 — (where Y, A, B, D, E and R 1 have the same meanings as (1) above).
  • Y is —O— or —S—;
  • B is —CF 2 —R 3 , R 3 is hydrogen, halogen or substituted or unsubstituted alkyl;
  • D is a single bond, -O -, - (CR 4 R 5) m-O -, - O- (CR 6 R 7) n -, - S -, - (CR 8 R 9) p-S -, - S- (CR 10 R 11 ) q-, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heterocyclic diyl, E is substituted or unsubstituted alkyl, substituted or unsubstitute
  • the pharmaceutical composition containing the compound of the present invention is a pharmaceutical, particularly hyperlipidemia, arteriosclerosis, atherosclerosis, hypercholesterolemia, hypertriglyceridemia. It is very useful as a medicament for the treatment and / or prevention of diabetes, obesity and / or syndrome X.
  • the compound of the present invention selectively inhibits vascular endothelial lipase and has high selectivity for hepatic lipase (Hepatic Lipase) and pancreatic lipase (Pancreatic Lipase). In addition, it is a compound having utility as a medicine.
  • a point, a point with a small clearance, or a point having a sufficiently long half-life for exhibiting a medicinal effect are included.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Alkyl means a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert -Butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • alkyl having 1 to 6 or 1 to 4 carbon atoms for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso Examples include pentyl, neopentyl, n-hexyl, and isohexyl.
  • Alkenyl means a linear or branched alkenyl having 2 to 8 carbon atoms having one or more double bonds to the above “alkyl”, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl and the like can be mentioned.
  • Alkynyl means a linear or branched alkynyl having 2 to 8 carbon atoms having one or more triple bonds to the above “alkyl”, and examples thereof include ethynyl, propynyl, butynyl and the like. Can be mentioned. Furthermore, it may have one or more double bonds.
  • Cycloalkyl means a cyclic saturated hydrocarbon group having 3 to 15 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclic hydrocarbon group, spiro hydrocarbon. Groups and the like. Preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a bridged cyclic hydrocarbon group are used.
  • “Bridged cyclic hydrocarbon group” includes a group formed by removing one hydrogen from an aliphatic ring having 5 to 8 carbon atoms in which two or more rings share two or more atoms. To do. Specifically, bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and bicyclo [3.2.1] octyl, tricyclo [2.2. 1.0] heptyl and the like.
  • the “spiro hydrocarbon group” includes a group formed by removing one hydrogen from a ring in which two hydrocarbon rings share one carbon atom. Specific examples include spiro [3.4] octyl.
  • Cycloalkenyl means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 7 carbon atoms, and examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, preferably cyclopropenyl, cyclobutenyl. , Cyclopentenyl and cyclohexenyl. Cycloalkenyl also includes bridged cyclic hydrocarbon groups and spiro hydrocarbon groups having an unsaturated bond in the ring.
  • Aryl means a monocyclic aromatic hydrocarbon group (eg, phenyl) and a polycyclic aromatic hydrocarbon group (eg, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1 -Phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl and the like.
  • Heteroaryl means a monocyclic aromatic heterocyclic group and a condensed aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group is a substitutable optional group derived from a 5- to 8-membered aromatic ring which may contain 1 to 4 oxygen, sulfur and / or nitrogen atoms in the ring. Means a group which may have a bond at the position.
  • the fused aromatic heterocyclic group has 1 to 4 5 to 8 5 to 8 membered aromatic rings which may contain 1 to 4 oxygen, sulfur and / or nitrogen atoms in the ring. It means a group which may have a bond at any substitutable position which is fused with a member aromatic carbocyclic ring or other 5- to 8-membered aromatic heterocycle.
  • heteroaryl examples include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl).
  • Imidazolyl eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl
  • pyrazolyl eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl
  • triazolyl eg, 1,2,4-triazole-1-) Yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl
  • tetrazolyl eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl
  • oxazolyl eg 2- Oxazolyl, 4-oxazolyl, 5-oxazolyl
  • isoxazolyl eg 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl) Lyl
  • thiazolyl eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl
  • thiadiazolyl isothiazolyl (eg 3-isothi
  • Heterocycle refers to a non-aromatic group that may contain 1 to 4 oxygen, sulfur and / or nitrogen atoms in the ring, and may have a bond at any substitutable position. Means a heterocyclic group. Further, such a non-aromatic heterocyclic group may be further bridged with an alkyl chain having 1 to 4 carbon atoms, and a cycloalkane (preferably a 5- to 6-membered ring) or a benzene ring may be condensed. Good. If it is non-aromatic, it may be saturated or unsaturated. A 5- to 8-membered ring is preferred.
  • Acyl refers to formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, By substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heterocyclecarbonyl is meant.
  • Alkylene includes a divalent group of 1 to 6 consecutive methylenes, and specifically includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • Alkenylene includes a divalent group in which 2 to 6 methylenes are continuous and at least one carbon-carbon bond is a double bond.
  • Alkynylene includes a divalent group in which 2 to 6 methylenes are continuous and at least one of carbon-carbon bonds is a triple bond.
  • Heterocyclic diyl includes a divalent group formed by removing one hydrogen atom from the above “heteroaryl”.
  • alkenyl part of “substituted or unsubstituted alkenylcarbonyl” means the above “alkenyl”.
  • the cycloalkyl part of “substituted or unsubstituted cycloalkylcarbonyl” means the above “cycloalkyl”.
  • the cycloalkenyl part of “substituted or unsubstituted cycloalkenylcarbonyl” means the above “cycloalkenyl”.
  • the aryl part of “substituted or unsubstituted arylalkyl”, “substituted or unsubstituted arylsulfonyl”, “substituted or unsubstituted arylcarbonyl” and “substituted or unsubstituted aryloxy” means the above “aryl” To do.
  • the heteroaryl part of “substituted or unsubstituted heteroarylcarbonyl” means the above “heteroaryl”.
  • the heterocycle part of “substituted or unsubstituted heterocyclecarbonyl” means the above “heterocycle”.
  • the “nitrogen-containing heterocyclic ring” means a ring having at least one N in the ring and further may have O, S, N (R 2 ).
  • the ring includes a single ring or a condensed ring, and may be an aromatic heterocyclic ring or a non-aromatic heterocyclic ring. For example, the following are mentioned. (Here, R 2 has the same meaning as described above.)
  • substituents of “substituted or unsubstituted amino”, “substituted or unsubstituted carbamoyl”, and “substituted or unsubstituted sulfamoyl” include alkyl, alkenyl, aryl, heteroaryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl , Heterocyclecarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocycleoxycarbonyl, sulfamoyl, alkylsulfonyl, carbamoyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclesulfonyl, hydroxy, sulfonyl, sulfinyl , Amino and the like.
  • aryl part of “aryloxycarbonyl” means the above “aryl”.
  • heteroaryl part of “heteroaryloxycarbonyl” means the above “heteroaryl”.
  • heterocycle part of “heterocycleoxycarbonyl” means the above “heterocycle”.
  • Alkylsilyloxy means a silyloxy group substituted with 1 to 3 alkyl groups. For example, tert-butyldimethylsilyloxy and the like are included.
  • Examples of Z include nitrogen-containing heterocycles.
  • the following rings are mentioned.
  • R 2 has the same meaning as described above.
  • the following rings are preferable.
  • R 2 has the same meaning as described above.
  • More preferably, the following rings are mentioned. (Here, R 2 has the same meaning as described above.)
  • r examples include an integer of 0 to 3. Preferably, it is 0 or 1. Particularly preferred is 0.
  • R 1 is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted alkylsilyloxy, substituted Or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfony
  • halogen hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkenyl Substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted alkylsilyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted Acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkyloxycarbamoyl, substituted or unsubstit
  • Y includes —O—, —S—, —NR 2 — or ⁇ N—. Preferred is —O— or —S—.
  • R 2 includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkyloxycarbonyl, or substituted or unsubstituted acyl. Preferably, it is hydrogen or substituted or unsubstituted alkyl.
  • B includes —CF 2 —R 3 or —CN. Preferred is —CF 2 —R 3 .
  • R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Examples include alkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle. Preferably, it is hydrogen, halogen or substituted or unsubstituted alkyl. Halogen is particularly preferable, and fluorine is used.
  • a single bond —O—, — (CR 4 R 5 ) m—O—, —O— (CR 6 R 7 ) n—, —S—, — (CR 8 R 9 ) p—S—, -S- (CR 10 R 11 ) q-, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, or substituted or unsubstituted heterocyclic diyl.
  • — (CR 4 R 5 ) m—O—, — (CR 8 R 9 ) p—S—, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene are preferable.
  • R 4 to R 11 each independently include hydrogen, halogen, or substituted or unsubstituted alkyl. Preferably, it is hydrogen.
  • R 12 includes hydrogen or substituted or unsubstituted alkyl. Preferably, it is hydrogen.
  • n, p and q each independently represents an integer of 1 to 5.
  • each is independently 1 to 3.
  • E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or Examples include unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkyloxycarbonyl.
  • substituted or unsubstituted alkyl substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted carbamoyl, substituted or Unsubstituted amino, substituted or unsubstituted alkoxy or substituted or unsubstituted alkyloxycarbonyl.
  • E is preferably the following substituents.
  • R a has the same meaning as in the above (16), and b is an integer of 1 to 3.
  • b is preferably an integer of 1 or 2. More preferably, E includes the following substituents. (Here, Ra is as defined in (16) above.)
  • R a is halogen, hydroxy, carboxy, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted alkylsilyloxy, substituted Or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfon
  • halogen substituted or unsubstituted alkyl, cyano, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, Substituted or unsubstituted silyloxy, hydroxy, substituted or unsubstituted alkyloxycarbonyl or substituted or unsubstituted heterocycle.
  • substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted silyloxy, hydroxy or substituted or unsubstituted Substituted alkyloxycarbonyl is preferred.
  • particularly preferable substituents of “substituted or unsubstituted alkyl” in R a include halogen.
  • Particularly preferred substituents for “substituted or unsubstituted aryl” for R a include cyano.
  • substituents of “substituted or unsubstituted amino” in R a include acyl, arylsulfonyl, alkyloxycarbonyl, and alkylsulfonyl.
  • Particularly preferred substituents of “substituted or unsubstituted alkoxy” in R a include aryl, heterocycle, cycloalkyl, arylthio, and alkoxy.
  • Examples of the pharmaceutically acceptable salt of the compound of the present invention include the following salts.
  • Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt , Triethanolamine salt, procaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt or other aliphatic amine salt; N, N-dibenzylethylenediamine, venetamine salt or other aralkylamine salt; pyridine salt, picoline salt, quinoline salt, isoquinoline Heterocyclic aromatic amine salts such as salts; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt
  • the acid salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate; Examples include acidic amino acids such as aspartate and glutamate.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate
  • acetate, propionate, lactate maleate
  • Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate
  • sulfonates such as methanesulfonate, isethionate, benzen
  • the solvate means a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof, and examples thereof include alcohol (eg, ethanol) solvate and hydrate.
  • examples of the hydrate include monohydrate, dihydrate and the like.
  • the general production method of the compound of the present invention is exemplified below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment. (When Z is a monocyclic nitrogen-containing heterocycle) (In the formula, each symbol has the same meaning as described above, and the compound represented by the formula (II′-1) may be a known compound or a compound derived from a known compound by a conventional method. “LG” means a leaving group, and includes halogen, —OMs, —OTs, —OTf, —ONs, etc.
  • Ms is a methanesulfonyl group
  • Ts is a paratoluenesulfonyl group
  • Tf represents a trifluoromethanesulfonyl group
  • Ns represents an orthonitrobenzenesulfonyl group
  • ak represents an alkyl having 1 to 3 carbon atoms.
  • First Step This is a step for producing an isothiocyanate represented by the formula (II′-2) from a compound represented by the formula (II′-1). It can be synthesized according to the method described in WO96 / 17850.
  • Second Step The second step is a step for producing a compound represented by the formula (II′-3) by hydrolyzing a compound represented by the formula (II′-2).
  • Reaction solvents include N, N-dimethylformamide, dimethyl sulfoxide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), halogenated hydrocarbons ( Examples, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (eg, methyl acetate, ethyl acetate, etc.), ketones (Eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), alcohols (eg, methanol, ethanol, t-butanol, etc.), water and a mixed solvent thereof.
  • Examples of the base include metal hydrides (eg, sodium hydride), metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonates (eg, sodium carbonate) , Calcium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), sodium hydrogen carbonate, metallic sodium, organic amine (eg, triethylamine, diisopropylethylamine, DBU, 2, 6-lutidine, etc.), pyridine, alkyl lithium (n-BuLi, sec-BuLi, tert-BuLi) and the like.
  • metal hydrides eg, sodium hydride
  • metal hydroxides eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide
  • metal carbonates eg, sodium carbonate
  • Calcium carbonate calcium carbonate
  • cesium carbonate etc
  • an ether eg, tetrahydrofuran, diethyl ether, dioxane, etc.
  • a metal hydroxide eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.
  • the reaction may be performed at ⁇ 78 to 30 ° C. for 0.5 to 24 hours.
  • the compound represented by the formula (II′-3) is reacted with the compound represented by the formula (E-LG) to produce the compound represented by the formula (II′-4).
  • the reaction solvent the solvent described in Step 2 can be used.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • N, N-dimethylformamide may be used.
  • the base the base described in Step 2 can be used.
  • a metal carbonate eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • the reaction may be performed at ⁇ 10 to 30 ° C. for 0.5 to 24 hours.
  • Examples of the compound represented by the formula (E-LG) include benzyl bromide.
  • Step 2 A compound represented by the formula (II′-4) and a compound represented by the formula: AB—O-ak or a compound represented by the formula: A—B—O—B—A in the presence of a base
  • a solvent the solvent described in Step 2 can be used.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • alkyl lithium n-BuLi, sec-BuLi, tert-BuLi
  • the reaction may be performed at ⁇ 78 to 30 ° C.
  • Examples of the compound represented by the formula: AB—O-ak include ethyl trifluoroacetate.
  • Examples of the compound represented by the formula: AB—O—B—A include (CF 3 CO) 2 O.
  • each symbol has the same meaning as described above, and the compound represented by the formula (II′-5) may be a known compound or a compound derived from a known compound by a conventional method.
  • the above scheme is another method for synthesizing the compound represented by the formula (II′-2).
  • Fifth step is a step of producing a compound represented by the formula (II'-6) from a compound represented by the formula (II'-5). It can be synthesized according to the method described in WO96 / 17850.
  • Sixth step is a step of producing a compound represented by the formula (II'-2) from a compound represented by the formula (II'-6). It can be synthesized according to the method described in WO2004 / 067532. (Wherein each symbol has the same meaning as described above, and the compound represented by the formula (II′-7) may be a known compound or a compound derived from a known compound by a conventional method)
  • LG means a leaving group, and includes halogen, —OMs, —OTs, —OTf, —ONs, etc.
  • Ms is a methanesulfonyl group
  • Ts is a paratoluenesulfonyl group
  • Tf represents a trifluoromethanesulfonyl group
  • Ns represents an orthonitrobenzenesulfonyl group.
  • a compound represented by the formula (II′-7) is reacted with a compound represented by the formula: EDH or a compound represented by the formula: EDB (OH) 2 in the presence of a palladium catalyst.
  • the compound represented by the formula (II′-8) is produced.
  • the reaction solvent the solvent described in Step 2 can be used.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • water e.g., water, and a mixed solvent thereof may be used.
  • the reaction is performed using a microwave, the reaction can be performed under conditions that do not use a solvent.
  • the base the base described in Step 2 can be used.
  • a metal carbonate eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • an organic amine eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.
  • the reaction is carried out at the temperature at which the solvent used refluxes in the presence of a palladium catalyst (eg Pd (PPh 3 ) 4 , PdCl 2 , Pd (dba) 2 etc.) and a phosphine ligand (eg PPh 3 , BINAP etc.).
  • a palladium catalyst eg Pd (PPh 3 ) 4 , PdCl 2 , Pd (dba) 2 etc.
  • a phosphine ligand eg PPh 3 , BINAP etc.
  • Examples of the compound represented by the formula: EDH include ethynylacetylene. Examples of the compound represented by the formula: EDB (OH) 2 include styrylboronic acid.
  • Eighth step is a step of producing a compound represented by the formula (II-2) from a compound represented by the formula (II′-8).
  • the reaction may be performed under the conditions described in Step 4. (Wherein each symbol has the same meaning as described above, and the compound represented by the formula (II′-9) may be a known compound or a compound derived from a known compound by a conventional method) (The above scheme is an alternative method when Z is an oxazole ring.)
  • the ninth step is a step of reacting a compound represented by the formula (II′-9) with Tosmic (tosylmethyl isocyanide) to produce a compound represented by the formula (II′-10).
  • the solvent the solvent described in Step 2 can be used.
  • alcohols eg, methanol, ethanol, t-butanol, etc.
  • the base the base described in Step 2 can be used.
  • a metal carbonate eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • the reaction may be carried out at a temperature from 30 ° C. to the reflux temperature of the solvent used for 0.5 to 12 hours.
  • the tenth step is a step of producing a compound represented by the formula (II-3) from a compound represented by the formula (II'-10).
  • the reaction may be performed under the conditions described in Step 4.
  • each symbol is as defined above, and the compound represented by the formula (III′-1) may be a known compound, or a compound derived from a known compound by a conventional method may be used.
  • “Ak” means alkyl having 1 to 3 carbon atoms.
  • Eleventh step is a step of producing a compound represented by the formula (III'-2) from a compound represented by the formula (III'-1) by Horner-Wadsworth-Emmons reaction.
  • the reaction solvent the solvent described in Step 2 can be used.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • the base the base described in Step 2 can be used.
  • metal alkoxide eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.
  • metal hydride eg, sodium hydride, etc.
  • the reaction may be performed at ⁇ 20 to 40 degrees for 0.5 to 12 hours.
  • Twelfth step is a step of producing a compound represented by the formula (III-1) from a compound represented by the formula (III'-2).
  • the reaction may be performed under the conditions described in Step 4.
  • Z is a bicyclic nitrogen-containing heterocyclic ring
  • each symbol is as defined above, and the compound represented by the formula (I′-1) may be a known compound, or a compound derived from a known compound by a conventional method may be used.
  • “Ak” means alkyl having 1 to 3 carbon atoms.
  • Thirteenth step is a step of producing a compound represented by formula (I'-2) from a compound represented by formula (I'-1).
  • a substituent represented by the formula: -DE may be introduced.
  • Step 14 This is a step for producing a compound of formula (I-1) from a compound of formula (I′-2).
  • the reaction may be performed under the conditions described in Step 4.
  • the group represented by the formula: -AB can be introduced before the group represented by the formula: -DE is introduced.
  • LG means a leaving group, and includes halogen, —OMs, —OTs, —OTf, —ONs, etc.
  • Ms is a methanesulfonyl group
  • Ts is a paratoluenesulfonyl group
  • Tf represents a trifluoromethanesulfonyl group
  • Ns represents an orthonitrobenzenesulfonyl group.
  • Step 7 ′ This is a step of producing a compound represented by the formula (II′-8 ′) from a compound represented by the formula (II′-7).
  • the reaction may be performed under the conditions described in Step 8.
  • Step 8 ′ This is a step of producing a compound represented by the formula (II-2) from a compound represented by the formula (II′-8 ′).
  • the reaction may be performed under the conditions described in Step 7.
  • Fifteenth step is a step of producing a compound represented by the formula (I'-4) from a compound represented by the formula (I'-3).
  • a substituent represented by the formula: -B may be introduced into the formyl group (carbonyl group) of the compound represented by the formula (I'-3) by a nucleophilic reaction.
  • Sixteenth step is a step of producing a compound represented by the formula (I-1) by oxidizing a compound represented by the formula (I′-4). For example, it may be performed under conditions such as Jones oxidation, Collins oxidation, PCC oxidation, MnO 2 oxidation, and Swern oxidation.
  • the compound of the present invention includes the following carbonyl compounds and hydrates.
  • the carbonyl compound may be partially or wholly hydrated after synthesis to form a hydrate.
  • the compound of the present invention is present as a carbonyl compound.
  • the compound of the present invention has excellent vascular endothelial lipase inhibitory activity. Therefore, it can be used for the treatment or prevention of diseases involving vascular endothelial lipase, particularly diseases such as hyperlipidemia, diabetes, obesity, arteriosclerosis, atherosclerosis and / or syndrome X. In particular, it is useful in the treatment or prevention of hyperlipidemia, arteriosclerosis and dyslipidemia.
  • the compound used in the present invention can be administered orally or parenterally.
  • the compound used in the present invention is a usual preparation, for example, solid preparations such as tablets, powders, granules, capsules; liquid preparations; oil suspensions; or liquid preparations such as syrups or elixirs. It can be used also as any dosage form.
  • the compound used in the present invention can be used as an aqueous or oily suspension injection or nasal solution.
  • conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like can be arbitrarily used.
  • Formulations of the compounds used in the present invention are prepared by combining (eg, mixing) a therapeutically effective amount of a compound used in the present invention with a pharmaceutically acceptable carrier or diluent.
  • the preparation of the compound used in the present invention is produced by a known method using well-known and readily available components.
  • the dose of the compound used in the present invention varies depending on the administration method, the patient's age, weight, condition, and type of disease, but usually about 0.05 mg to 3000 mg per day for an adult when administered orally, preferably May be administered in an amount of about 0.1 mg to 1000 mg divided if necessary. In the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg is administered per day for an adult. In administration, it can be used in combination with other therapeutic agents.
  • Compound 2 was synthesized from 2-aminothiazole 1 according to the method described in WO96 / 17850.
  • Compound 3 was synthesized from 2-amino-5-thiocyanate thiazole 2 according to the method described in WO2004 / 067532.
  • a solution of 1.00 g (7.03 mmol) of 5-thiocyanate thiazole 3 in anhydrous THF was ice-cooled, 1.41 ml (7.03 mmol) of 5M NaOH aqueous solution was added, and the mixture was stirred for 15 minutes under ice cooling.
  • n-BuLi (7.1 mL, 11.4 mmol, 1.5M solution in nHexane) was added to a solution of dodecane-1-thiol (2.72 mL, 11.4 mmol) in HMPA (4 mL). After stirring at room temperature for 10 minutes, Compound 11 (1.24 g, 5.71 mmol) was added, and the mixture was stirred at 80 ° C. for 2 hours. Water was added to the reaction solution, and the temperature was raised to room temperature, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate.
  • E Ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate 24
  • Ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate 24 Ethylylbenzene 69mg (0.68mmol), PdCl2 (PPh3) 2 36.4mg (0.05mmol), Copper iodide in 100ml (0.52mmol) DMF 1ml solution 14.8 mg (0.078 mmol) and triethylamine 220 ⁇ l (1.56 mmol) were added, and the mixture was reacted at 100 ° C. for 20 minutes using a microwave reactor.
  • Hard gelatin capsules are manufactured using the following ingredients: Dose (mg / capsule) Active ingredient 250 Starch (dried) 200 Magnesium stearate 10 Total 460mg
  • Tablets are manufactured using the following ingredients: Dose (mg / tablet) Active ingredient 250 Cellulose (microcrystal) 400 Silicon dioxide (fume) 10 Stearic acid 5 665mg total The ingredients are mixed and compressed into tablets each weighing 665 mg.
  • Aerosol solution is prepared containing the following ingredients: weight Active ingredient 0.25 Ethanol 25.75 Propellant 22 (chlorodifluoromethane) 74.00 Total 100.00
  • the active ingredient and ethanol are mixed and this mixture is added to a portion of the propellant 22, cooled to -30 ° C and transferred to a filling device. The required amount is then fed into a stainless steel container and diluted with the remaining propellant. Attach the bubble unit to the container.
  • a tablet containing 60 mg of active ingredient is prepared as follows: Active ingredient 60mg 45mg starch Microcrystalline cellulose 35mg Polyvinylpyrrolidone (10% solution in water) 4mg Sodium carboxymethyl starch 4.5mg Magnesium stearate 0.5mg Talc 1mg 150mg total The active ingredients, starch, and cellulose are no. 45 mesh U.F. S. And mix well. An aqueous solution containing polyvinylpyrrolidone was mixed with the obtained powder, and the mixture was 14 mesh U.S. S. Pass through a sieve. The granules thus obtained were dried at 50 ° C. 18 mesh U.F. S. Pass through a sieve. No. 60 mesh U.S. S. Sodium carboxymethyl starch, magnesium stearate, and talc passed through a sieve are added to the granules, mixed and then compressed on a tablet press to obtain tablets each weighing 150 mg.
  • Capsules containing 80 mg of active ingredient are prepared as follows: Active ingredient 80mg Starch 59mg Microcrystalline cellulose 59mg Magnesium stearate 2mg Total 200mg Mix the active ingredient, starch, cellulose and magnesium stearate; 45 mesh U.F. S. Through the sieve and filled into hard gelatin capsules 200 mg each.
  • a suppository containing 225 mg of active ingredient is prepared as follows: Active ingredient 225mg Saturated fatty acid glyceride 2000mg Total 2225mg The active ingredient is No. 60 mesh U.S. S. And suspended in a saturated fatty acid glyceride that has been heated and melted to the minimum necessary. The mixture is then cooled in an apparent 2 g mold.
  • a suspension containing 50 mg of active ingredient is prepared as follows: Active ingredient 50mg Sodium carboxymethylcellulose 50mg Syrup 1.25ml Benzoic acid solution 0.10ml Fragrance q. v. Dye q. v. 5ml in total with purified water The active ingredient is No. 45 mesh U.F. S. And is mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. Add the benzoic acid solution and perfume diluted with a portion of the water and stir. Then add a sufficient amount of water to the required volume.
  • the intravenous formulation is manufactured as follows: Active ingredient 100mg Saturated fatty acid glyceride 1000ml Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.
  • the compound according to the present invention exhibits vascular endothelial lipase inhibitory action. Therefore, the compound according to the present invention is very useful as a therapeutic agent for dyslipidemia, a therapeutic agent for hyperlipidemia, and a therapeutic agent for arteriosclerosis.

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Abstract

L'invention porte sur un composé utile comme inhibiteur de lipase endothéliale. Plus précisément, l'invention porte sur un composé représenté par la formule, sur un sel de qualité pharmaceutique de celui-ci, ou sur un solvate du composé ou du sel de qualité pharmaceutique. [Dans la formule, Z représente un noyau hétérocyclique azoté; R1 représente un halogène, un hydroxy, un cyano ou autre; r représente un entier de 0 à 3; Y représente -O-, -S-, -NR2- ou =N-; R2 représente un hydrogène, un alkyle substitué ou non substitué ou autre; A représente -C(=O)- ou -C(OH)2-; B représente -CF2-R3 ou –CN; R3 représente un hydrogène, un halogène, un alkyle substitué ou non substitué ou autre; D représente une liaison simple, -O-, -(CR4R5)m-O-, -O-(CR6R7)n-, -S-, -(CR8R9)p-S-, -S-(CR10R11)q-, -NR12- ou autre; R4 à R11 représentent indépendamment un hydrogène, un halogène ou autre; R12 représente un hydrogène ou un alkyle substitué ou non substitué; m, n, p et q représentent indépendamment un entier de 1 à 5, et E représente un alkyle substitué ou non substitué, un alcényle substitué ou non substitué ou autre.]
PCT/JP2009/056598 2008-04-02 2009-03-31 Dérivé hétérocyclique ayant une activité inhibitrice sur la lipase endothéliale WO2009123164A1 (fr)

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WO2011074560A1 (fr) 2009-12-15 2011-06-23 塩野義製薬株式会社 Dérivé d'oxadiazole ayant une activité d'inhibition de la lipase endothéliale
WO2013049096A1 (fr) 2011-09-27 2013-04-04 Bristol-Myers Squibb Company Composés de pyrrolinone-carboxamide utiles en tant qu'inhibiteurs de lipase endothéliale
WO2013048982A1 (fr) 2011-09-27 2013-04-04 Bristol-Myers Squibb Company Composés de pyrrolinone-carboxamide utiles en tant qu'inhibiteurs de lipase endothéliale
WO2013049104A1 (fr) 2011-09-30 2013-04-04 Bristol-Myers Squibb Company Pyridinedione carboxamides convenant comme inhibiteurs de la lipase endothéliale
WO2013048930A1 (fr) 2011-09-30 2013-04-04 Bristol-Myers Squibb Company Inhibiteurs pyridinedione carboxamide de lipase endothéliale
WO2013048942A1 (fr) 2011-09-30 2013-04-04 Bristol-Myers Squibb Company Inhibiteurs quinoléinone carboxamide de lipase endothéliale
WO2013048928A1 (fr) 2011-09-27 2013-04-04 Bristol-Myers Squibb Company Composés pyrrolinone carboxamide utiles comme inhibiteurs de lipase endothéliale
WO2013151923A1 (fr) 2012-04-03 2013-10-10 Bristol-Myers Squibb Company Pyrimidinone carboxamides en tant qu'inhibiteurs d'une lipase endothéliale
WO2013151877A1 (fr) 2012-04-03 2013-10-10 Bristol-Myers Squibb Company Inhibiteurs à base de pyrimidinedionecarboxamide de lipase endothéliale
WO2014011513A1 (fr) 2012-07-09 2014-01-16 Bristol-Myers Squibb Company Inhibiteurs de lipase endothéliale de type benzothiazole contenant un sulfonyle
WO2014011461A1 (fr) 2012-07-09 2014-01-16 Bristol-Myers Squibb Company Dérivés de benzothiazole substitués par amide ou urée en tant qu'inhibiteurs de lipase endothéliale
WO2014015088A1 (fr) 2012-07-19 2014-01-23 Bristol-Myers Squibb Company Inhibiteurs de lipase endothéliale à base de benzothiazole liés à une amine, l'urée ou un sulfone amide
WO2015105749A1 (fr) 2014-01-07 2015-07-16 Bristol-Myers Squibb Company Composés benzothiazole à liaison amide sulfone utilisés en tant qu'inhibiteurs de la lipase endothéliale
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CN104974116A (zh) * 2014-04-01 2015-10-14 中国科学院昆明植物研究所 韧革菌素酰胺类衍生物及其制备方法与应用
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US8754113B2 (en) 2009-12-15 2014-06-17 Shionogi & Co., Ltd. Oxadiazole derivative having endothelial lipase inhibitory activity
US9249096B2 (en) 2011-09-27 2016-02-02 Bristol-Myers Squibb Company Pyrrolinone carboxamide compounds useful as endothelial lipase inhibitors
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WO2015105749A1 (fr) 2014-01-07 2015-07-16 Bristol-Myers Squibb Company Composés benzothiazole à liaison amide sulfone utilisés en tant qu'inhibiteurs de la lipase endothéliale
CN104974116A (zh) * 2014-04-01 2015-10-14 中国科学院昆明植物研究所 韧革菌素酰胺类衍生物及其制备方法与应用
CN104974117B (zh) * 2014-04-01 2017-12-01 中国科学院昆明植物研究所 韧革菌素二级醇酸酯衍生物及其药物组合物和其应用
CN104974116B (zh) * 2014-04-01 2017-12-01 中国科学院昆明植物研究所 韧革菌素酰胺类衍生物及其制备方法与应用
CN104974117A (zh) * 2014-04-01 2015-10-14 中国科学院昆明植物研究所 韧革菌素二级醇酸酯衍生物及其药物组合物和其应用
WO2017214005A1 (fr) 2016-06-06 2017-12-14 Bristol-Myers Squibb Company Dérivés de 2-(benzothiazol-2-yl)-2-cyano-acétamide et leur utilisation en tant qu'inhibiteurs de la lipase endothéliale
CN114957171A (zh) * 2022-06-21 2022-08-30 广东工业大学 一种新颖五元杂环取代的苯乙烯衍生物及其制备方法和应用
CN114957171B (zh) * 2022-06-21 2024-07-30 广东工业大学 一种新颖五元杂环取代的苯乙烯衍生物及其制备方法和应用

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