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WO2006080406A1 - Composes tricycliques - Google Patents

Composes tricycliques Download PDF

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Publication number
WO2006080406A1
WO2006080406A1 PCT/JP2006/301248 JP2006301248W WO2006080406A1 WO 2006080406 A1 WO2006080406 A1 WO 2006080406A1 JP 2006301248 W JP2006301248 W JP 2006301248W WO 2006080406 A1 WO2006080406 A1 WO 2006080406A1
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Prior art keywords
group
carbon atoms
formula
ring
hydrogen atom
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PCT/JP2006/301248
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English (en)
Japanese (ja)
Inventor
Minoru Taguchi
Ryo Suzuki
Ayako Mikami
Koji Yamamoto
Takumi Sekine
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Taisho Pharmaceutical Co., Ltd.
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Publication of WO2006080406A1 publication Critical patent/WO2006080406A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/84—Naphthothiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/74—Naphthothiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel tricyclic compound. Specifically, it is a novel tricyclic compound that suppresses the expression of SREBP-lc. More specifically, by suppressing the expression of SREBP-lc, it has the effect of lowering triglycerides in the liver and lowering blood glucose levels, resulting in diabetes, hyperlipidemia, fatty liver, obesity, glucose intolerance, diabetic complications (Eg, nephropathy, neuropathy, retinopathy, etc.), metabolic syndrome, and syndrome X
  • SREBPs are transcription factors belonging to the basic helix loop one helix bite icin zipper (bHLH-Zip) family.
  • SRE sterol regulatory element
  • SREBP-la SREBP-la
  • lc SREBP-1 and SREBP-2
  • SREBP-1 and SREBP-2 show about 47% amino acid homology.
  • SREBP-lc is a repo-enzyme gene group related to synthesizing a fatty acid such as acety ⁇ CoA carb oxylase, fatty acia synthase ⁇ glycerol- «3-phosphate phosphatetransferase
  • SREBP-2 is HMG-CoA reductase, LDL receptor It has been reported that cholesterol metabolism-related genes such as SREBP-la are involved in both of these transcriptional controls (Non-patent Document 2).
  • SREBP-la and SREBP-lc are regulated by different promoters existing in the same gene. Due to this alternative splicing, the first exon is expressed as a different isoform, and SREBP-la has a longer region bound to acidic amino acids, which are transcriptional active domains located on the N-terminal side than SREBP-lc. It has strong transcriptional activity and induces not only fatty acid synthesis system but also cholesterol synthesis system.
  • SREBP-la is a highly expressed medium in lymphoid tissues such as spleen and thymus, and mucosal epithelium of the intestinal tract. Expression is elevated in highly proliferative cells such as feeder cells, and it is thought that lipids required for division are supplied. In tissues such as the liver, SREBP-lc is expressed more than REBP-la, and it is known to play a role as a master regulator of the reposienic enzyme responsible for fatty acid synthesis. (Non-Patent Document 3)
  • Nicotinic acid preparations, fibrates and the like exist as compounds having a triglyceride lowering action.
  • nicotinic acid preparations are known to rather deteriorate glucose tolerance, and for fibrate drugs, bezafibrate improves insulin resistance, resulting in hypoglycemic effects such as sulfonylurea drugs used in combination.
  • hypoglycemic effects such as sulfonylurea drugs used in combination.
  • sulfo-urea drugs As compounds having hypoglycemic activity, sulfo-urea drugs, thiazolidine derivatives, biguanides, darcosidase inhibitors, etc. are present. Other than thiazolidine derivatives have action on lipids! ,. Thiazolidine derivatives are known as compounds having a triglyceride lowering action and a blood glucose level lowering action, but all have a chemical structure different from that of the compound of the present invention.
  • Non-Patent Document 1 Brown, M.S., et al., Cell, 89, 331-40 (1997)
  • Non-Patent Document 2 Horton, J.D., et al., J. Clin. Invest., 101, 2331-9 (1998)
  • Non-Patent Document 3 Shimano, H “et al, J. Biol. Chem., 274, 35832-35839 (1999)
  • Non-Patent Document 4 Shimomura, I., et al" Genes Dev., 12, 3182-94 ( 1998)
  • Non-Patent Document 5 Hasty, A.H., et al "J. Biol. Chem., 275, 31069-31077 (2000) Disclosure of the Invention
  • R 1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • a ring is represented by the following formula:
  • R 2 is a hydroxyalkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 6 carbon atoms, an amide group having 1 to 10 carbon atoms (provided that N, O-dimethylhydroxy And a nitrile group, an alkyl group having 1 to 6 carbon atoms, an amino group, an acylamino group having 2 to 6 carbon atoms, or a hydroxyiminoalkyl group having 1 to 6 carbon atoms.)
  • ring B is represented by the following formula: [0017] [Chemical 3]
  • R 3 and R 4 independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a substituted alkoxy having 1 to 6 carbon atoms.
  • W represents the formula -CH- or the formula-(CH)-.
  • a ring represents Formula A-1
  • R 2 represents an alkyl group having 1 to 6 carbon atoms or an acyl group having 2 to 6 carbon atoms
  • W represents the formula —CH—
  • R 1 represents hydrogen.
  • An atom and the B ring is of the formula B-
  • R 3 and R 4 are not hydrogen compounds, alkyl groups having 1 to 6 carbon atoms, and compounds having 1 to 6 carbon atoms.
  • Ring A represents Formula A-1
  • R 2 represents an amide group having 1 to 10 carbon atoms (excluding N, O-dimethylhydroxycarboxamide group) or -tolyl group, and W is- CH-
  • R 1 represents a hydrogen atom
  • ring B represents formula B-1.
  • R 3 and R 4 are not hydrogen compounds. Or a pharmaceutically acceptable salt thereof.
  • the A ring is the formula A-1
  • R 2 is a hydroxyalkyl group having 1 to 6 carbon atoms
  • W is the formula -CH 2-
  • the B ring is the formula B-1.
  • R 1 is a hydrogen atom or a carbon atom number 1 to 6
  • R 1 is a hydrogen atom
  • R 3 and R 4 are substituted alkoxy groups having 1 to 6 carbon atoms
  • R 1 is an alkyl group having 1 to 6 carbon atoms
  • R 3 and R 4 are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a substituted alkoxy group having 1 to 6 carbon atoms, represented by the above formula (I).
  • Compound or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt thereof.
  • the A ring is the formula A-1
  • R 2 is an acyl group
  • W is —CH 2 —
  • the B ring is the formula A-1
  • R 2 is an acyl group
  • W is —CH 2 —
  • R 1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • R 1 is a hydrogen atom
  • R 3 and R 4 are independently a cetoxy group or a carbon atom.
  • R 1 is a substituted alkoxy group having 1 to 6 carbon atoms
  • R 1 is an alkyl group having 1 to 6 carbon atoms
  • R 3 and R 4 are independently A tricyclic compound represented by the above formula (I), which is an elementary atom, an alkyl group having 1 to 6 carbon atoms, an acetoxy group, or a substituted alkoxy group having 1 to 6 carbon atoms, or a pharmaceutically acceptable product thereof. It is a salt.
  • the present invention is a SREBP-lc expression inhibitor comprising as an active ingredient a tricyclic compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention is a triglyceride lowering agent comprising as an active ingredient a tricyclic compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention is also a blood glucose level-lowering agent comprising as an active ingredient a tricyclic compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides diabetes, hyperlipidemia, fatty liver, obesity, which comprises a tricyclic compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Glucose intolerance, diabetic complications Glucose intolerance, diabetic complications
  • the present invention is also a triglyceride lowering agent that also has a compound power having an SREBP-lc expression inhibitory action.
  • the present invention is also a hypoglycemic agent that also has a compound ability to suppress SREBP-lc expression.
  • the present invention also relates to the prevention or prevention of diabetes, hyperlipidemia, fatty liver, obesity, glucose intolerance, diabetic complications, metabolic syndrome, syndrome X comprising a compound having a SREBP-lc expression inhibitory action. It is a therapeutic agent.
  • the tricyclic compound of the present invention that suppresses the expression of SREBP-lc has a triglyceride lowering action and a blood sugar level lowering action in the liver, and it has diabetes, hyperlipidemia, fatty liver, obesity. Syndrome, glucose intolerance, diabetic complications (eg nephropathy, neuropathy, retinopathy, etc.), metabolic syndrome, syndrome X prevention and Z or therapeutic effects.
  • the alkyl group having 1 to 6 carbon atoms means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, Propyl group, t-butyl group, cyclopentyl group, cyclohexyl group, cyclopentylmethyl group Can be mentioned.
  • the acyl group having 2 to 6 carbon atoms refers to a linear, branched or cyclic acyl group having 2 to 6 carbon atoms such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group. And cyclopentyl carbo yl group.
  • the amide group having 1 to 10 carbon atoms refers to a linear, branched or cyclic amide group having 1 to 10 carbon atoms, for example, a rubamoyl group, a methylamide group, a propylamide group. , T-butylamide group, cyclopentylamide group, dimethylamide group, and arylide group.
  • the acyl group having 2 to 6 carbon atoms is a linear, branched or cyclic acyl group having 2 to 6 carbon atoms, and includes, for example, an acetylamino group, a propio-lamino group, an isobutylylamino group, And a cyclopentylcarbo-lamino group.
  • the hydroxyiminoalkyl group having 1 to 6 carbon atoms represents a linear, branched or cyclic hydroxyiminoalkyl group having 1 to 6 carbon atoms, such as a hydroxyiminomethyl group, Examples include 1-hydroxyiminoethyl group, 1-hydroxyiminopropyl group, and (hydroxyimino) monocyclopentylmethyl group.
  • the alkoxy group having 1 to 6 carbon atoms refers to a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, such as methoxy group, ethoxy group, propoxy group, t- Examples include butoxy, cyclopentyloxy, cyclohexyloxy, and cyclopentylmethyloxy.
  • the substituent of the substituted alkoxy group having 1 to 6 carbon atoms includes a halogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, an unsubstituted or substituted amino group, an amide group, a cyano group, and the number of carbon atoms. It may be substituted with a 2 to 6 acyl group, a carboxy group, a C2 to C6 alkoxycarbonyl group, a phenoxy group, a phenolthio group, a C1 to C6 alkyl group, or a halogen atom.
  • the substituted amino group refers to an amino group substituted with an alkyl group having 1 to 6 carbon atoms, and examples thereof include a methylamino group, an ethylamino group, and a dimethylamino group. Further, a methanesulfonamino group, an acetylamino group, a pyrrolidi- Group, piperidyl group or morpholinyl group.
  • the amide group is as described above.
  • an amide group that is substituted with an alkyl group having 1 to 6 carbon atoms that may be substituted with a hydroxyl group such as (hydroxymethyl) amide group, ) Amido group, and (N, O dimethylhydroxycarboxamide group, t-butoxycarboxamide group, and amide group)
  • Alkoxycarbonyl group having 2 to 6 carbon atoms is linear or branched.
  • a linear or cyclic C2-C6 alkoxy carbonyl group is exemplified, and examples thereof include a methoxy carbo ol group, an ethoxy carbo ol group, a propoxy carbo ol group and a t-butoxy carbo ol group.
  • the acyloxy group having 2 to 6 carbon atoms means a linear, branched or cyclic acyloxy group having 2 to 6 carbon atoms, such as an acetoxy group, a propio-loxy group, isobutyryl. An oxy group, and a cyclopentylcarbo-loxy group.
  • the alkylsulfonyloxy group having 1 to 6 carbon atoms refers to a linear, branched or cyclic alkylsulfoxy group having 1 to 6 carbon atoms, such as a methanesulfoxy group.
  • the pharmaceutically acceptable salt in the present invention is an acid or alkali addition salt.
  • Acids include salts with mineral acids such as sulfuric acid, hydrochloric acid, and phosphoric acid, and salts with organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, and benzenesulfonic acid.
  • alkali include metal ions such as sodium and potassium, and ammonium ions such as alkyl ammonium.
  • the compound of the present invention may be a single compound or a mixture of stereoisomers.
  • the compound of this invention can exist also as various solvates. It may also be a surface hydrate of applicability as a medicine.
  • the compounds of the present invention also include compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, sulfur atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful for metabolic and pharmacokinetic studies, or for biological analysis as receptor ligands.
  • the compound of the present invention can be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical preparation.
  • the above carrier, excipient and diluent Examples include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, methyl cellulose , Polybulurpyrrolidone, alkyl parahydroxybenzosorbate, tanolec, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil, and other oils.
  • additives such as extenders, binders, disintegrants, pH adjusters, and solubilizers that are generally used as necessary are mixed with the above carriers, excipients, or diluents, so that usual preparations are mixed.
  • it can be prepared as an oral or parenteral pharmaceutical such as tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, injections, skin patches and the like.
  • the compound of the present invention can be administered orally or parenterally to an adult patient in an amount of 0.001 to 500 mg once or several times a day. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.
  • the compound of the present invention can be produced, for example, according to the method shown below.
  • WSC 'HCl is 1-ethyl 3- (3 dimethylaminopropyl) carbodiimide hydrochloride
  • DCC is dicyclohexylcarbodiimide
  • HOBt is 1-hydroxybenzotriazole
  • DEAD is jetyl.
  • Azodicarboxylate, Boc represents a t-butoxycarbonyl group.
  • R 1 represents a hydrogen atom
  • a ring represents Formula A-1
  • R 2 represents an acyl group having 2 to 6 carbon atoms
  • B ring represents Formula B-1.
  • Method A a method in which a phenol intermediate (1) and a substituted alkyl halide are reacted in the presence of a base
  • Method B a method in which a phenol intermediate (1) and a substituted alcohol are reacted by Mitsunobu. This can be synthesized.
  • R 5 is an acyl group having 2 to 6 carbon atoms
  • R 6 represents a substituted alkoxy group having 1 to 6 carbon atoms.
  • R 1 represents a hydrogen atom
  • a ring represents Formula A-1
  • R 2 represents an acyl group having 2 to 6 carbon atoms
  • B ring represents Formula B-1
  • R 3 represents a hydrogen atom
  • R 4 represents the formula [0048]
  • R 9 represents an alkyl group having 1 to 6 carbon atoms
  • R 8 represents a formula
  • R 1 represents a hydrogen atom
  • the heel ring represents Formula A-1
  • R 2 represents carbon.
  • An acyl group having 2 to 6 atoms ring B represents formula B-1
  • R 3 represents a hydrogen atom
  • R 4 represents a formula [0057] [Chemical 9]
  • R 1Q is an alkyl group having 1 to 6 carbon atoms which may be substituted with a hydrogen atom or a hydroxyl group
  • R 11 is an alkyl group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group.
  • Compound (5) in which W represents the formula -CH 2- is a compound of the compound (4) as shown in Reaction Scheme 3.
  • a method for converting to amide a method using a condensing agent such as WSC 'HC1, DCC, or a method via acid chloride can be used.
  • R 1 represents a hydrogen atom
  • a ring represents Formula A-1
  • R 2 represents an acyl group having 2 to 6 carbon atoms
  • B ring represents Formula B-1
  • R 3 represents a hydrogen atom
  • R 4 represents the formula [0064] [Chemical 12]
  • R 13 represents an acyl group having 2 to 6 carbon atoms or an alkylsulfonyl group having 1 to 6 carbon atoms
  • W represents the formula —CH 2 — (7 )
  • R 5 has the same meaning as described above, and R 14 represents the formula
  • R 15 is the formula
  • R 13 is as defined above.
  • R 1 represents a hydrogen atom
  • a ring represents Formula A-1
  • R 2 represents an acyl group having 2 to 6 carbon atoms
  • B ring represents Formula B-1
  • R 3 represents a hydrogen atom
  • R 4 represents the formula [0073]
  • hydrolysis method examples include a method using t-butyl alcohol in potassium butyl alcohol and a method of heating in hydrochloric acid.
  • R 5 has the same meaning as described above, and R 16 represents the formula
  • R 1 represents a hydrogen atom
  • a ring represents Formula A-1
  • R 2 represents an acyl group having 2 to 6 carbon atoms
  • B ring represents Formula B-1
  • R 3 represents a hydrogen atom
  • R 4 represents the formula [0082] [Chemical 20]
  • clotting agent thiolucyl lide, methanesulfol sulfide, carbon tetrachloride triphenylphosphine, phosphoryl chloride and the like can be used.
  • R 5 has the same meaning as described above, and R 18 represents the formula
  • R 19 is the formula
  • R 1 represents a hydrogen atom
  • the A ring represents Formula A-1
  • R 2 represents an amide group having 1 to 10 carbon atoms (provided that ⁇ , ⁇ -dimethylhydroxycarboxamide group)
  • the ring represents formula B-1
  • R 3 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms
  • R 4 represents carbon.
  • Compound (13) which represents an alkyl group having 1 to 6 atoms or an alkoxy group having 1 to 6 carbon atoms, and wherein W represents the formula —CH 2 — is represented by Reaction Scheme 7
  • R ° represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms
  • R 21 represents an alkyl group having 1 to 6 carbon atoms or carbon.
  • An alkoxy group having 1 to 6 atoms is represented
  • R 22 represents an amide group having 1 to 10 carbon atoms (excluding ⁇ , ⁇ ⁇ ⁇ ⁇ ⁇ -dimethylhydroxycarboxamide group).
  • R 1 represents a hydrogen atom
  • the heel ring represents Formula A-1
  • R 2 represents a -tolyl group
  • the B ring represents Formula B-1
  • R 3 represents A hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms
  • R 4 represents an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms
  • W represents the formula -CH 2-(14)
  • compound (12) can be obtained by subjecting compound (12) to a condensation reaction with aqueous ammonia to convert it into strong rubamoyl and dehydrating it.
  • dianhydride pentalin, phosphorus pentachloride, thionyl chloride, methanesulfonyl chloride, salt cyanur and the like can be used as dehydrating agents for amides.
  • R A 1 is as defined above.
  • R 1 represents a hydrogen atom
  • the A ring represents Formula A-1
  • R 2 represents the formula
  • Ring B represents formula B-1
  • R 3 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms
  • R 1 represents an alkoxy group having 1 to 6 carbon atoms
  • R 4 represents an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms
  • W represents the formula —CH 2 —
  • R 2 °, R 21 is as defined above, and represents an alkyl group having 6 carbon atoms
  • R 1 represents a hydrogen atom
  • a ring represents Formula A-1
  • R 2 represents an alkyl group having 1 to 6 carbon atoms
  • B ring represents Formula B-1
  • R 3 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms
  • R 4 represents an alkyl group having 1 to 6 carbon atoms or an alkyl group having 1 to 6 carbon atoms.
  • W represents the formula -CH-
  • compound (17) reduces the carbo group of compound (16). You can get it by doing.
  • hydrazine, triethylsilane, zinc amalgam, or the like can be used as the reducing agent.
  • ⁇ is as defined above, and represents an acyl group having 2 to 6 carbon atoms, and R ′ b represents an alkyl group having 1 to 6 carbon atoms.
  • R 1 represents a hydrogen atom
  • a ring represents Formula A-1
  • R 2 represents a hydroxyiminoalkyl group having 1 to 6 carbon atoms
  • B ring represents Formula B
  • R 3 represents an elementary atom or an alkyl group having 1 to 6 carbon atoms
  • R 4 represents an alkyl group having 1 to 6 carbon atoms
  • W represents a formula —CH 2 — (18 ) Is a compound (16) as shown in Reaction Scheme 11.
  • ⁇ R z R is as defined above, and represents a hydroxyiminoalkyl group having 1 to 6 carbon atoms.
  • R 1 represents a hydrogen atom
  • the ⁇ ring represents Formula A-2
  • R 2 represents an acyl group having 2 to 6 carbon atoms
  • the B ring represents Formula B-1.
  • R 3 and R 4 independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms
  • W represents a compound represented by the formula —CH 2 — (20 ) Is 2-acetyltetra, as shown in Reaction Scheme 12.
  • R z represents independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, and R 29 represents 2 to 6 carbon atoms. Represents the acyl group.
  • R 1 represents a hydrogen atom
  • the ⁇ ring represents Formula A-3
  • R 2 represents an acyl group having 2 to 6 carbon atoms
  • the B ring represents Formula B-1
  • R 3 and R 4 independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms
  • W represents a compound represented by the formula —CH 2 — (23 ) Is obtained by the method shown in Reaction Scheme 13.
  • the compound (22) can be obtained by alkylation after conversion to the amide of Winelev.
  • a metal lithium reagent such as methyl reagent or methyl lithium can be used.
  • R 1 represents a hydrogen atom
  • a ring represents Formula A-1
  • R 2 represents an acyl group having 2 to 6 carbon atoms
  • B ring represents Formula B-2
  • Formula B-3 or Formula B-4 is shown
  • W is formula- Compound (26) showing CH 2-is obtained by the method shown in Reaction Scheme 14.
  • the Ron derivative (24) is subjected to Vilsmeier reaction, reacted with thioglycolic acid ethyl ester, and the ester is hydrolyzed to obtain the compound (25).
  • the compound (26) can be obtained by converting to amide of wine lev and alkylating.
  • the above-mentioned reagents can be used as the alkylating agent.
  • ring B represents the formula B-2, the formula B-3 or the formula B-4, and is as defined above.
  • R 1 represents a hydrogen atom
  • a ring represents Formula A-1
  • R 2 represents an acyl group having 2 to 6 carbon atoms
  • B ring represents Formula B-1
  • R 3 and R 4 independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms
  • W represents — (CH 2) 2 — 29) is a tetralone derivative (27) as shown in Reaction Scheme 15.
  • R 1 represents an alkyl group having 1 to 6 carbon atoms
  • a ring represents formula A -1
  • R 2 represents an acyl group having 2 to 6 carbon atoms
  • B The ring represents Formula B-1
  • R 3 and R 4 1S independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms
  • W represents the formula -CH Compound (32) indicating-is as shown in Reaction Scheme 16.
  • tetralone derivative (30) force can also be obtained using the same method as described above.
  • R z R z is as defined above, and represents an alkyl group having 1 to 6 carbon atoms.
  • R 1 represents a hydrogen atom
  • the ⁇ ring represents Formula A-1
  • R 2 represents an acyl group having 2 to 6 carbon atoms
  • the B ring represents Formula B-1
  • R 4 represents a trifluoromethyl group or a trifluoromethoxy group
  • W represents the formula —CH 2 — is shown in Reaction Scheme 17.
  • Te Tolonone derivative (33) force Can be obtained using the same method as described above.
  • R 31 represents a hydrogen atom, a trifluoromethyl group or a trifluoromethoxy group
  • R 32 represents a trifluoromethyl group or a trifluoromethoxy group.
  • R 1 represents a hydrogen atom
  • a ring represents Formula A-1
  • R 2 represents an acyl group having 2 to 6 carbon atoms
  • B ring represents Formula B-1
  • R 3 represents a hydrogen atom
  • R 4 represents an acyloxy group having 2 to 6 carbon atoms, an alkylsulfooxy group having 1 to 6 carbon atoms, a phenylsulfo-loxy group, or p-tolylsulfo-oxyloxy.
  • Compound (36) which represents a group and W represents the formula —CH 2 —, can be obtained from phenol derivative (1) as shown in Reaction Scheme 18.
  • R 5 is as defined above, and R 33 is an acyloxy group having 2 to 6 carbon atoms, an alkylsulfo-oxy group having 1 to 6 carbon atoms, a phenylsulfo-loxy group, or p-tolyl sulfo-loxy group.
  • R 1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • a ring represents Formula A-1
  • R 2 represents a hydroxyalkyl group having 1 to 6 carbon atoms.
  • the ring B is Formula Bl, Formula B-2, Formula B-3 or Formula B-4, wherein R 3 and R 4 forces are independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, and 1 to 6 carbon atoms.
  • W represents the formula —CH—
  • R 1 represents a hydrogen atom
  • ring B
  • R 3 and R 4 exclude a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, and an alkoxy group having 1 to 6 carbon atoms.
  • R 3 and R 4 exclude a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, and an alkoxy group having 1 to 6 carbon atoms.
  • sodium hydrogen hydride, lithium aluminum hydride, or the like can be used as the reducing agent.
  • ring B represents formula Bl, formula B-2, formula B-3 or formula B-4, and R 3 and R 4 independently represent a hydrogen atom, a carbon atom number of 1
  • R 34 has 1 carbon atom.
  • ring A represents formula A-1
  • R 2 represents a hydroxyalkyl group having 1 to 6 carbon atoms
  • ring B represents formula B-1
  • R 3 and R 4 represent , Independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms
  • W represents the formula -CH-
  • R 1 represents a hydrogen atom. Excluding things. )
  • trifluorophosphine was added to a solution of 0.20 g of 2 fluoroethanol in 50 ml of tetrahydrofuran.
  • 1- (7-hydroxy-1,4,5 dihydronaphtho [1,2, -b] chen-2-yl) ethanone 0.50 g was added, and DEAD1.4 ml of tetrahydrofuran 1 Oml was added dropwise. Thereafter, the mixture was stirred overnight at room temperature. After the reaction, water was added and the mixture was extracted with ethyl acetate.
  • Test example SREBP-lc mRNA expression suppression test
  • Chang Liver cells were cultured for 24 hours in the presence of 10% FBS in Dulbecco's modified Eagle medium in the presence of 5% carbon dioxide at 37 ° C in the presence of the specimen. After completion of the culture, RNA was collected from the cells using an RNeasy 96 kit (Qiagen), and the expression level of SREBP-lc mRNA was quantified from real-time RT-PCR.
  • ABI PRISM7700 (Applied Biosystems) was used for the reaction. First, a reverse transcription reaction at 60 ° C for 30 minutes, an inactivation reaction at 95 ° C for 5 minutes, and then at 94 ° C for 20 minutes. Second, the reaction for 1 minute at 62 ° C was repeated 40 cycles. Usually modified at the 5 'end of the TaqMan probe The fluorescent dye FAM is also quenched by the fluorescent dye TAMRA modified at the 3 'end. The fluorescent dye FAM is released by the exonuclease activity accompanying the amplification reaction with the thermostable DNA polymerase. Since the amount depends on the amount of template mRNA, SREBP-lc expression can be quantified. Using the above method, the SREBP-lc expression inhibitory action of the compounds of Examples 70, 72, 74, 80, and 81 was evaluated.

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Abstract

La présente invention concerne les maladies comprenant l’hypertriglycéridémie, le diabète, l’intolérance au glucose, l’obésité et la stéatose hépatique, syndromes composites définis comme étant des maladies liées au mode de vie. Il apparaît que la cause fondamentale de ces maladies réside dans l’hypermétabolisme des acides gras du foie ou des tissus adipeux en raison de l’accumulation de graisse viscérale. On sait que la capacité de synthèse accélérée des acides gras peut être généralement améliorée en inhibant l’effet de SREBP-1c qui est un facteur transcriptionnel contrôlant intégralement la famille des enzymes lipogènes. Ainsi, on suppose que la synthèse des acides gras peut être plus efficacement réduite de cette manière. Un nouveau composé tricyclique ou un sel pharmaceutiquement acceptable de celui-ci qui exerce des effets de réduction du niveau de triglycérides dans le foie et de réduction du niveau de glycémie en inhibant l’expression de SREBP-1c et, par conséquent, est utile en tant qu’agent prophylactique ou thérapeutique pour le diabète, l’hyperlipémie, la stéatose hépatique, l’obésité, l’intolérance au glucose, les complications diabétiques (par exemple, la néphropathie, les troubles nerveux, la rétinopathie, etc.), le syndrome métabolique et le syndrome X.
PCT/JP2006/301248 2005-01-28 2006-01-26 Composes tricycliques WO2006080406A1 (fr)

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Cited By (7)

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WO2008097835A2 (fr) 2007-02-02 2008-08-14 Baylor College Of Medicine Compositions et procédés de traitement de troubles métaboliques
US20120302562A1 (en) * 2011-05-27 2012-11-29 Joseph Barbosa 4h-thieno[3,2-c]chromene-based inhibitors of notum pectinacetylesterase and methods of their use
WO2013114403A1 (fr) * 2012-01-31 2013-08-08 Council Of Scientific & Industrial Research 4,5-dihydro-2h-benzo[e]indazole-9-carboxylates substitués destinés au traitement du diabète et de troubles apparentés
US9085566B2 (en) 2007-02-02 2015-07-21 Baylor College Of Medicine Compositions and methods for the treatment of metabolic and related disorders
US9187485B2 (en) 2007-02-02 2015-11-17 Baylor College Of Medicine Methods and compositions for the treatment of cancer and related hyperproliferative disorders
US9212179B2 (en) 2007-02-02 2015-12-15 Baylor College Of Medicine Compositions and methods for the treatment of metabolic disorders
US9233941B2 (en) 2007-02-02 2016-01-12 Baylor College Of Medicine Methods and compositions for the treatment of body weight related disorders

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US9085566B2 (en) 2007-02-02 2015-07-21 Baylor College Of Medicine Compositions and methods for the treatment of metabolic and related disorders
EP2120580A2 (fr) * 2007-02-02 2009-11-25 Baylor College Of Medicine Compositions et procédés de traitement de troubles métaboliques
EP2120580A4 (fr) * 2007-02-02 2011-09-28 Baylor College Medicine Compositions et procédés de traitement de troubles métaboliques
US8207196B2 (en) 2007-02-02 2012-06-26 Baylor College Of Medicine Compositions and methods for the treatment of metabolic disorders
WO2008097835A2 (fr) 2007-02-02 2008-08-14 Baylor College Of Medicine Compositions et procédés de traitement de troubles métaboliques
US9713613B2 (en) 2007-02-02 2017-07-25 Motonari Uesugi Methods and compositions for the treatment of cancer and related hyperproliferative disorders
US9233941B2 (en) 2007-02-02 2016-01-12 Baylor College Of Medicine Methods and compositions for the treatment of body weight related disorders
US9212179B2 (en) 2007-02-02 2015-12-15 Baylor College Of Medicine Compositions and methods for the treatment of metabolic disorders
US8778976B2 (en) 2007-02-02 2014-07-15 Baylor College Of Medicine Compositions and methods for the treatment of metabolic disorders
US9187485B2 (en) 2007-02-02 2015-11-17 Baylor College Of Medicine Methods and compositions for the treatment of cancer and related hyperproliferative disorders
US8927578B2 (en) 2007-02-02 2015-01-06 Baylor College Of Medicine Compositions and methods for the treatment of metabolic disorders
US20120302562A1 (en) * 2011-05-27 2012-11-29 Joseph Barbosa 4h-thieno[3,2-c]chromene-based inhibitors of notum pectinacetylesterase and methods of their use
JP2014517848A (ja) * 2011-05-27 2014-07-24 レクシコン ファーマシューティカルズ インコーポレイテッド ＮＯＴＵＭペクチンアセチルエステラーゼの４Ｈ−チエノ［３，２−ｃ］クロメン系阻害剤及びその使用方法
CN103649072A (zh) * 2011-05-27 2014-03-19 莱西肯医药有限公司 基于4h-噻吩并[3,2-c]色烯的背板胶质乙酰酯酶抑制剂及其用法
WO2012166458A1 (fr) 2011-05-27 2012-12-06 Lexicon Pharmaceuticals, Inc. Inhibiteur de pectine acétylestérase de notum à base de 4h-thiéno[3,2-c]chromène et leurs procédés d'utilisation
US9096539B2 (en) 2012-01-31 2015-08-04 Council Of Scientific & Industrial Research Substituted 4,5-dihydro-2H-benzo[e]indazole-9-carboxylates for the treatment of diabetes and related disorders
WO2013114403A1 (fr) * 2012-01-31 2013-08-08 Council Of Scientific & Industrial Research 4,5-dihydro-2h-benzo[e]indazole-9-carboxylates substitués destinés au traitement du diabète et de troubles apparentés

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