WO2002046154A1 - Activateurs $g(d) de recepteur active par un proliferateur du peroxysome - Google Patents

Activateurs $g(d) de recepteur active par un proliferateur du peroxysome Download PDF

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WO2002046154A1
WO2002046154A1 PCT/JP2001/010576 JP0110576W WO0246154A1 WO 2002046154 A1 WO2002046154 A1 WO 2002046154A1 JP 0110576 W JP0110576 W JP 0110576W WO 0246154 A1 WO0246154 A1 WO 0246154A1
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group
carbon atoms
alkyl
alkyl group
atom
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PCT/JP2001/010576
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Toshihiro Takahashi
Shogo Sakuma
Tsuyoshi Endo
Atsushi Tendo
Shinichi Yoshida
Kunio Kobayashi
Nobutaka Mochiduki
Tomio Yamakawa
Takashi Kanda
Seiichiro Masui
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Nippon Chemiphar Co., Ltd.
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Priority to JP2002547893A priority Critical patent/JPWO2002046154A1/ja
Priority to AU2002224138A priority patent/AU2002224138A1/en
Publication of WO2002046154A1 publication Critical patent/WO2002046154A1/fr

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    • 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
    • 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
    • A—HUMAN NECESSITIES
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    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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 peroxisome proliferator-activated receptor (5 activators).
  • Peroxisomes are organelles found in cells of animals and plants, and their matrices contain various enzymes such as lipase. ⁇ Zeroxisomers (eroX isome ro 1 iferator) is a substance that induces the growth of peroxisom, and is used in various forms such as antilipidemic drugs (fibrates), herbicides, and phthalate plasticizers. Compounds are known.
  • a nuclear receptor activated by this peroxisome proliferator was identified by Isseman et al., And a peroxisome proliferator-responsive receptor (perox is ome prolifera rat or activat edreceptor) was identified. : PP AR). (Nat ur, 347, p 645-650, 1990)
  • fibrate drugs have a ligand effect on PPARs, and a strong serum TG (triglyceride) lowering action has been recognized in clinical practice.
  • thiazolidinedione compounds which are therapeutic agents for diabetes, are known as ligands of PPAR • ⁇ .
  • PPAR (as a drug having J-activating action, for example, the following formula:
  • YM—16638 (Yamanouchi Pharmaceutical) and the like are known.
  • GW-2433 is described in WO 92 0468 for use as a prophylactic and therapeutic agent for atherosclerosis
  • L-165041 is described in WO 97/281 15 for use as a therapeutic agent for diabetes mellitus
  • WO 99/04815 describes that it has a serum cholesterol lowering effect and an LDL-cholesterol lowering effect.
  • PPARd ligands have been reported to promote their use as anti-cancer and anti-inflammatory agents (JBC, 272 (6), p3406-3410, 1997; Cell, 99, p335-345, 1999). It has been done.
  • the above-mentioned GW-2433 and the compound of the present invention commonly have a rare moiety, but the side chain having a carboxyl group is bonded to a benzene ring in GW-2433, while the following general formula (III) This side chain is bonded to the indole ring in the urea derivative represented by, and the structure is clearly different.
  • An object of the present invention is to provide a urea derivative represented by the following general formula (I), a urea derivative represented by the following general formula (III) or a salt thereof, which has an activity of activating the peroxisome proliferator-activated receptor 5. Is to do. Disclosure of the invention
  • Y represents an oxygen atom or a sulfur atom
  • ⁇ represents an integer from 0 to 4,
  • R 4 and R 5 represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms;
  • W is a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a sulfonic acid group Represents a phosphonic acid group, a cyano group, or a tetrazolyl group;
  • a double line consisting of a solid line and a broken line represents a single bond or a double bond
  • R a , R b and R e is a group represented by the following general formula (II), and the other two are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, and a carbon atom.
  • An aryl group or an arylalkyl group represented by the formulas 6 to 10 (the aryl moiety has 6 to 10 carbon atoms, and the alkyl moiety has 1 to 8 carbon atoms).
  • I 1 , R 2 and R 3 are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and 1 carbon atom.
  • the number is from 6 to 10, and the number of carbon atoms in the alkyl portion is 1 to 8), a heterocyclic group, or a heterocyclic alkyl group (the number of carbon atoms in the alkyl portion is 1 to 8), and
  • X is a carbon atom. Represents an alkylene chain of numbers 1 to 8.
  • R a , R b and R e the aryl part of the aryl group and the arylalkyl group and the heterocyclic part of the heterocyclic group and the heterocyclic alkyl group have 1 to 8 carbon atoms.
  • alkyl group an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, a carbon atom Numbers 2 to 8 of acyl group, formyl group, hydroxyl group, halogen atom, nitro group, cyano group, amino group, alkylamino group (alkyl group has 1 to 8 carbon atoms), dialkylamino group (carbon of alkyl group The number of atoms may be 1 to 8), a phenyl group, or a substituted phenyl group. )
  • Y Q represents an oxygen atom or a sulfur atom
  • R 8 and R 9 represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms
  • R represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms
  • a double line consisting of a solid line and a broken line represents a single bond or a double bond
  • R 6 and R 7 are an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or an alkoxy group having 1 to 8 carbon atoms.
  • X ° represents an alkylene chain having 1 to 8 carbon atoms.
  • the aryl moiety of the aryl group and the arylalkyl group, and the heterocyclic moiety of the heterocyclic group and the heterocyclic alkyl group are an alkyl group having 1 to 8 carbon atoms, An alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, a formyl group, Hydroxyl group, halogen atom, nitro group, cyano group, amino group, alkylamino group (alkyl group has 1 to 8 carbon atoms), dialkylamino group (alkyl group has 1 to 8 carbon atoms), phenyl group or It may have a substituent selected from a substituted phenyl group (the substituent is selected from a halogen atom, an alkyl group having 1 to 8 carbon atoms, or an
  • the present invention relates to a peroxisome proliferator-activated receptor containing a perea derivative represented by the above general formula (I), a perea derivative represented by the above general formula (III) or a salt thereof as an active ingredient.
  • Activator of body d Next, the present invention will be described in detail.
  • the alkyl group having 1 to 8 carbon atoms of RR 2 , R 3 , R 4 , R 5 , R a , R b and R e is a methyl group, an ethyl group, a propyl group. Isopropyl group, butyl group, i-butyl group, t-butyl group, pentyl group and the like.
  • Examples of the alkyl group having 1 to 8 carbon atoms substituted with a halogen atom represented by RRR 4 and R 5 include a methyl group and an ethyl group substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom or a bromine atom.
  • a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom.
  • Examples of the alkyl group having 1 to 8 carbon atoms substituted with an alkoxy group having 1 to 8 carbon atoms of R ⁇ R 2 and R 3 include a methyl group, an ethyl group, a methyl group substituted with a methoxy group, an ethoxy group, and the like. Propyl group or butyl group and the like.
  • Examples of the alkenyl group having 2 to 8 carbon atoms of RR 2 and R 3 include an aryl group and a 3-methyl-2-butenyl group.
  • Examples of the alkynyl group having 2 to 8 carbon atoms of RR 2 and R 3 include a propargyl group.
  • Examples of the cycloalkyl group having 3 to 7 membered carbon atoms of RR 2 and R 3 include a cyclohexyl group and a cyclopentyl group.
  • Examples of the alkyl group having 1 to 8 carbon atoms substituted with a cycloalkyl group having 3 to 7 carbon atoms of RR 2 and R 3 include a cyclopropylmethyl group and a cyclohexylmethyl group.
  • RR 2, R ⁇ R ⁇ R b and R e carbon atoms from 6 to; the Ariru group L 0, and the like phenyl group or a naphthyl group.
  • arylalkyl groups (the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 8 carbon atoms) Or a phenethyl group.
  • Examples of the heterocyclic alkyl group of RR 2 and R 3 include a chenyl group, a furyl group, a thiazolyl group, an oxazolyl group, a pyridyl group, an imidazolyl group, a quinolyl group, an indolyl group, or Examples include a methyl group, an ethyl group, a propyl group, and a butyl group substituted with a heterocyclic group such as a benzofuranyl group.
  • Examples of the alkoxycarbonyl group having 2 to 8 carbon atoms of W include a methoxycarbonyl group and an ethoxycarbonyl group.
  • examples of the alkyl group having 1 to 8 carbon atoms include a methyl group, an ethyl group, a propyl group, a butyl group, an i-butyl group and a t-butyl group, and the like.
  • Examples of the alkyl group having 1 to 8 carbon atoms substituted with an atom include a methyl group, an ethyl group, a propyl group, and an isopropyl group, which are substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom or a bromine atom. Or a butyl group, and the like.
  • Examples of the alkoxy group having 1 to 8 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, or a butoxy group, and an alkoxycarbonyl group having 2 to 8 carbon atoms.
  • Examples thereof include a methoxycarbonyl group and an ethoxycarbonyl group.
  • examples of the acetyl group having 2 to 8 carbon atoms include an acetyl group and a propionyl group.
  • examples of the halogen atom include a chlorine atom and a bromine atom. Is a fluorine atom, etc., an alkylamino group (the alkyl group has 1 to Examples of 8) include a methylamino group or an ethylamino group.
  • Examples of a dialkylamino group (the alkyl group has 1 to 8 carbon atoms) include a dimethylamino group or an ethylamino group.
  • Halogen atom fluorine atom, chlorine atom, etc.
  • alkyl group having 1 to 8 carbon atoms methyl group, ethyl group, propyl group, etc.
  • alkoxy group having 1 to 8 carbon atoms methoxy group, ethoxy group
  • a propyloxy group and the like.
  • the number of substituents which the above-mentioned heterocyclic group, phenyl group and the like may have is preferably 1 to 3.
  • the symbols in the general formula (III) will be described.
  • examples of the alkyl group having 1 to 8 carbon atoms of R 6 , R 7 , R 8 , R 9, and R include the alkyl groups exemplified in RR 2 and the like in the general formula (I). Groups.
  • R 6 and R 7 among the aryl groups of the aryl group and the arylalkyl group and the substituents that the heterocyclic group of the heterocyclic group and the heterocyclic alkyl group may have, An alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, C2 to C8 acyl group, halogen atom, a Alkylamino group (number of carbon atoms of the alkyl group is 1-8), 1 ⁇ dialkylamino groups likewise formula also (number of carbon atoms ho 1-8 of ⁇ alkyl group) (I), those exemplified such as R 2 Is mentioned.
  • the substituent of the phenyl group of the substituted phenyl group includes a bromine atom, a chlorine atom, and a fluorine atom.
  • substituents such as atoms, alkyl groups having 1 to 8 carbon atoms such as methyl group, ethyl group and propyl group, and alkoxy groups having 1 to 8 carbon atoms such as methoxy group, ethoxy group and propoxy group.
  • R a is a group represented by the general formula (II)
  • R b and IT are a hydrogen atom, and C 1 to C 1.
  • a salt thereof is preferred.
  • urea derivatives represented by the above general formula (I) or the urea derivatives described in (2) urea wherein W is a carboxyl group or an alkoxycarbonyl group having 2 to 8 carbon atoms. Derivatives or salts thereof are preferred.
  • the compound of the present invention is preferably a urea derivative represented by the above general formula (I), or a urea derivative represented by the formula (I) above, or a urea derivative wherein is a hydrogen atom, or a salt thereof.
  • R 6 is substituted as a substituent by an alkyl group having 1 to 8 carbon atoms or by 1 to 3 halogen atoms.
  • R 7 is an alkyl group having 1 to 8 carbon atoms, or a carbon atom as a substituent.
  • a perylene derivative which is a phenylalkyl group (the alkyl moiety has 1 to 8 carbon atoms) which may be possessed, or a salt thereof is preferable.
  • urea derivative represented by the above general formula (II) or a urea derivative described in 45, wherein a double line consisting of a solid line and a broken line is a double bond, or Its salts are preferred.
  • urea derivative represented by the above general formula (III) or a urea derivative described in ⁇ , wherein a double line consisting of a solid line and a broken line is a single bond, or a derivative thereof Salts are preferred.
  • urea derivatives represented by the above general formula (III) or the urea derivatives described in the above items 1 to 4 urea derivatives wherein R is a carboxyl group, or salts thereof are preferable.
  • the urea derivative (the compound of the present invention) represented by the above general formula (I) may also include cis and trans geometric isomers and optical isomers, and these isomers are also included in the present invention. It is.
  • the compounds of the present invention also include pharmaceutically acceptable salts such as alkali metal salts such as sodium salt and potassium salt.
  • the compound of the present invention contains hydrochloric acid. Salts and the like are also included.
  • R 2 H 3 0 R 3
  • ( ⁇ ) (B) (is a group represented by: wherein R a , R b and R e are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or aryl.
  • the urea derivative represented by the general formula (c) is prepared by mixing an amine (b) and an isocyanate (0 ° C to room temperature) in a solvent that does not participate in a reaction such as ethyl acetate. a) can be obtained by reacting
  • G 1 and G 2 represent a protecting group, Q represents a leaving group, and W 1 represents a lower alkoxycarbonyl group, a cyano group, or PO 3 R 2 (R is a lower alkyl group).
  • R 3 , R 4 , R 5 , R b , R ⁇ n, X and Y are the same as above
  • G 1 and G 2 represents a protecting group
  • Q represents a leaving group
  • W 1 is the low grade alkoxycarbonyl group
  • R 2 a R is a lower alkyl group
  • M represents 0 or 1
  • Z represents a chlorine atom or a hydroxyl group
  • X 1 represents a bond or an alkylene chain having 1 to 7 carbon atoms
  • R 3 , RR 5 , R ⁇ R ' ⁇ R ⁇ n, X and Y are the same as above
  • G 2 represents a protecting group
  • W 1 is a lower alkoxycarbonyl group
  • R 3, RR 5, R ⁇ R e, n, X and Y are the same as above
  • the urea derivative represented by the general formula (e) is represented by a compound represented by the following formula: 0 in a solvent such as THF, toluene, DMF or DMS0.
  • the compound can be obtained by reacting the rare derivative (c) with the compound of the general formula (d) in the presence of a base such as sodium hydride at a temperature of from ° C to the reflux temperature of the solvent.
  • the leaving group Q is a halogen atom such as a bromine atom or a tosyloxy group.
  • W in L is a carboxyl group or the like, it is desirable to carry out the above reaction after protecting these with a protecting group.
  • the urea derivative represented by the general formula (g) can be obtained by reacting the compound represented by the general formula (f) with a reducing agent such as a borane-vilidine complex in a solvent such as acetic acid at room temperature to the reflux temperature of the solvent. Can be.
  • W 1 when W 1 is a lower alkoxycarbonyl group or a nitrile group, W 2 represents a carboxyl group; when W 1 is a phosphonate ester, W 2 represents a phosphonic acid; and R a , R a b, RY, ⁇ , R 4 , R 5 and double line consisting of solid and dotted lines are the same as before follow.
  • the perylene derivative (i) is converted into an ester form (h) at a temperature of 0 to 60 ° C in a solvent such as ethanol-water by sodium hydroxide, It can be obtained by reacting with lime or lithium hydroxide.
  • methoxyphenyl H isophthalic 'chill (CH 2) 2 Me H 0 (6) 0 Me Me Me C0 2 H -Naphthyl H isotyl (GH 2 ) 2 Me H 0 (6) 0 Me Me Me C0 2 H-Quinolyl H isotyl (CH 2 ) 2 Me H 0 (6) 0 Me Me Me C0 2 H
  • 2,4-cyclocyclophenyl H isophenyl (CH,) 9 Me Ph 0 (6) 0 HH C0 2 H
  • 2,4-Siphenyl phenyl H isobutyl (GH 2 ) 2 HH 0 (5) 0 HH SOgH
  • 2,4-cyclocyclophenyl H isobutyl (CH 2 ) 2 Ph H 0 (5) 0 Me Me CO a H
  • the PPAR5 activating effect of the compound of the present invention is determined by the expression of chimeric receptor expression plasmid (GAL4-hPPARS LBD), repo overnight plasmid (UAS X4-TK-LUC) and CV-1 cells in CV-1 cells.
  • GAL4-hPPARS LBD chimeric receptor expression plasmid
  • UAS X4-TK-LUC repo overnight plasmid
  • CV-1 cells in CV-1 cells.
  • the luciferase activity was corrected by the G-AL activity, and the relative ligand activity was calculated by setting the luciferase activity of the cells treated with L-165041 as 100%. (Example 14 described later) As shown in Table 14, the compound of the present invention exhibited a PPAR d activating action equivalent to or higher than that of L-165041.
  • the urea derivative represented by the general formula (I) of the present invention has an excellent PPARi activating action, and is therefore a hypoglycemic agent, a lipid-lowering agent, obesity, syndrome X, hypercholesterolemia, and hyperliposome.
  • Metabolic disorders such as proteinemia, hyperlipidemia, arterial sclerosis, cardiovascular disease, bulimia, ischemic disease, malignant tumors such as lung cancer, breast cancer, colon cancer, colon cancer, ovarian cancer, Alzheimer's disease, inflammatory diseases, osteoporosis (ManoH. Et. A.1, (2000) J. Biol. Chem., 275: 8126-8132), Graves' ophthalmopathy, adrenoleukodystrophy, etc. It is expected as a preventive or therapeutic agent.
  • the compound of the present invention can be administered to humans by an appropriate administration method such as general oral administration or parenteral administration.
  • composition it can be manufactured into tablets, granules, powders, capsules, suspensions, injections, suppositories and the like by a usual method in the technical field of formulation.
  • excipients include lactose, D-mannitol, crystalline cellulose, glucose, etc.
  • disintegrants include starch, carboxymethylcellulose-scalcium (CMC-Ca), and the lubricants.
  • CMC-Ca carboxymethylcellulose-scalcium
  • binders include hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like.
  • the dosage is usually about 0.1 mg / day for the compound of the present invention, which is an active ingredient in an injection, and about 00 mg / L for oral administration, and 1 mg / day to 2000 mg / day for oral administration, but may vary depending on age, symptoms, etc. Can be.
  • the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.
  • Example 1 (2-methyl-1-2-[[1- [2- (phenethylamino) ethyl] indoline-5-yl] oxy] ethyl propionate (112 mg, 0.282 mmo 1) was used. In the same manner as in 7), 125 mg (76%) of the title compound was obtained as a colorless oil.
  • Example 1 (2) Using 5- (benzyloxy) indole (402 mg, 1.22 mmo 1) and isobutylamine (1.2 mL, 12 mmo 1), as in Example 1 (2), The title compound was obtained as a yellow oil (392 nig (100)).
  • Example 1 using 2- [1- [2- (isobutylamino) ethyl] indole-5-yl] oxy-2-ethylethyl propionate (65 mg, 0.19 mmo 1) In a similar manner to (7), 85 mg (85%) of the title compound was obtained as a colorless oil.
  • Example 1 (2-methyl-1-[[3- [2- (phenylethylamino) ethyl] indole-6-yl] oxy] ethyl propionate (16 mg, 0.038 mmo 1) In the same manner as in 7), 18 mg (80%) of the title compound was obtained as a pale yellow oil.
  • Test compounds [Examples 2, 3, 4, 6 and 7 and known PPAR agonist L-165041 (Berger 3 J. et al., (1999) J. Biol. Cem., 274: 6718- 6725)] of PPAR (5 It was measured.
  • African green monkey kidney fibroblasts ( ⁇ -1 cells) were obtained from Senyuichi Medical Cell Resource Center, Tohoku University Aging Medicine Laboratory. All test compounds were dissolved in dimethyl sulfoxide (DMSO) and final; used in the test at a DMSO concentration of 0.1%.
  • DMSO dimethyl sulfoxide
  • Receptor expression plasmid GAL 4— hPPARS LBD
  • UASX 4— TK— LUC luciferase expression plasmid
  • ⁇ galactosidase expression plasmid
  • CV-1 cells are seeded on a 24-well culture plate at a cell concentration of 2 x 10 5 cells / well and added with 4% fetal bovine serum (FCS) for 24 hours.
  • FCS fetal bovine serum
  • luciferase substrate solution 1001 Pieris Gene; manufactured by Nippon Gene Co., Ltd.
  • the amount of luminescence per second was determined using an electric company.
  • the method for measuring galactosidase activity is as follows.
  • Table 14 shows the test results 76
  • Example 2 2- [1- [2 - [[3- (2, 3-dichloro Phenyl) 1-phenylene] -reido] ethyl] indrin-5-yl-2-oxy-2-methylpropionic acid
  • Example 3 2-[1-[2-[[3-(2,3-dichlorophenyl) 1-Soptyl] ureido] ethyl] indole-5-yloxy-2-methylpropionic acid
  • Example 4 2-[1— [2 — [[3- (2,4-dichlorophenyl) —] 1-Soptyl] ' ⁇ Reid] Ethyl] indole-5-yl] oxy-2-methylpropionic acid
  • Example 6 2— [1— [2 — [[1—butyl—3— (2,3— Diclo mouth)) [Reid] ethyl] India 1-5-yl

Abstract

L'invention concerne des dérivés de l'urée représentés par la formule générale (III) ou leurs sels utilisés en tant qu'activateurs (PPARδ) δ du récepteur activé par un proliférateur du peroxysome : (III). Dans cette formule Y0 représente un atome d'oxygène ou de soufre, R8 et R9 représentent chacun un atome d'hydrogène ou un groupe alkyle en C¿1-8?, R représente un atome d'hydrogène ou un groupe alkyle en C1-8, ∫u⊃... ∫/u⊃représente une liaison simple ou double, R?6 et R7¿ représentent chacun un groupe alkyle en C¿1-8?, un groupe alkyle en C1-8 substitué par un à trois atomes d'halogène, un groupe aryle en C6-10, un groupe arylalkyle, un groupe hétérocyclique, ou analogue, et X?0¿ représente un groupe alkylène en C¿1-8?.
PCT/JP2001/010576 2000-12-05 2001-12-04 Activateurs $g(d) de recepteur active par un proliferateur du peroxysome WO2002046154A1 (fr)

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JP2002547893A JPWO2002046154A1 (ja) 2000-12-05 2001-12-04 ペルオキシソーム増殖剤応答性受容体δの活性化剤
AU2002224138A AU2002224138A1 (en) 2000-12-05 2001-12-04 Peroxisome proliferator activated receptor d activators

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WO2002070011A3 (fr) * 2001-02-02 2003-04-24 Smithkline Beecham Corp Regimes therapeutiques
FR2879194A1 (fr) * 2004-12-14 2006-06-16 Galderma Res & Dev Nouveaux composes bi-aromatiques modulateurs des recepteurs de type ppar, leur procede de preparation et leur utilisation dans des compositions cosmetiques ou pharmaceutiques
WO2006074789A1 (fr) * 2005-01-14 2006-07-20 Merck Patent Gmbh Derives d'acide 1h-indole-3-carboxylique et utilisation en tant qu'agonistes de ppar
WO2007003581A1 (fr) 2005-06-30 2007-01-11 Novo Nordisk A/S Acides phénoxyacétiques en tant qu'activateurs de rapp-delta
WO2010045361A1 (fr) 2008-10-17 2010-04-22 Metabolex, Inc. Procédés de réduction de petites particules denses de ldl
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
US7943613B2 (en) 2005-12-22 2011-05-17 High Point Pharmaceuticals, Llc Compounds, their preparation and use
US7943612B2 (en) 2006-03-09 2011-05-17 High Point Pharmaceuticals, Llc Compounds that modulate PPAR activity, their preparation and use
US7968723B2 (en) 2004-05-05 2011-06-28 High Point Pharmaceuticals, Llc Compounds, their preparation and use
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
US8053598B2 (en) 2004-05-05 2011-11-08 High Point Pharmaceuticals, Llc Compounds, their preparation and use
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
US10456406B2 (en) 2013-09-09 2019-10-29 Vtv Therapeutics Llc Use of a PPAR-δ agonist for reducing loss of muscle strength, muscle mass, or type I muscle fibers in an immobilized limb
US11931365B2 (en) 2022-01-25 2024-03-19 Reneo Pharmaceuticals, Inc. Use of PPAR-delta agonists in the treatment of disease

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Publication number Priority date Publication date Assignee Title
WO2002070011A3 (fr) * 2001-02-02 2003-04-24 Smithkline Beecham Corp Regimes therapeutiques
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
US7968723B2 (en) 2004-05-05 2011-06-28 High Point Pharmaceuticals, Llc Compounds, their preparation and use
US8053598B2 (en) 2004-05-05 2011-11-08 High Point Pharmaceuticals, Llc Compounds, their preparation and use
FR2879194A1 (fr) * 2004-12-14 2006-06-16 Galderma Res & Dev Nouveaux composes bi-aromatiques modulateurs des recepteurs de type ppar, leur procede de preparation et leur utilisation dans des compositions cosmetiques ou pharmaceutiques
WO2006063863A1 (fr) * 2004-12-14 2006-06-22 Galderma Research & Development Composes biaromatiques qui modulent les recepteurs de type ppar, leur procede de preparation et leur utilisation dans les compositions cosmetiques ou pharmaceutiques
JP2008526902A (ja) * 2005-01-14 2008-07-24 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング １ｈ−インドール−３−カルボン酸誘導体およびｐｐａｒアゴニストとしてのその使用
US7754740B2 (en) 2005-01-14 2010-07-13 Merck Patent Gmbh 1H-indole-3-carboxylic acid derivatives and their use as PPAR agonists
FR2880889A1 (fr) * 2005-01-14 2006-07-21 Merck Sante Soc Par Actions Si Derives de l'acide 1h-indole-3-carboxylique, procedes pour leur preparation, compositions pharmaceutiques les contenant et applications en therapeutique
WO2006074789A1 (fr) * 2005-01-14 2006-07-20 Merck Patent Gmbh Derives d'acide 1h-indole-3-carboxylique et utilisation en tant qu'agonistes de ppar
WO2007003581A1 (fr) 2005-06-30 2007-01-11 Novo Nordisk A/S Acides phénoxyacétiques en tant qu'activateurs de rapp-delta
US8426473B2 (en) 2005-06-30 2013-04-23 High Point Pharnaceuticals, LLC Phenoxy acetic acids as PPAR delta activators
US8217086B2 (en) 2005-06-30 2012-07-10 High Point Pharmaceuticals, Llc Phenoxy acetic acids as PPAR delta activators
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US7943669B2 (en) 2005-06-30 2011-05-17 High Point Pharmaceuticals, Llc Phenoxy acetic acids as PPAR delta activators
US9663481B2 (en) 2005-12-22 2017-05-30 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPARδ agonists
US10947180B2 (en) 2005-12-22 2021-03-16 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists
US7943613B2 (en) 2005-12-22 2011-05-17 High Point Pharmaceuticals, Llc Compounds, their preparation and use
EP2386540A1 (fr) 2005-12-22 2011-11-16 High Point Pharmaceuticals, LLC Nouveaux composés, leur utilisation et préparation
US9855274B2 (en) 2005-12-22 2018-01-02 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists
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US8551993B2 (en) 2005-12-22 2013-10-08 High Point Pharmaceuticals, Llc Phenoxy acetic acids as PPAR delta activators
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US11007162B2 (en) 2008-10-17 2021-05-18 Cymabay Therapeutics, Inc. Methods of reducing small, dense LDL particles
WO2010045361A1 (fr) 2008-10-17 2010-04-22 Metabolex, Inc. Procédés de réduction de petites particules denses de ldl
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
EP3243385A1 (fr) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
US10456406B2 (en) 2013-09-09 2019-10-29 Vtv Therapeutics Llc Use of a PPAR-δ agonist for reducing loss of muscle strength, muscle mass, or type I muscle fibers in an immobilized limb
EP3756661A1 (fr) 2013-09-09 2020-12-30 vTv Therapeutics LLC Utilisation d'un agoniste de ppar-delta pour le traitement de l'atrophie musculaire
US11096946B2 (en) 2013-09-09 2021-08-24 Vtv Therapeutics Llc Use of a PPAR-δ agonist for reducing loss of muscle strength, muscle mass, or type I muscle fibers in an immobilized limb
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
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US11931365B2 (en) 2022-01-25 2024-03-19 Reneo Pharmaceuticals, Inc. Use of PPAR-delta agonists in the treatment of disease

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