WO2001034200A1 - Inhibiteurs de prise de poids - Google Patents
Inhibiteurs de prise de poids Download PDFInfo
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- WO2001034200A1 WO2001034200A1 PCT/JP2000/007879 JP0007879W WO0134200A1 WO 2001034200 A1 WO2001034200 A1 WO 2001034200A1 JP 0007879 W JP0007879 W JP 0007879W WO 0134200 A1 WO0134200 A1 WO 0134200A1
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Definitions
- the present invention relates to a PPAR agonist-like substance-derived inhibitor of body weight gain, which is useful in the treatment of diabetes and the like.
- peroxisome proliferator-activated receptor gamma (sometimes abbreviated as PPARa), which is one of the retinoid-related receptor ligands, is represented by steroid hormone receptors and thyroid hormone receptors. It is a member of the nuclear family of hormone receptor superfamilies, whose expression is induced very early in adipocyte differentiation, and plays an important role in adipocyte differentiation as a master regulator.
- PPARr forms a dimer with the retinoid X receptor (RXR) by binding to a ligand, and directly controls (activates) the transcription efficiency by binding to the responsive site of the target gene in the nucleus.
- RXR retinoid X receptor
- peroxisome proliferator-responsive receptor Delta (sometimes abbreviated as P PAR ⁇ 5 in this specification), one of the retinoid-related receptors, is a peroxisome proliferator-responsive as well as PPARa.
- P PAR ⁇ 5 peroxisome proliferator-responsive receptor
- Such a PPAR ⁇ agonist is described in WO 97/28149.
- This compound acts as a P PAR ⁇ agonist, increases plasma HDL levels, is effective in the treatment and prevention of atherosclerotic coronary artery sclerosis, and is used in combination with HMG-Co reductase inhibitor Reported that it is effective in treating and preventing atherosclerotic coronary arteriosclerosis.
- Preadipocytes Preadipocytes
- PPAR ⁇ adipocytes
- UCP-2 protein adipocytes
- calorie control up-regulate
- insulin-improving drugs eg, troglitazone, piogliyuzone, oral diglyugonezone, etc.
- PPAR® agonist action
- an object of the present invention is to develop a drug that does not increase the weight of a patient even when a therapeutically effective PPAR agonist substance is administered in the treatment of diabetes and other diseases. Disclosure of the invention
- the present inventors have found for the first time that administration of a PPAR agonist agonist during administration of a PPAR agonist agonist suppresses weight gain in diabetic patients and completes the present invention. Reached.
- An inhibitor of PPAR agonist-like substance-derived weight gain comprising a PPAR ⁇ agonist-like substance
- P PAR ⁇ agonist-like substance and P PAR agonist-like substance Is the same substance as described in (1) above;
- R 1 represents an optionally substituted hydrocarbon group or a heterocyclic group
- X represents a bond, one CO—, —CH (OH) one or one NR 6 — (R 6 is a hydrogen atom or an optionally substituted alkyl group.); N represents 1 to Indicates an integer of 3;
- Y represents an oxygen atom, a sulfur atom, one S ⁇ —, _S02— or one NR 7 _ (where R 7 represents a hydrogen atom or an optionally substituted alkyl group);
- Ring A further represents a benzene ring optionally having 1 to 3 substituents; p represents an integer of 1 to 8;
- R 2 represents a hydrogen atom, an optionally substituted hydrocarbon group or a heterocyclic group
- Q represents an integer of 0 to 6;
- n 0 or 1
- R 3 is a hydroxy group, one OR 8 (R 8 is an optionally substituted hydrocarbon group) or one NR 9 R 1 G (R 9 and R 1 Q are the same or different and are hydrogen atoms, substituted Represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted acyl group, and R 9 and R 1 Q may be combined to form a ring. Good) is shown;
- R 4 and R 5 are the same or different and each represent a hydrogen atom or an optionally substituted hydrocarbon group, and R 4 may combine with R 2 to form a ring.
- the agent according to the above (1) which is a compound represented by the formula: or a salt thereof;
- a method for suppressing weight gain derived from a P PAR 7 "agonist-like active substance which comprises administering an effective amount of a P PAR ⁇ agonist-like active substance to a mammal; (8) a P PAR agonist-like substance Use of a PPAR ⁇ agonist-like agent for the manufacture of an agent-derived weight gain inhibitor;
- a therapeutic agent for diabetes comprising a PPAR delta agonist-like substance and a PPAR agonist-like substance, and suppressing weight gain derived from the PPAR agonist-like substance to about 80% or less;
- the PPAR ⁇ agonist-like agent used in the present invention may be any agonist against PPAR ⁇ .
- PPAR ⁇ agonist-like agonists directly regulate gene expression of the UCP-2 protein, which is not directly an agonist of PPAR (5), but is involved in the control of body energy balance, body weight control, and calorie control. Any substance that exerts a P PAR ⁇ -related effect can be used.
- the PPAR ⁇ agonist-like substance is, for example, a substance that shows a clear effect at a concentration of 10 / zM or less in vitro, and specifically, in the test example 1 described below, the EC 5 Substances and the like having a zero value of IO ZM or less are preferred.
- Preferred examples of PPAR ⁇ agonist-like agents include:
- cPGI carbaprostacycl in
- L-165041 Journal Biological Chemistry, 274, 6718-6728 (1999 Merck)
- P PAR ⁇ agonist-like substances that can be used in the present invention.
- cPGI is known as an agonist for both ⁇ R ⁇ and PPAR.
- a substance which acts as an agonist against both P PAR ⁇ and P PARa described later can also be used in the present invention. Substance.
- the PPAR ⁇ agonist-like substance used in the present invention may be any agonist against PPARr, and may be any substance that exhibits the same action.
- the PPAR agonist-like active substance is a substance that shows a clear effect at a concentration of 10 M or less in vitro, for example.
- the EC 50 value Is preferably 10 M or less.
- Preferred examples of PPAR agonist-like agents include Torodari evening, mouth sigli evening, englitazone, ciglitazone, peodari evening, PG, GI-262 570, JTT-501, MCC-555, Insulin resistance improvers such as YM-440, KRP-297, CS-011, FK-614 and the like. Needless to say, a substance acting as an agonist against both P PAR ⁇ and P PAR described later is also a P PAR agonist-like substance that can be used in the present invention.
- the PPAR delta agonist-like substance and the PPAR agonist-like substance may be different substances or the same substance.
- Examples of such the same substance include YM-16638 (Japanese Patent Publication No. 63-35626), p- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] phenylbutyric acid (Nos. 281, 130 Czech Patent Publication and W099 / 04815 Publication), Les 165461,
- R—X— (CH 2 ) n— ⁇ ” 1 [wherein, R 1 represents an optionally substituted hydrocarbon group or a heterocyclic group;
- X represents a bond, one CO—, one CH (OH) — or one NR 6 — (R 6 is a hydrogen atom or an optionally substituted alkyl group); n represents an integer of 1 to 3;
- Y represents an oxygen atom, a sulfur atom, one SO—, —S02— or one NR 7 — (where R 7 represents a hydrogen atom or an optionally substituted alkyl group);
- Ring A further represents a benzene ring optionally having 1 to 3 substituents; P represents an integer of 1 to 8;
- R 2 represents a hydrogen atom, an optionally substituted hydrocarbon group or a heterocyclic group
- Q represents an integer of 0 to 6;
- n 0 or 1
- R 3 is a hydroxy group, one OR 8 (R 8 is an optionally substituted hydrocarbon group.) Or — NR 9 R 1 Q (R 9 and R 1G are the same or different and are hydrogen atoms, Represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted acyl group, and R 9 and R 1 Q may combine to form a ring ));
- R 4 and R 5 are the same or different and each represent a hydrogen atom or an optionally substituted hydrocarbon group, and R 4 may combine with R 2 to form a ring. Or a salt thereof; compounds described in EP-A 612743, EP-A629624 (for example, 5- [3- [4-[(5-methyl-2-phenyl-1,3-thiazolyl)]; 41-yl) methoxy] phenyl] propyl] -11,3-oxazolidin-12,4-dione, etc.).
- EP-A 612743 for example, 5- [3- [4-[(5-methyl-2-phenyl-1,3-thiazolyl)]; 41-yl) methoxy] phenyl] propyl] -11,3-oxazolidin-12,4-dione, etc.
- examples of the hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R 1 include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an alicyclic-aliphatic Examples include a hydrocarbon group, an araliphatic hydrocarbon group, and an aromatic hydrocarbon group.
- the number of carbon atoms in these hydrocarbon groups is preferably from 1 to 14.
- Definition of hydrocarbon group of R 1 As the aliphatic hydrocarbon group, an aliphatic hydrocarbon group having 1 to 8 carbon atoms is preferable.
- Examples of the aliphatic hydrocarbon group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se-butyl, t.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, and octyl.
- a saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms (eg, an alkyl group); for example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2- Methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexenyl, 5- Hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentyne 2-, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3_hexynyl, 2,4-hexa
- Unsaturated aliphatic hydrocarbon group having up to 8 carbon atoms eg, alkenyl group having 2 to 8 carbon atoms, alkadienyl group having 4 to 8 carbon atoms, alkenyl alkynyl group having 2 to 8 carbon atoms, alkadinyl having 4 to 8 carbon atoms
- alkenyl group having 2 to 8 carbon atoms alkadienyl group having 4 to 8 carbon atoms
- alkenyl alkynyl group having 2 to 8 carbon atoms alkadinyl having 4 to 8 carbon atoms
- an alicyclic hydrocarbon group having 3 to 7 carbon atoms is preferable.
- the alicyclic hydrocarbon group include a saturated alicyclic hydrocarbon group having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl (eg, cycloalkyl group);
- unsaturated alicyclic hydrocarbon groups having 5 to 7 carbon atoms eg, cycloalkenyl group, cycloalkadienyl group, and the like
- Examples of the alicyclic-aliphatic hydrocarbon group include those in which the alicyclic hydrocarbon group and the aliphatic hydrocarbon group are bonded (eg, a cycloalkyl monoalkyl group, a cycloalkenyl-alkyl group, and the like). Among them, an alicyclic monoaliphatic hydrocarbon group having 4 to 9 carbon atoms is preferable.
- Examples of the alicyclic monoaliphatic hydrocarbon group include: Mouth propylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, Cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl and the like.
- an araliphatic hydrocarbon group having 7 to 13 carbon atoms eg, an aralkyl group having 1 to 13 carbon atoms, an arylalkenyl group having 8 to 13 carbon atoms, and the like
- 7 to 13 carbon atoms eg, an aralkyl group having 1 to 13 carbon atoms, an arylalkenyl group having 8 to 13 carbon atoms, and the like
- Examples of the araliphatic hydrocarbon group include phenylalkyl having 7 to 9 carbon atoms such as benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl; Methyl, ⁇ -naphthylethyl, 3-naphthylmethyl, naphthylalkyl having 11 to 13 carbon atoms such as 3-naphthylethyl; phenylalkenyl having 8 to 10 carbon atoms such as styryl; 2- (2-naphthylvinyl And naphthylalkenyl having 12 to 13 carbon atoms.
- an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, an aryl group) is preferable.
- the aromatic hydrocarbon group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like, and among them, phenyl, 1-naphthyl and 2-naphthyl are preferred.
- the heterocyclic group in the “optionally substituted heterocyclic group” represented by R 1 may include, as a ring-constituting atom, an oxygen atom, a sulfur atom and a nitrogen atom other than a carbon atom. Examples thereof include a 5- to 7-membered monocyclic heterocyclic group or a fused heterocyclic group containing 1 to 4 selected hetero atoms.
- condensed heterocyclic ring examples include, for example, a condensed ring composed of a 5- to 7-membered monocyclic heterocyclic ring and a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring, or a 5-membered ring containing 1 sulfur atom.
- heterocyclic group examples include 2-pyridyl, 3-zelidyl, and 4-pyridyl. Lysyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3_pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, isooxazolyl, isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5 —Oxazolyl, 1,2,4—Oxaziaziroyl 5-yl, 1,3,4 Oxaziaziroyl 2-yl, 1,3,4-thiadiazole—2-yl, 1,2,4—
- the heterocyclic group is preferably pyridyl, oxazolyl, thiazolyl, benzoxazolyl or benzothiazolyl.
- substituents examples include an optionally substituted aliphatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, and an optionally substituted A good aromatic heterocyclic group, a non-aromatic heterocyclic group which may be substituted, a halogen atom, a nitro group, an amino group which may be substituted, an acyl group which may be substituted, and which may be substituted Examples thereof include a hydroxy group, a thiol group which may be substituted, and a carboxyl group which may be esterified or amidated.
- the "optionally substituted aliphatic hydrocarbon group, optionally substituted alicyclic hydrocarbon group, optionally substituted aromatic hydrocarbon group, optionally substituted aromatic heterocyclic group” examples include an alkyl group, ( ⁇ -6 alkoxy group, halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), nitro group, the number of mouth alkyl groups include C 3 _ 6 C port alkoxy group. substituents, for example 1 to three.
- the aliphatic hydrocarbon group a linear or branched of 1 to 1 to 5 carbon atoms
- examples include a branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group, and an alkynyl group.
- alkyl group examples include an alkyl group having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se-butyl, isopropyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl. Hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.
- alkenyl group examples include alkenyl groups having 2 to 10 carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-11-propyl, 1-butenyl, 2- Butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3_pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl Cenyl, 1-heptenyl, 1-octenyl and the like can be mentioned.
- alkynyl group examples include alkynyl groups having 2 to 10 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, and 3-pentynyl. , 4-pentinyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-1 heptynyl, 1-octynyl and the like.
- alicyclic hydrocarbon group examples include a saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms, such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkenyl group.
- cycloalkyl group examples include a cycloalkyl group having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, Bicyclo [4.3.1] decyl.
- cycloalkyl group having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicycl
- cycloalkenyl group examples include cycloalkenyl groups having 3 to 10 carbon atoms, for example, 2-cyclopentene-1-yl, 3-cyclopentene-1-yl, 2-cyclohexene-1-yl, 3 —Cyclohexene-11-yl and the like.
- cycloalkadienyl group examples include a cycloalkadienyl group having 4 to 10 carbon atoms, for example, 2,4-cyclopentadiene-1f, 2,4-cyclohexadiene-11yl, 2,5 — Cyclohexagene 11-yl, etc.
- the aromatic hydrocarbon group include an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, an aryl group), for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. Among them, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.
- Preferred examples of the aromatic heterocyclic group include, for example, furyl, phenyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazo Lil, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-one-year-old oxadiazolyl, 1,3,4-oxadiazolyl, furzanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1 , 3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, and other ring-constituting atoms other than carbon atoms, such as oxygen and sulfur 5- to 7-membered aromatic monocyclic heterocyclic group containing 1 to 4 heteroatoms
- non-aromatic heterocyclic group examples include those having 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring-constituting atom and having 2 to 10 carbon atoms.
- examples thereof include oxilanil, azetidinyl, oxedinyl, cedinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydroviranyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidino, morpholino, and thiomorpholino.
- halogen atoms include fluorine, chlorine, bromine and iodine, Of these, fluorine and chlorine are preferred.
- Examples of the amino group which may be substituted include an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, and 3 to 10 carbon atoms.
- a cycloalkenyl group of 1 to 13 carbon atoms eg, an alkanoyl group of 2 to 10 carbon atoms, an arylcarbonyl group of 1 to 13 carbon atoms, etc.
- the acyl group referred to herein has the same definition as the below-mentioned optionally substituted acyl group.
- substituted amino group examples include methylamino, dimethylamino, ethylamino, acetylamino, propylamino, dibutylamino, diarylamino, cyclohexylamino, acetylamino, propionylamino, benzoylamino, phenylamino, N-methyl-N-phenylamino, and the like. I can do it.
- acyl group in the optionally substituted acyl group examples include an acyl group having 1 to 13 carbon atoms, specifically, formyl, an alkyl group having 1 to 10 carbon atoms, and an alkyl group having 3 to 10 carbon atoms. Cycloalkyl group, alkenyl group having 2 to 10 carbon atoms, cycloalkenyl group having 3 to 10 carbon atoms, aryl group having 6 to 12 carbon atoms or aromatic heterocyclic group (eg, chenyl, furyl, pyridyl, etc.) And a carbonyl group.
- Preferred examples of the acryl group include, for example, acetyl, propionyl, butyryl, isoptyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanol, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, cycloheptanecarbonyl , 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, isonicotinoyl and the like.
- the acyl group may have 1 to 3 substituents at substitutable positions.
- substituents include an alkyl group having 1 to 3 carbon atoms, for example, an alkyl group having 1 to 3 carbon atoms.
- examples include an alkoxy group, a halogen (eg, fluorine, chlorine, iodine, etc.), nitro, hydroxy, amino and the like.
- Another form of the acyl group is represented by the following general formula.
- R 11 , R 14 , R 15 , R 16 and R 17 are the same or different and may be substituted hydrocarbon groups.
- Examples of the hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R 11 , R 14 , R 15 , R 16 and R 17 include an alkyl group having 1 to 10 carbon atoms and a carbon number of 3 A cycloalkyl group having up to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, and an aryl group having 6 to 12 carbon atoms.
- Examples of the substituent in the “optionally substituted hydrocarbon group” include a C 6 alkyl group (except when the hydrocarbon group is an alkyl group), an alkoxy group, and a halogen atom (eg, fluorine). , Chlorine, bromine, iodine, etc.), nitro group, haloalkyl group, C, -ehaloalkoxy group.
- the number of substitution groups is, for example, 1 to 3.
- examples of the substituted hydroxy group include an alkoxy group, an alkenyloxy group, an aralkyloxy group, an acryloxy group and an aryloxy group each of which may be substituted.
- alkoxy group examples include an alkoxy group having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, se-butoxy, shi-butoxy, pentyloxy, isopentyloxy, neopentyloxy.
- Xy hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
- alkenyloxy group examples include an alkenyloxy group having 2 to 10 carbon atoms, such as allyloxy, croteloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, and 2-cycloalkyl. Hexenylmethoxy and the like.
- aralkyloxy group examples include an aralkyloxy group having 7 to 10 carbon atoms, for example, phenyl-alkyloxy (eg, benzyloxy, phenoxy) Etc.) and the like.
- acyloxy group examples include an alkoxy group having 2 to 13 carbon atoms, more preferably an alkanoyloxy group having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, butyryloxy, isoptyryloxy, etc.) and the like. Are mentioned.
- aryloxy group examples include an aryloxy group having 6 to 14 carbon atoms, such as phenoxy and naphthyloxy.
- alkoxy group, alkenyloxy group, aralkyloxy group, acyloxy group and aryloxy group may have one or two substituents at substitutable positions.
- substituents include halogen (eg, fluorine, chlorine, bromine, etc.), and an alkoxy group having 1 to 3 carbon atoms.
- the substituted aryloxy group includes, for example, 4-chlorophenoxy, 2-methoxyphenoxy and the like.
- examples of the substituted thiol group include alkylthio, cycloalkylthio, aralkylthio, acylthio, arylthio, heteroarylthio and the like.
- alkylthio group examples include an alkylthio group having 1 to 10 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio, sodium butylthio, pentylthio, isopentylthio, and neopentyl. Pentylthio, hexylthio, heptylthio, nonylthio and the like.
- cycloalkylthio group examples include a cycloalkylthio group having 3 to 10 carbon atoms, for example, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
- aralkylthio group examples include carbon number? ⁇ 1 0 Ararukiruchio group, for example phenylene Lou C I 4 alkylthio (e.g., benzylthio, Fuenechiruchi O, etc.) and the like.
- acylthio group examples include an acylthio group having 2 to 13 carbon atoms, more preferably an alkanolthio group having 2 to 4 carbon atoms (eg, acetylthio, Pionylthio, butyrylthio, isobutyrylthio, etc.).
- alkanolthio group having 2 to 4 carbon atoms eg, acetylthio, Pionylthio, butyrylthio, isobutyrylthio, etc.
- arylthio group examples include an arylthio group having 6 to 14 carbon atoms, such as phenylthio and naphthylthio.
- heteroarylthio group examples include 2-pyridylthio, 3-pyridylthio and the like, 2-imidazolylthio, 1,2,4-triazole-5-ylthio and the like.
- the alkylthio group, cycloalkylthio group, aralkylthio group, acylthio group and arylthio group, and heteroarylthio group may have one or two substituents at substitutable positions.
- substituents include halogen (eg, fluorine, chlorine, bromine and the like), an alkoxy group having 1 to 3 carbon atoms, and the like.
- examples of the carboxyl group which has been esterified include alkoxycarbonyl groups having 2 to 5 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), 8 to 10 aralkyloxycarbonyl groups (eg, benzyloxycarbonyl, etc.), 1 to 2 carbon atoms which may be substituted by an alkyl group having 1 to 3 carbon atoms? ⁇ 15 aryloxycarbonyl groups
- R 12 and R 13 are the same or different and each represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
- hydrocarbon group in the ⁇ optionally substituted hydrocarbon group '' and the heterocyclic group in the ⁇ optionally substituted heterocyclic group '' represented by R 12 and R 13 are respectively the same as those described above.
- exemplified fat as and "hydrocarbon group in the" optionally substituted carbon hydrocarbon group "represented by scale 1", “heterocyclic group in represented by scale 1" optionally substituted heterocyclic group "," Group hydrocarbon group, lunar Examples include a cyclic hydrocarbon group, an aromatic hydrocarbon group, and a heterocyclic group.
- the hydrocarbon group and the heterocyclic group may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include halogen (eg, fluorine, chlorine, bromine). , Iodine, etc.), an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and the like.
- the substituent in the hydrocarbon group and the heterocyclic group represented by R 1 is preferably an alkyl group having 1 to 10 carbon atoms, an aromatic heterocyclic group, or an aryl having 6 to 14 carbon atoms. And more preferably alkyl having 1 to 3 carbon atoms, furyl, phenyl, phenyl, phenyl, naphthyl.
- Substituents on the hydrocarbon group and the heterocyclic group represented by R 1 are, when they are an alicyclic hydrocarbon group, an aromatic hydrocarbon group, an aromatic heterocyclic group or a non-aromatic heterocyclic group, Each substituent may have one or more, preferably 1 to 3 suitable substituents, such as an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, A cycloalkyl group having 3 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms (eg, phenyl, naphthyl, etc.), an aromatic heterocyclic group (eg, chenyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), non- Aromatic heterocyclic group (eg, tetrahydrofuryl, morpholino, thiomololino, piperidino, pyrrolidinyl, piperazinyl, etc.),
- Examples include a thio group (eg, phenylthio, naphthylthio, etc.), a sulfo group, a cyano group, an azide group, a nitro group, a nitroso group, and a halogen atom (eg, fluorine, chlorine, bromine, iod
- R 1 is preferably an optionally substituted heterocyclic group, and more preferably an optionally substituted pyridyl, oxazolyl, thiazolyl or triazolyl.
- R 1 is particularly preferably pyridyl, oxazolyl which may have 1 or 2 substituents each selected from alkyl having 13 carbons, cycloalkyl having 37 carbons, furyl, phenyl, phenyl, phenyl and naphthyl , Thiazolyl or triazolyl.
- furyl, phenyl, phenyl, and naphthyl are substituted with alkyl having 13 carbons, alkoxy having 13 carbons, halogen (eg, fluorine, chlorine, bromine, iodine, etc.) or haloalkyl having 13 carbons. It may have one or two.
- R 1 include an optionally substituted heterocyclic group or an optionally substituted cyclic hydrocarbon group represented by the following formula.
- These groups may have one or two substituents selected from phenyl, furyl, phenyl and alkyl having 14 carbon atoms.
- the phenyl, furyl and phenyl are alkyl having 16 carbons, alkoxy having 16 carbons, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, haloalkyl having 16 carbons, carbon having 1 carbon It may have one or two substituents selected from the above 6 alkoxy.
- Alkyl having 14 carbon atoms means alkoxy having 16 carbon atoms, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), It may have one or two substituents selected from nitro, haloalkyl having 1 to 6 carbon atoms, and haloalkoxy having 1 to 6 carbon atoms.
- halogen eg, fluorine, chlorine, bromine, iodine, etc.
- R 1 is more preferably a group represented by the following formula. ,
- Ph represents an optionally substituted phenyl group
- R ′′ represents a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms.
- Examples of the substituent in the phenyl group represented by Ph and the alkyl group having 1 to 6 carbon atoms represented by R “include alkoxy having 1 to 6 carbon atoms, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), Examples thereof include nitro, haloalkyl having 1 to 6 carbon atoms, and haloalkoxy having 1 to 6 carbon atoms
- the number of substituents is, for example, 1 to 3.
- X is a bond, -CO-, -CH (OH) one or - a group NR 6 one (R 6 represents a hydrogen atom or an optionally substituted alkyl group) represented by And a bond, —CH (OH) — or —NR 6 — is preferable, and a bond or one NR 6 — is more preferable.
- alkyl group in the “optionally substituted alkyl group” represented by R 6 an alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se- Butyl, -butyl and the like.
- the alkyl group may have 1 to 3 substituents at substitutable positions.
- substituents examples include halogen (eg, fluorine, chlorine, bromine, iodine) and carbon atoms of 1 ⁇ 4 alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, se-butoxy, t.-butoxy, etc.), hydroxy group, nitro group, C 1-4 acyl group (Examples are C1-C4 alkenyl groups such as formyl, acetyl, and propionyl).
- n represents an integer of 1 to 3, and is preferably 1 or 2.
- Y represents —O—, one S—, one S ⁇ , —S ⁇ 2— or —NR 7 — (R 7 represents a hydrogen atom or an optionally substituted alkyl group. ), But preferably 100%, 1S— or —NR 7 —.
- R 7 represents a hydrogen atom or an optionally substituted alkyl group.
- examples of the “optionally substituted alkyl group” represented by R 7 include the same as the aforementioned “optionally substituted alkyl group” represented by R 6 .
- ring A represents a benzene ring, and the benzene ring may further have 1 to 3 substituents at substitutable positions.
- substituents include an alkyl group, an optionally substituted hydroxy group, a halogen atom, an optionally substituted acyl group, a nitro group, and an optionally substituted diamino group, As these, those exemplified as the substituents in the hydrocarbon group and the heterocyclic group represented by R 1 are used.
- the substituent is preferably an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halogen atom.
- p represents an integer of 1 to 8, and is preferably an integer of 1 to 3.
- R 2 is preferably an optionally substituted hydrocarbon group.
- R 2 is more preferably an optionally substituted aliphatic hydrocarbon group, alicyclic hydrocarbon group, araliphatic hydrocarbon group or aromatic hydrocarbon group, and particularly preferably An alkyl group having 1 to 4 carbon atoms, a phenylalkenyl group having 8 to 10 carbon atoms, and an aryl group having 6 to 14 carbon atoms.
- the substituents which these hydrocarbon groups may have are preferably a halogen atom, an alkoxy group having 1 to 4 carbon atoms, an aryloxy group having 6 to 14 carbon atoms, and an aromatic heterocyclic group (eg, furyl, chenyl) ).
- the number of substituents is, for example, 1 to 3. (7) Definition of q and m
- Q represents an integer of 0 to 6, preferably 0 to 4.
- m is 0 or 1.
- R 3 is a hydroxy group
- R 8 represents an optionally substituted hydrocarbon group
- R 9 and R 1 Q are the same or different and are hydrogen atoms
- substituted Re represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted acyl group
- R 9 and R 1 Q may be combined to form a ring.
- examples of the “optionally substituted hydrocarbon group” represented by R 8 include those exemplified as the “optionally substituted hydrocarbon group” represented by R 1 .
- R 8 is “an alkyl group having 1 to 4 carbon atoms” and “an alkyl group having 1 to 4 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with a halogen atom”.
- examples of the alkyl group having 1 to 4 carbon atoms include methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, and t-butyl, and among them, methyl and ethyl are preferable.
- halogen in the ⁇ alkyl group having 1 to 4 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted by a halogen atom '' include fluorine, chlorine, bromine, and iodine.
- aryl group having 6 to 10 carbon atoms include phenyl and naphthyl, with phenyl being preferred.
- the ⁇ optionally substituted acyl group '' represented by the ⁇ optionally substituted hydrocarbon group '' exemplified as the substituent which the ⁇ optionally substituted hydrocarbon group '' represented by R 1 may have And the same as the “good acyl group”.
- R 9 and R 1 Q may combine to form a 5- to 7-membered cyclic amino group, and specific cyclic amino groups include 1-pyrrolidinyl, 1-piberidinyl, 1-hexamethyleneiminyl, 4 One morpholino, 4-thiomorpholino and the like. (9) Definition of R 4 and R 5
- R 4 and R 5 are the same or different and each represent a hydrogen atom or an optionally substituted hydrocarbon group, and R 4 may be bonded to R 2 to form a ring. Good.
- R 4 may be bonded to R 2 to form a ring.
- the ring formed by the bonding of R 4 and R 2 include a cycloalkene having 5 to 11 carbon atoms and a cycloalkene having 5 to 11 carbon atoms, and specifically, cyclopentane Cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, cyclooctane, cyclooctene, cyclononane, cyclononene, cyclodecane, cyclodecene, cycloundecane and cycloundecene.
- the compound represented by the general formula (I) has (E) -form and (Z) -form with respect to imino bond.
- the compound includes the (E) -form and the (Z) -form alone and a mixture thereof.
- Preferred specific examples of the compound represented by the general formula (I) include a compound represented by the following general formula.
- R ′ is alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, alkyl having 1 to 6 carbons and R "represents a hydrogen atom or an optionally substituted C1-C6 phenyl, furyl or phenyl group, each of which may be substituted with one or two substituents selected from haloalkoxy having 1-6 carbon atoms; 6 alkyl
- R 2 ′ is a hydrogen atom, A phenyl group which may be substituted with at least one substituent selected from the group consisting of alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, and halogen;
- Q is an integer of 1 to 6;
- R 3 ′ is hydroxy, alkoxy having 1 to 6 carbon atoms, or — a group represented by NR 9 R 1Q (R 9 and R 1G are the same or different and are a hydrogen atom, an optionally substituted hydrocarbon group, Represents an optionally substituted heterocyclic group, an optionally substituted acyl group, or R 9 and R 1 Q may combine to form a ring.);
- Ring A is substituted Or a salt thereof.] Or a salt thereof.
- Preferred specific examples of the compound represented by the general formula (I) include a compound represented by the following general formula.
- Preferred examples of the compound represented by the general formula (I) include, for example, the following compounds (1) to (10).
- a salt of the compound represented by the general formula (I) (hereinafter may be simply abbreviated as compound (I))
- a pharmacologically acceptable salt is preferable.
- a salt with an inorganic base examples thereof include salts with bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.
- the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt.
- Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like. Salts.
- salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluenesulfonic acid and the like.
- Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like.
- Preferred examples of the salt with an acidic amino acid include For example, salts with aspartic acid, dalminic acid and the like can be mentioned.
- Compound (I) can be produced, for example, according to the method described in JP-A-2000-34266 (Japanese Patent Application No. 11-130543, WO 99/58510). Examples of such a method include the following manufacturing method.
- Z is a hydroxy group, a halogen atom or RS ⁇ 2 R 18 (R 18 is an alkyl group having 1 to 4 carbon atoms, and may be substituted with an alkyl group having 1 to 4 carbon atoms, Represents an aryl group of 10.) represents a group represented by, and the other symbols have the same meanings as described above. ]
- Examples of the alkyl group of 4 include methyl, ethyl, propyl, and Examples include isopropyl, butyl, isobutyl, sec.-butyl, and t.-butyl, with methyl being preferred.
- compound (II) is produced by reacting compound ( ⁇ ⁇ ) with compound (IV).
- this reaction is carried out by a method known per se, for example, the method described in Synthesis, page 1, (1981), or a method analogous thereto. That is, this reaction is usually performed in the presence of an organic phosphorus compound and an electrophile in a solvent that does not adversely affect the reaction.
- organic phosphorus compound examples include triphenylphosphine, triptylphosphine, and the like.
- electrophilic agent examples include getyl azodicarboxylate, diisopropyl azodicarboxylate, azodicarbodilpiperazine and the like.
- the amount of the organic phosphorus compound and the electrophilic agent to be used is preferably 1 to 5 molar equivalents relative to compound (IV).
- Solvents that do not adversely affect the reaction include, for example, ethers such as getyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; and aromatic hydrocarbons such as benzene, toluene, and xylene. Amides such as N, N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
- the reaction temperature is usually from ⁇ 50 to 150 ° C., preferably from ⁇ 10 to: L 0 ° C.
- the reaction time is 0.5 to 20 hours.
- a group Z is represented by a halogen atom or OS_ ⁇ 2 R 1 8
- this reaction is carried out according to a conventional method, the presence of a base in a solvent that does not adversely influence the reaction.
- a base for example, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate Alkali metal salts such as lithium and potassium carbonate; amines such as pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] pentacar 7-ene; potassium hydride, Metal hydrides such as sodium hydride; and metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t.-butoxide.
- the amount of the base to be used is preferably 1 to 5 molar equivalents relative to compound (IV).
- solvents that do not adversely affect the reaction include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran and dioxane; ketones such as acetone and 2-butaneone; Halogenated hydrocarbons such as oral form and dichloromethane; amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide. These solvents may be used in a mixture at an appropriate ratio.
- aromatic hydrocarbons such as benzene, toluene, and xylene
- ethers such as tetrahydrofuran and dioxane
- ketones such as acetone and 2-butaneone
- Halogenated hydrocarbons such as oral form and dichloromethane
- amides such as N, N-dimethylformamide
- sulfoxides such as dimethyl sulfoxide.
- the reaction temperature is usually from 50 to: L50T, preferably from -10 to 100 ° C.
- the reaction time is usually 0.5 to 20 hours.
- This hydrolysis reaction is carried out in a water-containing solvent in the presence of an acid or a base according to a conventional method.
- Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, and hydrobromic acid.
- Examples of the base include alkali metal carbonates such as potassium carbonate and sodium carbonate; alkali metal alkoxides such as sodium methoxide; alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide.
- the amount of the acid or base used is usually in excess with respect to the compound (II).
- the amount of the acid used is 2 to 50 equivalents to the compound (II)
- the amount of the base used is 1.2 to 5 equivalents to the compound (II).
- aqueous solvent examples include alcohols such as methanol and ethanol; Ethers such as tetrahydrofuran and dioxane; and a mixed solvent of water with one or more solvents selected from dimethyl sulfoxide, acetone, and the like.
- the reaction temperature is usually from -20 to 15 Ot :, preferably from 1 to 10: L00.
- the reaction time is usually 0.1 to 20 hours.
- the compounds (II) and (II ") thus obtained are isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. be able to.
- the compound ( ⁇ ) and the compound (IV) used as the starting compound in the above-mentioned production method are known compounds.
- the compound (III) in which Z is a hydroxy group is described in EP-A 710659.
- the compound ( ⁇ ) is described in EP-A 629624 (JP-A-7-53555), WO 98/03505 and the like.
- compound (III) can also be produced by a method according to the method described in these publications.
- the compound (IV) is described in, for example, European fur Praktician Chemie, Vol. 31, pp. 370 (1969); Canadian Journal of Chemistry, Vol. 48, 1948. Page (1970); Journal of Heterocyclic Chemistry, 25, 1283 (1988), and the like.
- Compound (IV) can also be produced by a method according to the method described in these documents.
- the PPAR ⁇ agonist-like substance and the PPARagonist-like substance are not limited to the above examples, and any substance can be used as long as it has such an action. Further, they may further have a PP ARa function regulating action (agonist or angolinist action).
- P PAR (5-agonist-like action and P PAR agonist-like action).
- P PAR (5-agonist-like action and P PAR agonist-like action).
- Specific examples of such substances include the above-mentioned compound (I), YM-16638 (supra), p- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] phenylbutyric acid (previously described). ), 5— [3— [4-1-((5-Methyl-2-phenyl-1,3-thiazole_4-yl) methoxy] phenyl] propyl] -1,1,3-oxazolidine—2, 4 dione (see above).
- compositions each containing a PPAR ⁇ agonist-like substance and a PPARagonist-like substance are also an embodiment of the present invention.
- preferred combinations include, for example, the insulin resistance PP AR agonists of improvers (eg, troglitazone, rosiglitazone, englitazone, sigliyuzon, pioglisunzone, etc.) and the carbaprostacycl in (cPGI), L-
- Compound (I) itself has both P PAR (5-agonist-like action and P PAR agonist-like action) properties, and thus can be used in combination with an insulin resistance improving agent.
- the dose of the agent of the present invention may be within the effective dose range of each substance.
- the active substance and the P PAR ⁇ agonist-like active substance are the same substance, they may be within the effective dose of the substance.
- the dosage When the agent of the present invention is orally administered to, for example, an adult diabetic patient (body weight: 60 kg), the dosage may be, for example, about 0.1 to about 60 as a PPARagonist-like active substance or a PPAR ⁇ agonist-like active substance.
- Omg / day preferably about 12 to about 24 Omg / day. These amounts may be administered once a day or may be administered in two or three divided doses.
- the agent of the present invention has low toxicity, and is useful for mammals (eg, humans, mice, rats, rabbits, dogs, cats, rabbits, horses, pigs, monkeys, etc.) for various diseases described below. It can be used as a preventive and therapeutic agent.
- the agent of the present invention may contain a pharmacologically acceptable carrier.
- various organic or inorganic carrier substances commonly used as a drug substance can be used, such as excipients, lubricants, binders, and disintegrants in solid preparations; solvents, dissolution aids, and suspensions in liquid preparations.
- a turbidity agent, tonicity agent, buffering agent, soothing agent and the like can be used.
- excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, Gum arabic, dextrin, pullulan, light caustic anhydride, synthetic aluminum silicate, magnesium aluminate metasilicate, and the like.
- Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like.
- Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, arabia gum, methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, Hydroxypropyl methylcellulose, polyvinylpyrrolidone and the like.
- Preferred examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, light gay anhydride, low-substituted hydroxypropylcellulose, and the like.
- the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
- solubilizers include, for example, polyethylene glycol, Examples include lenglycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and the like.
- suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; Hydrophilic polymers such as alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.
- surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate
- Hydrophilic polymers such as alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropyl
- Preferred examples of the tonicity agent include sodium chloride, glycerin, D-manniyl, D-sorbitol, glucose and the like.
- buffers such as phosphate, acetate, carbonate, citrate and the like.
- the soothing agent include benzyl alcohol and the like.
- preservatives include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
- Preferred examples of the antioxidant include, for example, sulfite, ascorbate and the like.
- the colorant include, for example, water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows 4 and 5, edible blue Nos. 1 and 2, water-insoluble lake dyes) (Eg, aluminum salt of the water-soluble edible tar dye, etc.), and natural pigments (eg,; 3-potency rotin, chlorophyll, bengalara, etc.).
- water-soluble edible tar dyes eg, edible dyes such as edible red Nos. 2 and 3, edible yellows 4 and 5, edible blue Nos. 1 and 2, water-insoluble lake dyes
- natural pigments eg,; 3-potency rotin, chlorophyll, bengalara, etc.
- sweeteners include, for example, sodium saccharin, glycyrrhiz Nini potassium, aspartame, stevia and the like.
- the agent of the present invention may be a single preparation containing both substances, or may contain only one of them. Two different formulations may be used. In that case, the dosage forms of the drug product do not need to be identical. As these preparations, dosage forms usually used in medicine are appropriately selected for each active ingredient.
- Examples of the dosage form of the agent of the present invention include oral preparations such as tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions, and suspensions; and injections (eg, subcutaneous injections) Preparations, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (eg, nasal preparations, transdermal preparations, ointments, etc.), suppositories (eg, rectal suppositories, vaginal suppositories) And parenteral preparations such as pellets, drops and sustained-release preparations, which can be safely administered orally or parenterally, respectively.
- oral preparations such as tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions, and suspensions
- injections eg, subcutaneous injections
- Preparations eg, intravenous injections, intramuscular
- the agent of the present invention can be produced by a method commonly used in the technical field of formulation, for example, the method described in the Japanese Pharmacopoeia. Hereinafter, the specific production method of the drug product will be described in detail.
- active ingredients include, for example, excipients (eg, lactose, sucrose, starch, D-mannitol, etc.), disintegrants (eg, carboxymethylcellulose cellulose, etc.), binders (eg, pregelatinized starch) , Gum arabic, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 600, etc.) and compression-molded.
- excipients eg, lactose, sucrose, starch, D-mannitol, etc.
- disintegrants eg, carboxymethylcellulose cellulose, etc.
- binders eg, pregelatinized starch
- Gum arabic carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.
- lubricants eg, talc, magnesium stearate, polyethylene glycol 600, etc.
- the coating base examples include a sugar coating base, a water-soluble film coating base, an enteric film coating base, a sustained release film coating base, and the like.
- a sugar-coating base sucrose is used, and one or more kinds selected from talc, precipitated calcium carbonate, gelatin, acacia, pullulan, carnapalow and the like may be used in combination.
- water-soluble film coating base examples include cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinylacetate-rugetylaminoacetate, aminoalkyl Synthetic polymers such as methacrylate copolymer E (Eudragit E (trade name), Rohm Pharma Co., Ltd.) and polyvinylpyrrolidone; and polysaccharides such as pullulan.
- cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose
- polyvinylacetate-rugetylaminoacetate aminoalkyl Synthetic polymers
- methacrylate copolymer E Eudragit E (trade name), Rohm Pharma Co., Ltd.) and polyvinylpyrrolidone
- polysaccharides such as pullulan.
- enteric film coating base examples include cellulosic polymers such as hydroxypropyl pyrmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; L (Eudragit L (trade name), Kuchiichi Mufarma Co., Ltd.), Copolymer methacrylate LD (Eudragit L-1 30 D55 (trade name), Rohm Farma Co., Ltd.), methacrylic acid copolymer S (Eudragit S ( Acrylic acid-based polymers such as trade name) and Rohm Pharma Co .; natural products such as shellac.
- cellulosic polymers such as hydroxypropyl pyrmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate
- L Eudragit L (trade name), Kuchiichi Mufarma Co., Ltd.)
- sustained-release film coating base examples include cellulosic polymers such as ethylcellulose; aminoalkyl methacrylate copolymer RS [Odragit RS (trade name), Rohm Pharma Co., Ltd.]; Acrylic acid-based polymers such as methyl acrylate copolymer suspension [Eudragit NE (trade name), Rohm Pharma Co., Ltd.].
- the above-mentioned coating bases may be used by mixing two or more kinds thereof at an appropriate ratio.
- a light-shielding agent such as titanium oxide or iron sesquioxide may be used.
- Injectables contain active ingredients as dispersants (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, etc.), polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc., preservatives (eg, methyl paraben, Propylparaben, benzyl alcohol, chlorobutanol, phenol, etc.), tonicity agent (eg, sodium chloride, glycerin, D-mannitol, D-sorbitol, dextrose, etc.) and aqueous solvents (eg, distilled water, physiological saline) It is manufactured by dissolving, suspending, or emulsifying in an oily solvent (eg, vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol, etc.).
- an oily solvent eg, vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol, etc.
- additives such as a solubilizing agent (eg, sodium salicylate, sodium acetate, etc.), a stabilizer (eg, human serum albumin, etc.), a soothing agent (eg, benzyl alcohol, etc.) may be used. .
- solubilizing agent eg, sodium salicylate, sodium acetate, etc.
- a stabilizer eg, human serum albumin, etc.
- a soothing agent eg, benzyl alcohol, etc.
- oral preparations such as tablets and capsules are particularly preferred from the viewpoint of convenience of administration.
- the agent of the present invention is effective in suppressing the weight gain observed in patients with various diseases (eg, diabetes) taking PPAR agonist-like active substances (eg, insulin sensitizers). It is useful for the treatment and prevention of ⁇ -related diseases (eg, hypercholesterolemia, hypoHDLemia).
- the agent of the present invention suppresses the increase in body weight derived from a PPAR agonist-like agent observed in patients taking a PPAR agonist-like agent (eg, a patient with diabetes mellitus) to, for example, about 80% or less. be able to.
- a PPAR agonist-like agent eg, a patient with diabetes mellitus
- the agent of the present invention includes, for example, diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, postprandial hyperlipidemia) ), Diabetic complications (eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, etc.), impaired glucose tolerance (IGT), obesity, osteoporosis, cachexia (eg, Cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological cachexia, endocrine disease cachexia, cachexia due to infectious cachexia or acquired immunodeficiency syndrome), fatty liver, hypertension, many Cystic ovary syndrome, gestational diabetes mellitus, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive renal sclerosis, end-stage renal disease, etc.), muscular
- the agent of the present invention can also be used in the treatment for the purpose of improving insulin resistance, enhancing insulin sensitivity, and suppressing the transition from impaired glucose tolerance to diabetes.
- the agent of the present invention can be used to regulate appetite and food intake in patients undergoing treatment for diabetes.
- diabetes is defined as a fasting blood glucose level (Dalcos concentration in venous plasma) of 126 mgZd or more, 75 g transglucose tolerance test (75 g OGTT), and a 2-hour value (glucose concentration in venous plasma). Is 200 mgZd 1 or more, and the blood glucose level (glucose concentration in venous plasma) is 200 mgZd 1 or more.
- diabetes is defined as a fasting blood glucose level (glucose concentration in venous plasma) of 126 mgZd 1 or more, and a 2-hour value of glucose in a 75 g glucose tolerance test (glucose concentration in venous plasma). This is a state showing 200 mgZd l or more.
- impaired glucose tolerance refers to a fasting blood glucose level (glucose concentration in venous plasma) of less than 126 mg Zd1 and a 2-hour value of 75 g translobulin glucose tolerance test (venous plasma Is less than 140 mg / dI and less than 20 Omg / d1.
- the ADA reported that fasting blood glucose (venous plasma glucose) was 11 Omg.
- the state of Zd 1 or more and 126 mg Zd 1 or less is called IFG (Impaired Fasting Glucose).
- IFG Impaired Fasting Glucose
- the condition that the 2-hour value (glucose concentration in venous plasma) of the 75 g transglucose tolerance test is less than 14 OmgZd 1 is defined as IFG (Impaired Fasting Glucose). Fasting Glycemia).
- the agent of the present invention is also used as a prophylactic / therapeutic agent for diabetes, borderline type, impaired glucose tolerance, I FG (I immediately aired Fasting Glucose) and I FG (Impaired Fasting Glycemia) determined by the above new criteria.
- the agent of the present invention can also prevent the progression from borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) to diabetes.
- the agent of the present invention includes agents for treating diabetes, agents for treating diabetic complications, antihyperlipidemic agents, antihypertensive agents, diuretics, chemotherapeutic agents, immunotherapeutic agents, etc. ) Can be used in combination.
- the agent of the present invention itself may contain these concomitant drugs.
- the term “combination” may mean either a form in which separate drugs are administered or a form in which a single drug is combined.
- the timing of administration of the agent of the present invention and the concomitant drug is not limited, and they may be administered to the subject at the same time or with a time lag. Further, two or more concomitant drugs may be used in combination at an appropriate ratio.
- the dose of the concomitant drug can be appropriately selected based on the clinically used dose of each drug.
- the compounding ratio of the agent of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination, and the like.
- the antidiabetic agent examples include insulin preparations (eg, animal insulin preparations extracted from the tongue of P. elegans and bushus; human insulin preparations that have been genetically synthesized using Escherichia coli and yeast).
- Darcosidase inhibitor eg, Glibose, acarbose, miglitol, emiglitate, etc.
- biguanides eg, phenformin, metformin, buformin, etc.
- insulin secretagogues eg, sulfonylprea agents (eg, tolbumid, dalibenclamide, gliclazide, chlorid) Propamide, tolazamide, acetohexamide, glicloviramide, glimepiride, glibizide, dalibzole, etc.), repaglinide, senaglinide, nateglinide, mitiglinide or its calcium salt hydrate, GLP-1 etc.], amylinagonist (eg, pr
- Therapeutic agents for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalles evening, zenarestat, zopolrestat, minal restat, fidales evening, SNK-860, (: 1-11, etc.) , Neurotrophic factors (eg, NGF, NT-3, BDNF, etc.), neurotrophic factor production enhancers, PKC inhibitors (eg, LY-333531, etc.), AGE inhibitors (eg, ALT946, pimagedin, pyratoxatin, N_phenacyl thiazolium bromide (ALT 766), EXO-226, etc., active oxygen scavenger (eg, thioic acid, etc.), cerebral vasodilator (eg, tiapride, mexiletine, etc.)
- statin compounds that are cholesterol synthesis inhibitors (eg, pravathine, simbasthine, oral bath,
- Antihypertensive drugs include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, oral salinine, candesartan cilexetil, eprosartan, valsantan, telmisartan, ilbesartan, tazosartan) And calcium antagonists (eg, manidipine, difludipine, amronidipine, efonidipine, dicardipine, etc.) and the like.
- angiotensin converting enzyme inhibitors eg, captopril, enalapril, delapril, etc.
- angiotensin II antagonists eg, oral salinine, candesartan cilexetil, eprosartan, valsantan, telmisartan, ilbesartan, tazosartan
- calcium antagonists eg
- anti-obesity agents include central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampuepramone, dexamphetamine, mazindol, phenylpropanolamine, clovenzolex, etc.), Lipase inhibitors (eg, orulis sunset),) 33 agonists (eg, CL-316243, SR-5861 1-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140, etc.), peptide appetite suppressants (eg, lebutin, CNTF (ciliary neurotrophic factor), etc.), cholecystokininagonist (eg, lynch tribute, FPL-15849, etc.), etc. .
- central anti-obesity agents eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampue
- diuretics examples include xanthine derivatives (eg, sodium theobromine salicylate, calcium theopromine salicylate, etc.), thiazide-based preparations (eg, ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, ventilhydrochloride) Oral thiazide, penflutide, polythiazide, methyclothiazide, etc., anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, casease zolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlortarari) , Mefluside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid, pyrethrinide, bumetanide, fu
- Chemotherapeutic agents include, for example, alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexet, 5-fluoroperacil, etc.), anticancer antibiotics (eg, mitomycin, Adriamycin, etc.), plant-derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cis bratin, carboblatin, etopoxide and the like.
- alkylating agents eg, cyclophosphamide, ifosfamide, etc.
- antimetabolites eg, methotrexet, 5-fluoroperacil, etc.
- anticancer antibiotics eg, mitomycin, Adriamycin, etc.
- plant-derived anticancer agents eg, vincristine, vindesine, taxol, etc.
- cis bratin carboblatin, etopoxide and the like.
- Immunotherapeutic agents include, for example, microbial or bacterial components (eg, Murami
- cytotoxicity obtained by genetic engineering techniques (eg, interferon, interleukin (IL), etc.), colony sting Extensive factors (eg, granulocyte colony stimulating factor, erythropoietin, etc.) and the like, among which IL-11, IL_2, IL-12 and the like are preferable.
- IL-11, IL_2, IL-12 and the like are preferable.
- drugs that have been shown to improve cachexia in animal models and clinically ie, cyclooxygenase inhibitors (eg, indomethacin, etc.) [Cancer-Research, 49 Vol., 5935-5939, 1989], progesterone derivatives (eg, megesterol acetate) [Journal of Clinical Oncology, Vol. 12, pp.
- Carbohydrate steroids eg, dexamethasone, etc.
- metoclobramide drugs e.g., metoclobramide drugs
- tetrahydrocannabinol drugs all references are the same as above
- fat metabolism improvers eg, eicosapentaenoic acid, etc.
- growth hormone IGF-1 or cachexia Is a factor that guide TNF- shed, L I F, I L- 6, also including antibodies to Onkosu evening Chin M may be used in conjunction with the present invention a pharmaceutical.
- Preferred examples of the concomitant drug include the following.
- Insulin secretagogues such as sulfonylurea agents
- Insulin secretagogues such as sulfonylprea agents and biguanides
- Insulin secretagogues such as sulfonylprea agents and mono-dalcosidase inhibitors
- Insulin sensitizer for example, active substance for PPARragonist
- 12 a combination of an insulin sensitizer and the agent described in 1) to 10) above;
- the agent of the present invention When the agent of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range considering the adverse effects of those agents.
- insulin dosage enhancers such as insulin preparations and sulfonylprea agents and biguanides can be reduced from the usual dosage. Therefore, side effects that may be caused by these agents can be safely prevented.
- the dosage of diabetic complications, antihyperlipidemics and antihypertensives can be reduced, effectively preventing the side effects that might be caused by these agents.
- the PCR was carried out using
- the PCR reaction was performed by the Hot Start method using AmpliWax PCR Gem 100 (Takara Shuzo).
- 10 1 of 10X LA PCR Buffer 2 l ⁇ K 2.5 mM dNTP solution 31 and 12.5 uM primer solution 1 were mixed with 10 1 of 2.5 K sterile distilled water.
- 10 1 of human heart cDNA (Ong / ml) as type II, 10 x LA PCR Buffer 31, 2.5 mM dNTP solution 11, TaKaRa LA Taq DA polymerase (Takara Shuzo) 0.5 iK sterile distilled water 24.5 1 were mixed.
- One Ampli Wax PCR Gem 100 (Takara Shuzo) was added to the prepared lower layer mixture, treated at 70 ° C for 5 minutes and on ice for 5 minutes, and the upper layer mixture was added to prepare a PCR reaction solution.
- the tube containing the reaction solution was set in a thermal cycler (Pakkin Elmer Co., Ltd.) and treated at 95 ° C for 2 minutes. Further, a cycle of 95 ° C for 15 seconds and 68 ° C for 2 minutes was repeated 45 times, followed by treatment at 72 ° C for 8 minutes.
- telomere sequence is recovered from the gel, and then inserted into the pT7Blue-T vector (Takara Shuzo) to generate plasmid pTBT-.
- hPPAR ⁇ was prepared.
- the human RXR ⁇ gene was cloned using a kidney cDNA (manufactured by Toyobo, trade name: QUICK-Clone cDNA) as type III, and reported by Mangelsdori, D. and others. Nature, 1990, 345 (6272), 224—229].
- XRA-L 5 '-CCC CTC GAG CTA AGT CAT TTG GTG CGG CGC CTC-3' (SEQ ID NO: 4)
- the PCR reaction was performed by the Hot-Start method using A Immediate liWax PCR Gem 100 (Takara Shuzo).
- human kidney cDNA (1 ngZml) was used as type III in 1, 10 XLAP CR Buffer 31, 2.5 mM d NTP solution lxl, TaKaRa LA Taq DNA polymerase (Takara Shuzo) 0.5 ⁇ .
- Sterile distilled water 24.5 1 was mixed to obtain an upper layer mixture.
- One AmpliWax PC Gem 100 (manufactured by Takara Shuzo) was added to the lower mixture, and the mixture was treated at 70 ° C. for 5 minutes and on ice for 5 minutes, and the upper mixture was added to prepare a PCR reaction solution.
- the tube containing the reaction solution was set on a thermocycler (manufactured by PerkinElmer Inc., USA), and then treated at 95 ° C for 2 minutes. Further, a cycle of 15 seconds at 95 and a cycle of 2 minutes at 68 ° C was repeated 35 times, followed by treatment at 72 for 8 minutes.
- the resulting PCR product was subjected to agarose gel (1%) electrophoresis, and a 1.4 kb DNA fragment containing the RXRa gene was recovered from the gel.
- the fragment was inserted into pT7Blue-II vector (Takara Shuzo), and plasmid pTBT — I got hRXR ⁇ .
- the plasmid pTBT-hPPAR ⁇ described in Preparation Example 1 was cleaved with Sail, and then blunt-ended by T4 DNA polymerase (Takara Shuzo) treatment. Then cut with Kpnl As a result, a 1.4 kb DNA fragment containing the PPAR ⁇ gene was obtained.
- the plasmid ⁇ VgRXR2-hPPAR (5 was constructed by ligating both fragments.
- a DNA fragment containing the PPAR-responsive element (PPRE) of acyl CoA oxidase was prepared using the following 5'-terminal phosphorylated synthetic DNA.
- PPRE-U 5'-pTCGACAGGGGACCAGGACAAAGGTCACGTTCGGGAG-3 '(SEQ ID NO: 5)
- PPRE-L 5'-pTCGACTCCCGAACGTGACCTTTGTCCTGGTCCCCTG-3' (SEQ ID NO: 6) It was inserted into the Sail site of pBlueScript SK +. By determining the nucleotide sequence of the inserted fragment, a plasmid pBS S—P PRE4 in which four PPREs were linked in tandem was selected.
- TK promoter thymidine 'kinase' minimum 'Thymidine kinase minimum promoter
- TK-U 5'-CCCAGATCTCCCCAGCGTCTTGTCATTG-3 '(SEQ ID NO: 7)
- TK-L 5'-TCACCATGGTCAAGCTTTTAAGCGGGTC-3 '(SEQ ID NO: 8)
- the PCR reaction was performed by the Hot Start method using A Immediate liWax PCR Gem 100 (Takara Shuzo). First, 3 L of 10 XL A PCR Buffer 2 ⁇ , 2.5 mM dNTP solution, 2.5 1 of each 12.5 M primer solution, and 10 / il of sterile distilled water were mixed to obtain a lower layer mixture. In addition, pRL-TK vector (Promega, USA) was used as a ⁇ type for 11, 10 X LA PCR Buffer 31 and 2.5 mM (] 1 ⁇ ?
- the resulting PCR product was subjected to agarose gel (1%) electrophoresis, and a DNA fragment of 14 Ob including TK Promoter was recovered from the gel and inserted into pT7 Blue-II vector (Takara Shuzo).
- the TK promoter-containing fragment obtained by digesting this plasmid with the restriction enzymes Bglll and Ncol was ligated to the Bglll-Ncol fragment of the plasmid pGL3-Basic vector [Promega, USA] to obtain the plasmid pGL3- TK was prepared.
- Plasmid PGL3-4ERPP-TK was prepared by ligating the obtained 4.9 kb Nhel-Xhol fragment of plasmid pGL3-TK with the Nhel-Xhol fragment 200b of plasmid pBS S-PPRE4.
- This plasmid pGL3-4ERPP-TK was digested with BamHI (Takara Shuzo) and blunt-ended by treatment with T4 DNA polymerase (Takara Shuzo) to obtain a DNA fragment.
- pGFP-Cl (manufactured by Toyobo) was digested with Bsu36I (NEB), and then blunt-ended by treatment with T4 DNA polymerase (manufactured by Takara Shuzo) to obtain a 1.6 kb DNA fragment.
- CHO-K1 cells grown in 750 ml (culture) tissue culture flasks using Ham FI2 medium (Nissui Pharmaceutical) containing fetal serum (Lifetech Oriental) 0.5 g / L trypsin-0.2 After detaching by g / L EDTA (Lifetech Oriental) treatment, wash the cells with PBS (Lifetech Oriental) Then, the mixture was centrifuged (lOOikpm, 5 minutes) and suspended in PBS. Next, DNA was introduced into the cells using Genepulsa 1 (Biorad) under the following conditions.
- the plasmid pGL3-4ERPP-TK neo was added overnight, and electroporation was performed under a voltage of 0.25 kV and a capacity of 960 mF.
- the cells were then transferred to Ham's F12 medium containing 10% fetal calf serum, cultured for 24 hours, cells were again detached and centrifuged, then 500 g / ml of dienecin (Lifetech Oriental) and Zeocin (Invitrogen) were added. 250 mu.
- the resulting transformant is cultured on a 24-well plate (coming), and a luciferase-expressing strain, PPAR (5: RXR a: 4 ERP), is induced by adding 10 mM Iloprost. P / CHO-K1 was selected.
- PPAR luciferase-expressing strain
- the human PPARa gene was cloned using a heart cDNA (manufactured by Toyobo, trade name: QUICK—Clone cDNA) as type III, reported by Greene et al. [Gene Expr. 5 years, Vol. 4 (4-5), pp. 281-129], which was prepared with reference to the nucleotide sequence of the PPARa gene.
- a heart cDNA manufactured by Toyobo, trade name: QUICK—Clone cDNA
- PAG-L 5'-GGG GTC GAC CAG GAC TCT CTG CTA GTA CAA GTC-3 '(SEQ ID NO: 10)
- the PCR reaction was performed by the Hot Start method (Hot Start) using AmpliWax PCR Gem 100 (Takara Shuzo).
- 10 XLA PCR Buffer 2 U 2.5 mM dNTP solution 3 il, 12.5 ⁇ primer solution 2.51, Sterile distilled water 10 ⁇ 1 was mixed to form a lower layer mixture.
- human heart cDNA (1 ng / ml) was used as type II in 11 and 10 XLA PCR Buffer 3 // 1, 2.5 mM d NTP solution 11 and TaKaRa LA Taq DNA polymerase (Takara Shuzo) 0. 5 Sterile distilled water 24.5 1 was mixed to obtain an upper layer mixed solution.
- One AmpliWax PCR Gem100 (manufactured by Takara Shuzo) was added to the above lower mixture, and the mixture was treated at 70 ° C for 5 minutes and on ice for 5 minutes, and the upper mixture was added to prepare a PCR reaction solution.
- the tube containing the reaction solution was set in a thermal cycler (manufactured by Perkin Pharma Co., USA) and treated at 95 ° C for 2 minutes. Further, a cycle of 95 ° C. for 15 seconds and 68 ° C. for 2 minutes was repeated 35 times, followed by treatment at 72 ° C. for 8 minutes.
- the resulting PCR product was subjected to agarose gel (1%) electrophoresis, and a 1.4 kb DNA fragment containing the PPARr gene was recovered from the gel, and inserted into the pT7Blue-II vector (Takara Shuzo), and the plasmid was removed.
- pTBT—hP PAR was obtained.
- the plasmid pTBT-hPPARr obtained in Preparation Example 6 was digested with SalI, and then blunt-ended by treatment with T4 DNA polymerase (Takara Shuzo). Subsequently, a DNA fragment containing a 1.4 kb human PPARa gene was obtained by digestion with Kpnl.
- fetal serum 10% fetal serum [Life Technologies, Inc. CHO_K grown in a tissue culture flask 7 50 ml [Corning Costar Corporation, USA] using Ham F12 medium (Nissui Pharmaceutical) containing 1 Cells were detached by treatment with 0.5 g / L trypsin-0.2 gZL EDTA (ethylenediaminetetraacetic acid) [Life Technologies, Inc., USA], and the cells were removed using PBS (Phosphate-buffered). saline) [Life Technologies, Inc., USA], washed, centrifuged (1 000 rpm, 5 minutes), and suspended in PBS. Next, DNA was introduced into the cells using Gene Pulser (Bio-Rad Laboratories, USA) under the following conditions.
- Gene Pulser Bio-Rad Laboratories, USA
- Suspension (US), SOO zgZml and Zeocin (Invitrogen, USA) at a concentration of 250 g / ml in 10% fetal ham F12 medium. 0 Diluted to 4 cells / ml and inoculated into a 96-well plate [Corning Costar Corporation, USA] and cultured overnight at 37 ° C in carbon dioxide gas sink As a result, a transformant resistant to dieneticin and zeocin was obtained.
- the obtained transformant was cultured in a 24-well plate [Corning Costar Coi ⁇ poration, USA], and then added with 10 xM pioglitazone hydrochloride to produce lucifera.
- Ham F12 containing PPAR5: RXR ⁇ : 4 ERPPZCHO-K1 cells obtained in Preparation Example 5 containing 10% fetal serum [Life Technologies, Inc., USA] After culturing in a medium (manufactured by Nissui Pharmaceutical Co., Ltd.), the cells were seeded at a density of 2 ⁇ 10 4 cells / well in a 96-well white plate [CorningCoster Coi ⁇ poration, USA]. The cells were cultured overnight at 37 ° C. in a gas carbonate bath.
- the ham F12 medium containing 901 0.1% fatty acid-free cyserum albumin (BSA) and the test compound (manufactured by (Compound of Example 3) 10 ⁇ 1 was added, and the cells were cultured in a carbon dioxide incubator at 37 ° C for 48 hours. After removing the medium, add 40 1 of Pitka Gene 7.5 (manufactured by Wako Pure Chemical Industries, Ltd.), and after stirring, make use of Lumistar (BMG Labtechnologies GmbH), Germany ] To determine luciferase activity.
- PBS Phosphate-buffered saline
- the induction ratio was calculated from the luciferase activity of each test compound, assuming that the luciferase activity of the test compound non-administration group was 1.
- the EC50 value of rosiglitazone (the compound concentration showing 50% of the maximum value of the induction factor) was calculated in the same manner as in Test Example 1 above. The result was 146 ⁇ M.
- PPARa obtained in Preparation Example 8 RXR ⁇ : 4 ERP PZC ⁇ — ⁇ 1 cell contains 10% ⁇ fetal serum [Life Technologies, Inc., USA] After culturing in Ham's F12 medium (Nissui Pharmaceutical), 96 ⁇ Why Bok plate [U-learning course evening one company (Corning Coster Corporation), manufactured by US] were seeded such that 2 X 1 0 4 cellsZwell to and over ⁇ cultured in 37 ° carbon dioxide gas Thin particulate beta one C .
- the induction ratio was calculated from the luciferase activity of each test compound, assuming that the luciferase activity of the test compound non-administration group was 1.
- the EC50 value of the test compound is determined by analyzing the concentration of the test compound and the value of the induction factor using Prism (PRISM) 2.01 [GraphPad Software, Inc., USA]. (Concentration of the compound showing 50% of the maximum value of the induction factor) was calculated. The result was 0.024M.
- the compound of Production Example 3 exhibited excellent PPARar RXRa heterodimer ligand activity.
- a PPAR agonist acting drug or the like that is effective for treatment tends to cure the target disease but increase the weight of the patient. Can suppress the weight gain of such patients.
- a drug having both a P PAR ⁇ agonist-like action and a P PAR agonist-like action can significantly suppress weight gain of a patient while advancing treatment for diabetes and the like.
Description
Claims
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KR1020027006002A KR20020060227A (ko) | 1999-11-10 | 2000-11-09 | 체중 증가 억제제 |
EP00974859A EP1304121A4 (en) | 1999-11-10 | 2000-11-09 | INHIBITORS OF BODY WEIGHT GAIN |
AU13033/01A AU1303301A (en) | 1999-11-10 | 2000-11-09 | Body weight gain inhibitors |
HU0203837A HUP0203837A2 (hu) | 1999-11-10 | 2000-11-09 | Testtömegnövekedést gátló szerek |
CA002390932A CA2390932A1 (en) | 1999-11-10 | 2000-11-09 | Body weight gain inhibitors |
NO20022214A NO20022214L (no) | 1999-11-10 | 2002-05-08 | Vektökningshemmere |
US11/168,357 US20050239854A1 (en) | 1999-11-10 | 2005-06-29 | Body weight gain inhibitors |
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AU (1) | AU1303301A (ja) |
CA (1) | CA2390932A1 (ja) |
HU (1) | HUP0203837A2 (ja) |
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HUP0101366A2 (hu) * | 1997-12-19 | 2001-09-28 | Merck & Co., Inc. | Aril-tiazolidin-dion-származékok, eljárás az előállításukra és e vegyületeket tartalmazó gyógyászati készítmények |
TWI249401B (en) * | 1999-04-14 | 2006-02-21 | Takeda Chemical Industries Ltd | Agent for improving ketosis |
AU7958000A (en) * | 1999-10-29 | 2001-05-14 | Takeda Chemical Industries Ltd. | Process for the preparation of oxyiminoalkanoic acid derivatives |
-
2000
- 2000-11-09 HU HU0203837A patent/HUP0203837A2/hu unknown
- 2000-11-09 WO PCT/JP2000/007879 patent/WO2001034200A1/ja not_active Application Discontinuation
- 2000-11-09 KR KR1020027006002A patent/KR20020060227A/ko not_active Application Discontinuation
- 2000-11-09 PL PL00356745A patent/PL356745A1/xx not_active Application Discontinuation
- 2000-11-09 CN CN00818288A patent/CN1423566A/zh active Pending
- 2000-11-09 AU AU13033/01A patent/AU1303301A/en not_active Abandoned
- 2000-11-09 EP EP00974859A patent/EP1304121A4/en not_active Withdrawn
- 2000-11-09 CA CA002390932A patent/CA2390932A1/en not_active Abandoned
-
2002
- 2002-05-08 NO NO20022214A patent/NO20022214L/no not_active Application Discontinuation
-
2005
- 2005-06-29 US US11/168,357 patent/US20050239854A1/en not_active Abandoned
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WO1996002507A1 (en) * | 1994-07-18 | 1996-02-01 | Abbott Laboratories | Iminoxycarboxylates and derivatives as inhibitors of leukotriene biosynthesis |
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Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1229026A4 (en) * | 1999-11-10 | 2003-09-24 | Takeda Chemical Industries Ltd | ALKOXYIMINOALKANSÄURE DERIVATIVES |
EP1229026A1 (en) * | 1999-11-10 | 2002-08-07 | Takeda Chemical Industries, Ltd. | Alkoxyiminoalkanoic acid derivatives |
EP1277730A4 (en) * | 2000-03-28 | 2005-03-16 | HEMMER OF NEOVASCULARIZATION | |
EP1277730A1 (en) * | 2000-03-28 | 2003-01-22 | Takeda Chemical Industries, Ltd. | Neovascularization inhibitors |
WO2002070011A3 (en) * | 2001-02-02 | 2003-04-24 | Smithkline Beecham Corp | Treatment of ppar mediated diseases |
WO2002087580A1 (fr) * | 2001-04-25 | 2002-11-07 | Takeda Chemical Industries, Ltd. | Promoteurs d'expression d'abc |
WO2003082865A1 (fr) * | 2002-04-01 | 2003-10-09 | Sankyo Company, Limited | Composition médicinale antitumorale |
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 |
WO2007003581A1 (en) | 2005-06-30 | 2007-01-11 | Novo Nordisk A/S | Phenoxy acetic acids as ppar delta activators |
EP2298742A1 (en) | 2005-06-30 | 2011-03-23 | High Point Pharmaceuticals, LLC | Phenoxy acetic acids as PPAR delta activators |
US7943669B2 (en) | 2005-06-30 | 2011-05-17 | High Point Pharmaceuticals, Llc | Phenoxy acetic acids as PPAR delta activators |
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 |
EP2386540A1 (en) | 2005-12-22 | 2011-11-16 | High Point Pharmaceuticals, LLC | Novel compounds, their preparation and use |
US10947180B2 (en) | 2005-12-22 | 2021-03-16 | Vtv Therapeutics Llc | Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists |
US8362016B2 (en) | 2005-12-22 | 2013-01-29 | High Point Pharmaceuticals, Llc | Phenyl propionic acids as PPAR delta activators |
US7943613B2 (en) | 2005-12-22 | 2011-05-17 | High Point Pharmaceuticals, Llc | Compounds, their preparation and use |
US8551993B2 (en) | 2005-12-22 | 2013-10-08 | 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 |
US9855274B2 (en) | 2005-12-22 | 2018-01-02 | Vtv Therapeutics Llc | Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists |
US11420929B2 (en) | 2005-12-22 | 2022-08-23 | Vtv Therapeutics Llc | Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists |
US10471066B2 (en) | 2005-12-22 | 2019-11-12 | Vtv Therapeutics Llc | Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists |
US7943612B2 (en) | 2006-03-09 | 2011-05-17 | High Point Pharmaceuticals, Llc | Compounds that modulate PPAR activity, their preparation and use |
EP3756661A1 (en) | 2013-09-09 | 2020-12-30 | vTv Therapeutics LLC | Use of a ppar-delta agonist for treating muscle atrophy |
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 |
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) | 2023-01-25 | 2024-03-19 | Reneo Pharmaceuticals, Inc. | Use of PPAR-delta agonists in the treatment of disease |
Also Published As
Publication number | Publication date |
---|---|
EP1304121A1 (en) | 2003-04-23 |
AU1303301A (en) | 2001-06-06 |
NO20022214L (no) | 2002-07-09 |
EP1304121A4 (en) | 2004-06-23 |
PL356745A1 (en) | 2004-06-28 |
US20050239854A1 (en) | 2005-10-27 |
CN1423566A (zh) | 2003-06-11 |
CA2390932A1 (en) | 2001-05-17 |
HUP0203837A2 (hu) | 2003-03-28 |
NO20022214D0 (no) | 2002-05-08 |
KR20020060227A (ko) | 2002-07-16 |
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