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WO2007066615A1 - Nouvel activateur de recepteur orphelin nucleaire et son utilisation - Google Patents

Nouvel activateur de recepteur orphelin nucleaire et son utilisation Download PDF

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Publication number
WO2007066615A1
WO2007066615A1 PCT/JP2006/324171 JP2006324171W WO2007066615A1 WO 2007066615 A1 WO2007066615 A1 WO 2007066615A1 JP 2006324171 W JP2006324171 W JP 2006324171W WO 2007066615 A1 WO2007066615 A1 WO 2007066615A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
receptor activator
alkyl group
alkyl
ring
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2006/324171
Other languages
English (en)
Japanese (ja)
Inventor
Toshiyuki Shimizu
Takuro Niwa
Kan Chiba
Masakiyo Hosokawa
Kaoru Kobayashi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chiba University NUC
Mitsubishi Tanabe Pharma Corp
Original Assignee
Chiba University NUC
Mitsubishi Pharma Corp
Mitsubishi Tanabe Pharma Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chiba University NUC, Mitsubishi Pharma Corp, Mitsubishi Tanabe Pharma Corp filed Critical Chiba University NUC
Publication of WO2007066615A1 publication Critical patent/WO2007066615A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/34—Phthalazines with nitrogen atoms directly attached to carbon atoms of the nitrogen-containing ring, e.g. hydrazine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention further relates to a Gunan X-solvent (hereinafter referred to as PX) useful as a therapeutic drug for a patient and a medicine containing the same.
  • PX Gunan X-solvent
  • 002 PX is a molecule that binds to the target gene sequence when Gand binds and activates the target gene transcription. Although the gand is not clarified, it is classified as an anabolic substance, but an anabolic acid or the like may increase the expression of a target gene such as CP (tocum P45) 34 via PX.
  • CP tocum P45
  • C P34 is constitutively expressed in the small intestine of the liver, and it is known to be induced by the plant such as guan.
  • C P34 has the action of excreting not only xenobiotics but also toxic acid in the body.
  • the administration of the C P3 4 agent to another person reduced the amount of the living body's bin, and the therapeutic effect was obtained.
  • the patient was observed at the time of early cirrhosis. There are reports that it is also effective for medical treatment (
  • target genes such as CP34 can be activated via PX.
  • 0004 Discussed to solve the above problems. As a result, they found that the substance shown in (1) below activates PX, and completed the study. 005 That is, it is as follows.
  • C to C ac C to C ac and gene ⁇ C ac
  • C ⁇ C ki ⁇ C ac Represents a di or a group
  • It represents a group which may have an upper position selected from Aki or C to C Aki, C 4 to C Aki and a gene. Or represents a group Represents an nzen, an on or a lan ring.
  • 000 Akira P-Activator is generally contained in or contained in, or those as an active ingredient.
  • 2 may have an upper position selected from KU to C achi, C to C achi and gen, and ⁇ C aki, C to C aki and gen. It may have an upper position selected from: ⁇ A of C, A of C ⁇ C and an upper position selected from a gene.
  • Examples of the ac of C to C include meth, chi, puppy, puppy, chi, and chi, and examples of the ac of C to C include ibis, ibis, pupoki, pupoki, ibis, ibis, Examples of the gene include a fluorine atom, a chlorine atom, and an atom atom.
  • a compound that represents a Nzen ring or an ON ring Preferred is a compound that represents a Nzen ring or an ON ring, and a NENSEN ring is particularly preferable.
  • the type of salt is not particularly limited as long as it is physiologically acceptable.
  • ( ⁇ ) and its salts may exist in the form of dissolved (or included), these (and included) can also be an active ingredient of the clear PXR agent.
  • An acid is particularly preferable.
  • Treatments using the clear P agent can include all, all and other acute illnesses.
  • Ming PX is also useful as a hepatic and therapeutic drug.
  • Myx PX is also useful as a therapeutic drug for hypertension, arteriosclerosis, illness, obesity, and steatosis (detailed in 2004 004 901 027) Can also be used in combination with other drugs used for prevention and / or treatment of disease. Akira PX can be co-administered with these other drugs at the same time or at different times.
  • a general-purpose object activates PX, for example, as will be described later, such as a P-plus, a PX-lase-like pottery, etc.
  • PX for example, as will be described later, such as a P-plus, a PX-lase-like pottery, etc.
  • humans include humans, but humans are preferred, and humans include tanks having the sequence of SEQ ID NO: 2, and further, SEQ ID NO: 2 for all of the SEQ ID NOS: 2, preferably 95. , Which activates the target gene in response to Gand.
  • 001 ( ⁇ ) products if they are compounded with them, can be used as disintegrating agents, binding agents, lubricants, teing agents, pigments, diluents, bases, agents, etc. .
  • the dosage form of the active agent is not particularly limited, but for oral administration, it may include agents, capsules, powders, fine granules, agents, capsules, etc., and for oral administration, injection, infusion, An agent etc. can be mentioned.
  • the clear agent may be used in combination with other agents.
  • the route of administration of the active agent of Ming is not particularly limited, and it can be administered orally. It can be determined according to age, weight, general health status, sex, diet, duration of administration, administration method, excretion level, combination of drugs, and the degree of medical condition of the patient being treated at that time. . Day patient
  • the cells were seeded on 96 uts at a rate of 4.50 u and cultivated for 24 hours. Then, I transcribed PXR Plus Potass Plus using po c amne 2000 (nvogen). After 24 hours, the compound (DM 2 O 3) of each time was added, and further 24 cycles were performed. After completion of the experiment, the Lae Note was measured using D a Gocease Assay (Pomega).
  • Table 2 shows the results of the plug-in carried out by a fan (adjunc company).
  • the M50 PXR and E50 were 0.63 M (han) and 0.084 M (), respectively. As a result, it was found that the compound activated X more frequently than the fan.
  • HepG2 cells were supplemented with 0.2 or 4 or 4 vanes and cultivated at 37C. After completion, total RNA was isolated from the cells using Tozo (nVogen). The total RNA of u was reverse transcribed using a random mixer pe cp Tansc pon em em (nv ogen) to synthesize c. Shaped c as shown in Figure 5 to form 5 ply (7) 3 ply
  • 002 clear PX agent can be effectively used for the treatment of patients treated by PX, such as illnesses such as eczema, hypertension and the like.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention concerne un composé de formule générale (I) ou un sel pharmaceutiquement acceptable de celui-ci ou un solvate du composé ou du sel, pouvant être utilisé en tant qu'activateur de récepteur de prégnane. Dans la formule (I): R1 représente un groupe cyclohexyle, un groupe phényle pouvant avoir au moins un substituant choisi parmi un groupe alkyle en C1-C4, un groupe alcoxy en C1-C4 et un atome d'halogène, un groupe thiényle pouvant avoir au moins un substituant choisi parmi un groupe alkyle en C1-C4, un groupe alcoxy en C1-C4 et un atome d'halogène, un groupe furyle pouvant avoir au moins un substituant choisi parmi un groupe alkyle en C1-C4, un groupe alcoxy en C1-C4 et un atome d'halogène, un groupe thiazolyle, un groupe phénoxy, un groupe phénylalkyle en C1-C4, un groupe phénylthio, un groupe morpholino, un groupe pipéridyle, un groupe pyrrolidinyle, un groupe pyridyle, ou un groupe imidazolyle; R2 représente -CHR3R4 (où R3 représente un atome d'hydrogène ou un groupe alkyle en C1-C4; et R4 représente un groupe alkyle en C1-C4, un groupe cylcohexyle, un groupe thiényle ou un groupe phényle pouvant avoir au moins un substituant choisi parmi un groupe alkyle en C1-C4, un groupe alcoxy en C1-C4 et un atome d'halogène) ou un groupe cyclohexyle; et le noyau A représente un noyau benzène, un noyau thiophène ou un noyau furanne.
PCT/JP2006/324171 2005-12-05 2006-12-04 Nouvel activateur de recepteur orphelin nucleaire et son utilisation Ceased WO2007066615A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2005350440A JP2009120486A (ja) 2005-12-05 2005-12-05 核内オーファン受容体の新規活性化剤及びその用途
JP2005-350440 2005-12-05

Publications (1)

Publication Number Publication Date
WO2007066615A1 true WO2007066615A1 (fr) 2007-06-14

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Country Link
JP (1) JP2009120486A (fr)
WO (1) WO2007066615A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115417856A (zh) * 2021-09-30 2022-12-02 成都奥睿药业有限公司 一类取代杂芳酞嗪衍生物的药学用途及其制备方法
EP4076418A4 (fr) * 2019-12-20 2024-01-24 Mirati Therapeutics, Inc. Inhibiteurs de sos1

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11618751B1 (en) 2022-03-25 2023-04-04 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives
US11319319B1 (en) 2021-04-07 2022-05-03 Ventus Therapeutics U.S., Inc. Compounds for inhibiting NLRP3 and uses thereof
US12331048B2 (en) 2022-10-31 2025-06-17 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors

Citations (9)

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JPS60218377A (ja) * 1984-04-16 1985-11-01 Mitsubishi Yuka Yakuhin Kk ４−フエニルフタラジン誘導体及びそれを有効成分とする循環改善剤
JPS60243074A (ja) * 1985-04-15 1985-12-03 Mitsubishi Yuka Yakuhin Kk ４−フエニルフタラジン誘導体
JPH02129180A (ja) * 1988-11-04 1990-05-17 Morishita Pharmaceut Co Ltd １−（１ｈ−イミダゾール−１−イル）フタラジン誘導体
JPH06135938A (ja) * 1991-09-26 1994-05-17 Mitsubishi Kasei Corp ３，６−ジ置換ピリダジン誘導体
JPH10114657A (ja) * 1996-08-20 1998-05-06 Eisai Co Ltd 縮合ピリダジン系化合物の勃起機能不全症治療剤
JP2000256194A (ja) * 1999-01-06 2000-09-19 Mitsui Chemicals Inc 核内レセプタ作動薬およびその効果増強剤
JP2003535912A (ja) * 2000-06-21 2003-12-02 グラクソ グループ リミテッド 核内オーファン受容体
JP2004513964A (ja) * 2000-11-22 2004-05-13 ノバルティス　アクチエンゲゼルシャフト Ｖｅｇｆ活性低減剤およびｅｇｆ活性低減剤を含む組合せ剤
WO2004058234A2 (fr) * 2002-12-27 2004-07-15 Schering Aktiengesellschaft Nouvelle association pharmaceutique

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60218377A (ja) * 1984-04-16 1985-11-01 Mitsubishi Yuka Yakuhin Kk ４−フエニルフタラジン誘導体及びそれを有効成分とする循環改善剤
JPS60243074A (ja) * 1985-04-15 1985-12-03 Mitsubishi Yuka Yakuhin Kk ４−フエニルフタラジン誘導体
JPH02129180A (ja) * 1988-11-04 1990-05-17 Morishita Pharmaceut Co Ltd １−（１ｈ−イミダゾール−１−イル）フタラジン誘導体
JPH06135938A (ja) * 1991-09-26 1994-05-17 Mitsubishi Kasei Corp ３，６−ジ置換ピリダジン誘導体
JPH10114657A (ja) * 1996-08-20 1998-05-06 Eisai Co Ltd 縮合ピリダジン系化合物の勃起機能不全症治療剤
JP2000256194A (ja) * 1999-01-06 2000-09-19 Mitsui Chemicals Inc 核内レセプタ作動薬およびその効果増強剤
JP2003535912A (ja) * 2000-06-21 2003-12-02 グラクソ グループ リミテッド 核内オーファン受容体
JP2004513964A (ja) * 2000-11-22 2004-05-13 ノバルティス　アクチエンゲゼルシャフト Ｖｅｇｆ活性低減剤およびｅｇｆ活性低減剤を含む組合せ剤
WO2004058234A2 (fr) * 2002-12-27 2004-07-15 Schering Aktiengesellschaft Nouvelle association pharmaceutique

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Title
JOHNSEN M. ET AL.: "New antithrombotic 1-Phthalazinamines with Serotonin Antagonistic Properties", ARCHIV. DER PHARMAZIE PHARMACEUTICAL AND MEDICINAL CHEMISTRY, vol. 336, no. 12, December 2003 (2003-12-01), pages 591 - 597, XP003013892 *
SONODA J. ET AL.: "Pregnane X receptor prevents hepatorenal toxicity from cholesterol metabolites", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 102, no. 6, 8 February 2005 (2005-02-08), pages 2198 - 2203, XP003013891 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4076418A4 (fr) * 2019-12-20 2024-01-24 Mirati Therapeutics, Inc. Inhibiteurs de sos1
US12304915B2 (en) 2019-12-20 2025-05-20 Mirati Therapeutics, Inc. SOS1 inhibitors
CN115417856A (zh) * 2021-09-30 2022-12-02 成都奥睿药业有限公司 一类取代杂芳酞嗪衍生物的药学用途及其制备方法
WO2023051761A1 (fr) * 2021-09-30 2023-04-06 成都奥睿药业有限公司 Utilisation pharmaceutique et procédé de préparation d'un dérivé d'hétéroaryl-phtalazine substitué
CN115417856B (zh) * 2021-09-30 2025-06-27 成都奥睿药业有限公司 一类取代杂芳酞嗪衍生物的药学用途及其制备方法
AU2022355409B2 (en) * 2021-09-30 2025-10-16 Origiant Pharmaceutical Co., Ltd. Pharmaceutical use and preparation method for substituted heteroaryl phthalazine derivative

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