WO2007122981A1 - DÉRIVÉ DE COUMARINE SUSCEPTIBLE D'INHIBER LA MONOXYDE D'AZOTE SYNTHASE INDUCTIBLE (iNOS) - Google Patents

DÉRIVÉ DE COUMARINE SUSCEPTIBLE D'INHIBER LA MONOXYDE D'AZOTE SYNTHASE INDUCTIBLE (iNOS) Download PDF

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Publication number
WO2007122981A1
WO2007122981A1 PCT/JP2007/057378 JP2007057378W WO2007122981A1 WO 2007122981 A1 WO2007122981 A1 WO 2007122981A1 JP 2007057378 W JP2007057378 W JP 2007057378W WO 2007122981 A1 WO2007122981 A1 WO 2007122981A1
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WO
WIPO (PCT)
Prior art keywords
inos
substituent
coumarin compound
group
compound
Prior art date
Application number
PCT/JP2007/057378
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English (en)
Japanese (ja)
Inventor
Tsutomu Ishikawa
Shingo Yano
Tomonori Nakamura
Takuya Kumamoto
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National University Corporation Chiba University
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
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Application filed by National University Corporation Chiba University filed Critical National University Corporation Chiba University
Publication of WO2007122981A1 publication Critical patent/WO2007122981A1/fr

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D311/00Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/18Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted otherwise than in position 3 or 7
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/08Antiallergic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a coumarin compound, more specifically, allergic airway inflammation, pneumonia, arthritis, vasculitis, spleen ⁇ 8 cell self-destruction, allograft acute rejection at the time of organ transplantation, etc.
  • the present invention relates to a substance having iNOS inhibitory activity capable of suppressing a number of inflammatory diseases.
  • Nitric oxide is an essential endogenous substance involved in various biological maintenance mechanisms, but also has a negative aspect of being a causative substance such as inflammation. It is thought that inducible monoxide-nitrogen synthase (iNOS) is involved in the production of NO, which works on this negative side, and finding compounds that inhibit iN OS can help create new anti-inflammatory drugs. It is thought to be connected.
  • iNOS inducible monoxide-nitrogen synthase
  • Non-Patent Document 1 Agric. Food Chem., 1999, 47 pp. 333-339
  • Non-Patent Document 2 Bioorg. Med. Chem., 2000, 8 ⁇ , pp. 2701-2707
  • Non-Patent Document 3 Chem. Pharm. Bull., 2004, 52 ⁇ , 1215-1218
  • Non-patent Literature 4 Nat. Chem., 2004, 67 ⁇ , 432-436
  • Non-Patent Document 5 Bioorg. Med. Chem., 2005, 13 ⁇ , pages 2723-2739 Disclosure of the Invention
  • the present inventors conducted a screening test using iNOS inhibitory activity as an index for tropical plants, and found that a strong inhibitory activity was observed in the Citrus Clausena plant, and that the active body was a coumarin compound. As a result, the present invention has been completed.
  • the coumarin compound that inhibits inducible monoacid-nitrogen synthase according to one embodiment of the present invention is represented by the following formula (1).
  • X is a hydrogen atom or a substituent !, a hydrocarbon group or a substituent is an aryl group, and R and R are optionally substituted carbon atoms.
  • Z is a hydrogen atom or a hydrocarbon group which may have a substituent.
  • R, R, Y and Z are
  • a coumarin compound that inhibits inducible nitric oxide synthase according to another embodiment of the present invention is represented by the following formula (2) or (3).
  • a novel coumariny compound having stronger iNOS inhibitory activity can be provided, and an iNOS inhibitor using the same can be further provided.
  • the coumarin compound according to the embodiment is a 5,7-dioxycoumarin compound represented by the following formula (1).
  • X represents a hydrogen atom, a hydrocarbon group that may have a substituent, or an aryl group that may have a substituent.
  • a hydrocarbon group the number of carbons is not limited, but is preferably in the range of 1 to 4.
  • the substituent is not limited, but examples thereof include an aldehyde group, a ketone group, a hydroxyl group, an amino group, an alkoxy group, a carboxyl group, an alkoxycarbo group, a carbooxy group, and a halogen atom.
  • R and R are hydrocarbon groups which may have a substituent
  • the number of carbons is not limited but is preferably in the range of 1-4.
  • examples of the hydrocarbon group are not limited, but examples thereof include methyl, ethyl, propyl, butyl, isobutyl, and t-butyl.
  • the substituent is not limited, but examples thereof include an aldehyde group, a ketone group, a hydroxyl group, an amino group, an alkoxy group, a carboxyl group, an alkoxycarbo group, a carbooxy group, and a halogen atom. be able to.
  • Y and Z are hydrocarbon groups which may have a hydrogen atom or a substituent, and Y and Z may be the same or different.
  • the number of carbons in the hydrocarbon group is not limited, but a hydrocarbon group in the range of 2 to 5 may contain a double bond.
  • the substituent is not limited, but for example, an aldehyde group, a ketone group, a hydroxyl group, an amino group, an alkoxy group, a carboxyl group, an alkoxycarbo group, a carbooxy group, or a halogen atom. I can give you.
  • the method for obtaining the 5,7-dioxycoumariny compound represented by the above formula (1) is not limited and can be obtained by various methods.
  • the present embodiment can provide a novel coumariny compound having iNOS inhibitory activity.
  • the coumariny compound of the present embodiment can be used as an iNOS inhibitor.
  • iNOS inhibitors are pharmaceutically acceptable ordinary carriers, binders, stabilizers, excipients, diluents, pH buffering agents, disintegrating agents, solubilizers, solubilizing aids. Ingredients for various preparations such as agents and isotonic agents can be added.
  • an appropriate dose corresponding to the patient's sex, weight and symptoms can be administered orally or parenterally.
  • compositions can be administered orally in commonly used dosage forms, such as powders, granules, capsules, syrups, suspensions, etc. These can be administered parenterally in the form of injections, and can also be administered intranasally in the form of sprays.
  • the present inventors prepared a concentrated solution (lmgZml) by dissolving ethanol extract in dimethyl sulfoxide for a tropical plant, diluted to 5; ⁇ 71111, and used 1? ⁇ 03 inhibitory activity as an index.
  • a screening test revealed strong inhibitory activity in Citrus Clausena plants, revealing that it is a coumariny compound with active activity.
  • a plurality of coumarin compounds were prepared, each of which was dissolved in dimethyl sulfoxide and prepared as a concentrated solution (1 ⁇ M), and diluted as appropriate (1 to: LOOnM) to prepare test samples.
  • Mouse macrophage RAW264.7 cells were seeded on a 24-well plate, cultured until semi-confluent, then changed to serum-free medium, and LPS (50 ng Zml) and the test sample were added. After 16 hours of incubation, the cells were homogenized and protein quantification followed by Western blotting to measure the expression levels of iNOS and TNF- ⁇ protein. (2J NO measurement
  • xant hoxyletin derived from Clausena glauillauminii (see the compound represented by the following formula (A)).
  • This xathoxyletin also inhibited other inflammation-related factors such as TNF- ⁇ expression and NO production in a concentration-dependent manner.
  • xanthoxyletin represented by the formula (A) is a compound having a coumarin skeleton in its structure. Regarding coumarins, physiological functions such as antitumor activity, sensitization promotion, coronary vasodilatation, antibacterial action, and anti-inflammation Effects have been reported.
  • the compounds (2) and (3) are those of TNF-a, which is a kind of inflammatory site force-in. It was also important to suppress protein expression relatively strongly.
  • Table 2 shows the results of diluting a concentrated solution (1 ⁇ ) obtained by dissolving a coumarin compound in dimethyl sulfoxide to ⁇ .
  • the coumariny compound according to the present invention has antiallergic airway inflammation activity, antipneumonitis activity, antiarthritis activity, antivasculitis activity, inhibition of splenocyte self-destruction, allograft acute rejection Expected to have reaction inhibition, it has industrial applicability as a drug that suppresses numerous inflammatory diseases (anti-inflammatory drug).
  • FIG. 1 is a diagram showing the iNOS enzyme activity of the coumariny compound according to the example.

Abstract

La présente invention a pour objet un inhibiteur de monoxyde d'azote synthase inductible qui comprend un dérivé de coumarine de formule (1) et qui est particulièrement actif. (1) où X représente un atome d'hydrogène, un groupement hydrocarbure éventuellement substitué, ou un groupement aryle éventuellement substitué ; R1 et R2 représentent indépendamment un groupement hydrocarbure éventuellement substitué ; et Y et Z représentent indépendamment un atome d'hydrogène ou un groupement hydrocarbure éventuellement substitué, à la condition que R1, R2, Y et Z puissent être identiques ou différents les uns des autres.
PCT/JP2007/057378 2006-04-21 2007-04-02 DÉRIVÉ DE COUMARINE SUSCEPTIBLE D'INHIBER LA MONOXYDE D'AZOTE SYNTHASE INDUCTIBLE (iNOS) WO2007122981A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006118234A JP2007290981A (ja) 2006-04-21 2006-04-21 誘導型一酸化窒素合成酵素(iNOS)を阻害するクマリン化合物
JP2006-118234 2006-04-21

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WO2007122981A1 true WO2007122981A1 (fr) 2007-11-01

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JP (1) JP2007290981A (fr)
WO (1) WO2007122981A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105412084A (zh) * 2015-11-20 2016-03-23 西安交通大学 长春七中sesibricin的抗炎应用及其提取方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6059510B2 (ja) * 2012-11-05 2017-01-11 花王株式会社 セラミド産生促進剤

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005026143A1 (fr) * 2003-09-05 2005-03-24 Aventis Pharmaceuticals Inc. Coumarines comme inhibiteurs de l'oxyde nitrique synthase inductible (inos)

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005026143A1 (fr) * 2003-09-05 2005-03-24 Aventis Pharmaceuticals Inc. Coumarines comme inhibiteurs de l'oxyde nitrique synthase inductible (inos)

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ISHII H. ET AL.: "Studies on the Chemical Constituents of Rutaceous Plants. LXVI. The Chemical Constituents of Toddalia asiatica (L.) LAM. (T. aculeate PERS.). (1). Chemical Constituents of the Root Bark", YAKUGAKU ZASSHI, vol. 111, 1991, pages 365 - 375, XP003012945 *
ISHII H. ET AL.: "Synthetic Studies on Naturally Occurring Coumarins. II. Synthesis of 6,7-Dimethoxy- and 7,8-Dimethoxy-5-[(E)-3-oxo-1-butenyl]coumarins", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 40, no. 10, 1992, pages 2614 - 2619, XP002950709 *
ISHII H. ET AL.: "The Absolute Stereochemistries of (+)-Toddalolactone and its Related Chiral Coumarins from Toddalia asiatica (L.) Lam. (T. aculeata Peres.) and their Optical Purities", JOURNAL OF THE CHEMICAL SOCIETY PERKIN TRANSACTIONS 1, no. 13, 1992, pages 1681 - 1684, XP003012946 *
MALI R.S. ET AL.: "Efficient syntheses of 6-prenylcoumarins and linear pyranocoumarins: Total synthesis of suberosin, toddaculin, O-methylapigravin (O-methylbrosiperin), O-methylbalsamiferone, dihydroxanthyletin, xanthyletin and luvangetin", JOURNAL OF THE CHEMICAL SOCIETY PERKIN TRANSACTIONS 1, no. 3, 2002, pages 371 - 376, XP003012947 *
REISCH J. ET AL.: "New Constituents from Toddalia aculeate PERS", RUTACEAE, PHARMAZIE, vol. 37, no. 12, 1982, pages 862 - 863, XP003012944 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105412084A (zh) * 2015-11-20 2016-03-23 西安交通大学 长春七中sesibricin的抗炎应用及其提取方法
CN105412084B (zh) * 2015-11-20 2019-04-12 西安交通大学 长春七中sesibricin的抗炎应用及其提取方法

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