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WO2008140251A2 - Inhibiteurs de la cyclooxygénase-2 - Google Patents

Inhibiteurs de la cyclooxygénase-2 Download PDF

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Publication number
WO2008140251A2
WO2008140251A2 PCT/KR2008/002677 KR2008002677W WO2008140251A2 WO 2008140251 A2 WO2008140251 A2 WO 2008140251A2 KR 2008002677 W KR2008002677 W KR 2008002677W WO 2008140251 A2 WO2008140251 A2 WO 2008140251A2
Authority
WO
WIPO (PCT)
Prior art keywords
5dione
pyrrole
pharmaceutically acceptable
acceptable salt
phenyl
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/KR2008/002677
Other languages
English (en)
Other versions
WO2008140251A3 (fr
Inventor
Jae Yeol Lee
Dong Joon Choo
Kyung Tae Lee
Jong Taik Moon
Ji Young Jeon
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.)
Kyung Hee University
Original Assignee
Kyung Hee 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
Publication date
Priority claimed from KR1020080014364A external-priority patent/KR100989141B1/ko
Application filed by Kyung Hee University filed Critical Kyung Hee University
Publication of WO2008140251A2 publication Critical patent/WO2008140251A2/fr
Publication of WO2008140251A3 publication Critical patent/WO2008140251A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/60—Two oxygen atoms, e.g. succinic anhydride
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to lH-pyrrole or furan-2,5dione derivatives and a pharmaceutical composition for inhibiting cyclooxygenase-2(COX-2), more specifically for treating or preventing inflammation, an allergic disorder, inflammatory dermatosis, an immunologic disorder, a neurodegenerative disorder, arthritis, pain or fever comprising the same.
  • Cyclooxygenase- 1 is also called prostaglandin ⁇ jsynthase and expressed in most of tissues. Prostaglandin ⁇ jproduced by cyclooxygenase- 1 is involved in the synthesis and supply of arachidonic acid metabolites to regulate physiological processes such as protection of gastrointestinal cells, kidney function and platelet aggregation. Meanwhile, cy- clooxygenase-2 is also known as prostaglandin ⁇ synthase, which produces prostaglandin ⁇ to induce inflammation and pain. Cyclooxygenase-2 is expressed only
  • Non-steroidal anti-inflammation drugs such as aspirin and ibuprofen exhibit their medicinal effects through inhibiting the activity of cyclooxygenases and suppressing the biosynthesis of prostaglandins.
  • the non-steroidal anti-inflammatory drugs not only inhibit the activity of cyclooxygenase-2 to reduce inflammation but also inhibit the activity of cyclooxygenase- 1 to cause adverse effects such as renal toxicity and gastrointestinal ulceration. Therefore, there has been a need in the art for the development of an anti-inflammation drug selectively inhibiting cyclooxygenase-2 over cyclooxygenase- 1.
  • Cyclooxygenase-2 inhibitors which have been commercialized until now include celecoxib (Celebrex) and valdecoxib (Bextra) developed by Pfizer, and rofecoxib (Vioxx) developed by Merck.
  • Celecoxib (Celebrex) (a) can be used for the treatment of arthritis and severe pain
  • rofecoxib (Vioxx) (b) can be used for the treatment of pain and inflammation
  • valdecoxib (Bextra) c) can be extensively used for the treatment of rheumatism and arthritis.
  • An object of the present invention is, therefore, to provide a compound of the following formula (I) or pharmaceutically acceptable salt thereof having excellent cyclooxygenase-2 inhibitory effect.
  • Another object of the present invention is to provide a pharmaceutical composition for inhibiting cyclooxygenase-2 comprising the compound of the following formula (I) or pharmaceutically acceptable salt thereof as an active ingredient.
  • One aspect of the present invention relates to a compound of the following formula (I) or pharmaceutically acceptable salt thereof having excellent cyclooxygenase-2 inhibitory effect.
  • R , R and R are each independently hydrogen, hydroxy, C -C lower alkoxy, R
  • R is C -C lower alkyl
  • X is O or NH.
  • the heterocycle is, preferably, dioxolane or dioxane; and R is, most preferably, methyl.
  • C -C lower alkoxy as used herein means a straight or branched alkoxy group having 1 to 5 carbon atoms, which includes methoxy, ethoxy, propanoxy, etc. but is not limited thereto.
  • Heterocycle as used herein means a 4 to 74nembered ring having 1 to 3 heteroatom(s) selected from the group consisting of oxygen, sulfur and nitrogen, which includes dioxolane, dioxane, etc. but is not limited thereto.
  • C -C lower alkyl as used herein means a straight or branched hydrocarbon having 1 to 5 carbon atoms, which includes methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. but is not limited thereto.
  • the most preferable compound among the compounds of the present invention is selected from the following group.
  • a furan-2,5dione derivative(3) can be prepared by reacting phenylgly oxalic acid (1) and phenylacetic acid (2) in acetic anhydride.
  • the acetic anhydride is used as a reactant as well as solvent.
  • the reaction temperature is preferably from room temperature to 13O 0 C, most preferably about 100 0 C.
  • the reaction time is preferably 2-10 hours, most preferably about 3 hours.
  • an acid catalyst can be used, which includes titanium chloride(TiCl ), BF (OEt) , thionyl chloride (SOCl ), etc. but is not limited
  • a lH-pyrrole-2,5dione derivative(4) can be prepared by treating a furan-2,5dione derivative (3) with methanol, dimethyl- formamide (DMF) and hexamethyldisilazane (HMDS).
  • the reaction temperature is most preferably room temperature, and the reaction time is preferably 10-36 hours, most preferably 12 hours.
  • ammonia gas can be used in a solvent such as acetonitrile and lower alcohol including methanol.
  • a lH-pyrrole-2,5dione derivative(5) wherein R , R and/or R are hydroxy can be prepared by dealkylating a lH-pyrrole-2,5dione derivative(4) wherein R , R and/or R are alkoxy or taken together with the carbon atoms to which they are attached form dioxolane or dioxane.
  • the dealkylating agent includes boron tribromide (BBr ), trimethylsilane iodide (TMSI), aluminium chloride (AlCl ), etc. but is not limited thereto.
  • a lH-pyrrole-2,5dione derivative (4) according to the present invention can be prepared by coverting phenylacetic acid (2) to acyl chloride, and then treating the acyl chloride with ammonia water to give pheny- lacetamide (6), followed by the condensation of the phenylacetamide (6) with an ester compound (7).
  • Another aspect of the present invention relates to a pharmaceutical composition for inhibiting cyclooxygenase-2 comprising the compound of the above formula (I) or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be used for treating or preventing inflammation, an allergic disorder, inflammatory dermatosis, an immunologic disorder, a neurodegenerative disorder, arthritis, pain or fever.
  • the pharmaceutical composition according to the present invention can be administered orally, e.g., ingestion or inhalation; or parenterally, e.g., injection, deposition, implantation or suppositories.
  • the injection can be, for example, intravenous, intradermal, subcutaneous, intramuscular or intraperitoneal.
  • the pharmaceutical composition of the present invention may be formulated as tablets, capsules, granules, fine subtilae, powders, sublingual tablets, suppositories, ointments, injection solutions, emulsions, suspensions, syrups, aerosols, etc.
  • composition of the present invention can be prepared in a manner well known in the art using a pharmaceutically acceptable carrier(s) which are usually used for each form.
  • pharmaceutically acceptable carriers include excipient, filler, expander, binder, disintegrator, lubricant, preservative, antioxidant, isotonic agent, buffer, coating agent, sweetening agent, dissolvent, base, dispersing agent, wetting agent, suspending agent, stabilizer, colorant, aromatic, etc.
  • the pharmaceutical composition of the present invention contains 0.01 to 100 wt% of the compound according to the present invention or pharmaceutically acceptable salt thereof depending on the form thereof.
  • the specific dosage of the present pharmaceutical composition can be varied with species of mammals including a human-being, route of administration, body weight, gender, age, severity of disease, judgment of doctor, etc. It is preferable that 0.01 to 50 mg of the active ingredient is administered per kg of body weight a day for oral use, while 0.01 to 10 mg of the active ingredient is administered per kg of body weight a day for parenteral use.
  • the total daily dosage can be administered once or over several times depending on the severity of disease, judgment of doctor, etc.
  • the compounds of the present invention have excellent cyclooxygenase-2 inhibitory activity and low cytotoxicity. Therefore, the compounds of the present invention can be used for preparing pharmaceutical compositions for treating or preventing inflammation, an allergic disorder, inflammatory dermatosis, an immunologic disorder, a neurodegenerative disorder, arthritis, pain or fever. Best Mode for Carrying Out the Invention
  • the resulting solid was filtered and the filtrate was saturated with a saline solution and extracted with ethyl acetate three times.
  • the organic phase was dried with anhydrous magnesium sulfate(MgSO ) and distilled under reduced pressure to give a solid product.
  • the solid product combined with the previously obtained solid was re- crystallized with acetone to give the target compound as a white solid(Q9 g, 33 %).
  • Example 11 Preparation of (4-thiomethoxyphenyl)oxoacetic acid [114] To the compound(4 g, 17.835 mmol) obtained in Example 5 was dropped 2N NaOH(8.9 ml) at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was acidified with concentrated HCl to pH 2 and extracted with CH Cl three times. The
  • Example 15 Preparation of 3.4-diphenyl-l H -pyrrole-2.5dione (MCR-SOOD [134] 3,4-diphenylfuran-2,5dione was used according to the same procedure as Example
  • Example 16 Preparation of 3-(3.4.5-trimethoxyphenyl s )-4-phenyl-l H - pyrrole-2.5dione fMCR-SX) ⁇ [139] 3-(3,4,5-trimethoxyphenyl)-4-phenylfuran-2,5dione obtained in Example 13 was used according to the same procedure as Example 14 to give the target compound(97
  • reaction mixture (0.179 g, 0716 mmol) at -78 °C, and the reaction mixture was left to room temperature and stirred for 12 hours. After the reaction was completed, the reaction mixture was neutralized with a saturated NaHCO aqueous solution and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried with anhydrous magnesium sulfate(MgSO ) and distilled under reduced pressure to give the
  • Example 18 Preparation of 3-(3A5-trihvdroxyphenyl)-4-phenyl-l H - pyrrole-2.5dione (MCR- 3009 s ) [149] 3-(3,4,5-trimethoxyphenyl)-4-phenyl-l H-pyrrole-2,5dione obtained in Example 16 was used according to the same procedure as Example 17 to give the target compound(88 %). [150] 1 H NMR (430 MHz, DMSO ⁇ i ) ⁇ 11.02 (IH, s, -NH), 9.00 (2H, s, OH), 8.61 (IH, s,
  • cell viability was measured according to a 3-(4,5dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) assay.
  • Raw264.7 cells (murine macrophage cell line), which were obtained from Korean Cell Line Bank(KCLB), were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS), penicillin(100 units/mL) and streptomycin sulfate(10Q7g/mL) at 37 0 C in a humidified atmosphere with 5% CO .
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • penicillin(100 units/mL) penicillin(100 units/mL)
  • streptomycin sulfate 10Q7g/mL
  • Lipopolysaccharide(LPS) was added at l ⁇ g/mL and incubated for 24 hours(or appropriate time). The obtained supernatant was diluted five fold. 150 ⁇ L of analysis buffer was added to non specific binding(NSB) wells and lOO ⁇ L of analysis buffer was added to zero standard(BO) wells. lOO ⁇ L of standard samples were added to the other wells. 50 ⁇ L of PGE conjugates were added (except for NSB). Then, 50 ⁇ L of PGE antibody solution was added and shaken for 2 hours. Each well was subject to suction and washed with washing buffer five times.
  • EIA Enzyme ImmunoAssay
  • PG screening antiserum was added in 50 ⁇ L aliquots except for TA, NSB and BIk, and left at room temperature for 18 hours. Each well was subject to suction and washed with washing buffer 5 times. Ellman's reagent was added in 200 ⁇ L aliquots and tracer was added in 5 ⁇ L aliquots to only TA wells. The plates were shaken for 60-90 minutes with shielding the light and the absorbance was measured at 4)5 nm. The inhibition of COX-2 activity was evaluated using the measured absorbance and standard curve, and the concentration to inhibit by 50% (IC
  • Raw264.7 cells (murine macrophage cell line) were cultured in Dulbecco's modified Eagle's medium(DMEM) containing 10% fetal bovine serum(FBS), penicillin(100 units/mL) and streptomycin sulfate(100 //g/mL) at 37 0 C in a humidified atmosphere with 5% CO .
  • the cells were collected by centrifugation and scraper, and added in 1x10 cells/well to 96- well plates having lOO ⁇ L of Roswell Park Memorial Institute(RPM) 164) medium containing 10% FBS.
  • 50 50 means the concentration to exhibit 50% reduction in the number of cells compared to the group which was not treated with compounds. The results are summarized in Table 2, where the values were obtained from three independent experiments.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention porte sur des dérivées du IH-pyrrole ou du furan-2,5dione et sur une composition pharmaceutique inhibitrice de la cyclooxygénase-2 (COX-2), et plus spécifiquement sur une telle composition traitant ou prévenant l'inflammation, les troubles allergiques, la dermatose inflammatoire, les troubles immunologiques, les troubles neurodégénératifs, l'arthrite, la douleur ou la fièvre.
PCT/KR2008/002677 2007-05-14 2008-05-14 Inhibiteurs de la cyclooxygénase-2 Ceased WO2008140251A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20070046489 2007-05-14
KR10-2007-0046489 2007-05-14
KR1020080014364A KR100989141B1 (ko) 2007-05-14 2008-02-18 시클로옥시게나제-2 저해제
KR10-2008-0014364 2008-02-18

Publications (2)

Publication Number Publication Date
WO2008140251A2 true WO2008140251A2 (fr) 2008-11-20
WO2008140251A3 WO2008140251A3 (fr) 2009-01-15

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Application Number Title Priority Date Filing Date
PCT/KR2008/002677 Ceased WO2008140251A2 (fr) 2007-05-14 2008-05-14 Inhibiteurs de la cyclooxygénase-2

Country Status (1)

Country Link
WO (1) WO2008140251A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101538256A (zh) * 2009-04-28 2009-09-23 沈阳药科大学 3,4-二芳基呋喃-2,5-二酮类衍生物与3,4-二芳基-1h-吡咯-2,5-二酮类衍生物及其用途
WO2010069150A1 (fr) * 2008-12-18 2010-06-24 Mao Jinlong Derives d'acide acrylique de para-hydroxybenzene et utilisations associees
JP2013014534A (ja) * 2011-07-04 2013-01-24 Daicel Corp ベンゾイルギ酸化合物、及びその製造方法
CN103804108A (zh) * 2012-11-15 2014-05-21 沈阳药科大学 一种制备伯胺的方法
CN103951594A (zh) * 2009-12-18 2014-07-30 毛近隆 对羟基苯丙烯酸衍生物及其应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT626969E (pt) * 1992-02-11 2000-11-30 Smithkline Beecham Corp Inibidores de co.a-it e de p.a.f.
DE69512930T2 (de) * 1994-10-27 2000-05-18 Merck Frosst Canada & Co., Halifax Stilben-derivate verwendbar als cyclooxygenase-2 hemmer
DE19711428A1 (de) * 1997-03-19 1998-09-24 Merck Patent Gmbh Endothelin-Rezeptor-Antagonisten
DE10155076A1 (de) * 2001-11-09 2003-05-22 Merck Patent Gmbh Verwendung von Endothelin-Rezeptor-Antagonisten zur Behandlung von Tumorerkrankungen

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010069150A1 (fr) * 2008-12-18 2010-06-24 Mao Jinlong Derives d'acide acrylique de para-hydroxybenzene et utilisations associees
CN101910144A (zh) * 2008-12-18 2010-12-08 毛近隆 对羟基苯丙烯酸衍生物及其应用
CN101910144B (zh) * 2008-12-18 2014-04-23 毛近隆 对羟基苯丙烯酸衍生物及其应用
CN101538256A (zh) * 2009-04-28 2009-09-23 沈阳药科大学 3,4-二芳基呋喃-2,5-二酮类衍生物与3,4-二芳基-1h-吡咯-2,5-二酮类衍生物及其用途
CN101538256B (zh) * 2009-04-28 2014-05-21 沈阳药科大学 3，4-二芳基呋喃-2，5-二酮类衍生物与3，4-二芳基-1h-吡咯-2，5-二酮类衍生物及其用途
CN103951594A (zh) * 2009-12-18 2014-07-30 毛近隆 对羟基苯丙烯酸衍生物及其应用
JP2013014534A (ja) * 2011-07-04 2013-01-24 Daicel Corp ベンゾイルギ酸化合物、及びその製造方法
CN103804108A (zh) * 2012-11-15 2014-05-21 沈阳药科大学 一种制备伯胺的方法
CN103804108B (zh) * 2012-11-15 2016-08-03 沈阳药科大学 一种制备伯胺的方法

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