WO2006023562A2 - 5-[3-(4-benzyloxyphenylthio)-fur-2-yl]-imidazolidin-2, 4-dione and analogues as inhibitors of macrophage elastase - Google Patents

5-[3-(4-benzyloxyphenylthio)-fur-2-yl]-imidazolidin-2, 4-dione and analogues as inhibitors of macrophage elastase Download PDF

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Publication number
WO2006023562A2
WO2006023562A2 PCT/US2005/029259 US2005029259W WO2006023562A2 WO 2006023562 A2 WO2006023562 A2 WO 2006023562A2 US 2005029259 W US2005029259 W US 2005029259W WO 2006023562 A2 WO2006023562 A2 WO 2006023562A2
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WO
WIPO (PCT)
Prior art keywords
mmp
methoxyphenyl
dione
inhibitors
fur
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/US2005/029259
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English (en)
French (fr)
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WO2006023562B1 (en
WO2006023562A3 (en
Inventor
Fude Yang
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.)
QPS LLC
Original Assignee
QPS LLC
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 QPS LLC filed Critical QPS LLC
Priority to KR1020077006294A priority Critical patent/KR101197325B1/ko
Priority to MX2007001940A priority patent/MX2007001940A/es
Priority to JP2007527975A priority patent/JP5042833B2/ja
Priority to CN2005800285556A priority patent/CN101014338B/zh
Priority to AT05786673T priority patent/ATE508744T1/de
Priority to CA2577430A priority patent/CA2577430C/en
Priority to HK08101512.9A priority patent/HK1107774B/xx
Priority to BRPI0514470A priority patent/BRPI0514470B8/pt
Priority to AU2005277432A priority patent/AU2005277432B2/en
Priority to DK05786673.3T priority patent/DK1789036T3/da
Priority to EP05786673A priority patent/EP1789036B1/en
Priority to NZ553258A priority patent/NZ553258A/en
Priority to SI200531283T priority patent/SI1789036T1/sl
Publication of WO2006023562A2 publication Critical patent/WO2006023562A2/en
Publication of WO2006023562A3 publication Critical patent/WO2006023562A3/en
Publication of WO2006023562B1 publication Critical patent/WO2006023562B1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • This invention is directed to novel compounds, which are useful as inhibitors of matrix metaloproteinases in treating diseases associated with these enzymes.
  • MMPs Matrix metaloproteinases
  • connective tissue which relates to a few disease processes such as rheumatoid arthritis, osteoarthritis, gastric ulceration, asthma, emphysema, and tumor metastasis. Therefore, inhibition of one or more MMPs may be of benefit in these diseases.
  • MMP-12 Human macrophage elastase exhibits all the characteristics of other MMPs, but is preferentially produced from macrophages infiltrating into tissues where injury or remodeling is occurring and degrades extracellular matrix.
  • MMP-12 knocked out mouse model also demonstrated no development of emphysema by being exposed for a lengthy period of time to cigarette smoke (Science, 1997, 277: 2002-2004). More recently, using MMP-12 deficient model of asthma, the investigator suggested the involvement of MMP-12 in the development of chronic asthma (FASEB, 2002,16: A590).
  • MMP-12 has been shown to be secreted from alveolar macrophages of smokers (Shapiro et al, 1993, Journal of Biological Chemistry, 268:
  • MMP-12 inhibitors are known (see e.g., published PCT Patent Application No. WO 00/40577; EP 1 288 199 A1 , 2001 , Shionogi & Co. MMP-12 Inhibitor; U.S. Patent No. 6,352,9761 , and U.S. Patent Application Publication No. 2004/0072871 ; published European Patent Application EP1394159). Lately, there is a new class of MMP inhibitors disclosed in this field.
  • a published PCT Patent Application No. WO 02/096426 describes hydantoin derivatives of formula
  • Ri, R 4 , R 5 , and Rn were also broadly defined.
  • the derivatives in these two patents are also said, in general term, to be inhibitors of metalloproteinase and in particular for TACE and aggrecanase. Still, there were no biological data demonstrated.
  • 2004/020415 discloses a group of MMP-12 inhibitors of formula
  • Hydantoin derivatives are a new class of MMP inhibitors. It is desirable to find more new compound of this class with improved specificity, potency, and pharmacological characteristics.
  • the compounds of formula (IV) are MMP-12 inhibitors and may be used in the treatment of diseases or conditions mediated by MMP-12, such as asthma, chronic obstructive pulmonary diseases (COPD), arthritis, cancer, heart disease and nephritis.
  • diseases or conditions mediated by MMP-12 such as asthma, chronic obstructive pulmonary diseases (COPD), arthritis, cancer, heart disease and nephritis.
  • COPD chronic obstructive pulmonary diseases
  • Fig. 1 illustrates the reaction scheme for the synthesis of the compounds of the present invention.
  • the enzymatic activities of MMPs were assayed according to manufacture protocols (Biomol Reseaerch Laboratory, Inc. E-mail: info@biomol.com). All the enzymes are recombinant human active domains from E. coli (Biomol).
  • the fluorescent substrate has the sequence of (J- methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu-N-3-(2,4-dinitrophenyl)-L- ⁇ , ⁇ -diaminopropionyl-Ala-Arg-NH 2 .AcOH. All the assays were conducted at room temperature with 96 well flat bottom black plate (Nalge Nunc International, Catalog number, 465200).
  • the IC50 was obtained by plotting the fluorescences versus the concentrations of the inhibitors of each assay with Prism software. The IC50s obtained range from 0.007 uM to 0.26 uM. Mechanism studies reveal that the inhibitors are competitive. For competitive inhibitor:
  • Ki IC50/(l+[S]/Km) [0023] In the assay conditions, [S](4 uM) is smaller than Km (20 uM for MMP-12). So Ki equal to IC50/1.2, which is little smaller than IC50, or roughly equal to IC50.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Cardiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/US2005/029259 2004-08-19 2005-08-17 5-[3-(4-benzyloxyphenylthio)-fur-2-yl]-imidazolidin-2, 4-dione and analogues as inhibitors of macrophage elastase Ceased WO2006023562A2 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
KR1020077006294A KR101197325B1 (ko) 2004-08-19 2005-08-17 대식 세포 엘라스타아제의 억제제인 5-［3-(4-벤질옥시페닐티오)-퓨르-2-일］-이미다졸리딘-2,4-디온 및 유사 화합물
MX2007001940A MX2007001940A (es) 2004-08-19 2005-08-17 5-[3-(4-benciloxifeniltio)-fur-2-il]-imidazolidin-2,4-diona y analogos como inhibidores de macrofago elastasa.
JP2007527975A JP5042833B2 (ja) 2004-08-19 2005-08-17 マクロファージエラスターゼの阻害剤としての５−［３−（４−ベンジルオキシフェニルチオ）−フラ−２−イル］−イミダゾリジン−２，４−ジオン及び類似体
CN2005800285556A CN101014338B (zh) 2004-08-19 2005-08-17 作为巨噬细胞弹性蛋白酶抑制剂的5-[3-(4-苄氧基苯基硫代)-呋喃-2-基]-咪唑烷-2,4-二酮和类似物
AT05786673T ATE508744T1 (de) 2004-08-19 2005-08-17 5-ä3-(4-benzyloxyphenylthio)-fur-2-ylü- imidazolidin-2, 4-dion und analoga als hemmer der makrophagenelastase
CA2577430A CA2577430C (en) 2004-08-19 2005-08-17 5-[3-(4-benzyloxyphenylthio)-fur-2-yl]-imidazolidin-2,4-dione and analogues as inhibitors of macrophage elastase
HK08101512.9A HK1107774B (en) 2004-08-19 2005-08-17 5-[3-(4-benzyloxyphenylthio)-fur-2-yl]-imidazolidin-2, 4-dione and analogues useful as inhibitors of macrophage elastase
BRPI0514470A BRPI0514470B8 (pt) 2004-08-19 2005-08-17 composto 5-[3-(4-benziloxifeniltio)-fur-2-il]-imidazolin-2,4-diona e composição farmacêutica
AU2005277432A AU2005277432B2 (en) 2004-08-19 2005-08-17 5-[3-(4-benzyloxyphenylthio)-fur-2-yl]-imidazolidin-2, 4-dione and analogues as inhibitors of macrophage elastase
DK05786673.3T DK1789036T3 (da) 2004-08-19 2005-08-17 5-[3-(4-benzyloxyphenylthio)-fur-2-yl]-imidazolidin-2,4-dion og analoger som inhibitorer af makrofagelastase
EP05786673A EP1789036B1 (en) 2004-08-19 2005-08-17 5-[3-(4-benzyloxyphenylthio)-fur-2-yl]-imidazolidin-2, 4-dione and analogues as inhibitors of macrophage elastase
NZ553258A NZ553258A (en) 2004-08-19 2005-08-17 5-[3-(4-Benzyloxyphenylthio)-fur-2-yl]-imidazolidin-2,4-dione and analogues as inhibitors of macrophage elastase
SI200531283T SI1789036T1 (sl) 2004-08-19 2005-08-17 5-(3-(4-benziloksifeniltio)-fur-2-il)-imidazolidin-2, 4-dion in analogi kot inhibitorji elastaze makrofaga

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US60273604P 2004-08-19 2004-08-19
US60/602,736 2004-08-19

Publications (3)

Publication Number Publication Date
WO2006023562A2 true WO2006023562A2 (en) 2006-03-02
WO2006023562A3 WO2006023562A3 (en) 2006-04-20
WO2006023562B1 WO2006023562B1 (en) 2006-06-22

Family

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Family Applications (1)

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PCT/US2005/029259 Ceased WO2006023562A2 (en) 2004-08-19 2005-08-17 5-[3-(4-benzyloxyphenylthio)-fur-2-yl]-imidazolidin-2, 4-dione and analogues as inhibitors of macrophage elastase

Country Status (16)

Country Link
US (1) US7179831B2 (enExample)
EP (1) EP1789036B1 (enExample)
JP (1) JP5042833B2 (enExample)
KR (1) KR101197325B1 (enExample)
CN (1) CN101014338B (enExample)
AT (1) ATE508744T1 (enExample)
AU (1) AU2005277432B2 (enExample)
BR (1) BRPI0514470B8 (enExample)
CA (1) CA2577430C (enExample)
DK (1) DK1789036T3 (enExample)
ES (1) ES2364068T3 (enExample)
MX (1) MX2007001940A (enExample)
NZ (1) NZ553258A (enExample)
RU (1) RU2391339C2 (enExample)
SI (1) SI1789036T1 (enExample)
WO (1) WO2006023562A2 (enExample)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2907512A1 (en) 2014-02-14 2015-08-19 Commissariat A L'energie Atomique Et Aux Energies Alternatives Inhibitors of MMP-12 as antiviral Agents
AU2019269409B2 (en) * 2018-05-15 2023-11-23 Foresee Pharmaceuticals Usa, Inc. Matrix metalloproteinase (MMP) inhibitors and methods of use thereof

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008051260A1 (en) * 2006-01-13 2008-05-02 Battelle Memorial Institute Methods for assessing copd-retlated diseases
US10532102B2 (en) * 2016-08-19 2020-01-14 Foresee Pharmaceuticals Co., Ltd. Pharmaceutical composition and methods of uses
ES2910833T3 (es) * 2016-08-19 2022-05-13 Foresee Pharmaceuticals Co Ltd Composición farmacéutica y procedimientos de usos
ES2865854T3 (es) * 2016-09-23 2021-10-18 Kaken Pharma Co Ltd Método para producir (r)-5-(3,4-difluorofenil)-5-[(3-metil-2-oxopiridin-1(2h)-il)metil]imidazolidin-2,4-diona y un producto intermedio para producir la misma
DK4058437T3 (da) * 2019-11-14 2025-01-20 Foresee Pharmaceuticals Usa Inc Matrix-metalloproteinase-(MMP)-inhibitorer og fremgangsmåder til anvendelse heraf
AU2022290589A1 (en) * 2021-06-08 2023-11-23 Foresee Pharmaceuticals Usa, Inc. Safe administration of mmp-12 inhibitor
RU2766551C1 (ru) * 2021-07-19 2022-03-15 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" (ПГНИУ) 5-(4-хлорфенил)-3-((4-хлорфенил)амино)-5-(фенилтио)фуран-2(5н)-он, обладающий противомикробной активностью

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WO2000040577A1 (en) 1998-12-31 2000-07-13 Aventis Pharmaceuticals Inc. 1-carboxymethyl-2-oxo-azepan derivatives useful as selective inhibitors of mmp-12
US6352976B1 (en) * 1998-12-31 2002-03-05 Aventis Pharmaceuticals Inc. Selective inhibitors of MMP-12
RU2150469C1 (ru) * 1999-06-01 2000-06-10 Уфимский государственный нефтяной технический университет Способ получения 2-(фурил-2)-1,3-имидазолидинов
EP1288199A4 (en) 2000-04-28 2005-10-12 Shionogi & Co INHIBITORS OF MMP-12
SE0100903D0 (sv) 2001-03-15 2001-03-15 Astrazeneca Ab Compounds
CA2447475A1 (en) 2001-05-25 2002-12-05 Chu-Biao Xue Hydantion derivatives as inhibitors of matrix metalloproteinases
EP1394159A1 (fr) * 2002-08-13 2004-03-03 Warner-Lambert Company LLC Nouveaux dérivés de thiophène, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
GB0219896D0 (en) 2002-08-27 2002-10-02 Bayer Ag Dihydropyridine derivatives
SE0202539D0 (sv) 2002-08-27 2002-08-27 Astrazeneca Ab Compounds
US7041693B2 (en) * 2002-10-04 2006-05-09 Bristol-Myers Squibb Company Hydantoin derivatives as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme (TACE)
US7132432B2 (en) * 2003-06-05 2006-11-07 Bristol-Myers Squibb Company Hydantoin derivatives as inhibitors of tumor necrosis factor-alpha converting enzyme (TACE)

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Title
See references of EP1789036A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2907512A1 (en) 2014-02-14 2015-08-19 Commissariat A L'energie Atomique Et Aux Energies Alternatives Inhibitors of MMP-12 as antiviral Agents
AU2019269409B2 (en) * 2018-05-15 2023-11-23 Foresee Pharmaceuticals Usa, Inc. Matrix metalloproteinase (MMP) inhibitors and methods of use thereof
AU2019270975B2 (en) * 2018-05-15 2023-12-14 Foresee Pharmaceuticals Usa, Inc. Matrix metalloproteinase (MMP) inhibitors and methods of use thereof
AU2024200323B2 (en) * 2018-05-15 2025-06-05 Foresee Pharmaceuticals Usa, Inc. Matrix metalloproteinase (MMP) inhibitors and methods of use thereof

Also Published As

Publication number Publication date
CA2577430A1 (en) 2006-03-02
SI1789036T1 (sl) 2011-09-30
WO2006023562B1 (en) 2006-06-22
RU2391339C2 (ru) 2010-06-10
HK1107774A1 (en) 2008-04-18
DK1789036T3 (da) 2011-06-27
RU2007105822A (ru) 2008-09-27
CN101014338B (zh) 2010-06-16
BRPI0514470B1 (pt) 2021-01-05
JP5042833B2 (ja) 2012-10-03
KR20070045330A (ko) 2007-05-02
CN101014338A (zh) 2007-08-08
NZ553258A (en) 2011-02-25
EP1789036B1 (en) 2011-05-11
MX2007001940A (es) 2007-07-24
BRPI0514470A (pt) 2008-06-10
KR101197325B1 (ko) 2012-11-05
ATE508744T1 (de) 2011-05-15
WO2006023562A3 (en) 2006-04-20
EP1789036A2 (en) 2007-05-30
BRPI0514470B8 (pt) 2021-07-20
AU2005277432B2 (en) 2011-11-24
US7179831B2 (en) 2007-02-20
CA2577430C (en) 2010-12-07
ES2364068T3 (es) 2011-08-24
JP2008510701A (ja) 2008-04-10
EP1789036A4 (en) 2008-08-27
US20060041000A1 (en) 2006-02-23
AU2005277432A1 (en) 2006-03-02

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