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WO1999018099B1 - Aryl thiophene derivatives as pde iv inhibitors - Google Patents

Aryl thiophene derivatives as pde iv inhibitors

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Publication number
WO1999018099B1
WO1999018099B1 PCT/CA1998/000931 CA9800931W WO9918099B1 WO 1999018099 B1 WO1999018099 B1 WO 1999018099B1 CA 9800931 W CA9800931 W CA 9800931W WO 9918099 B1 WO9918099 B1 WO 9918099B1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
hydrogen
independently
3alkyl
halo
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/CA1998/000931
Other languages
French (fr)
Other versions
WO1999018099A1 (en
Inventor
Yongxin Han
Dwight Macdonald
Andre Giroux
Robert N Young
Helene Perrier
Carole Lepine
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.)
Merck Frosst Canada and Co
Original Assignee
Merck Frosst Canada and Co
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 GBGB9808109.4A external-priority patent/GB9808109D0/en
Application filed by Merck Frosst Canada and Co filed Critical Merck Frosst Canada and Co
Priority to CA002305414A priority Critical patent/CA2305414A1/en
Priority to AU93347/98A priority patent/AU732406B2/en
Priority to EP98946190A priority patent/EP1019399A1/en
Priority to JP2000514910A priority patent/JP3409029B2/en
Publication of WO1999018099A1 publication Critical patent/WO1999018099A1/en
Publication of WO1999018099B1 publication Critical patent/WO1999018099B1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Landscapes

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

Abstract

The invention encompasses the novel compound of Formula (I) useful in the treatment of diseases, including asthma, by raising the level of cyclic adenosine-3',5'-monophosphate (cAMP) through the inhibition of phosphodiesterase IV (PDE IV). The invention also encompasses certain pharmaceutical compositions and methods for treatment of diseases by inhibition of PDE IV, resulting in an elevation of cAMP, comprising the use of compounds of Formula (I).

Claims

AMENDED CLAIMS[received by the International Bureau on 29 March 1999 (29.03.99); original claims 1-16 replaced by amended claims 1-15 (25 pages)]
1. A compound of Formula I
Figure imgf000003_0001
or a pharmaceutically acceptable'" salt thereof wherein:
Arl is an aromatic ring selected from phenyl, quinolinyl, pyridinyl, furyl, thienyl or thiazolyl, optionally substituted with up to two substituents chosen independently from among: a) Ci-6alkyl, optionally substituted with -OH, -CO2H, CO2C1-
3alkyl, and CN, b) Ci-3alkoxy, c) Ci-3alkylthio, d) Ci-3alkylsulfinyl, e) Ci-3alkylsulfonyl, f) Cl-3fluoroalkyl, optionally substituted with -OH, g) halo, h) -OH, i) -CO2H, j) -CO2Ci-3alkyl, k) -CH=CH-C(Me)2OH, 1) -CONR4R5> m) -S(0)2NE6R7, n) tetrazol-5-yl, or o) -CH=N-0-CH2C02H;
-128- Ri is -Xl-Yi-Ar2 , wherein:
Xl is -CH2- and
Y1 is -S-; Ar2 is an aromatic ring selected from phenyl, naphthyl, pyrimidinyl, pyridinyl or thienyl, optionally substituted with up to two substituents chosen independently among:
1) Ci-βal l,
2) Cl-6alkoxy, 3) -OH,
4) halo, or
5) CF3;
R2 is selected from: a) hydrogen or b) Ci-3alkyl.
R3 is selected from phenyl, naphthyl, pyridinyl, furyl, thienyl, or ethinyl, optionally substituted with up to two substituents chosen independently among: a) Ci-3alkyl, b) Ci-3fluoroalkyl, c) Ci-6alkoxy, d) Ci-3fluoroalkoxy, e) Ci-3alkylthio, f) halo, g) -OH, h) -N02, i) -CH2OH, j) -NHCONR9R10, k) -S(O)2NR11R12,
1) -SCH2(l,l-c-Pr)CH2CO2H, m) 1-piperazinyl, optionally substituted with Cι_3alkyl, n) 4-morpholinyl, or 0) -χ2.γ2.Ar3 }
-129- wherein,
X2 is 1) -CH2-,
2) -C(=NOH)-, or
3) a bond; Y2 is 1) -O-,
2) -S-, or
3) a bond;
Ar3 is phenyl, pyridinyl, pyrimidinyl or pyrazinyl, optionally substituted with up to two substituents chosen independently among:
1) Cι_3alkyl, optionally substituted with -OH, or
2) -CH2CO2H.
R4 and R^ are independently selected from: a) hydrogen, b) Ci-3alkyl, c) -S(O)2Ci-3alkyl, or d) -S(O)2phenyl, optionally mono-substituted with Ci-3alkyl, Ci-3alkoxy, Ci-3alkylthio or halo.
R and R? are independently chosen from among: a) hydrogen, b) C1.4alkyl, c) -CO-C^alkyl, or d) -CO-phenyl, optionally mono-substituted with C-^alkyl,
Ci-3alkoxy, Ci-3alkylthio or halo;
R° is chosen from among: a) hydrogen, or b) Ci-5alkyl; R9 and RlO a e independently chosen from among: a)hydrogen, b) Cl-4alkyl, or c) phenyl; and
Rll and l2 are independently chosen from among:
-130- a) hydrogen or b) Ci-δalkyl.
2. A compound according to Claim 1 wherein is hydrogen.
3. A compound according to Claim 1 wherein:
Ar2 is pyrimidinyl, optionally substituted with up to two substituents chosen independently among: 1) Cι_6alkyl,
2) Ci-6alkoxy,
3) -OH, or
4) halo, and the remaining substituents are de ined as in Claim 1.
4. A compound according to Claim 1 wherein
AJ-1 is an aromatic ring selected from phenyl, quinolinyl, pyridinyl, furyl, thienyl or thiazolyl, optionally substituted with up to two substituents chosen independently from among: a) Ci-βalkyl, optionally substituted with -OH, -CO2H, CO2C1-
3alkyl, and CN, b) Ci-3alkoxy, c) Ci_3alkylthio, d) Ci-3alkylsulfϊnyl, e) Ci-3alkylsulfonyl, f) Cl-3 luoroalkyl, optionally substituted with -OH, g) halo, h) -OH, i) -CO2H, j) -CO2Ci-3alkyl,
Ar2 is pyrimidinyl optionally substituted with up to two substituents chosen independently among:
1) Ci-βalkyl,
-131- 2) Ci-6alkoxy,
3) -OH, or
4) halo,
R is hydrogen;
R3 is selected from phenyl, naphthyl, pyridinyl, furyl, or thienyl, optionally substituted with up to two substituents chosen independently among: a) Cι.3alkyl, b) Cχ-3fluoroalkyl, c) Ci-βalkoxy, d) Ci-3fluoroalkoxy^ e) C i-3 alky lthio, f) halo, g) -OH, h) -NO2, i) -CH2OH, j) -NHCONR9R10, k) -S(O)2NR1:LR12,
1) -SCH2(l,l-c-Pr)CH2CO2H or m) -X -Y2-Ar3 , wherein,
X2 is 1) -CH2-, 2) -C(=NOH)-, or
3) a bond; Y2 is 1) -O-,
2) -S-, or
3) a bond; Ar3 is phenyl, pyridinyl, or pyrimidinyl optionally substituted with up to two substituents chosen independently among:
1) Ci-3alkyl, optionally substituted with -OH, or
2) -CH2CO2H.
R4 and R^ are independently selected from:
-132- a) hydrogen, b) Ci-3alkyl, c) -S(0)2Cι_3alkyl, or
R6 and Η are independently chosen from among: a) hydrogen, b) C^alkyl, c) -CO-C^alkyl, or
R° is chosen from among: a) hydrogen, or b) Ci-δalkyl;
R9 and RlO are independently chtfsen from among: a)hydrogen, b) Ci-4alkyl, and
RU and R^-2 are independently chosen from among: a) hydrogen or b) Ci-δalkyl.
5. A compound according to Claim 1 wherein χl is an aromatic ring selected from phenyl, quinolinyl, pyridinyl, furyl, thienyl or thiazolyl, optionally substituted with up to two substituents chosen independently from among: a) Ci-βalkyl, optionally substituted with -OH, -CO2H, CO2C1- 3alkyl, and CN, b) Ci-3alkoxy, c) Cl-3alkylthio, d) Ci-3alkylsulfinyl, e) Ci-3alkylsulfonyl, ) Ci-3fluoroalkyl, optionally substituted with -OH, g) halo, h) -OH, i) -CO2H, j) -CO2Ci-3alkyl,
-133- R1 is selected from: b) Ci-3alkyl, optionally substituted with -OH, or c) -X1-Y1-Ar2 , wherein:
Xl-Y1 is CH 2Sκ-'.
Ar2 is pyrimidinyl optionally substituted with up to two substituents chosen independently among: 1) Ci-βalkyl,
2) Cι_6alkoxy,
3) -OH, or
4) halo,
R2 is hydrogen;
R3 is selected from phenyl, pyridinyl, furyl, or thienyl, optionally substituted with up to two substituents chosen independently among: a) C i-3 alky 1, b) Ci-3 luoroalkyl, c) Ci-βalkoxy, d) Ci-3fluoroalkoxy, e) C i-3 alky lthio, f halo, g) -OH, h) -N02, i) -CH2OH, j) -NHCONR9R10, k) -X2-γ2-Ar3 , wherein,
X2 is 1) -CH2-, or
2) a bond; Y2 is 1) -O-,
2) -S-, or
-134- 3) a bond;
Ar3 is phenyl, pyridinyl, or pyrimidinyl optionally substituted with up to two substituents chosen independently among:
1) Ci-3alkyl, optionally substituted with -OH, or
2) -CH2CO2H. R4 and R0^ are independently selected from: a) hydrogen, b) Ci-3alkyl,
Rβ and R7 are independently chosen from among: a) hydrogen, b) C^alkyl,
RSI RU and R^2 are chosen from among: a) hydrogen, or b) Ci-5alkyl; and
R9 and R^-0 are independently chosen from among: a)hydrogen, b) Ci-4alkyl.
6. A compound according to Claim 1 selected from the group consisting of
-135-
Figure imgf000011_0001
Figure imgf000011_0002
Figure imgf000011_0003
Figure imgf000011_0004
136-
Figure imgf000012_0001
Figure imgf000012_0002
Figure imgf000012_0003
Figure imgf000012_0004
-137-
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0003
Figure imgf000013_0004
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0003
Figure imgf000014_0004
-139-
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0003
Figure imgf000015_0004
-140-
Figure imgf000016_0001
Figure imgf000016_0002
Figure imgf000016_0003
-141-
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000017_0003
Figure imgf000017_0004
-142-
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000018_0003
Figure imgf000018_0004
■143-
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000019_0003
Figure imgf000019_0004
-144-
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000020_0003
Figure imgf000020_0004
-145-
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000021_0003
-146-
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000022_0003
Figure imgf000022_0004
•147-
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000023_0003
-148-
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000024_0003
-149-
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000025_0003
■150-
7. A pharmaceutical composition for treating asthma comprising a non-toxic therapeutically effective amount of a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition for treating a phosphodiesterase IN mediated disease by increasing the cellular level of c AMP, comprising a non-toxic therapeutically effective amount of a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.
9. A method of treating asthma comprising administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
10. A method of treating a phosphodiesterase IV mediated disease by inhibiting PDE IN comprising administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound according to claim 1.
11. An anti-asthma pharmaceutical formulation comprising an acceptable, non-toxic, therapeutically effective amount of a compound of formula (I), as defined in claim 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
12. A phosphodiesterase IN inhibitor pharmaceutical composition comprising an acceptable phosphodiesterase IV inhibiting amount, effective to increase the cellular level of cAMP, of a compound of formula (I), as defined in claim 1 , 2, 3, 4, 5, or 6, or a pharmaceutically
-151- AMEΝDED SHEET ARTICLE 19 acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
13. A compound of formula (I), as defined in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for use in the treatment of asthma.
14. Use of a compound of formula (I), as defined in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating a phosphodiesterase IV mediated disease by increasing the cellular level of cAMP.
15. Use of a compound of formula (I), as defined in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof as a phosphodiesterase IV inhibitor.
-152-
PCT/CA1998/000931 1997-10-03 1998-10-01 Aryl thiophene derivatives as pde iv inhibitors Ceased WO1999018099A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002305414A CA2305414A1 (en) 1997-10-03 1998-10-01 Aryl thiophene derivatives as pde iv inhibitors
AU93347/98A AU732406B2 (en) 1997-10-03 1998-10-01 Aryl thiophene derivatives as PDE IV inhibitors
EP98946190A EP1019399A1 (en) 1997-10-03 1998-10-01 Aryl thiophene derivatives as pde iv inhibitors
JP2000514910A JP3409029B2 (en) 1997-10-03 1998-10-01 Arylthiophene derivatives as PDEIV inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US6091497P 1997-10-03 1997-10-03
US60/060,914 1997-10-03
GBGB9808109.4A GB9808109D0 (en) 1998-04-16 1998-04-16 Aryl thiophene derivatives as pde iv inhibitors
GB9808109.4 1998-04-16

Publications (2)

Publication Number Publication Date
WO1999018099A1 WO1999018099A1 (en) 1999-04-15
WO1999018099B1 true WO1999018099B1 (en) 1999-05-27

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Country Status (5)

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JP (1) JP3409029B2 (en)
AU (1) AU732406B2 (en)
CA (1) CA2305414A1 (en)
WO (1) WO1999018099A1 (en)

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WO2003027085A2 (en) * 2001-09-26 2003-04-03 Bayer Pharmaceuticals Corporation 3-pyridyl or 4-isoquinolinyl thiazoles as c17,20 lyase inhibitors
JP4331951B2 (en) * 2002-08-30 2009-09-16 富士フイルム株式会社 Novel compound and optical element using the same
WO2006023866A2 (en) 2004-08-23 2006-03-02 Wyeth Thiazolo-naphthyl acids as inhibitors of plasminogen activator inhibitor-1
MX2007002177A (en) 2004-08-23 2007-04-02 Wyeth Corp Pyrrolo-naphthyl acids as pai-1 inhibitors.
KR20070055563A (en) 2004-08-23 2007-05-30 와이어쓰 Oxazolo-naphthyl acid as a modulator of plasminogen activator inhibitor type 1 (PAI-1) useful in the treatment of thrombosis and cardiovascular disease
CN101429189B (en) * 2008-12-24 2014-07-23 沈阳药科大学 2,3-disubstituted aryl thiophene derivants and uses thereof
US20220315555A1 (en) 2009-05-26 2022-10-06 Abbvie Inc. Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases
US9034875B2 (en) 2009-05-26 2015-05-19 Abbvie Inc. Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases
DK2435432T6 (en) * 2009-05-26 2023-12-18 Abbvie Ireland Unlimited Co Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases
US8546399B2 (en) 2009-05-26 2013-10-01 Abbvie Inc. Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases
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WO2015018823A1 (en) 2013-08-08 2015-02-12 Galapagos Nv Thieno[2,3-c]pyrans as cftr modulators

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JP2001519347A (en) 2001-10-23
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WO1999018099A1 (en) 1999-04-15
CA2305414A1 (en) 1999-04-15
AU9334798A (en) 1999-04-27

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