CA2466477A1 - A2b adenosine receptor antagonists - Google Patents

A2b adenosine receptor antagonists Download PDF

Info

Publication number
CA2466477A1
CA2466477A1 CA002466477A CA2466477A CA2466477A1 CA 2466477 A1 CA2466477 A1 CA 2466477A1 CA 002466477 A CA002466477 A CA 002466477A CA 2466477 A CA2466477 A CA 2466477A CA 2466477 A1 CA2466477 A1 CA 2466477A1
Authority
CA
Canada
Prior art keywords
optionally substituted
compound
hydrogen
covalent bond
propyl
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.)
Granted
Application number
CA002466477A
Other languages
French (fr)
Other versions
CA2466477C (en
Inventor
Rao Kalla
Thao Perry
Elfatih Elzein
Vaibhav Varkhedkar
Xiaofen Li
Prabha Ibrahim
Venkata Palle
Dengming Xiao
Jeff Zablocki
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.)
Gilead Sciences Inc
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of CA2466477A1 publication Critical patent/CA2466477A1/en
Application granted granted Critical
Publication of CA2466477C publication Critical patent/CA2466477C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • 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
    • A61P1/12—Antidiarrhoeals
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline

Abstract

Disclosed are novel compounds of the Formula I or Formula II that are A2B adenosine receptor antagonists, useful for treating various disease states, including asthma and diarrhea.

Claims (41)

  1. WHAT IS CLAIMED IS:

    A compound of the Formula I or Formula II:
    wherein:
    Rl and R2 are independently chosen from hydrogen, optionally substituted alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl, or optionally substituted alkynyl, with the proviso that when D is a covalent bond E cannot be alkoxy;

    R3 is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;
    X is optionally substituted arylene or heteroarylene;
    Y is a covalent bond or alkylene in which one carbon atom can be optionally replaced by -O-,-S-or -NH-, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or -COR, in which R is hydroxy, alkoxy or amino;
    with the proviso that when the optional substitution is hydroxy or amino it cannot be adjacent to a heteroatom; and Z is hydrogen, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl;
    with the proviso that Z is hydrogen only when Y is a covalent bond and X is optionally substituted 1,4-pyrazolene; and, with the proviso that when X is optionally substituted arylene, Z is optionally substituted monocyclic heteroaryl.
  2. 2. The compound of claim 1, wherein:

    R1 and R2 are independently hydrogen, optionally substituted lower alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl, R3 is hydrogen;
    X is optionally substituted heteroarylene; and Y is a covalent bond or lower alkylene.
  3. 3. The compound of claim 2, wherein X is optionally substituted pyrazolene, Y
    is lower alkylene, and Z is optionally substituted phenyl or optionally substituted oxadiazole.
  4. 4. The compound of claim 3, wherein Rl is lower alkyl optionally substituted by cycloalkyl and R2 is hydrogen.
  5. 5. The compound of claim 4, wherein X is optionally substituted 1,4-pyrazolene.
  6. 6. The compound of claim 5, wherein Y is -CH2- or -CH(CH3)-, and Z is optionally substituted phenyl.
  7. 7. The compound of claim 6, wherein Rl is n-propyl, X is 1,4-pyrazolene, Y is -CH2-, and Z
    is 3-trifluoromethylphenyl, namely 1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]-methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.
  8. 8. The compound of claim 6, wherein Rl is n-propyl, X is 1,4-pyrazolene, Y is -CH2-, and Z
    is phenyl, namely 1-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.
  9. 9. The compound of claim 6, wherein Rl is n-butyl, X is 1,4-pyrazolene, Y is -CH2-, and Z
    is 3-fluorophenyl, namely 1-butyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.
  10. 10. The compound of claim 6, wherein Rl is n-propyl, X is 1,4-pyrazolene, Y is -CH(CH3)-, and Z is phenyl, namely 1-propyl-8-[1-(phenylethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.
  11. 11. The compound of claim 5, wherein Y is -CH2- or -CH(CH3)-, and Z is optionally substituted oxadiazole.
  12. 12. The compound of claim 1 l, wherein RI is n-propyl, X is 1,4-pyrazolene, Y
    is -CH2-, and Z is 5-(4-chlorophenyl)-[1,2,4]-oxadiazol-3-yl, namely 8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-propyl-1,3,7 trihydropurine-2,6-dione.
  13. 13. The compound of claim 11, wherein Rl is n-butyl, X is 1,4-pyrazolene, Y is -CH2-, and Z is 5-(4-chlorophenyl)-[1,2,4]-oxadiazol-3-yl, namely 8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl)pyrazol-4-yl)-1-butyl-1,3,7-trihydropurine-2,6-dione.
  14. 14. The compound of claim 2, wherein R1 and R2 are independently lower alkyl optionally substituted by cycloalkyl.
  15. 15. The compound of claim 14, wherein X is optionally substituted pyrazolene.
  16. 16. The compound of claim 15, wherein X is optionally substituted 1,4-pyrazolene, Y is -CH2-, -CH(CH3)- or a covalent bond-, and Z is hydrogen or optionally substituted phenyl.
  17. 17. The compound of claim 16, wherein Rl and R2 are n-propyl, Y is a covalent bond, and Z
    is hydrogen, namely 1,3-dipropyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione.
  18. 18. The compound of claim 16, wherein Rl is sec-butyl, R2 is methyl, Y is a covalent bond, and Z is hydrogen, namely 1-methyl-3-sec-butyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione.
  19. 19. The compound of claim 16, wherein R1 and R2 are independently methyl, n-propyl, or cyclopropylmethyl, Y is methylene, and Z is 3-trifluoromethylphenyl.
  20. 20. The compound of claim 16, wherein Rl and R2 are independently methyl, n-propyl, or cyclopropylmethyl, Y is rnethylene, and Z is 3-fluorophenyl.
  21. 21. The compound of claim 16, wherein Rl and R2 are n-propyl, Y is -CH(CH3)-, and Z is 3-trifluoromethylphenyl, namely 1,3-dipropyl-8-(1-{[3-(trifluoromethyl)-phenyl]ethyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.
  22. 22. The compound of claim 16, wherein Rl and R2 are n-propyl, Y is methylene, and Z is 4-carboxyphenyl, namely 1,3-dipropyl-8-{1-[(4-carboxyphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;
  23. 23. The compound of claim 16, wherein R1 and R2 are n-propyl, Y is -CH(CO2H)-, and Z is phenyl, namely 2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-2-phenylacetic acid;
  24. 24. The compound of claim 1, wherein:
    Rl and R2 are hydrogen, optionally substituted lower alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl, R3 is hydrogen;
    X is optionally substituted phenylene; and Y is a covalent bond or lower alkylene in which one carbon atom can be optionally replaced by -O-,-S-,or-NH-.
  25. 25. The compound of claim 24, wherein Rl and R2 are independently lower alkyl optionally substituted by cycloalkyl.
  26. 26. The compound of claim 25, wherein Rl and R2 are n-propyl and Y is -OCH2-.
  27. 27. The compound of claim 26, wherein Z is optionally substituted oxadiazole.
  28. 28. The compound of claim 27, wherein Z is 5-(2-methoxyphenyl)-(1,2,4-oxadiazol-3-yl), namely 8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;
  29. 29. The compound of claim 27, wherein Z is 5-(3-methoxyphenyl)-(1,2,4-oxadiazol-3-yl), namely 8-{4-[5-(3-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;
  30. 30. The compound of claim 27, wherein Z is 5-(4-fluorophenyl)-(1,2,4-oxadiazol-3-yl), namely 8-{4-[5-(4-fluorophenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;
  31. 31. A method of treating a disease state in a mammal that is alleviable by treatment with an A2B adenosine receptor antagonist, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of the formula:
    wherein:
    Rl and R2 are independently chosen from hydrogen, optionally substituted alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl, or optionally substituted alkynyl, with the proviso that when D is a covalent bond E cannot be alkoxy;
    R3 is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;
    X is optionally substituted arylene or heteroarylene;
    Y is a covalent bond or alkylene in which one carbon atom can be optionally replaced by -O-,-S-or -NH-, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or -COR, in which R is hydroxy, alkoxy or amino;
    with the proviso that when the optional substitution is hydroxy or amino it cannot be adjacent to a heteroatom; and Z is hydrogen, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl;
    with the proviso that when X is optionally substituted arylene, Z is optionally substituted monocyclic heteroaryl.
  32. 32. The method of claim 31, wherein the disease state is chosen from atherosclerosis, angiogenesis, diabetic retinopathy, cancer, and asthma.
  33. 33. The method of claim 31, wherein the disease state is an inflammatory gastrointestinal tract disorder.
  34. 34. The method of claim 33, wherein the inflammatory gastrointestinal tract disorder is diarrhea.
  35. 35. The method of claim 31, wherein the disease state is a neurological disorder.
  36. 36. The method of claim 35, wherein the neurological disorder is senile dementia, Alzheimer's disease, or Parkinson's disease.
  37. 37. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 31.
  38. 38. A process for the preparation of a compound of Formula I or Formula II:
    wherein:
    Rl and R2 are independently chosen from hydrogen, optionally substituted alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl, or optionally substituted alkynyl, with the proviso that when D is a covalent bond E cannot be alkoxy;

    R3 is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;
    X is optionally substituted arylene or heteroarylene;
    Y is a covalent bond or alkylene in which one carbon atom can be optionally replaced by -O-,-S
    or -NH-, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or -COR, in which R is hydroxy, alkoxy or amino;
    with the proviso that when the optional substitution is hydroxy or amino it cannot be adjacent to a heteroatom; and Z is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; or Z is hydrogen when X is optionally substituted heteroarylene and Y is a covalent bond;
    with the proviso that Z is hydrogen only when Y is a covalent bond and X is optionally substituted 1,4-pyrazolene; and, with the proviso that when X is optionally substituted arylene, Z is optionally substituted monocyclic heteroaryl.
    comprising:
    contacting a compound of the formula:
    in which Rl, R2 and R3 are as defined above;
    with a compound of the formula Z-Y-X-CO2H, in which X,Y,and Z are as defined above.
  39. 39. The process of claim 38, wherein Rl is n-butyl, and R2 and R3 are hydrogen.
  40. 40. The process of claim 39, wherein X is phenyl, Y is propylene, and Z is 1,4-pyrazolene:
    namely 1-[(3-fluorophenyl)methyl]pyrazole-4-carboxylic acid.
  41. 41. The process of claim 40, wherein the reaction is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in N,N-dimethylformamide.
CA2466477A 2001-11-09 2002-11-08 A2b adenosine receptor antagonists Expired - Fee Related CA2466477C (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US34822201P 2001-11-09 2001-11-09
US60/348,222 2001-11-09
US40140802P 2002-08-05 2002-08-05
US60/401,408 2002-08-05
PCT/US2002/035880 WO2003042214A2 (en) 2001-11-09 2002-11-08 A2b adenosine receptor antagonists

Publications (2)

Publication Number Publication Date
CA2466477A1 true CA2466477A1 (en) 2003-05-22
CA2466477C CA2466477C (en) 2012-10-02

Family

ID=26995608

Family Applications (1)

Application Number Title Priority Date Filing Date
CA2466477A Expired - Fee Related CA2466477C (en) 2001-11-09 2002-11-08 A2b adenosine receptor antagonists

Country Status (20)

Country Link
US (2) US6825349B2 (en)
EP (1) EP1444233B1 (en)
JP (1) JP4350517B2 (en)
KR (1) KR100937620B1 (en)
CN (1) CN100467469C (en)
AT (1) ATE520694T1 (en)
AU (1) AU2002359365B2 (en)
CA (1) CA2466477C (en)
CY (1) CY1112459T1 (en)
DK (1) DK1444233T3 (en)
HK (1) HK1071127A1 (en)
HU (1) HU229504B1 (en)
IL (2) IL161867A0 (en)
MX (1) MXPA04004388A (en)
NO (1) NO329692B1 (en)
NZ (1) NZ532816A (en)
PL (1) PL370207A1 (en)
PT (1) PT1444233E (en)
RU (1) RU2318824C2 (en)
WO (1) WO2003042214A2 (en)

Families Citing this family (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE47351E1 (en) 1999-06-22 2019-04-16 Gilead Sciences, Inc. 2-(N-pyrazolo)adenosines with application as adenosine A2A receptor agonists
US6403567B1 (en) * 1999-06-22 2002-06-11 Cv Therapeutics, Inc. N-pyrazole A2A adenosine receptor agonists
US20020012946A1 (en) 2000-02-23 2002-01-31 Luiz Belardinelli Method of identifying partial agonists of the A2A receptor
AU2001268958B2 (en) * 2000-07-04 2006-03-09 Novo Nordisk A/S Heterocyclic compounds, which are inhibitors of the enzyme dpp-iv
US7304070B2 (en) * 2001-11-09 2007-12-04 Cv Therapeutics, Inc. A2B adenosine receptor antagonists
US7317017B2 (en) * 2002-11-08 2008-01-08 Cv Therapeutics, Inc. A2B adenosine receptor antagonists
US20080318983A1 (en) * 2001-11-09 2008-12-25 Rao Kalla A2b adenosine receptor antagonists
US7125993B2 (en) * 2001-11-09 2006-10-24 Cv Therapeutics, Inc. A2B adenosine receptor antagonists
US20080194593A1 (en) * 2001-11-09 2008-08-14 Rao Kalla A2b adenosine receptor antagonists
US6977300B2 (en) * 2001-11-09 2005-12-20 Cv Therapeutics, Inc. A2B adenosine receptor antagonists
KR20040080939A (en) * 2002-02-01 2004-09-20 킹 파머슈티칼스 리서치 앤드 디벨로프먼트 아이엔씨 8-Heteroaryl Xanthine Adenosine A2B Receptor Antagonists
US7847101B2 (en) 2002-07-24 2010-12-07 Valocor Therapeutics, Inc. Pyrazolylbenzothiazole derivatives and their use as therapeutic agents
US8470801B2 (en) 2002-07-29 2013-06-25 Gilead Sciences, Inc. Myocardial perfusion imaging methods and compositions
US20050020915A1 (en) * 2002-07-29 2005-01-27 Cv Therapeutics, Inc. Myocardial perfusion imaging methods and compositions
CN1671399A (en) * 2002-07-29 2005-09-21 Cv医药有限公司 Myocardial perfusion imaging using A2A receptor agonists
AU2011224104B2 (en) * 2003-05-06 2012-06-28 Gilead Sciences, Inc. A2B adenosine receptor antagonists
DK1622908T3 (en) * 2003-05-06 2008-11-17 Cv Therapeutics Inc Xanthine derivatives as A2B adenosine receptor antagonists
ES2557310T3 (en) * 2003-08-25 2016-01-25 Dogwood Pharmaceuticals, Inc. 8-heteroaryl xanthines substituted
AU2004285013A1 (en) * 2003-10-31 2005-05-12 Cv Therapeutics, Inc. A2B adenosine receptor antagonists
AU2011202523B2 (en) * 2003-11-21 2013-05-30 Gilead Sciences, Inc. A2B adenosine receptor antagonists
GB0411056D0 (en) 2004-05-18 2004-06-23 Novartis Ag Organic compounds
CN101043889B (en) * 2004-09-01 2010-11-03 吉利德帕洛阿尔托股份有限公司 Use of A2b adenosine receptor antagonists in preparing medicine for promoting wound healing
KR20070063548A (en) * 2004-10-15 2007-06-19 씨브이 쎄러퓨틱스, 인코포레이티드 Method of preventing and treating airway remodeling and pulmonary inflammation using a2b adenosine receptor antagonists
AU2005295437B2 (en) 2004-10-20 2011-05-19 Gilead Palo Alto, Inc. Use of A2A adenosine receptor agonists
WO2006091898A2 (en) * 2005-02-25 2006-08-31 Adenosine Therapeutics, Llc Pyrazolyl substituted xanthines
WO2006091897A2 (en) * 2005-02-25 2006-08-31 Adenosine Therapeutics, Llc Derivatives of 8-substituted xanthines
US7598379B2 (en) * 2005-02-25 2009-10-06 Pgx Health, Llc Methods for the synthesis of unsymmetrical cycloalkyl substituted xanthines
AU2006259411B2 (en) * 2005-06-16 2012-03-22 Gilead Sciences, Inc. Prodrugs of A2B adenosine receptor antagonists
ES2270715B1 (en) 2005-07-29 2008-04-01 Laboratorios Almirall S.A. NEW DERIVATIVES OF PIRAZINA.
ES2274712B1 (en) 2005-10-06 2008-03-01 Laboratorios Almirall S.A. NEW IMIDAZOPIRIDINE DERIVATIVES.
GB0601951D0 (en) 2006-01-31 2006-03-15 Novartis Ag Organic compounds
PT1989214T (en) 2006-02-03 2016-09-22 Gilead Sciences Inc Process for preparing an a2a-adenosine receptor agonist and its polymorphs
CA2849661A1 (en) * 2006-03-17 2007-09-27 Gilead Sciences, Inc. Method of preventing and treating hepatic disease using a2b adenosine receptor antagonists
US7884100B2 (en) * 2006-06-16 2011-02-08 Pgxhealth, Llc Substituted 8-[6-amino-3-pyridyl]xanthines
US7767685B2 (en) * 2006-06-29 2010-08-03 King Pharmaceuticals Research And Development, Inc. Adenosine A2B receptor antagonists
US7470697B2 (en) * 2006-09-01 2008-12-30 Adenosine Therapeutics, Llc Pyrrolo[3,2-D] pyrimidines that are selective antagonists of A2B adenosine receptors
JP2010502649A (en) * 2006-09-01 2010-01-28 シーブイ・セラピューティクス・インコーポレイテッド Methods and compositions for increasing patient tolerance during myocardial imaging
US20090081120A1 (en) * 2006-09-01 2009-03-26 Cv Therapeutics, Inc. Methods and Compositions for Increasing Patient Tolerability During Myocardial Imaging Methods
WO2008042796A2 (en) * 2006-09-29 2008-04-10 Cv Therapeutics, Inc. Methods for myocardial imaging in patients having a history of pulmonary disease
RU2009120389A (en) 2006-10-30 2010-12-10 Новартис АГ (CH) HETEROCYCLIC COMPOUNDS AS ANTI-INFLAMMATORY AGENTS
US20080267861A1 (en) * 2007-01-03 2008-10-30 Cv Therapeutics, Inc. Myocardial Perfusion Imaging
CN101945868A (en) * 2007-12-11 2011-01-12 先灵公司 Gamma secretase modulators
US8431578B2 (en) 2008-01-11 2013-04-30 Novartis Ag Organic compounds
WO2009088518A1 (en) * 2008-01-11 2009-07-16 Cv Therapeutics, Inc. A2b adenosine receptor antagonists for the treatment of cancer
EP2268641B1 (en) * 2008-03-26 2014-09-03 Advinus Therapeutics Pvt. Ltd. Heterocyclic compounds as adenosine receptor antagonist
WO2009157938A1 (en) * 2008-06-26 2009-12-30 Cv Therapeutics, Inc. A2b adenosine receptor antagonists for treating cancer
WO2010009194A1 (en) * 2008-07-16 2010-01-21 King Pharmaceuticals Research And Development, Inc. Methods of treating atherosclerosis
EP2344145A1 (en) * 2008-09-29 2011-07-20 Gilead Sciences, Inc. Combinations of a rate control agent and an a-2-alpha receptor antagonist for use in multidetector computed tomography methods
US8859566B2 (en) * 2009-03-13 2014-10-14 Advinus Therapeutics Private Limited Substituted fused pyrimidine compounds
WO2011005871A1 (en) 2009-07-07 2011-01-13 Pgxhealth, Llc Substituted 8-[6-carbonylamine-3-pyridyl]xanthines as adenosine a2b antagonists
WO2011055391A1 (en) 2009-11-09 2011-05-12 Advinus Therapeutics Private Limited Substituted fused pyrimidine compounds, its preparation and uses thereof
EP2595630A1 (en) * 2010-06-30 2013-05-29 Gilead Sciences, Inc. Use of a2b adenosine receptor antagonists for treating pulmonary hypertension
WO2012034095A1 (en) 2010-09-09 2012-03-15 Irm Llc Compounds and compositions as trk inhibitors
US8637516B2 (en) 2010-09-09 2014-01-28 Irm Llc Compounds and compositions as TRK inhibitors
CN103261200B (en) * 2010-09-13 2016-03-30 阿迪维纳斯疗法有限公司 As the purine compound of the prodrug of A2B adenosine receptor antagonists, their preparation method and medicinal use
EP2465859A1 (en) * 2010-12-08 2012-06-20 Life & Brain GmbH 8-Triazolylxanthine derivatives, processes for their production and their use as adenosine receptor antagonists
WO2012116217A1 (en) 2011-02-25 2012-08-30 Irm Llc Compounds and compositions as trk inhibitors
AR085942A1 (en) * 2011-04-07 2013-11-06 Gilead Sciences Inc USE OF AADENOSINE RECEPTOR TO TREAT CARDIAC INSUFFICIENCY AND ARRITMIA IN POST-INFAR PATIENTS OF MYOCARDIUM
JP6095072B2 (en) * 2011-10-27 2017-03-15 プロテオテク, インコーポレイテッドProteoTech, Inc. Caffeine-containing compounds and compositions for the treatment of amyloid disease and synucleinopathies
CN102532137B (en) * 2011-12-05 2014-12-10 辽宁医学院 8-pyrazole substituted xanthine A2B adenosine receptor antagonist and synthesis method and application thereof
US9035071B2 (en) * 2011-12-27 2015-05-19 Allergan, Inc. Compounds acting at multiple prostaglandin receptors giving a general anti-inflammatory response
MY189912A (en) 2013-03-15 2022-03-21 Hydra Biosciences Llc Substituted xanthines and methods of use thereof
WO2014153424A1 (en) * 2013-03-19 2014-09-25 La Jolla Institute For Allergy And Immunology Reducing diabetes in patients receiving hmg-coa reductase inhibitors (statins)
CN104744469A (en) * 2014-10-31 2015-07-01 合肥平光制药有限公司 Preparation method for theophylline
WO2017060488A1 (en) * 2015-10-09 2017-04-13 Almirall, S.A. New trpa1 antagonists
AU2017217688B2 (en) 2016-02-10 2023-01-19 Wake Forest University Health Sciences Model system of liver fibrosis and method of making and using the same
MX2020009286A (en) * 2018-03-05 2020-12-11 Teon Therapeutics Inc Adenosine receptor antagonists and uses thereof.
US10710994B2 (en) 2018-03-19 2020-07-14 Genentech, Inc. Oxadiazole transient receptor potential channel inhibitors
KR20210061202A (en) 2019-11-19 2021-05-27 일동제약(주) Benzonitrile-substituted Fused pyrimidine derivatives and their pharmaceutical use
KR20210076693A (en) 2019-12-16 2021-06-24 일동제약(주) Fused pyrimidine derivatives substituted with a nitrogen-containing heterocyclic ring and their pharmaceutical use
WO2024015372A1 (en) 2022-07-14 2024-01-18 Teon Therapeutics, Inc. Adenosine receptor antagonists and uses thereof

Family Cites Families (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US4326525A (en) 1980-10-14 1982-04-27 Alza Corporation Osmotic device that improves delivery properties of agent in situ
US4452788A (en) 1982-04-21 1984-06-05 Warner-Lambert Company Substituted 8-phenylxanthines
US4593095A (en) 1983-02-18 1986-06-03 The Johns Hopkins University Xanthine derivatives
US4558051A (en) 1983-10-11 1985-12-10 Richardson-Vicks, Inc. Analgesic and anti-inflammatory compositions comprising xanthines and methods of using same
US5364620A (en) 1983-12-22 1994-11-15 Elan Corporation, Plc Controlled absorption diltiazem formulation for once daily administration
GB8510758D0 (en) 1985-04-27 1985-06-05 Wellcome Found Compounds
US5023252A (en) 1985-12-04 1991-06-11 Conrex Pharmaceutical Corporation Transdermal and trans-membrane delivery of drugs
US4992445A (en) 1987-06-12 1991-02-12 American Cyanamid Co. Transdermal delivery of pharmaceuticals
US5001139A (en) 1987-06-12 1991-03-19 American Cyanamid Company Enchancers for the transdermal flux of nivadipine
US4902514A (en) 1988-07-21 1990-02-20 Alza Corporation Dosage form for administering nilvadipine for treating cardiovascular symptoms
DE8817122U1 (en) * 1988-12-22 1993-02-04 Boehringer Ingelheim Kg, 6507 Ingelheim, De
IT1229195B (en) 1989-03-10 1991-07-25 Poli Ind Chimica Spa XANTHINIC DERIVATIVES WITH BRONCODILATORY ACTIVITY AND THEIR THERAPEUTIC APPLICATIONS.
DE4019892A1 (en) 1990-06-22 1992-01-02 Boehringer Ingelheim Kg New xanthine derivs. are selective A1 adenosine antagonists - useful for treating CNS disorders (e.g. senile dementia) and heart and circulation disorders
WO1995011681A1 (en) 1993-10-29 1995-05-04 Merck & Co., Inc. Human adenosine receptor antagonists
GB9415529D0 (en) * 1994-08-01 1994-09-21 Wellcome Found Phenyl xanthine derivatives
DE19535504A1 (en) 1995-09-25 1997-03-27 Bayer Ag Substituted xanthines
WO1999042092A2 (en) 1998-02-20 1999-08-26 Harbor Branch Oceanographic Institution, Inc. Compounds and methods of use for treatment of neurogenic inflammation
US6117878A (en) 1998-02-24 2000-09-12 University Of Virginia 8-phenyl- or 8-cycloalkyl xanthine antagonists of A2B human adenosine receptors
EP0956855B1 (en) 1998-04-24 2003-03-12 K.U. Leuven Research & Development Immunosuppressive effects of 8 substituted xanthine derivatives
DE29902571U1 (en) 1998-05-19 2000-03-23 Papst Motoren Gmbh & Co Kg Electronically commutated motor
US6060481A (en) 1998-05-28 2000-05-09 The Penn State Research Foundation Method for improving insulin sensitivity using an adenosine receptor antagonist
ES2273487T3 (en) 1998-06-01 2007-05-01 Astellas Pharma Inc. ADENOSINE A1 ANTAGONISTS AGAINST MALE STERILITY.
GB9817623D0 (en) 1998-08-13 1998-10-07 Glaxo Group Ltd Pharmaceutical compounds
US6545002B1 (en) * 1999-06-01 2003-04-08 University Of Virginia Patent Foundation Substituted 8-phenylxanthines useful as antagonists of A2B adenosine receptors
US6437154B1 (en) 2001-09-28 2002-08-20 Council Of Scientific And Industrial Research Process for the preparation of 10-deacetylbaccatin III
US7317017B2 (en) * 2002-11-08 2008-01-08 Cv Therapeutics, Inc. A2B adenosine receptor antagonists
US6977300B2 (en) * 2001-11-09 2005-12-20 Cv Therapeutics, Inc. A2B adenosine receptor antagonists
US7247639B2 (en) * 2003-06-06 2007-07-24 Endacea, Inc. A1 adenosine receptor antagonists

Also Published As

Publication number Publication date
JP2005509036A (en) 2005-04-07
EP1444233A2 (en) 2004-08-11
EP1444233B1 (en) 2011-08-17
AU2002359365B2 (en) 2008-07-10
KR20050044361A (en) 2005-05-12
HK1071127A1 (en) 2005-07-08
ATE520694T1 (en) 2011-09-15
IL161867A0 (en) 2005-11-20
JP4350517B2 (en) 2009-10-21
DK1444233T3 (en) 2011-10-17
NO329692B1 (en) 2010-12-06
US20050038045A1 (en) 2005-02-17
RU2318824C2 (en) 2008-03-10
HUP0401925A2 (en) 2005-01-28
AU2002359365A2 (en) 2003-05-26
US7105665B2 (en) 2006-09-12
MXPA04004388A (en) 2005-05-16
CA2466477C (en) 2012-10-02
PL370207A1 (en) 2005-05-16
HUP0401925A3 (en) 2007-05-29
CN100467469C (en) 2009-03-11
NO20042378L (en) 2004-07-20
WO2003042214A3 (en) 2004-03-04
NZ532816A (en) 2005-11-25
PT1444233E (en) 2011-09-29
IL161867A (en) 2015-01-29
US20030139428A1 (en) 2003-07-24
CY1112459T1 (en) 2015-12-09
RU2004114210A (en) 2005-09-10
KR100937620B1 (en) 2010-01-20
WO2003042214A2 (en) 2003-05-22
HU229504B1 (en) 2014-01-28
US6825349B2 (en) 2004-11-30
CN1585769A (en) 2005-02-23

Similar Documents

Publication Publication Date Title
CA2466477A1 (en) A2b adenosine receptor antagonists
JP2005509036A5 (en)
RU2007117907A (en) METHOD FOR PREVENTING AND TREATING RESIDENTIAL RESIDUAL MODELING AND LUNG INFLAMMATION USING A2B Adenosine Receptor Antagonists
US7317017B2 (en) A2B adenosine receptor antagonists
US6977300B2 (en) A2B adenosine receptor antagonists
JP2008516969A5 (en)
AU2002359365A1 (en) A2B adenosine receptor antagonists
HRP20120712T1 (en) Method of wound healing using a2b adenosine receptor antagonists
CA2544193A1 (en) A2b adenosine receptor antagonists
JP2613352B2 (en) Parkinson's disease treatment
JP2008511654A5 (en)
US7304070B2 (en) A2B adenosine receptor antagonists
JP2007509947A5 (en)
JP2006515316A5 (en)
EP1622908B1 (en) Xanthine derivatives as a2b adenosine receptor antagonists
WO2009157938A1 (en) A2b adenosine receptor antagonists for treating cancer
EP2324015B1 (en) Thiophene-2-carboxamide derivatives, preparation thereof and therapeutic use thereof
WO2009088518A1 (en) A2b adenosine receptor antagonists for the treatment of cancer
US20220362259A1 (en) Substituted pyrazoloazepin-4-ones and their use as phosphodiesterase inhibitors
KR20060055453A (en) Xanthine derivatives as a2b adenosine receptor antagonists

Legal Events

Date Code Title Description
EEER Examination request
MKLA Lapsed

Effective date: 20210831

MKLA Lapsed

Effective date: 20191108