USRE39681EExpiredUtility
1-(4-sulfamyaryl)-3-substituted-5-aryl-2-pyrazolines and inhibitors of cyclooxygenase-2
Est. expiryJun 16, 2019(expired)· nominal 20-yr term from priority
A61P 9/00A61P 7/06A61P 35/04A61P 37/06A61P 3/10A61P 9/10A61P 5/14A61P 43/00A61P 31/16A61P 31/04A61P 29/00A61P 27/06A61P 31/12A61P 27/02A61P 35/00A61P 27/16A61P 17/02A61P 21/04A61P 1/00A61P 11/00A61P 17/04A61P 15/00A61P 11/06A61P 13/12A61P 17/06A61P 19/06A61P 21/00A61P 1/04A61P 1/02A61P 19/02C07D 231/06C07D 403/04
55
PatentIndex Score
0
Cited by
38
References
54
Claims
Abstract
Compounds of the formula wherein: X is selected from the group consisting of trihalomethyl, C 1 -C 6 alkyl, and a group of formula II: wherein: R 3 and R 4 are independently selected from the group consisting of hydrogen; halogen; hydroxyl; nitro; C 1 -C 6 alkyl; C 1 -C 6 alkoxy; carboxy; C 1 -C 6 trihaloalkyl; and cyano; Z is selected from the group consisting of substituted and unsubstituted aryl; or a pharmaceutically acceptable salt thereof. The compounds are inhibitors of cyclooxygenase-2 activity. They are useful for treating cyclooxygenase-mediated disorders, including, for example, inflamation, neoplastic disorders and angiogenesis-mediated disorders.
Claims
exact text as granted — not AI-modified1. A compound of the formula I:
wherein:
X is selected from the group consisting of trihalomethyl and C 1 -C 6 alkyl ; and
Z is selected from the group consisting of substituted and unsubstituted aryl other than substituted and unsubstituted phenyl; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein Z is selected from the group consisting of substituted and unsubstituted heteroaryl; or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 2 wherein Z said heteroaryl is selected from the group consisting of substituted and unsubstituted indolyl, furyl, thienyl, pyridyl, benzofuryl, benzothienyl, imidazolyl, pyrazolyl, thiazolyl, benzothazolyl benzothiazolyl, quinolinyl, and 4-(2-benzyloxazolyl); or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1 wherein Z is 3-indolyl; or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 1 wherein X is trifluoromethyl.
6. A compound of the formula I:
wherein:
X is a group of formula II:
wherein:
R 3 and R 4 are independently selected from the group consisting of hydrogen; halogen; hydroxyl; nitro; carboxy; C 1 -C 6 trihaloalkyl; and cyano;
Z is selected from the group consisting of substituted and unsubstituted aryl, and heteroaryl; phenyl which is mono- substituted with hydroxyl, nitro, carboxy, C 1 -C 6 trihaloalkyl or cyano; phenyl which is di - substituted; and phenyl which is tri - substituted;
provided when Z is substituted or unsubstituted heteroaryl, it is selected from the group consisting of substituted and unsubstituted pyridyl, furyl, indolyl, benzothienyl, benzofuryl, imidazolyl, pyrazolyl, 2-thiazolyl, quinolinyl and 4-(2-benzyloxazolyl);
or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 6 wherein Z is selected from the group consisting of unsubstituted phenyl; and phenyl mono-substituted with hydroxyl, nitro, carboxy, C 1 -C 6 trihaloalkyl or cyano, di- di - substituted phenyl and tri-substituted phenyl.
8. A compound according to claim 7 wherein Z is phenyl substituted with one or more of halogen, hydroxyl, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or carboxy; or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 10 6 wherein Z is the group:
wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, fluorine, bromine, chlorine, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxyl and nitro; or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 6 wherein Z is substituted or unsubstituted heteroaryl, wherein said heteroaryl is indolyl, furyl, pyridyl or benzofuryl; or a pharmaceutically acceptable salt thereof.
11. A compound according to claim 10 wherein Z is substituted or unsubstituted 3-indolyl; or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1 which is 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-(3-indolyl)-2-pyrazoline; or a pharmaceutically acceptable salt thereof.
13. A compound of the formula I:
wherein:
X is a group of formula II:
wherein:
R 3 and R 4 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy;
Z is selected from the group consisting of phenyl; phenyl monosubstituted with halogen, hydroxyl, nitro or carboxy; disubstituted phenyl; trisubstituted phenyl; and substituted and unsubstituted heteroaryl, wherein said heteroaryl is selected from the group consisting of substituted and unsubstituted pyridyl, furyl, indolyl, benzothienyl, benzofuryl, imidazolyl, pyrazolyl, 2-thiazolyl, quinolinyl and 4-(2-benzyloxazolyl); or a pharmaceutically acceptable salt thereof.
14. A compound according to claim 13 wherein Z is the group:
wherein R 1 and R 2 are independently selected from the group consisting of fluorine, bromine, chlorine, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxyl and nitro; or a pharmaceutically acceptable salt thereof.
15. A compound according to claim 13 wherein Z is substituted or unsubstituted heteroaryl, wherein said heteroaryl is indolyl, furyl, pyridyl or benzofuryl; or a pharmaceutically acceptable salt thereof.
16. A compound according to claim 15 wherein Z is substituted or unsubstituted 3-indolyl; or a pharmaceutically acceptable salt thereof.
17. A compound of the formula V:
wherein:
X is selected from the group consisting of trihalomethyl, C 1 -C 6 alkyl, and a group of formula II:
wherein:
R 3 and R 4 are independently selected from the group consisting of hydrogen; halogen; hydroxyl; nitro; C 1 -C 6 alkyl; C 1 -C 6 alkoxy; carboxy; C 1 -C 6 trihaloalkyl; and cyano;
Z is substituted or unsubstituted heteroaryl; and
R 5 is selected from the group consisting of:
wherein R 6 is C 1 -C 6 alkyl and M is Na, K or Li; or a pharmaceutically acceptable salt thereof.
18. A compound of the formula V:
wherein:
X is a group of formula II:
wherein:
R 3 and R 4 are independently selected from the group consisting of hydrogen; halogen; hydroxyl; nitro; C 1 -C 6 , alkyl; C 1 -C 6 alkoxy; carboxy; C 1 -C 6 trihaloalkyl; and cyano;
Z is selected from the group consisting of substituted and unsubstituted aryl; and
R 5 is selected from the group consisting of:
wherein R 6 is C 1 -C 6 alkyl and M is Na, K or Li or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 17 or 18 , or a pharmaceutically acceptable salt thereof.
20. A method for treating a cyclooxygenase- 2 -mediated disorder comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 17 or 18 , or a pharmaceutically acceptable salt thereof, wherein said disorder is selected from the group consisting of colon cancer, breast cancer, brain cancer, prostate cancer, pancreatic cancer, lung cancer, and bladder cancer.
21. A method for treating inflammation or an inflammation-mediated disorder , wherein said inflammation is mediated by cyclooxygenase- 2 , comprising administering to a subject in need of such treatment an effective amount of a compound according to claim 17 or 18 , or a pharmaceutically acceptable salt thereof.
22. A method for treating a neoplasia comprising administering to a subject in need of such treatment an effective amount of a compound according to claim 17 or 18 , or a pharmaceutically acceptable salt thereof.
23. A method for treating an angiogenesis-mediated disorder administering to a subject in need of such treatment an effective amount of a compound according to claim 17 or 18 , or a pharmaceutically acceptable salt thereof.
24. A method for producing a compound of formula I:
wherein:
the group X is selected from the group consisting of trihalomethyl, C 1 -C 6 alkyl, and a radical of formula II:
wherein:
wherein R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; carboxy; C 1 -C 6 trihaloalkyl; and cyano ; and
Z is selected from the group consisting of substituted and unsubstituted aryl, other than substituted and unsubstituted phenyl;
the method comprising:
(a) reacting a compound of the formula IV:
wherein X and Z are so defined;
with 4-sulfamyl phenyl hydrazine or a salt thereof; and
(b) isolating a compound according to formula I from the reaction products.
25. A method according to claim 24 wherein Z is substituted or unsubstituted heteroaryl.
26. A method according to claim 24 wherein X is a radical of formula II.
27. A method for producing a compound of formula I:
wherein:
the group X is a radical of formula II:
wherein:
R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; carboxy; C 1 -C 6 trihaloalkyl; and cyano; and
Z is selected from the group consisting of substituted and unsubstituted aryl heteroaryl; phenyl which is mono- substituted with hydroxyl, nitro, carboxy; C 1 -C 6 trihaloalkyl or cyano; phenyl which is di - substituted, and phenyl which is tri - substituted ;
the method comprising:
(a) reacting a compound of the formula IV:
wherein X and Z are so defined;
with 4-sulfamyl phenyl hydrazine or salt thereof; and
(b) isolating a compound according to formula I from the reaction products.
28. A method according to claim 27 wherein the group X in the reactant compound of formula IV is a radical of formula II:
wherein:
wherein R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; and carboxy.
29. An isolated optical isomer of a compound according to claim 17 or 18 , or a pharmaceutically acceptable salt thereof.
30. An isolated optical isomer of a compound of the formula I:
wherein:
X is selected from the group consisting of trihalomethyl, C 1 -C 6 alkyl, and a group of formula II:
wherein:
R 3 and R 4 are independently selected from the group consisting of hydrogen; halogen; hydroxyl; nitro; C 1 -C 6 alkyl; C 1 -C 6 alkoxy; carboxy; C 1 -C 6 trihaloalkyl; and cyano;
Z is selected from the group consisting of substituted and unsubstituted aryl;
or a pharmaceutically acceptable salt thereof.
31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .
32. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 6 .
33. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 13 .
34. A method for treating a cyclooxygenase- 2 -mediated disorder comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 1 formula I:
wherein:
X is selected from the group consisting of trihalomethyl and C
1
-C
6
alkyl;
Z is selected from the group consisting of substituted and unsubstituted aryl other than substituted and unsubstituted phenyl; or a pharmaceutically acceptable salt thereof,
further wherein said disorder is selected from the group consisting of colon cancer, breast cancer, brain cancer, prostate cancer, pancreatic cancer, lung cancer, and bladder cancer.
35. A method for treating a cyclooxygenase- 2 -mediated disorder comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 6 formula I:
wherein:
X is a group of formula II:
wherein:
R
3
and R
4
are independently selected from the group consisting of hydrogen; halogen; hydroxyl; nitro; carboxy; C
1
-C
6
trihaloalkyl; and cyano;
Z is selected from the group consisting of substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl;
wherein said heteroaryl is selected from the group consisting of pyridyl, furyl, indolyl, benzothienyl, benzofuryl, imidazolyl, pyrazolyl, 2 - thiazolyl, quinolinyl and 4 -( 2 - benzyloxazolyl ) ; or a pharmaceutically acceptable salt thereof,
further wherein said disorder is selected from the group consisting of colon cancer, breast cancer, brain cancer, prostate cancer, pancreatic cancer, lung cancer, and bladder cancer.
36. A method for treating a cyclooxygenase- 2 -mediated disorder comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 13 formula I:
wherein:
X is a group of formula II:
wherein:
R
3
and R
4
are independently selected from the group consisting of C
1
-C
6
alkyl and C
1
-C
6
alkoxy;
Z is selected from the group consisting of phenyl; phenyl monosubstituted with halogen, hydroxyl, nitro or carboxy; disubstituted phenyl; trisubstituted phenyl; and substituted and unsubstituted heteroaryl, wherein said heteroaryl is selected from the group consisting of pyridyl, furyl, indolyl, benzothienyl, benzofuryl, imidazolyl, pyrazolyl, 2 - thiazolyl, quinolinyl and 4 -( 2 - benzyloxazolyl ) ; or a pharmaceutically acceptable salt thereof,
further wherein said disorder is selected from the group consisting of colon cancer, breast cancer, brain cancer, prostate cancer, pancreatic cancer, lung cancer, and bladder cancer.
37. A method for treating inflammation or an inflamation-mediated disorder , wherein said inflammation is mediated by cyclooxygenase- 2 , comprising administering to a subject in need of such treatment an effective amount of a compound according to claim 1 formula I:
wherein:
X is selected from the group consisting of trihalomethyl and C
1
-C
6
alkyl;
Z is selected from the group consisting of substituted and unsubstituted aryl other than substituted and unsubstituted phenyl; or a pharmaceutically acceptable salt thereof.
38. A method for treating inflammation or an inflamation-mediated disorder , wherein said inflammation is mediated by cyclooxygenase- 2 , comprising administering to a subject in need of such treatment an effective amount of a compound according to claim 6 formula I:
wherein:
X is a group of formula II:
wherein:
R
3
and R
4
are independently selected from the group consisting of hydrogen; halogen; hydroxyl; nitro; carboxy; C
1
-C
6
trihaloalkyl; and cyano;
Z is selected from the group consisting of substituted and unsubstituted aryl, and
when Z is heteroaryl, it is selected from the group consisting of substituted and unsubstituted pyridyl, furyl, indolyl, benzothienyl, benzofuryl, imidazolyl, pyrazolyl, 2 - thiazolyl, quinolinyl and 4 -( 2 - benzyloxazolyl ) ; or a pharmaceutically acceptable salt thereof.
39. A method for treating inflammation or an inflamation-mediated disorder , wherein said inflammation is mediated by cyclooxygenase- 2 , comprising administering to a subject in need of such treatment an effective amount of a compound according to claim 13 formula I:
wherein:
X is a group of formula II:
wherein:
R
3
and R
4
are independently selected from the group consisting of hydrogen, C
1
-C
6
alkyl and C
1
-C
6
alkoxy;
Z is selected from the group consisting of phenyl; phenyl monosubstituted with halogen, hydroxyl, nitro or carboxy; disubstituted phenyl; trisubstituted phenyl; and heteroaryl selected from the group consisting of substituted and unsubstituted pyridyl, furyl, indolyl, benzothienyl, benzofuryl, imidazolyl, pyrazolyl, 2 - thiazolyl, quinolinyl and 4 -( 2 - benzyloxazolyl ) ; or a pharmaceutically acceptable salt thereof.
40. A method for treating a neoplasia comprising administering to a subject in need of such treatment an effective amount of a compound of the formula:
wherein:
X is selected from the group consisting of trihalomethyl, C 1 -C 6 alkyl, and a group of formula II,
wherein:
R 3 and R 4 are independently selected from the group consisting of hydrogen; halogen; hydroxyl; nitro; C 1 -C 6 alkyl; C 1 -C 6 alkoxy; carboxy; C 1 -C 6 trihaloalkyl; and cyano;
Z is selected from the group consisting of substituted and unsubstituted aryl; or a pharmaceutically acceptable salt thereof.
41. A method for treating an angiogenesis-mediated disorder administering to a subject in need of such treatment an effective amount of a compound of the formula:
wherein:
X is selected from the group consisting of trihalomethyl, C 1 -C 6 alkyl, and a group of formula II:
wherein:
R 3 and R 4 are independently selected from the group consisting of hydrogen; halogen; hydroxyl; nitro; C 1 -C 6 alkyl; C 1 -C 6 alkoxy; carboxy; C 1 -C 6 trihaloalkyl; and cyano;
Z is selected from the group consisting of substituted and unsubstituted aryl; or a pharmaceutically acceptable salt thereof.
42. A method according to claim 40 or 41 wherein Z is selected from the group consisting of substituted and unsubstituted heteroaryl; or a pharmaceutically acceptable salt thereof.
43. A method according to claim 42 wherein Z is selected from the group consisting of substituted and unsubstituted indolyl, furyl, thienyl, pyridyl, benzofuryl, benzothienyl, imidazolyl, pyrazolyl, thiazolyl, benzothiazolyl, quinolinyl, and 4-(2-benzyloxazolyl); or a pharmaceutically acceptable salt thereof.
44. A method according to claim 43 wherein Z is substituted or unsubstituted 3-indolyl; or a pharmaceutically acceptable salt thereof.
45. A method according to claim 40 or 41 wherein X is trifluoromethyl.
46. A method according to claim 40 or 41 wherein X is a group according to formula II wherein R 3 and R 4 are independently selected from the group consisting of hydrogen; halogen; hydroxyl; nitro; C 1 -C 6 alkyl; C 1 -C 6 alkoxy; carboxy; C 1 -C 6 trihaloalkyl; and cyano; or a pharmaceutically acceptable salt thereof.
47. A method according to claim 46 wherein Z is selected from the group consisting of unsubstituted phenyl, and mono-, di- and tri-substituted phenyl.
48. A compound of the formula I:
wherein:
X is C
1
-C
6
alkyl; and
Z is selected from the group consisting of substituted and unsubstituted aryl other than substituted and unsubstituted phenyl;
provided when Z is heteroaryl, it is selected from the group consisting of substituted and unsubstituted pyridyl, indolyl, benzothienyl, benzofuryl, imidazolyl, pyrazolyl, 2 - thiazolyl, quinolinyl and 4 -( 2 - benzyloxazolyl ) ; or a pharmaceutically acceptable salt thereof.
49. A method for producing a compound of formula I:
wherein:
the group X is C
1
-C
6
alkyl; and
Z is selected from the group consisting of substituted and unsubstituted aryl, other than substituted and unsubstituted phenyl;
provided when Z is heteroaryl, it is selected from the group consisting of substituted and unsubstituted pyridyl, indolyl, benzothienyl, benzofuryl, imidazolyl, pyrazolyl, 2 - thiazolyl, quinolinyl and 4 -( 2 - benzyloxazolyl );
the method comprising:
( a ) reacting a compound of the formula IV:
wherein X and Z are so defined;
with 4 - sulfamyl phenyl hydrazine or a salt thereof; and ( b ) isolating a compound according to formula I from the reaction products.
50. An isolated optical isomer of a compound of the formula I:
wherein:
X is selected from the group consisting of trihalomethyl and C
1
-C
6
alkyl;
Z is selected from the group consisting of substituted and unsubstituted heteroaryl; phenyl that is mono - substituted or di - substituted with substituents independently selected from the group consisting of hydroxyl, nitro, and carboxy; and phenyl that is tri - substituted; or a pharmaceutically acceptable salt thereof.
51. A method for producing a compound of formula V:
wherein R 5 is: wherein R 6 is C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof; the method comprising: ( a ) reacting a compound of formula I:
wherein X is selected from the group consisting of trihalomethyl, C 1 -C 6 alkyl and a group of the formula II:
wherein:
R
3
and R
4
are independently selected from the group consisting of hydrogen; halogen; hydroxyl; nitro; C
1
-C
6
alkyl; C
1
-C
6
alkoxy; carboxy; C
1
-C
6
trihaloalkyl; and cyano; and
Z is substituted or unsubstituted heteroaryl;
with an anhydride of the formula:
or an acylating compound of the formula:
wherein R
6
is C
1
-C
6
alkyl; and
( b ) isolating a compound according to formula V from the reaction products.
52. A method for producing a compound of formula V:
wherein R 5 is: wherein R 6 is C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof; the method comprising: ( a ) reacting a compound of formula I:
wherein X is a group of the formula II:
wherein: R 3 and R 4 are independently selected from the group consisting of hydrogen; halogen; hydroxyl; nitro; C 1 -C 6 alkyl; C 1 -C 6 alkoxy; carboxy; C 1 -C 6 trihaloalkyl; and cyano; and Z is substituted or unsubstituted aryl; with an anhydride of the formula: or an acylating compound of the formula: wherein R 6 is C 1 -C 6 alkyl; and ( b ) isolating a compound according to formula V from the reaction products.
53. A method for producing a compound of formula V:
wherein R 5 is: wherein R 6 is C 1 -C 6 alkyl and M is Na, K or Li; or a pharmaceutically acceptable salt thereof; the method comprising: ( a ) reacting a compound of formula I:
wherein X is selected from the group consisting of trihalomethyl, C 1 -C 6 alkyl and a group of the formula II:
wherein: R 3 and R 4 are independently selected from the group consisting of hydrogen; halogen; hydroxyl; nitro; C 1 -C 6 alkyl; C 1 -C 6 alkoxy; carboxy; C 1 -C 6 trihaloalkyl; and cyano; and Z is substituted or unsubstituted heteroaryl; and R 5 is and wherein R 6 is as defined above, with an alkali hydroxide selected from the group consisting of NaOH, KOH and LiOH; and ( b ) isolating a compound according to formula V from the reaction products.
54. A method for producing a compound of formula V:
wherein R 5 is: wherein R 6 is C 1 -C 6 alkyl and M is Na, K or Li; or a pharmaceutically acceptable salt thereof; the method comprising: ( a ) reacting a compound of formula I:
wherein X is a group of the formula II:
wherein: R 3 and R 4 are independently selected from the group consisting of hydrogen; halogen; hydroxyl; nitro; C 1 -C 6 alkyl; C 1 -C 6 alkoxy; carboxy; C 1 -C 6 trihaloalkyl; and cyano; and Z is substituted or unsubstituted aryl; and R 5 is and wherein R 6 is as defined above, with an alkali hydroxide selected from the group consisting of NaOH, KOH and LiOH; and ( b ) isolating a compound according to formula V from the reaction products.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.