US2001031766A1PendingUtilityA1
Prostaglandin receptor ligands
Est. expiryOct 7, 2018(expired)· nominal 20-yr term from priority
A61P 37/00A61P 35/00A61P 43/00A61P 29/00A61P 25/28A61P 27/06A61P 19/06A61P 19/04A61P 19/02A61P 17/02A61P 15/06A61P 11/06A61P 1/02C07C 309/10C07C 59/66C07C 62/34C07D 333/34C07D 285/135C07D 215/36C07C 311/51C07D 317/60C07C 323/62C07C 323/60C07C 59/64C07D 257/04C07D 307/79C07D 215/18C07C 59/68C07D 333/28
44
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Claims
Abstract
Compounds and methods for treating prostaglandin mediated diseases, and certain pharmaceutical compositions thereof are disclosed. The compounds are represented by formula II: Ar 1 —W—Ar 2 —X—Q II The compounds of the invention are structurally different from NSAIDs and opiates, and are antagonists of the pain and inflammatory effects of E-type prostaglandins.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound represented by formula II:
Ar 1 —W—Ar 2 —X—Q II
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
Ar 1 is an aryl or heteroaryl group, optionally substituted with R 1 or R 3 ;
R 1 is Y m —R 2 , Y m —Ar 3 , halogen, N(R 5 ) 2 , CN, NO 2 , C(R 6 ) 3 , CON(R 5 ) 2 , S(O) n R 7 or OH;
Y represents a linker between R 2 or Ar 3 and Ar 1 containing 0-4 carbon atoms and not more than one heteroatom selected from O, N and S, said linker optionally containing CO, S(O) n , —C═C— or an acetylenic group, and said linker being optionally substituted by R 2 ;
m is 0 or 1;
n is 0, 1 or 2;
R 2 represents H, F, CHF 2 , CF 3 , lower alkyl or hydroxyC 1-6 alkyl, or two R 2 groups may be joined together and represent a carbocyclic ring of up to six members, said ring containing not more than one heteroatom selected from O, N and S;
Ar 3 represents an aryl or heteroaryl group, optionally substituted with R 3 ;
R 3 is R 4 , halogen, haloC 1-6 alkyl, N(R 5 ) 2 , CN, NO 2 , C(R 6 ) 3 , CON(R 5 ) 2 , OR 4 , SR 4 or S(O) n R 7 ;
R 4 is H, lower alkyl, lower alkenyl, lower alkynyl, CHF 2 or CF 3 ;
R 5 is R 4 , Ph or Bn, or two R 5 groups in combination with the atom to which they are attached represent a ring of up to 6 members containing carbon atoms and up to 2 heteroatoms selected from O, N and S;
R 6 is H, F, CF 3 or lower alkyl, or two R 6 groups may be taken together and represent a ring of up to 6 members containing carbon atoms and 0-2 heteroatoms selected from O, N and S;
R 7 is lower alkyl, lower alkenyl, lower alkynyl, CHF 2 , CF 3 , N(R 5 ) 2 , Ph(R 8 ) 2 or CH 2 Ph(R 8 ) 2 ;
R 8 is R 4 , OR 4 , SR 4 or halogen W represents a 3-6 membered linking group containing 0 to 2 heteroatoms selected from O, N and S, said linking group optionally containing CO, S(O) n , C═C or an acetylenic group, and optionally being substituted with R 9 ;
R 9 is R 2 , lower alkenyl, lower alkynyl, OR 4 or SR 4 ;
Ar 2 represents an aryl or heteroaryl group, optionally substituted with R 3 ;
R 10 represents R 4 , halogen, N(R 5 ) 2 , CN, NO 2 , C(R 6 ) 3 , OR 4 , SR 4 or S(O) n R;
X represents a linker which is attached to Ar 2 ortho to the attachment of W, said linker containing 0-4 carbon atoms and not more than one heteroatom selected from O, N and S, said linker further optionally containing CO, S(O) n , C═C or an acetylenic group, and said linker being optionally substituted with R 11 ;
R 11 is R 9 ;
Q represents a member selected from the group consisting of: CO 2 H, tetrazole, SO 3 H, hydroxamic acid, CONHSO 2 R 12 and SO 2 NHCOR 12 ;
R 12 represents a member selected from the group consisting of: CF 3 , lower alkyl, lower alkenyl, lower alkynyl and ZAr 4 , wherein Z is an optional linker containing 0-4 carbon atoms, optionally substituted with R 13 ;
R 13 is R 9 ;
Ar 4 is an aryl or heteroaryl group optionally substituted with R 14 , and
R 14 is R 10 or NHCOMe.
2 . A compound in accordance with claim 1 wherein R 1 is OH, OCH 2 Ar 3 , SCH 2 Ar 3 , OAr 3 , SAr 3 or NR 2 CH 2 Ar 3 .
3 . A compound in accordance with claim 1 wherein Ar 3 is an aryl or heteroaryl group selected from the group consisting of benzene, pyridine, thiophene, furan, oxazole and thiazole, said group being optionally substituted with R 3 .
4 . A compound in accordance with claim 1 wherein Ar 2 is an aryl or heteroaryl group selected from the group consisting of: benzene, pyridine, thiophene, furan, oxazole and thiazole, said group being optionally substituted with 1-5 groups selected from R 4 , OR 4 , SR 4 and halogen.
5 . A compound in accordance with claim 1 wherein W is selected from the group consisting of: CH 2 OCH 2 , (CH 2 ) 3 , CH 2 CH═CH, CH═CHCH 2 , CH(OH)CH═CH, CH═CHCH(OH), CH 2 C+C, C—CCH 2 , 1,2-c-Pr—CH 2 and -1,2-c-Pr—CH 2 —.
6 . A compound in accordance with claim 1 wherein X is selected from the group consisting of: (CH 2 ) 2 , CH═CH, C═C and 1,2-c-Pr.
7 . A compound in accordance with claim 1 wherein Q is CO 2 H or tetrazole.
8 . A compound in accordance with claim 1 wherein Z represents a 0-2 carbon atom linker that is unsubstituted.
9 . A compound in accordance with claim 1 wherein Ar 4 represents an aryl or heteroaryl group selected from the group consisting of benzene, pyridine, thiophene, furan, oxazole, thiazole, 1,3,4-thiadiazole and naphthalene, said group being optionally substituted with R 3 .
10 . A compound in accordance with claim 1 wherein:
Ar 1 is an aryl or heteroaryl group substituted by R 1 and R 3 ;
R 1 is OH, OCH 2 Ar 3 , SCH 2 Ar 3 , OAr 3 , SAr 3 or NR 2 CH 2 Ar 3 ;
Ar 3 is selected from the group consisting of benzene, pyridine, thiophene, furan, oxazole and thiazole, said group being optionally substituted with R 3 ;
Ar 2 represents a member selected from the group consisting of: benzene, pyridine, thiophene, furan, oxazole, and thiazole, said group being optionally substituted with 1-4 members selected from the group consisting of: R 4 , OR 4 , SR 4 and halogen;
W is selected from the group consisting of: CH 2 OCH 2 , (CH 2 ) 3 , CH 2 CH═CH, CH═CHCH 2 , CH(OH)CH═CH, CH═CHCH(OH), CH 2 C+C , C═CCH 2 1,2-c-Pr—CH 2 — and —CH 2 -1,2-c-Pr—;
X is selected from the group consisting of: (CH 2 ) 2 , CH═CH, C═C and 1,2-c-Pr;
and Q is CO 2 H or tetrazole.
11 . A compound in accordance with claim 1 wherein:
Ar 1 is an aryl or heteroaryl group optionally substituted with R 1 and R 3 ;
R 1 is OH, OCH 2 Ar 3 , SCH 2 Ar 3 , OAr 3 , SAr 3 or NR 2 CH 2 Ar 3 ;
Ar 3 represents a member selected from the group consisting of: benzene, pyridine, thiophene, furan, oxazole or thiazole, said group being optionally substituted with R 3 ;
W is selected from the group consisting of: CH 2 OCH 2 , (CH 2 ) 3 , CH 2 CH═CH, CH═CHCH 2 , CH(OH)CH═CH, CH═CHCH(OH), CH 2 C═C or C═CCH 2 ;
Ar 2 represents a member selected from the group consisting of: benzene, pyridine, thiophene, furan, oxazole or thiazole, said group being optionally substituted with R 8 ;
X is selected from the group consisting of: (CH 2 ) 2 , CH═CH, C═C and 1,2-c-Pr;
Q is CONHSO 2 ZAr 4 ;
Z is a 0-2 carbon linker and is unsubstituted;
Ar 4 is selected from the group consisting of: benzene, pyridine, thiophene, furan, oxazole, thiazole, 1,3,4-thiadiazole and naphthalene, and is optionally substituted by R 3 .
12 . A compound in accordance with claim 1 wherein:
Ar 1 is benzene or thiophene substituted in position 2 and/or position 4 relative to the attachment of W with a member selected from the group consisting of: OH, OCH 2 Ar 3 , SCH 2 Ar 3 , OAr 3 , SAr 3 and NR 2 CH 2 Ar 3 , and is optionally substituted in position 3 with a member selected from the group consisting of: OMe, OCHF 2 and lower alkyl;
Ar 3 is benzene or thiophene, optionally substituted with R 8 ;
W is selected from the group consisting of: CH 2 OCH 2 , (CH 2 ) 3 , CH 2 CH═CH, CH═CHCH 2 , CH(OH)CH═CH and CH═CHCH(OH),
Ar 2 is benzene or thiophene, optionally substituted with 1-4 members selected from R 4 , OR 4 , SR 4 and halogen;
X represents a member selected from the group consisting of: (CH 2 ) 2 , CH═CH and 1,2-c-Pr, and Q is CO 2 H.
13 . A compound in accordance with claim 1 wherein:
Ar 1 is a benzene or a thiophene unsubstituted or substituted in position 2 and/or position 4 relative to the point of attachment to W by a member selected from the group consisting of: OH, OCH 2 Ar 3 , SCH 2 Ar 3 , OAr 3 , SAr 3 and NR 2 CCH 2 Ar 3 ; and is optionally substituted at position 3 with one member selected from the group consisting of: OMe, OCHF 2 and lower alkyl;
Ar 3 is benzene or thiophene, optionally substituted with R 8 ;
W is selected from the group consisting of: CH 2 OCH 2 , (CH 2 ) 3 , CH 2 CH═CH, CH═CHCH 2 , CH(OH)CH═CH and CH═CHCH(OH);
Ar 2 is benzene or thiophene, optionally substituted with R 4 , OR 4 , SR 4 or halo;
X is selected from the group consisting of: (CH 2 ) 2 , CH═CH and 1,2-c-Pr,
Q is CONHSO 2 ZAr 4 ,
Z is a bond or CH 2 , and
Ar 4 is selected from the group consisting of: benzene, thiophene, 1,3,4-thiadiazole and naphthalene and is substituted with R 8 .
14 . A compound represented by formula II′:
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
Ar 1 represents phenyl, naphthyl, benzofuranyl or methylenedioxyphenyl;
R 1 represents H, OH, C 1-6 alkyl, C 1-6 alkoxy, hydroxyC 1-6 alkyl, aryl, aryloxy, arylalkoxy, haloaryl, haloheteroaryl, haloarylalkoxy, alkylaryl, haloalkylarylalkoxy, haloarylalkoxy and haloheteroarylalkoxy;
R 3 represents R 4 , halogen, OR 4 or SR 4 ;
R 4 represents H, lower alkyl, lower alkenyl, lower alkynyl, CHF 2 or CF 3 ;
X represents a member selected from the group consisting of:
—(CH 2 ) 1-2 —, 1,2-c-Pr, —CH═CH—, —CH 2 O—, —C+CCH 2 —, —C≡C—, and —CH 2 —C+C—;
W represents a member selected from the group consisting of:
—(CH 2 ) 3-6 —, —CH 2 CH═CH—, —CH═CHCH 2 —, —CH(OH)CH═CH—, —CH═CHCH(OH)—, —CH 2 -1,2-c-Pr—, -1,2-c-Pr—CH 2 —, —CH 2 —O—CH 2 —, —O—(CH 2 ) 1-3 —O—, —CH 2 —NHC(O)—, —CF 2 CH═CH—, —CH═CHCF 2 —, —CH 2 CH 2 —S—, —S—CH 2 CH 2 —, —CH 2 CH 2 —SO 2 —, —SO 2 —CH 2 CH 2 —, —O—(CH 2 ) 1-3 —, —(CH 2 ) 1-3 —O— and —CH═CHCH 2 CH 2 —, and
all other variables are as defined in claim 1 .
15 . A compound represented by formula II″:
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
Ar 1 represents phenyl, naphthyl, benzofuranyl or methylenedioxyphenyl;
R 1 represents H, OH, C 1-6 alkyl, C 1-6 alkoxy, hydroxyC 1-6 alkyl, aryl, aryloxy, arylalkoxy, haloaryl, haloheteroaryl, haloarylalkoxy, alkylaryl, haloalkylarylalkoxy, haloarylalkoxy and haloheteroarylalkoxy;
R 3 represents R 4 , halogen, OR 4 or SR 4 ;
R 4 represents H, lower alkyl, lower alkenyl, lower alkynyl, CHF 2 or CF 3 ;
X represents a member selected from the group consisting of:
—(CH 2 ) 1-2 —, -1,2-c-Pr—, —CH═CH—, —CH 2 O—, —C≡CCH 2 —, —C≡C—, and —CH 2 —C≡C—;
W represents a member selected from the group consisting of:
—(CH 2 ) 3-6 —, —CH 2 CH═CH—, —CH═CHCH 2 —, —CH(OH)CH═CH—, —CH═CHCH(OH)—, —CH 2 -1,2-c-Pr—, -1,2-c-Pr—CH 2 —, —CH 2 —O—CH 2 —, —O—(CH 2 ) 1-3 —O—, —CH 2 —NHC(O)—, —CF 2 CH═CH—, —CH═CHCF 2 —, —CH 2 CH 2 —S—, —S—CH 2 CH 2 —, —CH 2 CH 2 —SO 2 —, —SO 2 —CH 2 CH 2 —, —O—(CH 2 ) 1-3 —, —(CH 2 ) 1-3 —O— and —CH═CHCH 2 CH 2 —, and
R 12 is selected from the group consisting of: C 1-6 alkyl, thienyl, phenyl, naphthyl, biphenyl, quinolinyl, thiadiazolyl, tetrazolyl, —CH═CH-phenyl, said thienyl, phenyl, naphthyl, biphenyl, quinolinyl, thiadiazolyl, tetrazolyl and —CH═CH-phenyl groups being optionally substituted with R 3 .
16 . A compound in accordance with claim 1 falling withing the following table:
TABLE I
(Ar 1 —W—Ar 2 -X-Q)
Ex
Ar 1
W
Ar 2
X
Q
1
2-(BnO)-3-MePh
(CH 2 ) 3
1,2-Phe
(CH 2 ) 2
CO 2 H
2
2-(BnO)-3-MePh
CH 2 CH═CH
1,2-Phe
CH═CH
CONHSO 2 -2-
thienyl
3
2-(BnO)-3-MePh
CH═CHCH 2
1,2-Phe
CH═CH
CONHSO 2 -2-
thienyl
4
2-((2-Cl-4-FPh)CH 2 O)-
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
3-CF 3 Ph
5
2-((2-Cl-4-FPh)CH 2 O)-
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
3-CF 3 Ph
6
2-(BnO)Ph
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 − X +
7
2-(BnO)Ph
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 − X +
8
4-(BnO)-3,5-(MeO) 2 Ph
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 − X +
9
4-(BnO)-3,5-(MeO) 2 Ph
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 − X +
10
2-(BnO)-5-AcPh
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
11
2-(BnO)-5-AcPh
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
12
2-(BnO)-3-(MeO)Ph
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 − X +
13
2-(BnO)-3-(MeO)Ph
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 − X +
14
4-(BnO)-3-(MeO)Ph
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 − X +
15
4-(BnO)-3-(MeO)Ph
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 − X +
16
2-(BnO O)-3-MePh
CH 2 CH═CH
1,2-Phe
CH 2
CO 2 − X +
17
2-(BnO)-3-MePh
CH═CHCH 2
1,2-Phe
CH 2
CO 2 − X +
18
2-(BnO)-3-MePh
CH 2 CH═CH
5-Cl-1,2-Phe
CH 2
CO 2 − X +
19
2-(BnO)-3-MePh
CH═CHCH 2
5-Cl-1,2-Phe
CH 2
CO 2 − X +
20
4-(BnO)-3-(MeO)Ph
(CH 2 ) 3
1,2-Phe
1,2-c-Pr
CO 2 H
21
2-(BnO)-3-MePh
CH═CHCH 2
4,5-(MeO) 2 -
CH═CH
CO 2 H
1,2-Phe
22
2-(BnO)-3-MePh
CH 2 CH═CH
4,5-(MeO) 2 -
CH═CH
CO 2 H
1,2-Phe
23
3,4-(methylene
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
dioxy)Ph
24
3,4-(methylene
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
dioxy)Ph
25
Ph
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
26
Ph
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
27
2-(HO)-3-MePh
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
28
2-(BnO)-3-MePh
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 − X +
29
2-(BnO)-3-MePh
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 − X +
30
2-((7-Cl-2-
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
quinolinyl)CH 2 O)-3-
MePh
31
2-((7-Cl-2-
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
quinolinyl)CH 2 O)-3-
MePh
32
2-(BnO)-3-MePh
(CH 2 ) 3
1,2-Phe
bond
CO 2 H
33
2-(BnO)-3-MePh
CH═CHCH 2
1,2-Phe
bond
CO 2 − X +
34
2-(BnO)-3-MePh
CH 2 CH═CH
1,2-Phe
bond
CO 2 − X +
35
2-(BnO)-3-MePh
(CH 2 ) 3
1,2-Phe
CH═CH
CO 2 − X +
36
2-(BnO)-3-(MeO)Ph
(CH 2 ) 3
1,2-Phe
CH═CH
CO 2 − X +
37
4-(BnO)-3-(MeO)Ph
(CH 2 ) 3
1,2-Phe
CH═CH
CO 2 − X +
38
4-(MeO)Ph
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
39
4-(MeO)Ph
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
40
3,4-(MeO) 2 Ph
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
41
3,4-(MeO) 2 Ph
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
42
2-(BnO)Ph
CH(OH)CH═CH
1,2-Phe
CH═CH
CO 2 − X +
43
2-(BnO)-3-MePh
(CH 2 ) 3
1,2-Phe
(CH 2 ) 2
CON − X +
SO 2 -2-
thienyl
44
4-(BnO)-3-(MeO)Ph
CH 2 CH═CH
1,2-Phe
CH═CH
CON − X +
SO 2 -2-
thienyl
45
4-(BnO)-3-(MeO)Ph
CH═CHCH 2
1,2-Phe
CH═CH
CON − X +
SO 2 -2-
thienyl
46
2-(BnO)-3-MePh
CH 2 -1,2-c-Pr
1,2-Phe
CH═CH
CO 2 − X +
47
2-(BnO)-3-MePh
1,2-c-Pr-CH 2
1,2-Phe
CH═CH
CO 2 − X +
48
2-(BnO)-3-MePh
CH(OH)CH═CH
1,2-Phe
CH═CH
CO 2 − X +
49
2-(BnO)-3-MePh
CH═CHCH(OH)
1,2-Phe
CH═CH
CO 2 H
50
2-((2,6-Cl 2 Ph)CH 2 O)-
CH═CHCH(OH)
1,2-Phe
CH═CH
CO 2 H
3-MePh
51
2-((2,6-Cl 2 Ph)CH 2 O)-
CH(OH)CH═CH
1,2-Phe
CH═CH
CO 2 H
3-MePh
52
2-((4-FPh)CH 2 O)-3-
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
MePh
53
2-((4-FPh)CH 2 O)-3-
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 − X +
MePh
54
2-((3,4-F 2 Ph)CH 2 O)-
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
3-MePh
55
2-((3,4-F 2 Ph)CH 2 O)-
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 − X +
3-MePh
56
2-((3,5-F 2 Ph)CH 2 O)-
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
3-MePh
57
2-((3,5-F 2 Ph)CH 2 O)-
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 − X +
3-MePh
58
2-((2,6-Cl 2 Ph)CH 2 O)-
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
3-(HOCH 2 )Ph
59
2-((2,6-Cl 2 Ph)CH 2 O)-
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
3-(HOCH 2 )Ph
60
2-((2,6-Cl 2 Ph)CH 2 O)-
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
3-MePh
61
2-((2,6-Cl 2 Ph)CH 2 O)-
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 − X +
3-MePh
62
2-((4-CF 3 Ph)CH 2 O)-
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
3-MePh
63
2-((4-CF 3 Ph)CH 2 O)-
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 − X +
3-MePh
64
2-((4-(CHF 2 O)Ph)
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
CH 2 O)-3-MePh
65
2-((4-(CHF 2 O)Ph)
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 − X +
CH 2 O)-3-MePh
66
2-((4-CF 3 Ph)CH 2 O)-
CH═CHCH(OH)
1,2-Phe
CH═CH
CO 2 H
3-(HOCH 2 )Ph
67
2-((4-CF 3 Ph)CH 2 O)-
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
3-(HOCH 2 )Ph
68
2-((4-CF 3 Ph)CH 2 O)-
CH═CHCH(OH)
1,2-Phe
CH═CH
CO 2 H
3-MePh
69
2-(PhCH 2 O)-3-
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
(HOCH 2 )Ph
70
3-(PhO)Ph
CH 2 OCH 2
1,2-Phe
CH═CH
CO 2 − X +
71
2-(PhO)Ph
CH 2 OCH 2
1,2-Phe
CH═CH
CO 2 − X +
72
3-(BnO)Ph
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 − X +
73
3-(BnO)Ph
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 − X +
74
2-(BnO)Ph
O(CH 2 ) 3 O
1,2-Phe
CH═CH
CO 2 − X +
75
2-(PhCHMeO)-3-
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 − X +
MePh
76
2-(PhCHMeO)-3-
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
MePh
77
3-(PhO)Ph
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 − X +
78
3-(PhO)Ph
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 − X +
79
3-Phbenzofuran-7-yl
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 − X +
80
3-Phbenzofuran-7-yl
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 − X +
81
Ph
CH═CHCH 2
1,2-Phe
CH═CH
CONHSO 2 -
2-thienyl
82
Ph
CH 2 CH═CH
1,2-Phe
CH═CH
CONHSO 2 -
2-thienyl
83
4-(MeO)Ph
CH═CHCH 2
1,2-Phe
CH═CH
CONHSO 2 -2-
thienyl
84
4-(MeO)Ph
CH 2 CH═CH
1,2-Phe
CH═CH
CONHSO 2 -2-
thienyl
85
2-(BnO)-1-naphthyl
CH 2 NHCO
1,2-Phe
CH═CH
CO 2 H
86
2-((2-Cl-4-FPh)
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
CH 2 O)-3-MePh
87
2-((2-Cl-4-FPh)
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
CH 2 O)-3-MePh
88
2-((2,4-F 2 Ph)CH 2 O)-
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
3-MePh
89
2-((2,4-F 2 Ph)
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
CH 2 O)-3-MePh
90
2-((2,4,6-F 3 Ph)
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
CH 2 O)-3-MePh
91
2-((2,4,6-F 3 Ph)
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
CH 2 O)-3-MePh
92
2-((2,6-Cl 2 -4-FPh)
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
CH 2 O)-3-MePh
93
2-((2,6-Cl 2 -4-FPh)
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
CH 2 O)-3-MePh
94
2-((2,4-F 2 Ph)CH 2 O)-
CH 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
3-(CHF 2 O)Ph
95
2-((2,4-F 2 Ph)CH 2 O)-
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
3-(CHF 2 O)Ph
96
2-((4-FPh)CH 2 O)-
CF 2 CH═CH
1,2-Phe
CH═CH
CO 2 H
3-MePh
97
2-((4-FPh)CH 2 O)-
CH═CHCF 2
1,2-Phe
CH═CH
CO 2 H
3-MePh
98
2-((4-FPh)CH 2 O)-
(CH 2 ) 3
1,2-Phe
CH═CH
CONHSO 2 -
3-MePh
(4-i-PrPh)
99
2-((4-FPh)CH 2 O)-
(CH 2 ) 3
1,2-Phe
CH═CH
CONHSO 2 -
3-MePh
(4-t-BuPh)
100
2-((4-FPh)CH 2 O)-
CH 2 CH═CH
1,2-Phe
CH═CH
CONHSO 2 -
3-MePh
(4-(MeO)Ph)
101
2-((4-FPh)CH 2 O)-
CH═CHCH 2
1,2-Phe
CH═CH
CONHSO 2 -
3-MePh
(2,3-Cl 2 Ph)
102
2-((4-FPh)CH 2 O)-
CH═CHCH 2
4-Cl-1,2-Phe
CH═CH
CONHSO 2 -
3-MePh
(5-Br-2-
(MeO)Ph)
103
2-((4-FPh)CH 2 O)-
(CH 2 ) 2 S
3-F-1,2-Phe
CH═CH
CONHSO 2 -
3-MePh
(2,3,4-Cl 3 Ph)
104
2-((4-FPh)CH 2 O)-3-
(CH 2 ) 2 S
6-CF 3 -1,2-
CH═CH
CONHSO 2 -
MePh
Phe
(5-F-2-MePh)
105
2-((4-FPh)CH 2 O)-3-
(CH 2 ) 2 S
4,5-F 2 -1,2-
CH═CH
CONHSO 2 -
MePh
Ph
(2,5-Me 2 Ph)
106
2-((4-FPh)CH 2 O)-3-
(CH 2 ) 2 SO 2
1,2-Phe
CH═CH
CONHSO 2 -
MePh
(4-CF 3 Ph)
107
2-((4-FPh)CH 2 O)-3-
(CH 2 ) 2 SO 2
1,2-Phe
CH═CH
CONHSO 2 -2-
MePh
naphthyl
108
2-((4-FPh)CH 2 O)-3-
CH═CHCH 2
3-F-1,2-Phe
CH═CH
CONHSO 2 -
MePh
(3-Cl-4-FPh)
109
2-((4-FPh)CH 2 O)-3-
SO 2 (CH 2 ) 2
1,2-Phe
CH═CH
CONHSO 2 -
MePh
(4-n-PrPh)
110
2-((4-FPh)CH 2 O)-3-
SO 2 (CH 2 ) 2
1,2-Phe
CH═CH
CONHSO 2 -
(MeO)Ph
(2-ClPh)
111
2-((4-FPh)CH 2 O)-3-
SO 2 (CH 2 ) 2
1,2-Phe
CH═CH
CONHSO 2 -
(MeO)Ph
(4-FPh)
112
2-((4-FPh)CH 2 O)-3-
S(CH 2 ) 2
1,2-Phe
CH═CH
CONHSO 2 -
(MeO)Ph
(2-PhPh)
113
2-((4-FPh)CH 2 O)-3-
S(CH 2 ) 2
1,2-Phe
CH═CH
CONHSO 2 -
(MeO)Ph
(2-CF 3 Ph)
114
2-((4-FPh)CH 2 O)-3-
S(CH 2 ) 2
4-t-Bu-1,2-
CH═CH
CONHSO 2 -
(MeO)Ph
Phe
(4-Cl-2,5-
Me 2 Ph)
115
2-((4-FPh)CH 2 O)-3-
O(CH 2 ) 2
1,2-Phe
CH═CH
CONHSO 2 -
(MeO)Ph
(2,5-Cl 2 Ph)
116
2-((4-FPh)CH 2 O)-3-
O(CH 2 ) 2
1,2-Phe
CH═CH
CONHSO 2 -
(MeO)Ph
(4-Br-2-
(CF 3 O)Ph)
117
2-((4-FPh)CH 2 O)-3-
O(CH 2 ) 2
1,2-Phe
CH═CH
CONHSO 2 -
(MeO)Ph
CH 2 Ph
118
2-((4-FPh)CH 2 O)-3-
(CH 2 ) 2 O
1,2-Phe
CH═CH
CONHSO 2 -1-
(MeO)Ph
naphthyl
119
2-((4-FPh)CH 2 O)-3-
(CH 2 ) 2 O
4,5-F 2 -1,2-
CH═CH
CONHSO 2 -
(MeO)Ph
Phe
(2-FPh)
120
2-((4-FPh)CH 2 O)-3-
(CH 2 ) 2 O
1,2-Phe
CH═CH
CONHSO 2 -
(MeO)Ph
(2,4-Cl 2 Ph)
121
2-((4-FPh)CH 2 O)-3-
(CH 2 ) 3
1,2-Phe
CH═CH
CONHSO 2 -
(MeO)Ph
CH═CHPh
122
2-((4-F-Ph)CH 2 O)-3-
(CH 2 ) 3
1,2-Phe
CH═CH
CONHSO 2 -
(MeO)Ph
(3,5-
(CF 3 ) 2 Ph)
123
2-((4-FPh)CH 2 O)Ph
(CH 2 ) 3
1,2-Phe
CH═CH
CONHSO 2 -
(2,5-Cl 2 -3-
thienyl)
124
2-((4-FPh)CH 2 O)Ph
(CH 2 ) 4
3-F-1,2-Phe
CH═CH
CONHSO 2 -
(3-BrPh)
125
2-((4-FPh)CH 2 O)Ph
(CH 2 ) 4
3-MeO-1,2-
CH═CH
CONHSO 2 -
Phe
(2-BrPh)
126
2-((4-FPh)CH 2 O)Ph
(CH 2 ) 4
1,2-Phe
CH═CH
CONHSO 2 -
(2-NO 2 Ph)
127
2-((4-FPh)CH 2 O)Ph
(CH 2 ) 5
1,2-Phe
(CH 2 ) 2
CONHSO 2 -
(3-ClPh)
128
2-((4-FPh)CH 2 O)Ph
(CH 2 ) 5
1,2-Phe
(CH 2 ) 2
CONHSO 2 -
(4-(CF 3 O)Ph)
129
2-HOPh
CH═CH(CH 2 ) 2
1,2-Phe
(CH 2 ) 2
CONHSO 2 -8-
quinolinyl
130
2-((4-FPh)CH 2 O)Ph
CH═CH(CH 2 ) 2
5-(CF 3 O)-
(CH 2 ) 2
CONHSO 2 -
1,2-Phe
(3,4-Cl 2 Ph)
131
4-((2,6-Cl 2 -4-
CH═CH(CH 2 ) 2
3-F-1,2-Phe
(CH 2 ) 2
CONHSO 2 -
FPh)CH 2 O)-3-MePh
(4-EtPh)
132
2-((4-FPh)CH 2 O)Ph
CH 2 CH═CH
1,2-Phe
(CH 2 ) 2
CONHSO 2 -
(4-Cl-2-
NO 2 Ph)
133
2-((4-FPh)CH 2 O)Ph
CH═CHCH 2
4,5-F 2 -1,2-
CH═CH
CONHSO 2 -
Phe
(2-Cl-3-Br-5-
thienyl)
134
2-((4-FPh)CH 2 O)Ph
CH 2 CH═CH
4,5-F 2 -1,2-
CH═CH
CONHSO 2 -
Phe
(3,4-
(MeO) 2 Ph)
135
2-HOPh
CH═CHCH 2
4,5-F 2 -1,2-
CH═CH
CONHSO 2 -
Phe
(2,5-Cl 2 -3-Br-
4-thienyl)
136
4-((4-FPh)CH 2 O)-3-
CH 2 CH═CH
4,5-F 2 -1,2-
CH═CH
CONHSO 2 -
(MeO)Ph
Phe
(4-Br-2,5-
F 2 Ph)
137
4-((4-FPh)CH 2 O)-3-
CH═CHCH 2
1,2-Phe
CH═CH
CONHSO 2 -
(MeO)Ph
(5-(AcNH)-
1,3,4-
thiadiazol-2-
yl)
138
4-((4-FPh)CH 2 O)-3-
CH 2 CH═CH
1,2-Phe
CH═CH
CONHSO 2 -
(MeO)Ph
(2,3,4,5,6-
F 5 Ph)
139
4-((2-Cl-4-FPh)CH 2 O)-
CH═CHCH 2
1,2-Phe
CH═CH
CONHSO 2 -
3-MePh
(2-CNPh)
140
2-((4-FPh)CH 2 O)Ph
CH 2 CH═CH
4-F-1,2-Phe
CH═CH
CONHSO 2 -
(2-Cl-6-
MePh)
141
2-HOPh
CH═CHCH 2
1,2-Phe
CH═CH
CONHSO 2 -
(2,4,6-
Me 3 Ph)
142
Ph
CH 2 CH═CH
1,2-Phe
CH═CH
CONHSO 2 -
(2,3-Br 2 -2-
thienyl)
143
2-((4-FPh)
CH═CHCH 2
1,2-Phe
CH 2 O
CONHSO 2 -
CH 2 O)Ph
(4-NO 2 Ph)
144
2-((4-FPh)
CH 2 CH═CH
1,2-Phe
CH 2 O
CONHSO 2 -
CH 2 O)Ph
(3,5-Cl 2 Ph)
145
2,4-((4-FPh)
CH═CHCH 2
1,2-Phe
prop-1-
CONHSO 2 -
CH 2 O) 2 Ph
yne-1,3-
(5-Cl-2-
diyl
thienyl)
146
4-((2,4-F 2 Ph)CH 2 O)-
CH 2 CH═CH
1,2-Phe
CH 2 O
CONHSO 2 -
3-(MeO)Ph
(4-CF 3 Ph)
147
2-HO-3-MePh
CH═CHCH 2
1,2-Phe
CH 2 O
CONHSO 2 -
(2,4-F 2 Ph)
148
2-((4-FPh)CH 2 O)Ph
CH 2 CH═CH
4-F-1,2-Phe
1,2-
CONHSO 2 -
ethyne
(4-ClPh)
diyl
149
2-((4-FPh)CH 2 O)Ph
CH═CHCH 2
1,2-Phe
1,2-
CONHSO 2 -
ethyne
(3-CF 3 Ph)
diyl
150
4-HOPh
CH 2 CH═CH
1,2-Phe
1,2-
CONHSO 2 -
ethyne
Ph
diyl
151
2-((4-FPh)
CH═CHCH 2
1,2-Phe
prop-2-
CONHSO 2 -
CH 2 O)Ph
yne-1,3-
(5-Br-2-
diyl
thienyl)
152
2,4-((4-FPh)
CH 2 CH═CH
1,2-Phe
1,2-
CONHSO 2 -
CH 2 O) 2 Ph
ethynediyl
Me
153
2,4-((4-FPh)
CH═CHCH 2
1,2-Phe
1,2-c-Pr
CONHSO 2 -
CH 2 O) 2 Ph
(2,5-
(MeO) 2 Ph)
154
6-((4-FPh)CH 2 O)-
CH 2 CH═CH
4-F-1,2-Phe
1,2-c-Pr
CONHSO 2 -
2-naphthyl
(3-MePh)
155
2-((4-FPh)
CH═CHCH 2
1,2-Phe
1,2-c-Pr
CONHSO 2 -
CH 2 O)Ph
(4-MePh)
156
4-HO-3-(MeO)Ph
CH 2 CH═CH
1,2-Phe
1,2-c-Pr
CONHSO 2 -n-
Bu
157
4-((4-FPh)CH 2 O)-
CH═CHCH 2
1,2-Phe
1,2-c-Bu
CONHSO 2 -
1-naphthyl
(2-Cl-4-FPh)
158
Ph
CH 2 CH═CH
1,2-Phe
CH═CH
CONHSO 2 -
(2-MePh)
159
2-((4-FPh)
CH═CHCH 2
1,2-Phe
CH═CH
CONHSO 2 -
CH 2 O)Ph
c-Pr
160
2,4-((4-FPh)
CH═CHCH 2
1,2-Phe
CH═CH
CO 2 H
CH 2 O) 2 Ph
161
4-((2,4-F 2 Ph)
(CH 2 ) 3
4-F-1,2-Phe
CH═CH
1H-tetrazol-
CH 2 O)-3-(MeO)Ph
5-yl
162
2-((4-FPh)
CH═CHCH 2
3-MeO-
CH═CH
1H-tetrazol-
CH 2 O)Ph
1,2-Phe
5-yl
163
2,4-((4-FPh)
CH═CHCH 2
1,2-Phe
CH═CH
1H-tetrazol-
CH 2 O) 2 Ph
5-yl
164
4-HO-3-(MeO)Ph
CH═CHCH 2
1,2-Phe
1,2-c-Pr
1H-tetrazol-
5-yl
165
Ph
CH═CHCH 2
1,2-Phe
(CH 2 ) 2
1H-tetrazol-
5-yl
166
2-((4-FPh)CH 2 O)-
CH═CHCH 2
1,2-Phe
CH═CH
SO 3 H
3-(MeO)Ph
167
2-((4-FPh)CH 2 O)-
(CH 2 ) 3
4-F-1,2-Phe
(CH 2 ) 2
SO 3 H
3-MePh
17 . A compound in accordance with claim 16 wherein X + represents a cation selected from the group consisting of: ammonium, calcium, magnesium, potassium and sodium.
18 . A pharmaceutical composition comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
19 . A pharmaceutical composition in accordance with claim 18 further comprising a COX-2 selective inhibiting compound.
20 . A method of treating or preventing a prostaglandin mediated disease in a mammalian patient in need thereof, comprising admininstering to said patient a compound in accordance with claim 1 in an amount which is effective for treating or preventing said prostaglandin mediated disease.
21 . A method of treating or preventing a prostaglandin mediated disease in accordance with claim 20 further comprising administering to said patient an effective amount of a COX-2 selective inhibiting compound.
22 . A method of treating or preventing a prostaglandin mediated disease in accordance with claim 20 wherein the prostaglandin mediated disease is selected from the group consisting of:
Pain, fever, inflammation, rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, toothache, sprains, strains, myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout, ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures, immune and autoimmune diseases, cellular neoplastic transformations, metastatic tumor growth, prostaglandin-mediated proliferation disorders such as diabetic retinopathy and tumor angiogenesis, dysmenorrhea, premature labor, asthma, eosinophil related disorders, Alzheimer's disease, glaucoma, bone loss (osteoporosis), promotion of bone formation (treatment of fractures) and other bone diseases such as Paget's disease.
23 . A method of treating or preventing an E type prostaglandin mediated disease in a mammalian patient, comprising administering to said patient an amount of an E type prostaglandin ligand in an amount which is effective to treat or prevent said E type prostaglandin mediated disease.
24 . A method in accordance with claim 23 further comprising administering a COX-2 selective inhibitor.Join the waitlist — get patent alerts
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