U.S. patent application number 09/781385 was filed with the patent office on 2001-10-18 for prostaglandin receptor ligands.
This patent application is currently assigned to Merck Frosst Canada & Co.. Invention is credited to Belley, Michel, Chauret, Nathalie, Gallant, Michel, Labelle, Marc, Lachance, Nicholas, Trimble, Laird A..
Application Number | 20010031766 09/781385 |
Document ID | / |
Family ID | 22295855 |
Filed Date | 2001-10-18 |
United States Patent
Application |
20010031766 |
Kind Code |
A1 |
Belley, Michel ; et
al. |
October 18, 2001 |
Prostaglandin receptor ligands
Abstract
Compounds and methods for treating prostaglandin mediated
diseases, and certain pharmaceutical compositions thereof are
disclosed. The compounds are represented by formula II:
Ar.sup.1--W--Ar.sup.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.
Inventors: |
Belley, Michel;
(Pierrefonds, CA) ; Lachance, Nicholas;
(Pierrefonds, CA) ; Labelle, Marc; (St. Lazare,
CA) ; Gallant, Michel; (Pierrefonds, CA) ;
Chauret, Nathalie; (Ile Bizard, CA) ; Trimble, Laird
A.; (Pierrefonds, CA) |
Correspondence
Address: |
Merck & Co., Inc.
Patent Department
P.O. Box 2000 - RY60-30
Rahway
NJ
07065-0907
US
|
Assignee: |
Merck Frosst Canada &
Co.
|
Family ID: |
22295855 |
Appl. No.: |
09/781385 |
Filed: |
February 12, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09781385 |
Feb 12, 2001 |
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09411505 |
Oct 4, 1999 |
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6211197 |
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60103564 |
Oct 7, 1998 |
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Current U.S.
Class: |
514/307 ;
514/310; 514/415; 514/416; 514/432; 514/443; 514/456; 514/464;
546/139; 546/152; 549/23; 549/396; 549/462; 549/49 |
Current CPC
Class: |
C07C 59/64 20130101;
C07C 62/34 20130101; C07C 309/10 20130101; A61P 29/00 20180101;
A61P 11/06 20180101; C07C 323/60 20130101; A61P 1/02 20180101; C07D
215/36 20130101; A61P 43/00 20180101; C07D 307/79 20130101; C07C
59/66 20130101; C07D 333/28 20130101; C07C 59/68 20130101; A61P
35/00 20180101; A61P 19/04 20180101; A61P 19/06 20180101; A61P
25/28 20180101; C07D 257/04 20130101; A61P 27/06 20180101; C07D
333/34 20130101; A61P 17/02 20180101; A61P 37/00 20180101; A61P
15/06 20180101; C07D 317/60 20130101; A61P 19/02 20180101; C07C
323/62 20130101; C07D 215/18 20130101; C07C 311/51 20130101; C07D
285/135 20130101 |
Class at
Publication: |
514/307 ;
514/310; 514/415; 514/416; 514/432; 514/443; 514/456; 514/464;
549/396; 549/462; 549/49; 549/23; 546/139; 546/152 |
International
Class: |
A61K 031/47; A61K
031/404; A61K 031/4035 |
Claims
What is claimed is:
1. A compound represented by formula II:
Ar.sup.1--W--Ar.sup.2--X--Q II or a pharmaceutically acceptable
salt or hydrate thereof, wherein: Ar.sup.1 is an aryl or heteroaryl
group, optionally substituted with R.sup.1 or R.sup.3; R.sup.1 is
Y.sub.m--R.sup.2, Y.sub.m--Ar.sup.3, halogen, N(R.sup.5).sub.2, CN,
NO.sub.2, C(R.sup.6).sub.3, CON(R.sup.5).sub.2, S(O).sub.nR.sup.7
or OH; Y represents a linker between R.sup.2 or Ar.sup.3 and
Ar.sup.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).sub.n, --C.dbd.C-- or an acetylenic group, and
said linker being optionally substituted by R.sup.2; m is 0 or 1; n
is 0, 1 or 2; R.sup.2 represents H, F, CHF.sub.2, CF.sub.3, lower
alkyl or hydroxyC.sub.1-6 alkyl, or two R.sup.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.sup.3 represents an aryl or heteroaryl group,
optionally substituted with R.sup.3; R.sup.3 is R.sup.4, halogen,
haloC.sub.1-6alkyl, N(R.sup.5).sub.2, CN, NO.sub.2,
C(R.sup.6).sub.3, CON(R.sup.5).sub.2, OR.sup.4, SR.sup.4 or
S(O).sub.nR.sup.7; R.sup.4 is H, lower alkyl, lower alkenyl, lower
alkynyl, CHF.sub.2 or CF.sub.3; R.sup.5 is R.sup.4, Ph or Bn, or
two R.sup.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.sup.6 is
H, F, CF.sub.3 or lower alkyl, or two R.sup.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.sup.7 is
lower alkyl, lower alkenyl, lower alkynyl, CHF.sub.2, CF.sub.3,
N(R.sup.5).sub.2, Ph(R.sup.8).sub.2 or CH.sub.2Ph(R.sup.8).sub.2;
R.sup.8 is R.sup.4, OR.sup.4, SR.sup.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).sub.n, C.dbd.C or an acetylenic group, and optionally being
substituted with R.sup.9; R.sup.9 is R.sup.2, lower alkenyl, lower
alkynyl, OR.sup.4 or SR.sup.4; Ar.sup.2 represents an aryl or
heteroaryl group, optionally substituted with R.sup.3; R.sup.10
represents R.sup.4, halogen, N(R.sup.5).sub.2, CN, NO.sub.2,
C(R.sup.6).sub.3, OR.sup.4, SR.sup.4 or S(O).sub.nR; X represents a
linker which is attached to Ar.sup.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).sub.n, C.dbd.C or an acetylenic group, and said
linker being optionally substituted with R.sup.11; R.sup.11 is
R.sup.9; Q represents a member selected from the group consisting
of: CO.sub.2H, tetrazole, SO.sub.3H, hydroxamic acid,
CONHSO.sub.2R.sup.12 and SO.sub.2NHCOR.sup.12; R.sup.12 represents
a member selected from the group consisting of: CF.sub.3, lower
alkyl, lower alkenyl, lower alkynyl and ZAr.sup.4, wherein Z is an
optional linker containing 0-4 carbon atoms, optionally substituted
with R.sup.13; R.sup.13 is R.sup.9; Ar.sup.4is an aryl or
heteroaryl group optionally substituted with R.sup.14, and R.sup.14
is R.sup.10 or NHCOMe.
2. A compound in accordance with claim 1 wherein R.sup.1 is OH,
OCH.sub.2Ar.sup.3, SCH.sub.2Ar.sup.3, OAr.sup.3, SAr.sup.3 or
NR.sup.2CH.sub.2Ar.sup.3.
3. A compound in accordance with claim 1 wherein Ar.sup.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.sup.3.
4. A compound in accordance with claim 1 wherein Ar.sup.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.sup.4, OR.sup.4, SR.sup.4 and halogen.
5. A compound in accordance with claim 1 wherein W is selected from
the group consisting of: CH.sub.2OCH.sub.2, (CH.sub.2).sub.3,
CH.sub.2CH.dbd.CH, CH.dbd.CHCH.sub.2, CH(OH)CH.dbd.CH,
CH.dbd.CHCH(OH), CH.sub.2C+C, C--CCH.sub.2, 1,2-c-Pr--CH.sub.2 and
-1,2-c-Pr--CH.sub.2--.
6. A compound in accordance with claim 1 wherein X is selected from
the group consisting of: (CH.sub.2).sub.2, CH.dbd.CH, C.dbd.C and
1,2-c-Pr.
7. A compound in accordance with claim 1 wherein Q is CO.sub.2H 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.sup.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.sup.3.
10. A compound in accordance with claim 1 wherein: Ar.sup.1 is an
aryl or heteroaryl group substituted by R.sup.1 and R.sup.3;
R.sup.1 is OH, OCH.sub.2Ar.sup.3, SCH.sub.2Ar.sup.3, OAr.sup.3,
SAr.sup.3 or NR.sup.2CH.sub.2Ar.sup.3; Ar.sup.3 is selected from
the group consisting of benzene, pyridine, thiophene, furan,
oxazole and thiazole, said group being optionally substituted with
R.sup.3; Ar.sup.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.sup.4, OR.sup.4, SR.sup.4
and halogen; W is selected from the group consisting of:
CH.sub.2OCH.sub.2, (CH.sub.2).sub.3, CH.sub.2CH.dbd.CH,
CH.dbd.CHCH.sub.2, CH(OH)CH.dbd.CH, CH.dbd.CHCH(OH), CH.sub.2C+C ,
C.dbd.CCH.sub.2 1,2-c-Pr--CH.sub.2-- and --CH.sub.2-1,2-c-Pr--; X
is selected from the group consisting of: (CH.sub.2).sub.2,
CH.dbd.CH, C.dbd.C and 1,2-c-Pr; and Q is CO.sub.2H or
tetrazole.
11. A compound in accordance with claim 1 wherein: Ar.sup.1 is an
aryl or heteroaryl group optionally substituted with R.sup.1 and
R.sup.3; R.sup.1 is OH, OCH.sub.2Ar.sup.3, SCH.sub.2Ar.sup.3,
OAr.sup.3, SAr.sup.3 or NR.sub.2CH.sub.2Ar.sup.3; Ar.sup.3
represents a member selected from the group consisting of: benzene,
pyridine, thiophene, furan, oxazole or thiazole, said group being
optionally substituted with R.sup.3; W is selected from the group
consisting of: CH.sub.2OCH.sub.2, (CH.sub.2).sub.3,
CH.sub.2CH.dbd.CH, CH.dbd.CHCH.sub.2, CH(OH)CH.dbd.CH,
CH.dbd.CHCH(OH), CH.sub.2C.dbd.C or C.dbd.CCH.sub.2; Ar.sup.2
represents a member selected from the group consisting of: benzene,
pyridine, thiophene, furan, oxazole or thiazole, said group being
optionally substituted with R.sup.8; X is selected from the group
consisting of: (CH.sub.2).sub.2, CH.dbd.CH, C.dbd.C and 1,2-c-Pr; Q
is CONHSO.sub.2ZAr.sup.4; Z is a 0-2 carbon linker and is
unsubstituted; Ar.sup.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.sup.3.
12. A compound in accordance with claim 1 wherein: Ar.sup.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.sub.2Ar.sup.3, SCH.sub.2Ar.sup.3,
OAr.sup.3, SAr.sup.3 and NR.sup.2CH.sub.2Ar.sup.3, and is
optionally substituted in position 3 with a member selected from
the group consisting of: OMe, OCHF.sub.2 and lower alkyl; Ar.sup.3
is benzene or thiophene, optionally substituted with R.sup.8; W is
selected from the group consisting of: CH.sub.2OCH.sub.2,
(CH.sub.2).sub.3, CH.sub.2CH.dbd.CH, CH.dbd.CHCH.sub.2,
CH(OH)CH.dbd.CH and CH.dbd.CHCH(OH), Ar.sup.2 is benzene or
thiophene, optionally substituted with 1-4 members selected from
R.sup.4, OR.sup.4, SR.sup.4 and halogen; X represents a member
selected from the group consisting of: (CH.sub.2).sub.2, CH.dbd.CH
and 1,2-c-Pr, and Q is CO.sub.2H.
13. A compound in accordance with claim 1 wherein: Ar.sup.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.sub.2Ar.sup.3, SCH.sub.2Ar.sup.3, OAr.sup.3, SAr.sup.3 and
NR.sup.2CCH.sub.2Ar.sup.3; and is optionally substituted at
position 3 with one member selected from the group consisting of:
OMe, OCHF.sub.2 and lower alkyl; Ar.sup.3 is benzene or thiophene,
optionally substituted with R.sup.8; W is selected from the group
consisting of: CH.sub.2OCH.sub.2, (CH.sub.2).sub.3,
CH.sub.2CH.dbd.CH, CH.dbd.CHCH.sub.2, CH(OH)CH.dbd.CH and
CH.dbd.CHCH(OH); Ar.sup.2 is benzene or thiophene, optionally
substituted with R.sup.4, OR.sup.4, SR.sup.4 or halo; X is selected
from the group consisting of: (CH.sub.2).sub.2, CH.dbd.CH and
1,2-c-Pr, Q is CONHSO.sub.2ZAr.sup.4, Z is a bond or CH.sub.2, and
Ar.sup.4 is selected from the group consisting of: benzene,
thiophene, 1,3,4-thiadiazole and naphthalene and is substituted
with R.sup.8.
14. A compound represented by formula II': 14or a pharmaceutically
acceptable salt or hydrate thereof, wherein: Ar.sup.1 represents
phenyl, naphthyl, benzofuranyl or methylenedioxyphenyl; R.sup.1
represents H, OH, C.sub.1-6alkyl, C.sub.1-6alkoxy,
hydroxyC.sub.1-6alkyl, aryl, aryloxy, arylalkoxy, haloaryl,
haloheteroaryl, haloarylalkoxy, alkylaryl, haloalkylarylalkoxy,
haloarylalkoxy and haloheteroarylalkoxy; R.sup.3 represents
R.sup.4, halogen, OR.sup.4 or SR.sup.4; R.sup.4 represents H, lower
alkyl, lower alkenyl, lower alkynyl, CHF.sub.2 or CF.sub.3; X
represents a member selected from the group consisting of:
--(CH.sub.2).sub.1-2--, 1,2-c-Pr, --CH.dbd.CH--, --CH.sub.2O--,
--C+CCH.sub.2--, --C.ident.C--, and --CH.sub.2--C+C--; W represents
a member selected from the group consisting of:
--(CH.sub.2).sub.3-6--, --CH.sub.2CH.dbd.CH--,
--CH.dbd.CHCH.sub.2--, --CH(OH)CH.dbd.CH--, --CH.dbd.CHCH(OH)--,
--CH.sub.2-1,2-c-Pr--, -1,2-c-Pr--CH.sub.2--,
--CH.sub.2--O--CH.sub.2--, --O--(CH.sub.2).sub.1-3--O--,
--CH.sub.2--NHC(O)--, --CF.sub.2CH.dbd.CH--, --CH.dbd.CHCF.sub.2--,
--CH.sub.2CH.sub.2--S--, --S--CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2--SO.- sub.2--, --SO.sub.2--CH.sub.2CH.sub.2--,
--O--(CH.sub.2).sub.1-3--, --(CH.sub.2).sub.1-3--O-- and
--CH.dbd.CHCH.sub.2CH.sub.2--, and all other variables are as
defined in claim 1.
15. A compound represented by formula II": 15or a pharmaceutically
acceptable salt or hydrate thereof, wherein: Ar.sup.1 represents
phenyl, naphthyl, benzofuranyl or methylenedioxyphenyl; R.sup.1
represents H, OH, C.sub.1-6alkyl, C.sub.1-6alkoxy,
hydroxyC.sub.1-6alkyl, aryl, aryloxy, arylalkoxy, haloaryl,
haloheteroaryl, haloarylalkoxy, alkylaryl, haloalkylarylalkoxy,
haloarylalkoxy and haloheteroarylalkoxy; R.sup.3 represents
R.sup.4, halogen, OR.sup.4 or SR.sup.4; R.sup.4 represents H, lower
alkyl, lower alkenyl, lower alkynyl, CHF.sub.2 or CF.sub.3; X
represents a member selected from the group consisting of:
--(CH.sub.2).sub.1-2--, -1,2-c-Pr--, --CH.dbd.CH--, --CH.sub.2O--,
--C.ident.CCH.sub.2--, --C.ident.C--, and --CH.sub.2--C.ident.C--;
W represents a member selected from the group consisting of:
--(CH.sub.2).sub.3-6--, --CH.sub.2CH.dbd.CH--,
--CH.dbd.CHCH.sub.2--, --CH(OH)CH.dbd.CH--, --CH.dbd.CHCH(OH)--,
--CH.sub.2-1,2-c-Pr--, -1,2-c-Pr--CH.sub.2--,
--CH.sub.2--O--CH.sub.2--, --O--(CH.sub.2).sub.1-3- --O--,
--CH.sub.2--NHC(O)--, --CF.sub.2CH.dbd.CH--, --CH.dbd.CHCF.sub.2--,
--CH.sub.2CH.sub.2--S--, --S--CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2--SO.- sub.2--, --SO.sub.2--CH.sub.2CH.sub.2--,
--O--(CH.sub.2).sub.1-3--, --(CH.sub.2).sub.1-3--O-- and
--CH.dbd.CHCH.sub.2CH.sub.2--, and R.sup.12 is selected from the
group consisting of: C.sub.1-6alkyl, thienyl, phenyl, naphthyl,
biphenyl, quinolinyl, thiadiazolyl, tetrazolyl, --CH.dbd.CH-phenyl,
said thienyl, phenyl, naphthyl, biphenyl, quinolinyl, thiadiazolyl,
tetrazolyl and --CH.dbd.CH-phenyl groups being optionally
substituted with R.sup.3.
16. A compound in accordance with claim 1 falling withing the
following table:
5TABLE I (Ar.sup.1--W--Ar.sup.2-X-Q) Ex Ar.sup.1 W Ar.sup.2 X Q 1
2-(BnO)-3-MePh (CH.sub.2).sub.3 1,2-Phe (CH.sub.2).sub.2 CO.sub.2H
2 2-(BnO)-3-MePh CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH
CONHSO.sub.2-2- thienyl 3 2-(BnO)-3-MePh CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CONHSO.sub.2-2- thienyl 4 2-((2-Cl-4-FPh)CH.sub.2O)-
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H 3-CF.sub.3Ph 5
2-((2-Cl-4-FPh)CH.sub.2O)- CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CO.sub.2H 3-CF.sub.3Ph 6 2-(BnO)Ph CH.sub.2CH.dbd.CH 1,2-Phe
CH.dbd.CH CO.sub.2.sup.- X.sup.+ 7 2-(BnO)Ph CH.dbd.CHCH.sub.2
1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+ 8 4-(BnO)-3,5-(MeO).sub.2-
Ph CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+ 9
4-(BnO)-3,5-(MeO).sub.2Ph CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CO.sub.2.sup.- X.sup.+ 10 2-(BnO)-5-AcPh CH.sub.2CH.dbd.CH 1,2-Phe
CH.dbd.CH CO.sub.2H 11 2-(BnO)-5-AcPh CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2H 12 2-(BnO)-3-(MeO)Ph CH.sub.2CH.dbd.CH 1,2-Phe
CH.dbd.CH CO.sub.2.sup.- X.sup.+ 13 2-(BnO)-3-(MeO)Ph
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+ 14
4-(BnO)-3-(MeO)Ph CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH
CO.sub.2.sup.- X.sup.+ 15 4-(BnO)-3-(MeO)Ph CH.dbd.CHCH.sub.2
1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+ 16 2-(BnO O)-3-MePh
CH.sub.2CH.dbd.CH 1,2-Phe CH.sub.2 CO.sub.2.sup.- X.sup.+ 17
2-(BnO)-3-MePh CH.dbd.CHCH.sub.2 1,2-Phe CH.sub.2 CO.sub.2.sup.-
X.sup.+ 18 2-(BnO)-3-MePh CH.sub.2CH.dbd.CH 5-Cl-1,2-Phe CH.sub.2
CO.sub.2.sup.- X.sup.+ 19 2-(BnO)-3-MePh CH.dbd.CHCH.sub.2
5-Cl-1,2-Phe CH.sub.2 CO.sub.2.sup.- X.sup.+ 20 4-(BnO)-3-(MeO)Ph
(CH.sub.2).sub.3 1,2-Phe 1,2-c-Pr CO.sub.2H 21 2-(BnO)-3-MePh
CH.dbd.CHCH.sub.2 4,5-(MeO).sub.2- CH.dbd.CH CO.sub.2H 1,2-Phe 22
2-(BnO)-3-MePh CH.sub.2CH.dbd.CH 4,5-(MeO).sub.2- CH.dbd.CH
CO.sub.2H 1,2-Phe 23 3,4-(methylene CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2H dioxy)Ph 24 3,4-(methylene CH.sub.2CH.dbd.CH
1,2-Phe CH.dbd.CH CO.sub.2H dioxy)Ph 25 Ph CH.dbd.CHCH.sub.2
1,2-Phe CH.dbd.CH CO.sub.2H 26 Ph CH.sub.2CH.dbd.CH 1,2-Phe
CH.dbd.CH CO.sub.2H 27 2-(HO)-3-MePh CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2H 28 2-(BnO)-3-MePh CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2.sup.- X.sup.+ 29 2-(BnO)-3-MePh
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+ 30
2-((7-Cl-2- CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H
quinolinyl)CH.sub.2O)-3- MePh 31 2-((7-Cl-2- CH.sub.2CH.dbd.CH
1,2-Phe CH.dbd.CH CO.sub.2H quinolinyl)CH.sub.2O)-3- MePh 32
2-(BnO)-3-MePh (CH.sub.2).sub.3 1,2-Phe bond CO.sub.2H 33
2-(BnO)-3-MePh CH.dbd.CHCH.sub.2 1,2-Phe bond CO.sub.2.sup.-
X.sup.+ 34 2-(BnO)-3-MePh CH.sub.2CH.dbd.CH 1,2-Phe bond
CO.sub.2.sup.- X.sup.+ 35 2-(BnO)-3-MePh (CH.sub.2).sub.3 1,2-Phe
CH.dbd.CH CO.sub.2.sup.- X.sup.+ 36 2-(BnO)-3-(MeO)Ph
(CH.sub.2).sub.3 1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+ 37
4-(BnO)-3-(MeO)Ph (CH.sub.2).sub.3 1,2-Phe CH.dbd.CH CO.sub.2.sup.-
X.sup.+ 38 4-(MeO)Ph CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H
39 4-(MeO)Ph CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H 40
3,4-(MeO).sub.2Ph CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H 41
3,4-(MeO).sub.2Ph CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H 42
2-(BnO)Ph CH(OH)CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+
43 2-(BnO)-3-MePh (CH.sub.2).sub.3 1,2-Phe (CH.sub.2).sub.2
CON.sup.- X.sup.+ SO.sub.2-2- thienyl 44 4-(BnO)-3-(MeO)Ph
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CON.sup.- X.sup.+ SO.sub.2-2-
thienyl 45 4-(BnO)-3-(MeO)Ph CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CON.sup.- X.sup.+ SO.sub.2-2- thienyl 46 2-(BnO)-3-MePh
CH.sub.2-1,2-c-Pr 1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+ 47
2-(BnO)-3-MePh 1,2-c-Pr-CH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2.sup.-
X.sup.+ 48 2-(BnO)-3-MePh CH(OH)CH.dbd.CH 1,2-Phe CH.dbd.CH
CO.sub.2.sup.- X.sup.+ 49 2-(BnO)-3-MePh CH.dbd.CHCH(OH) 1,2-Phe
CH.dbd.CH CO.sub.2H 50 2-((2,6-Cl.sub.2Ph)CH.sub.2O)-
CH.dbd.CHCH(OH) 1,2-Phe CH.dbd.CH CO.sub.2H 3-MePh 51
2-((2,6-Cl.sub.2Ph)CH.sub.2O)- CH(OH)CH.dbd.CH 1,2-Phe CH.dbd.CH
CO.sub.2H 3-MePh 52 2-((4-FPh)CH.sub.2O)-3- CH.sub.2CH.dbd.CH
1,2-Phe CH.dbd.CH CO.sub.2H MePh 53 2-((4-FPh)CH.sub.2O)-3-
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+ MePh 54
2-((3,4-F.sub.2Ph)CH.sub.2O- )- CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH
CO.sub.2H 3-MePh 55 2-((3,4-F.sub.2Ph)CH.sub.2O)- CH.dbd.CHCH.sub.2
1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+ 3-MePh 56
2-((3,5-F.sub.2Ph)CH.sub.- 2O)- CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH
CO.sub.2H 3-MePh 57 2-((3,5-F.sub.2Ph)CH.sub.2O)- CH.dbd.CHCH.sub.2
1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+ 3-MePh 58
2-((2,6-Cl.sub.2Ph)CH.sub- .2O)- CH.sub.2CH.dbd.CH 1,2-Phe
CH.dbd.CH CO.sub.2H 3-(HOCH.sub.2)Ph 59
2-((2,6-Cl.sub.2Ph)CH.sub.2O)- CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CO.sub.2H 3-(HOCH.sub.2)Ph 60 2-((2,6-Cl.sub.2Ph)CH.sub.2O)-
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H 3-MePh 61
2-((2,6-Cl.sub.2Ph)CH.sub.2O)- CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CO.sub.2.sup.- X.sup.+ 3-MePh 62 2-((4-CF.sub.3Ph)CH.sub.2O)-
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H 3-MePh 63
2-((4-CF.sub.3Ph)CH.sub.2O)- CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CO.sub.2.sup.- X.sup.+ 3-MePh 64 2-((4-(CHF.sub.2O)Ph)
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 65
2-((4-(CHF.sub.2O)Ph) CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CO.sub.2.sup.- X.sup.+ CH.sub.2O)-3-MePh 66
2-((4-CF.sub.3Ph)CH.sub.2O)- CH.dbd.CHCH(OH) 1,2-Phe CH.dbd.CH
CO.sub.2H 3-(HOCH.sub.2)Ph 67 2-((4-CF.sub.3Ph)CH.sub.2O)-
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H 3-(HOCH.sub.2)Ph 68
2-((4-CF.sub.3Ph)CH.sub.2O)- CH.dbd.CHCH(OH) 1,2-Phe CH.dbd.CH
CO.sub.2H 3-MePh 69 2-(PhCH.sub.2O)-3- CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2H (HOCH.sub.2)Ph 70 3-(PhO)Ph CH.sub.2OCH.sub.2
1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+ 71 2-(PhO)Ph
CH.sub.2OCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+ 72
3-(BnO)Ph CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2.sup.-
X.sup.+ 73 3-(BnO)Ph CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CO.sub.2.sup.- X.sup.+ 74 2-(BnO)Ph O(CH.sub.2).sub.3O 1,2-Phe
CH.dbd.CH CO.sub.2.sup.- X.sup.+ 75 2-(PhCHMeO)-3-
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+ MePh 76
2-(PhCHMeO)-3- CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H MePh
77 3-(PhO)Ph CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2.sup.-
X.sup.+ 78 3-(PhO)Ph CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH
CO.sub.2.sup.- X.sup.+ 79 3-Phbenzofuran-7-yl CH.dbd.CHCH.sub.2
1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+ 80 3-Phbenzofuran-7-yl
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2.sup.- X.sup.+ 81 Ph
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2- 2-thienyl 82 Ph
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CONHSO.sub.2- 2-thienyl 83
4-(MeO)Ph CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2-2-
thienyl 84 4-(MeO)Ph CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH
CONHSO.sub.2-2- thienyl 85 2-(BnO)-1-naphthyl CH.sub.2NHCO 1,2-Phe
CH.dbd.CH CO.sub.2H 86 2-((2-Cl-4-FPh) CH.sub.2CH.dbd.CH 1,2-Phe
CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 87 2-((2-Cl-4-FPh)
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 88
2-((2,4-F.sub.2Ph)CH.sub.2O)- CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH
CO.sub.2H 3-MePh 89 2-((2,4-F.sub.2Ph) CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 90 2-((2,4,6-F.sub.3Ph)
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 91
2-((2,4,6-F.sub.3Ph) CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H
CH.sub.2O)-3-MePh 92 2-((2,6-Cl.sub.2-4-FPh) CH.sub.2CH.dbd.CH
1,2-Phe CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 93
2-((2,6-Cl.sub.2-4-FPh) CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CO.sub.2H CH.sub.2O)-3-MePh 94 2-((2,4-F.sub.2Ph)CH.sub.2O)-
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H 3-(CHF.sub.2O)Ph 95
2-((2,4-F.sub.2Ph)CH.sub.2O)- - CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CO.sub.2H 3-(CHF.sub.2O)Ph 96 2-((4-FPh)CH.sub.2O)-
CF.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H 3-MePh 97
2-((4-FPh)CH.sub.2O)- CH.dbd.CHCF.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H
3-MePh 98 2-((4-FPh)CH.sub.2O)- (CH.sub.2).sub.3 1,2-Phe CH.dbd.CH
CONHSO.sub.2- 3-MePh (4-i-PrPh) 99 2-((4-FPh)CH.sub.2O)-
(CH.sub.2).sub.3 1,2-Phe CH.dbd.CH CONHSO.sub.2- 3-MePh (4-t-BuPh)
100 2-((4-FPh)CH.sub.2O)- CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH
CONHSO.sub.2- 3-MePh (4-(MeO)Ph) 101 2-((4-FPh)CH.sub.2O)-
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2- 3-MePh
(2,3-Cl.sub.2Ph) 102 2-((4-FPh)CH.sub.2O)- CH.dbd.CHCH.sub.2
4-Cl-1,2-Phe CH.dbd.CH CONHSO.sub.2- 3-MePh (5-Br-2- (MeO)Ph) 103
2-((4-FPh)CH.sub.2O)- (CH.sub.2).sub.2S 3-F-1,2-Phe CH.dbd.CH
CONHSO.sub.2- 3-MePh (2,3,4-Cl.sub.3Ph) 104 2-((4-FPh)CH.sub.2O)-3-
(CH.sub.2).sub.2S 6-CF.sub.3-1,2- CH.dbd.CH CONHSO.sub.2- MePh Phe
(5-F-2-MePh) 105 2-((4-FPh)CH.sub.2O)-3- (CH.sub.2).sub.2S
4,5-F.sub.2-1,2- CH.dbd.CH CONHSO.sub.2- MePh Ph (2,5-Me.sub.2Ph)
106 2-((4-FPh)CH.sub.2O)-3- (CH.sub.2).sub.2SO.sub.2 1,2-Phe
CH.dbd.CH CONHSO.sub.2- MePh (4-CF.sub.3Ph) 107
2-((4-FPh)CH.sub.2O)-3- (CH.sub.2).sub.2SO.sub.2 1,2-Phe CH.dbd.CH
CONHSO.sub.2-2- MePh naphthyl 108 2-((4-FPh)CH.sub.2O)-3-
CH.dbd.CHCH.sub.2 3-F-1,2-Phe CH.dbd.CH CONHSO.sub.2- MePh
(3-Cl-4-FPh) 109 2-((4-FPh)CH.sub.2O)-3- SO.sub.2(CH.sub.2).sub.2
1,2-Phe CH.dbd.CH CONHSO.sub.2- MePh (4-n-PrPh) 110
2-((4-FPh)CH.sub.2O)-3- SO.sub.2(CH.sub.2).sub.2 1,2-Phe CH.dbd.CH
CONHSO.sub.2- (MeO)Ph (2-ClPh) 111 2-((4-FPh)CH.sub.2O)-3-
SO.sub.2(CH.sub.2).sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2- (MeO)Ph
(4-FPh) 112 2-((4-FPh)CH.sub.2O)-3- S(CH.sub.2).sub.2 1,2-Phe
CH.dbd.CH CONHSO.sub.2- (MeO)Ph (2-PhPh) 113
2-((4-FPh)CH.sub.2O)-3- S(CH.sub.2).sub.2 1,2-Phe CH.dbd.CH
CONHSO.sub.2- (MeO)Ph (2-CF.sub.3Ph) 114 2-((4-FPh)CH.sub.2O)-3-
S(CH.sub.2).sub.2 4-t-Bu-1,2- CH.dbd.CH CONHSO.sub.2- (MeO)Ph Phe
(4-Cl-2,5- Me.sub.2Ph) 115 2-((4-FPh)CH.sub.2O)-3-
O(CH.sub.2).sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2- (MeO)Ph
(2,5-Cl.sub.2Ph) 116 2-((4-FPh)CH.sub.2O)-3- O(CH.sub.2).sub.2
1,2-Phe CH.dbd.CH CONHSO.sub.2- (MeO)Ph (4-Br-2- (CF.sub.3O)Ph) 117
2-((4-FPh)CH.sub.2O)-3- O(CH.sub.2).sub.2 1,2-Phe CH.dbd.CH
CONHSO.sub.2- (MeO)Ph CH.sub.2Ph 118 2-((4-FPh)CH.sub.2O)-3-
(CH.sub.2).sub.2O 1,2-Phe CH.dbd.CH CONHSO.sub.2-1- (MeO)Ph
naphthyl 119 2-((4-FPh)CH.sub.2O)-3- (CH.sub.2).sub.2O
4,5-F.sub.2-1,2- CH.dbd.CH CONHSO.sub.2- (MeO)Ph Phe (2-FPh) 120
2-((4-FPh)CH.sub.2O)-3- (CH.sub.2).sub.2O 1,2-Phe CH.dbd.CH
CONHSO.sub.2- (MeO)Ph (2,4-Cl.sub.2Ph) 121 2-((4-FPh)CH.sub.2O)-3-
(CH.sub.2).sub.3 1,2-Phe CH.dbd.CH CONHSO.sub.2- (MeO)Ph
CH.dbd.CHPh 122 2-((4-F-Ph)CH.sub.2O)-3- (CH.sub.2).sub.3 1,2-Phe
CH.dbd.CH CONHSO.sub.2- (MeO)Ph (3,5- (CF.sub.3).sub.2Ph) 123
2-((4-FPh)CH.sub.2O)Ph (CH.sub.2).sub.3 1,2-Phe CH.dbd.CH
CONHSO.sub.2- (2,5-Cl.sub.2-3- thienyl) 124 2-((4-FPh)CH.sub.2O)Ph
(CH.sub.2).sub.4 3-F-1,2-Phe CH.dbd.CH CONHSO.sub.2- (3-BrPh) 125
2-((4-FPh)CH.sub.2O)Ph (CH.sub.2).sub.4 3-MeO-1,2- CH.dbd.CH
CONHSO.sub.2- Phe (2-BrPh) 126 2-((4-FPh)CH.sub.2O)Ph
(CH.sub.2).sub.4 1,2-Phe CH.dbd.CH CONHSO.sub.2- (2-NO.sub.2Ph) 127
2-((4-FPh)CH.sub.2O)Ph (CH.sub.2).sub.5 1,2-Phe (CH.sub.2).sub.2
CONHSO.sub.2- (3-ClPh) 128 2-((4-FPh)CH.sub.2O)Ph (CH.sub.2).sub.5
1,2-Phe (CH.sub.2).sub.2 CONHSO.sub.2- (4-(CF.sub.3O)Ph) 129 2-HOPh
CH.dbd.CH(CH.sub.2).sub.2 1,2-Phe (CH.sub.2).sub.2 CONHSO.sub.2-8-
quinolinyl 130 2-((4-FPh)CH.sub.2O)Ph CH.dbd.CH(CH.sub.2).sub- .2
5-(CF.sub.3O)- (CH.sub.2).sub.2 CONHSO.sub.2- 1,2-Phe
(3,4-Cl.sub.2Ph) 131 4-((2,6-Cl.sub.2-4- CH.dbd.CH(CH.sub.2).sub.2
3-F-1,2-Phe (CH.sub.2).sub.2 CONHSO.sub.2- FPh)CH.sub.2O)-3-MePh
(4-EtPh) 132 2-((4-FPh)CH.sub.2O)Ph CH.sub.2CH.dbd.CH 1,2-Phe
(CH.sub.2).sub.2 CONHSO.sub.2- (4-Cl-2- NO.sub.2Ph) 133
2-((4-FPh)CH.sub.2O)Ph CH.dbd.CHCH.sub.2 4,5-F.sub.2-1,2- CH.dbd.CH
CONHSO.sub.2- Phe (2-Cl-3-Br-5- thienyl) 134 2-((4-FPh)CH.sub.2O)Ph
CH.sub.2CH.dbd.CH 4,5-F.sub.2-1,2- CH.dbd.CH CONHSO.sub.2- Phe
(3,4- (MeO).sub.2Ph) 135 2-HOPh CH.dbd.CHCH.sub.2 4,5-F.sub.2-1,2-
CH.dbd.CH CONHSO.sub.2- Phe (2,5-Cl.sub.2-3-Br- 4-thienyl) 136
4-((4-FPh)CH.sub.2O)-3- CH.sub.2CH.dbd.CH 4,5-F.sub.2-1,2-
CH.dbd.CH CONHSO.sub.2- (MeO)Ph Phe (4-Br-2,5- F.sub.2Ph) 137
4-((4-FPh)CH.sub.2O)-3- CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CONHSO.sub.2- (MeO)Ph (5-(AcNH)- 1,3,4- thiadiazol-2- yl) 138
4-((4-FPh)CH.sub.2O)-3- CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH
CONHSO.sub.2- (MeO)Ph (2,3,4,5,6- F.sub.5Ph) 139
4-((2-Cl-4-FPh)CH.sub.2O)- CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CONHSO.sub.2- 3-MePh (2-CNPh) 140 2-((4-FPh)CH.sub.2O)Ph
CH.sub.2CH.dbd.CH 4-F-1,2-Phe CH.dbd.CH CONHSO.sub.2- (2-Cl-6-
MePh) 141 2-HOPh CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2-
(2,4,6- Me.sub.3Ph) 142 Ph CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH
CONHSO.sub.2- (2,3-Br.sub.2-2- thienyl) 143 2-((4-FPh)
CH.dbd.CHCH.sub.2 1,2-Phe CH.sub.2O CONHSO.sub.2- CH.sub.2O)Ph
(4-NO.sub.2Ph) 144 2-((4-FPh) CH.sub.2CH.dbd.CH 1,2-Phe CH.sub.2O
CONHSO.sub.2- CH.sub.2O)Ph (3,5-Cl.sub.2Ph) 145 2,4-((4-FPh)
CH.dbd.CHCH.sub.2 1,2-Phe prop-1- CONHSO.sub.2- CH.sub.2O).sub.2Ph
yne-1,3- (5-Cl-2- diyl thienyl) 146 4-((2,4-F.sub.2Ph)CH.sub.2O)-
CH.sub.2CH.dbd.CH 1,2-Phe CH.sub.2O CONHSO.sub.2- 3-(MeO)Ph
(4-CF.sub.3Ph) 147 2-HO-3-MePh CH.dbd.CHCH.sub.2 1,2-Phe CH.sub.2O
CONHSO.sub.2- (2,4-F.sub.2Ph) 148 2-((4-FPh)CH.sub.2O)Ph
CH.sub.2CH.dbd.CH 4-F-1,2-Phe 1,2- CONHSO.sub.2- ethyne (4-ClPh)
diyl 149 2-((4-FPh)CH.sub.2O)Ph CH.dbd.CHCH.sub.2 1,2-Phe 1,2-
CONHSO.sub.2- ethyne (3-CF.sub.3Ph) diyl 150 4-HOPh
CH.sub.2CH.dbd.CH 1,2-Phe 1,2- CONHSO.sub.2- ethyne Ph diyl 151
2-((4-FPh) CH.dbd.CHCH.sub.2 1,2-Phe prop-2- CONHSO.sub.2-
CH.sub.2O)Ph yne-1,3- (5-Br-2- diyl thienyl) 152 2,4-((4-FPh)
CH.sub.2CH.dbd.CH 1,2-Phe 1,2- CONHSO.sub.2- CH.sub.2O).sub.2Ph
ethynediyl Me 153 2,4-((4-FPh) CH.dbd.CHCH.sub.2 1,2-Phe 1,2-c-Pr
CONHSO.sub.2- CH.sub.2O).sub.2Ph (2,5- (MeO).sub.2Ph) 154
6-((4-FPh)CH.sub.2O)- CH.sub.2CH.dbd.CH 4-F-1,2-Phe 1,2-c-Pr
CONHSO.sub.2- 2-naphthyl (3-MePh) 155 2-((4-FPh) CH.dbd.CHCH.sub.2
1,2-Phe 1,2-c-Pr CONHSO.sub.2- CH.sub.2O)Ph (4-MePh) 156
4-HO-3-(MeO)Ph CH.sub.2CH.dbd.CH 1,2-Phe 1,2-c-Pr CONHSO.sub.2-n-
Bu 157 4-((4-FPh)CH.sub.2O)- CH.dbd.CHCH.sub.2 1,2-Phe 1,2-c-Bu
CONHSO.sub.2- 1-naphthyl (2-Cl-4-FPh) 158 Ph CH.sub.2CH.dbd.CH
1,2-Phe CH.dbd.CH CONHSO.sub.2- (2-MePh) 159 2-((4-FPh)
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2- CH.sub.2O)Ph c-Pr
160 2,4-((4-FPh) CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H
CH.sub.2O).sub.2Ph 161 4-((2,4-F.sub.2Ph) (CH.sub.2).sub.3
4-F-1,2-Phe CH.dbd.CH 1H-tetrazol- CH.sub.2O)-3-(MeO)Ph 5-yl 162
2-((4-FPh) CH.dbd.CHCH.sub.2 3-MeO- CH.dbd.CH 1H-tetrazol-
CH.sub.2O)Ph 1,2-Phe 5-yl 163 2,4-((4-FPh) CH.dbd.CHCH.sub.2
1,2-Phe CH.dbd.CH 1H-tetrazol- CH.sub.2O).sub.2Ph 5-yl 164
4-HO-3-(MeO)Ph CH.dbd.CHCH.sub.2 1,2-Phe 1,2-c-Pr 1H-tetrazol- 5-yl
165 Ph
CH.dbd.CHCH.sub.2 1,2-Phe (CH.sub.2).sub.2 1H-tetrazol- 5-yl 166
2-((4-FPh)CH.sub.2O)- CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH SO.sub.3H
3-(MeO)Ph 167 2-((4-FPh)CH.sub.2O)- (CH.sub.2).sub.3 4-F-1,2-Phe
(CH.sub.2).sub.2 SO.sub.3H 3-MePh wherein X.sup.+ represents a
cation.
17. A compound in accordance with claim 16 wherein X.sup.+
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.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to compounds and methods for treating
prostaglandin mediated diseases, and certain pharmaceutical
compositions thereof. More particularly, 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.
[0002] Two review articles describe the characterization and
therapeutic relevance of the prostanoid receptors as well as the
most commonly used selective agonists and antagonists: Eicosanoids:
From Biotechnology to Therapeutic Applications, Folco, Samuelsson,
Maclouf, and Velo eds, Plenum Press, New York, 1996, chap. 14,
137-154 and Journal of Lipid Mediators and Cell Signalling, 1996,
14, 83-87. An article from The British Journal of Pharmacology
(1994, 112, 735-740) suggests that Prostaglandin E.sub.2
(PGE.sub.2) exerts allodynia through the EP.sub.1 receptor subtype
and hyperalgesia through EP2 and EP.sub.3 receptors in the mouse
spinal cord.
[0003] Thus, selective prostaglandin ligands, agonists or
antagonists, depending on which prostaglandin E receptor subtype is
being considered, have anti-inflammatory, antipyretic and analgesic
properties similar to a conventional non-steroidal
anti-inflammatory drug, and in addition, inhibit hormone-induced
uterine contractions and have anti-cancer effects. These, compounds
have a diminished ability to induce some of the mechanism-based
side effects of NSAIDs which are indiscriminate cyclooxygenase
inhibitors. In particular, the compounds have a reduced potential
for gastrointestinal toxicity, a reduced potential for renal side
effects, a reduced effect on bleeding times and a lessened ability
to induce asthma attacks in aspirin-sensitive asthmatic
subjects.
[0004] PCT application nos WO 96/06822 (Mar. 7, 1996), WO 96/11902
(Apr. 25, 1996), WO 97/00863 (Jan. 9, 1997), WO 97/00864 (Jan. 9,
1997), WO 96/03380 (Feb. 8, 1996), and EP 752421-A1 (Jan. 08, 1997)
disclose compounds represented by Formula I as being useful in the
treatment of prostaglandin mediated diseases. 1
[0005] wherein:
[0006] A is phenyl, naphthyl, 5- or 6-membered heteroaryl
[0007] B is phenyl, 5- or 6-membered heteroaryl or a further
defined keto-dihydro ring;
[0008] D is phenyl, 5- or 6-membered heteroaryl;
[0009] R.sup.1 is COOH, carboxyalkyl, tetrazolyl(alkyl);
[0010] R.sup.3 is H or alkyl, and
[0011] Z is an alkylene bridge containing 0-1 nitrogen atom or a
further defined unsaturated bridge.
[0012] Compound Ia is one of the compounds specifically
claimed.
SUMMARY OF THE INVENTION
[0013] The present invention relates to compounds represented by
formula II:
Ar.sup.1--W--Ar.sup.2--X--Q II
[0014] as well as pharmaceutically acceptable salts and hydrates
thereof, wherein:
[0015] Ar.sup.1 is an aryl or heteroaryl group, optionally
substituted with R.sup.1 or R.sup.3;
[0016] R.sup.1 is Y.sub.m--R.sup.2, Y.sub.m--Ar.sup.3, halogen,
N(R.sup.5).sub.2, CN, NO.sub.2, C(R.sup.6).sub.3,
CON(R.sup.5).sub.2, S(O).sub.nR.sup.7 or OH;
[0017] Y represents a linker between R.sup.2 or Ar.sup.3 and
Ar.sup.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).sub.n, --C.dbd.C-- or an acetylenic group, and
said linker being optionally substituted by R.sup.2;
[0018] m is 0 or 1;
[0019] n is 0,1 or 2;
[0020] R.sup.2 represents H, F, CHF.sub.2, CF.sub.3, lower alkyl or
hydroxyC.sub.1-6 alkyl, or two R.sup.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;
[0021] Ar.sup.3 represents an aryl or heteroaryl group, optionally
substituted with R.sup.3;
[0022] R.sup.3 is R.sup.4, halogen, haloC.sub.1-6alkyl,
N(R.sup.5).sub.2, CN, NO.sub.2, C(R.sup.6).sub.3,
CON(R.sup.5).sub.2, OR.sup.4, SR.sup.4 or S(O).sub.nR.sup.7;
[0023] R.sup.4 is H, lower alkyl, lower alkenyl, lower alkynyl,
CHF.sub.2 or CF.sub.3;
[0024] R.sup.1 is R.sup.4, Ph or Bn, or two R.sup.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;
[0025] R.sup.6 is H, F, CF.sub.3 or lower alkyl, or two R.sup.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;
[0026] R.sup.7 is lower alkyl, lower alkenyl, lower alkynyl,
CHF.sub.2, CF.sub.3, N(R.sup.5).sub.2, Ph(R.sup.8).sub.2 or
CH.sub.2Ph(R.sup.8).sub.- 2;
[0027] R.sup.8 is R.sup.4, OR.sup.4, SR.sup.4 or halogen
[0028] 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).sub.n, C.dbd.C or an acetylenic group, and
optionally being substituted with R.sup.9;
[0029] R.sup.9 is R.sup.2, lower alkenyl, lower alkynyl, OR.sup.4
or SR.sup.4;
[0030] Ar.sup.2 represents an aryl or heteroaryl group, optionally
substituted with R.sup.3;
[0031] R.sup.10 represents R.sup.4, halogen, N(R.sup.5).sub.2, CN,
NO.sub.2, C(R.sup.6).sub.3, OR.sup.4, SR.sup.4 or S(O) R.sup.7;
[0032] X represents a linker which is attached to Ar.sup.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).sub.n, C.dbd.C or an
acetylenic group, and said linker being optionally substituted with
R.sup.11;
[0033] R.sup.11 is R.sup.9;
[0034] Q represents a member selected from the group consisting of:
CO.sub.2H, tetrazole, SO.sub.3H, hydroxamic acid,
CONHSO.sub.2R.sup.12 and SO.sub.2NHCOR.sup.12;
[0035] R.sup.12 represents a member selected from the group
consisting of: CF.sub.3, lower alkyl, lower alkenyl, lower alkynyl
and ZAr.sup.4, wherein Z is an optional linker containing 0-4
carbon atoms, optionally substituted with R.sup.13;
[0036] R.sup.13 is R.sup.9;
[0037] Ar.sup.4 is an aryl or heteroaryl group optionally
substituted with R.sup.14, and
[0038] R.sup.14 is R.sup.10 or NHCOMe.
[0039] Pharmaceutical compositions and methods of treatment are
also included.
DETAILED DESCRIPTION OF THE INVENTION
[0040] The present invention relates to compounds represented by
formula II:
Ar.sup.1--W--Ar.sup.2--X--Q II
[0041] as well as pharmaceutically acceptable salts and hydrates
thereof, wherein:
[0042] Ar.sup.1 is an aryl or heteroaryl group, optionally
substituted with R.sup.1 or R.sup.3;
[0043] R.sup.1 is Y.sub.m--R.sup.2, Y.sub.m--Ar.sup.3, halogen,
N(R.sup.5).sub.2, CN, NO.sub.2, C(R.sup.6).sub.3,
CON(R.sup.5).sub.2, S(O).sub.nR.sup.7 or OH;
[0044] Y represents a linker between R.sup.2 or Ar.sup.3 and
Ar.sup.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).sub.n, --C.dbd.C-- or an acetylenic group, and
said linker being optionally substituted by R.sup.2;
[0045] m is 0 or 1;
[0046] n is 0, 1 or 2;
[0047] R.sup.2 represents H, F, CHF.sub.2, CF.sub.3, lower alkyl or
hydroxyC.sub.1-6 alkyl, or two R.sup.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;
[0048] Ar.sup.3 represents an aryl or heteroaryl group, optionally
substituted with R.sup.3;
[0049] R.sup.3 is R.sup.4, halogen, haloC.sub.1-6alkyl,
N(R.sup.5).sub.2, CN, NO.sub.2, C(R.sup.6).sub.3,
CON(R.sup.5).sub.2, OR.sup.4, SR.sup.4 or S(O).sub.nR.sup.7;
[0050] R.sup.4 is H, lower alkyl, lower alkenyl, lower alkynyl,
CHF.sub.2 or CF.sub.3;
[0051] R.sup.5 is R.sup.4, Ph or Bn, or two R.sup.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;
[0052] R.sup.6 is H, F, CF.sub.3 or lower alkyl, or two R.sup.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;
[0053] R.sup.7 is lower alkyl, lower alkenyl, lower alkynyl,
CHF.sub.2, CF.sub.3, N(R.sup.5).sub.2, Ph(R.sup.8).sub.2 or
CH.sub.2Ph(R.sup.8).sub.- 2;
[0054] R.sup.8 is R.sup.4, OR.sup.4, SR.sup.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).sub.n, C.dbd.C or an acetylenic group, and
optionally being substituted with R.sup.9;
[0055] R.sup.9 is R.sup.2, lower alkenyl, lower alkynyl, OR.sup.4
or SR.sup.4;
[0056] Ar.sup.2 represents an aryl or heteroaryl group, optionally
substituted with R.sup.3;
[0057] R.sup.10 represents R.sup.4, halogen, N(R.sup.5).sub.2, CN,
NO.sub.2, C(R.sup.6).sub.3, OR.sup.4, SR.sup.4 or
S(O).sub.nR.sup.7;
[0058] X represents a linker which is attached to Ar.sup.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).sub.n, C.dbd.C or an
acetylenic group, and said linker being optionally substituted with
R.sup.11;
[0059] R.sup.11 is R.sup.9;
[0060] Q represents a member selected from the group consisting of:
CO.sub.2H, tetrazole, SO.sub.3H, hydroxamic acid,
CONHSO.sub.2R.sup.12 and SO.sub.2NHCOR.sup.12;
[0061] R.sup.12 represents a member selected from the group
consisting of: CF.sub.3, lower alkyl, lower alkenyl, lower alkynyl
and ZAr.sup.4, wherein Z is an optional linker containing 0-4
carbon atoms, optionally substituted with R.sup.13;
[0062] R.sup.13 is R.sup.9;
[0063] Ar.sup.4is an aryl or heteroaryl group optionally
substituted with R.sup.14, and
[0064] R.sup.14 is R.sup.10 or NHCOMe.
[0065] As used herein, the following terms and definitions apply
unless indicated otherwise.
[0066] The following abbreviations have the indicated meanings:
[0067] Ac=acetyl
[0068] AIBN=2,2'-azobisisobutyronitrile
[0069] Bn=benzyl
[0070] DHP=2,3-dihydro-4H-pyran
[0071] DIBAL=diisobutyl aluminum hydride
[0072] DIPHOS=1,2-bis(diphenylphosphino)ethane
[0073] DMAP=4-(dimethylamino)pyridine
[0074] DMF=N,N-dimethylformamide
[0075] DMSO=dimethyl sulfoxide
[0076] EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
[0077] Et.sub.3N=triethylamine
[0078] Fur=furandiyl
[0079] HBBS=Hanks balanced salt solution
[0080] HEPES=N-[2-hydroxyethyl]piperazine-N-[2-ethanesulfonic
acid]
[0081] KHMDS=potassium hexamethyldisilazane
[0082] LDA=lithium diisopropylamide
[0083] LPS=lipopolysaccharide
[0084] MCPBA=metachloroperbenzoic acid
[0085] MES=2-[N-morpholino]ethanesulfonic acid
[0086] Ms=methanesulfonyl=mesyl
[0087] MsO=methanesulfonate=mesylate
[0088] NBS=N-bromosuccinimide
[0089] NCS=N-chlorosuccinimide
[0090] NSAID=non-steroidal anti-inflammatory drug
[0091] PCC=pyridinium chlorochromate
[0092] PDC=pyridinium dichromate
[0093] Ph=phenyl
[0094] Phe=benzenediyl
[0095] PPTS=pyridinium p-toluenesulfonate
[0096] pTSA=p-toluenesulfonic acid
[0097] Pye=pyridinediyl
[0098] r.t.=room temperature
[0099] rac.=racemic
[0100] Tf=trifluoromethanesulfonyl=triflyl
[0101] TfO=trifluoromethanesulfonate=triflate
[0102] Th=2- or 3-thienyl
[0103] THF=tetrahydrofuran
[0104] Thi=thiophenediyl
[0105] THP=tetrahydropyran-2-yl
[0106] Thz=thiazol-2-yl
[0107] TLC=thin layer chromatography
[0108] Ts=p-toluenesulfonyl=tosyl
[0109] TsO=p-toluenesulfonate=tosylate
[0110] Tz=1H (or 2H)-tetrazol-5-yl
[0111] C.sub.3H.sub.5=allyl
[0112] Alkyl group abbreviations
[0113] Me=methyl
[0114] Et=ethyl
[0115] n-Pr=normal propyl
[0116] i-Pr=isopropyl
[0117] n-Bu=normal butyl
[0118] i-Bu=isobutyl
[0119] s-Bu=secondary butyl
[0120] t-Bu=tertiary butyl
[0121] c-Pr=cyclopropyl
[0122] c-Bu=cyclobutyl
[0123] c-Pen=cyclopentyl
[0124] c-Hex=cyclohexyl
[0125] The terms alkyl, alkenyl, and alkynyl mean linear, branched,
and cyclic structures and combinations thereof.
[0126] "Alkyl" and the alkyl portions of alkoxy, arylalkyl,
alkylaryl and the like include "cycloalkyl" and "lower alkyl" and
extends to cover carbon fragments having up to 20 carbon atoms.
Examples of alkyl groups include octyl, nonyl, undecyl, dodecyl,
tridecyl, tetradecyl, pentadecyl, eicosyl,
3,7-diethyl-2,2-dimethyl-4-propylnonyl, and the like.
[0127] "Lower alkyl" includes "lower cycloalkyl" and means alkyl
groups of from 1 to 7 carbon atoms. Examples of lower alkyl groups
include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl,
pentyl, hexyl, heptyl, and the like.
[0128] "Cycloalkyl" includes "lower cycloalkyl" and means a
hydrocarbon, containing one or more rings of from 3 to 12 carbon
atoms, with the hydrocarbon having up to a total of 20 carbon
atoms. Examples of cycloalkyl groups are cyclopropyl, cyclopentyl,
cycloheptyl, adamantyl, cyclododecylmethyl,
2-ethyl-1-bicyclo[4.4.0]decyl, and the like.
[0129] "Lower cycloalkyl" means a hydrocarbon containing one or
more rings of from 3 to 7 carbon atoms, with the hydrocarbon having
up to a total of 7 carbon atoms. Examples of lower cycloalkyl
groups are cyclopropyl, cyclopropylmethyl, cyclobutyl,
2-cyclopentylethyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, and the
like.
[0130] The term "alkenyl" includes "cycloalkenyl" and "lower
alkenyl" and means alkenyl groups of 2 to 20 carbon atoms. Examples
of alkenyl groups include allyl, 5-decen-1-yl, 2-dodecen-1-yl, and
the like.
[0131] "Lower alkenyl" includes "lower cycloalkenyl" and means
alkenyl groups of 2 to 7 carbon atoms. Examples of lower alkenyl
groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl,
heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the
like.
[0132] "Cycloalkenyl" includes "lower cycloalkenyl" and means
alkenyl groups of 3 to 20 carbon atoms, which include a ring of 3
to 12 carbon atoms, and in which the alkenyl double bond may be
located anywhere in the structure. Examples of cycloalkenyl groups
are cyclopropen-1-yl, cyclohexen-3-yl, 2-vinyladamant-1-yl,
5-methylene-dodec-1-yl and the like.
[0133] "Lower cycloalkenyl" means alkenyl groups of 3 to 7 carbon
atoms, which include a ring of 3 to 7 carbon atoms and in which the
double bond may be located anywhere in the structure. Examples of
lower cycloalkenyl groups are cyclopropen-1-yl, cyclohexen-3-yl,
2-cyclopentylethen-1-yl, and the like.
[0134] The term "alkynyl" includes "cycloalkynyl" and "lower
alkynyl" and means alkynyl groups of 2 to 20 carbon atoms. Examples
of alkynyl groups are ethynyl, 2-pentadecyn-1-yl, 1-eicosyn-1-yl,
and the like.
[0135] "Lower alkynyl" includes "lower cycloalkynyl" and means
alkynyl groups of 2 to 7 carbon atoms. Examples of lower alkynyl
groups include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl
and the like.
[0136] "Cycloalkynyl" includes "lower cycloalkynyl" and means
alkynyl groups of 5 to 20 carbon atoms, which include a ring of 3
to 20 carbon atoms. The alkynyl triple bond may be located anywhere
in the group, with the proviso that if it is within a ring, such a
ring must be of 10 members or greater. Examples of cycloalkynyl are
cyclododecyn-3-yl, 3-cyclohexyl-1-propyn-1-yl, and the like.
[0137] "Lower cycloalkynyl" means alkynyl groups of 5 to 7 carbon
atoms which include a ring of 3 to 5 carbon atoms. Examples of
lower cycloalkynyl are cyclopropylethynyl,
3-(cyclobutyl)-1-propynyl, and the like.
[0138] Halogen includes F, Cl, Br and I. When a group is
"halogenated", it is substituted with one or more halogen atoms, up
to the maximum number of positions available for substitution,
i.e., it is "perhalogenated".
[0139] The definition of any substituent (e.g., R.sup.6, R.sup.10,
etc.) in a particular molecule is independent of its definition
elsewhere in the molecule. Thus, --N(R.sup.5).sub.2 represents
--NHH, --NHCH.sub.3, --NHC.sub.6H.sub.5, and the like.
[0140] Examples of rings formed when two R.sup.2 groups join
include cyclopropane, cyclobutane, cyclopentane, cyclohexane,
cycloheptane, oxetane, tetrahydrofuran, tetrahydropyran,
tetrahydrothiophene, tetrahydrothiopyran, pyrrolidine and
piperidine.
[0141] The heterocycles formed when two R.sup.5 groups join through
N include pyrrolidine, piperidine, morpholine, thiamorpholine,
piperazine and N-methylpiperazine.
[0142] Aryl and the aryl portions of arylalkyl, aryloxy, arylalkoxy
and the like refer to aromatic as well as partially aromatic 6-12
membered ring systems. Examples include benzene, naphthalene,
biphenyl and tetrahydronaphthalene.
[0143] Heteroaryl and the heteroaryl portion of heteroarylalkyl,
heteroarylalkoxy, heteroaryloxy and the like refer to 5-15 membered
aromatic and partially aromatic ring systems, containing 1-4
heteroatoms selected from O, S and N. Examples include pyridine,
quinoline, isoquinoline, furan, benzofuran, thiophene,
benzothiophene, oxazole, thiazole, benzothiazole,
1,3,4-thiadiazole, thienopyridine, indole, tetrazole, imidazole,
benzoxazole, pyrrole and methylenedioxyphenyl.
[0144] Haloaryl and haloheteroaryl refer to aryl and heteroaryl
groups respectively having at least one halo atom attached, up to
perhalogenated, as indicated above. Haloalkyl refers to alkyl
groups which have one or more halogen atoms attached, including up
to the maximum number of positions which can be substituted, i.e.,
perhalogenated alkyl groups. In haloalkylarylalkoxy, the terminal
alkyl portion is halogenated. In haloarylalkoxy, the aryl portion
is halogenated, and in haloheteroarylalkoxy the heteroaryl portion
is halogenated.
[0145] Aryl, heteroaryl and other groups are termed optionally
substituted as described herein. When a moiety is optionally
substituted, this means that the moiety is unsubstituted or is
substituted with 1-5 of the substituent groups, as permitted with
respect to the availability for substitution. In particular, this
applies to Ar.sup.1, which is optionally substituted with 1-5
R.sup.1 and/or R.sup.3 groups. Y is optionally substituted with 1-5
R.sup.2 groups. Ar.sup.3 is optionally substituted with 1-5 R.sup.3
groups. W is optionally substituted with 1-5 R.sup.9 groups.
Ar.sup.2 is optionally substituted with 1-5 R.sup.3 groups. X is
optionally substituted with 1-5 R.sup.11 groups. Z is optionally
substituted with 1-5 R.sup.13 groups, and Ar.sup.4 is optionally
substituted with 1-5 R.sup.14 groups.
[0146] Y represents an optional linking group between Ar.sup.1 and
R.sup.2 or R.sup.3. When m is 0, Y is absent and when m is 1, Y is
present. The linking group contains 0-4 carbon atoms and 0-1
heteroatoms selected from O, S and N, and further is optionally
substituted with R.sup.2. Examples of suitable linking groups
include: O, S, NR.sup.2, OCH.sub.2, CH.dbd.CH, SO.sub.2CH.sub.2,
NHCHMeCH.sub.2,O, CH.sub.2, CH.sub.2CH.dbd.CH and the like.
[0147] 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).sub.n, C.dbd.C or an acetylenic group, and
optionally being substituted with R.sup.9. Examples include
OCH.sub.2CH.sub.2, CH.dbd.CHCH.sub.2, CH.sub.2SO.sub.2CH.sub.2,
NHCHMeCH.sub.2, (CH.sub.2).sub.5, CH.sub.2CH.dbd.CHCH.sub.2,
O(CH.sub.2).sub.3O, CH.sub.2NHCO, CH.sub.2C+C, CH.sub.2OCH.sub.2,
CH.sub.2CH.dbd.CH, 1,2-c-Pr-CH.sub.2, CH.sub.2-1,2-c-Pr and the
like.
[0148] X represents a linker that is attached to Ar.sup.2 ortho to
the attachment of W. The linker contains 0-4 carbon atoms and not
more than one heteroatom selected from O, N and S. Linker X further
optionally contains a group CO, S(O).sub.n, C.dbd.C or an
acetylenic group, and said linker is optionally substituted with
R.sup.11. Examples of X include OCH.sub.2, CH.dbd.CH,
SO.sub.2CH.sub.2, NHCHMeCH.sub.2,O, CH.sub.2, CH.sub.2 CH.dbd.CH,
1,2-c-Pr, (CH.sub.2).sub.2O, C+C and the like.
[0149] In ZAr.sup.4, Z represents an optional linker having 0-4
carbon atoms, and being optionally substituted with R.sup.13.
Examples of such a linker include a bond, CH.sub.2CH.sub.2,
CH.dbd.CH, CHMeCH.sub.2, CH.sub.2, CH.sub.2CH.dbd.CH, 1,2-c-Pr, and
the like.
[0150] One aspect of the invention that is of particular interest
relates to compounds of formula II wherein R.sup.1 is OH,
OCH.sub.2Ar.sup.3, SCH.sub.2Ar.sup.3, OAr.sup.3, SAr.sup.3 or
NR.sup.2CH.sub.2Ar.sup.3. Within this subset, all other variables
are as originally defined.
[0151] Another aspect of the invention that is of particular
interest relates to compounds of formula II wherein Ar.sup.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.sup.3. Within this
subset, all other variables are as originally defined.
[0152] Another aspect of the invention that is of particular
interest relates to compounds of formula II wherein Ar.sup.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.sup.4, OR.sup.4, SR.sup.4 and halogen.
[0153] Another aspect of the invention that is of particular
interest relates to compounds of formula II wherein W is selected
from the group consisting of: CH.sub.2OCH.sub.2, (CH.sub.2).sub.3,
CH.sub.2CH.dbd.CH, CH.dbd.CHCH.sub.2, CH(OH)CH.dbd.CH,
CH.dbd.CHCH(OH), CH.sub.2C+C, C+CCH.sub.2, 1,2-c-Pr-CH.sub.2 and
-1,2-c-Pr-CH.sub.2-. Within this subset, all other variables are as
originally defined.
[0154] Another aspect of the invention that is of particular
interest relates to compounds of formula II wherein X is selected
from the group consisting of: (CH.sub.2).sub.2, CH.dbd.CH, C+C and
1,2-c-Pr. Within this subset, all other variables are as originally
defined.
[0155] Another aspect of the invention that is of particular
interest relates to compounds of formula II wherein Q is CO.sub.2H
or tetrazole. Within this subset, all other variables are as
originally defined.
[0156] Another aspect of the invention that is of particular
interest relates to compounds of formula II wherein Z represents a
0-2 carbon atom linker that is unsubstituted. Within this subset,
all other variables are as originally defined.
[0157] Another aspect of the invention that is of particular
interest relates to compounds of formula II wherein Ar.sup.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.sup.3. Within this subset, all other
variables are as originally defined.
[0158] A preferred aspect of the invention relates to compounds
represented by formula II wherein:
[0159] Ar.sup.1 is an aryl or heteroaryl group substituted by
R.sup.1 and R.sup.3;
[0160] R.sup.1 is OH, OCH.sub.2Ar.sup.3, SCH.sub.2Ar.sup.3,
OAr.sup.3, SAr.sup.3 or NR.sup.2CH.sub.2Ar.sup.3;
[0161] Ar.sup.3 is selected from the group consisting of benzene,
pyridine, thiophene, furan, oxazole and thiazole, said group being
optionally substituted with R.sup.3;
[0162] Ar.sup.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.sup.4, OR.sup.4, SR.sup.4
and halogen;
[0163] W is selected from the group consisting of.
CH.sub.2OCH.sub.2, (CH.sub.2).sub.3, CH.sub.2CH.dbd.CH,
CH.dbd.CHCH.sub.2, CH(OH)CH.dbd.CH, CH.dbd.CHCH(OH), CH.sub.2C+C,
C+CCH.sub.2 1,2-c-Pr-CH.sub.2-- and --CH.sub.2-1,2-c-Pr--;
[0164] X is selected from the group consisting of:
(CH.sub.2).sub.2, CH.dbd.CH, C+C and 1,2-c-Pr;
[0165] and Q is CO.sub.2H or tetrazole. Within this subset, all
other variables are as originally defined.
[0166] Another preferred aspect of the invention relates to
compounds represented by formula II wherein:
[0167] Ar.sup.1 is an aryl or heteroaryl group optionally
substituted with R.sup.1 and R.sup.3;
[0168] R.sup.1 is OH, OCH.sub.2Ar.sup.3, SCH.sub.2Ar.sup.3,
OAr.sup.3, SAr.sup.3 or NR.sub.2CH.sub.2Ar.sup.3;
[0169] Ar.sup.3 represents a member selected from the group
consisting of: benzene, pyridine, thiophene, furan, oxazole or
thiazole, said group being optionally substituted with R.sup.3;
[0170] W is selected from the group consisting of:
CH.sub.2OCH.sub.2, (CH.sub.2).sub.3, CH.sub.2CH.dbd.CH,
CH.dbd.CHCH.sub.2, CH(OH)CH.dbd.CH, CH.dbd.CHCH(OH), CH.sub.2C+C or
C+CCH.sub.2;
[0171] Ar.sup.2 represents a member selected from the group
consisting of: benzene, pyridine, thiophene, furan, oxazole or
thiazole, said group being optionally substituted with R.sup.8;
[0172] X is selected from the group consisting of:
(CH.sub.2).sub.2, CH.dbd.CH, C+C and 1,2-c-Pr;
[0173] Q is CONHSO.sub.2ZAr.sup.4;
[0174] Z is a 0-2 carbon linker and is unsubstituted;
[0175] Ar.sup.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.sup.3. Within
this subset, all other variables are as originally defined.
[0176] A more preferred aspect of the invention relates to
compounds represented by formula II wherein:
[0177] Ar.sup.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.sub.2Ar.sup.8,
SCH.sub.2Ar.sup.8, OAr.sup.3, SAr.sup.3 and
NR.sup.2CH.sub.2Ar.sup.3, and is optionally substituted in position
3 with a member selected from the group consisting of: OMe,
OCHF.sub.2 and lower alkyl;
[0178] Ar.sup.3 is benzene or thiophene, optionally substituted
with R.sup.8;
[0179] W is selected from the group consisting of:
CH.sub.2OCH.sub.2, (CH.sub.2).sub.3, CH.sub.2CH.dbd.CH,
CH.dbd.CHCH.sub.2, CH(OH)CH.dbd.CH and CH.dbd.CHCH(OH),
[0180] Ar.sup.2 is benzene or thiophene, optionally substituted
with 1-4 members selected from R.sup.4, OR.sup.4, SR.sup.4 and
halogen;
[0181] X represents a member selected from the group consisting of:
(CH.sub.2).sub.2, CH.dbd.CH and 1,2-c-Pr, and
[0182] Q is CO.sub.2H.
[0183] Within this subset, all other variables are as originally
defined.
[0184] Another more preferred aspect of the invention relates to
compounds represented by formula II wherein:
[0185] Ar.sup.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.sub.2Ar.sup.3, SCH.sub.2Ar.sup.3, OAr.sup.3, SAr.sup.3
and NR.sup.2CH.sub.2Ar.sup.3; and is optionally substituted at
position 3 with one member selected from the group consisting of:
OMe, OCHF.sub.2 and lower alkyl;
[0186] Ar.sup.3 is benzene or thiophene, optionally substituted
with R.sup.8;
[0187] W is selected from the group consisting of:
CH.sub.2OCH.sub.2, (CH.sub.2).sub.3, CH.sub.2CH.dbd.CH,
CH.dbd.CHCH.sub.2, CH(OH)CH.dbd.CH and CH.dbd.CHCH(OH);
[0188] Ar.sup.2 is benzene or thiophene, optionally substituted
with R.sup.4, OR.sup.4, SR.sup.4 or halo;
[0189] X is selected from the group consisting of:
(CH.sub.2).sub.2, CH.dbd.CH and 1,2-c-Pr,
[0190] Q is CONHSO.sub.2ZAr.sup.4,
[0191] Z is a bond or CH.sub.2, and
[0192] Ar.sup.4 is selected from the group consisting of: benzene,
thiophene, 1,3,4-thiadiazole and naphthalene and is substituted
with R.sup.8.
[0193] Within this subset, all other variables are as originally
defined.
[0194] A particularly preferred aspect of the present invention
that is of interest relates to compounds represented by formula
II': 2
[0195] as well as pharmaceutically acceptable salts and hydrates
thereof, wherein:
[0196] Ar.sup.1 represents phenyl, naphthyl, benzofuranyl or
methylenedioxyphenyl;
[0197] R.sup.1 represents H, OH, C.sub.1-6alkyl, C.sub.1-6alkoxy,
hydroxyC.sub.1-6alkyl, aryl, aryloxy, arylalkoxy, haloaryl,
haloheteroaryl, haloarylalkoxy, alkylaryl, haloalkylarylalkoxy,
haloarylalkoxy and haloheteroarylalkoxy;
[0198] R.sup.3 represents R.sup.4, halogen, OR.sup.4 or
SR.sup.4;
[0199] R.sup.4 represents H, lower alkyl, lower alkenyl, lower
alkynyl, CHF.sub.2 or CF.sub.3;
[0200] X represents a member selected from the group consisting
of:
[0201] --(CH.sub.2).sub.1-2--, 1,2-c-Pr, --CH.dbd.CH--,
--CH.sub.2O--, --C+CCH.sub.2--, --C+C--, and --CH.sub.2--C+C--;
[0202] W represents a member selected from the group consisting
of:
[0203] --(CH.sub.2).sub.3-6--, --CH.sub.2CH.dbd.CH--,
--CH.dbd.CHCH.sub.2--, --CH(OH)CH.dbd.CH--, --CH.dbd.CHCH(OH)--,
--CH.sub.2-1,2-c-Pr--, -1,2-c-Pr--CH.sub.2--,
--CH.sub.2--O--CH.sub.2--, --O--(CH.sub.2).sub.1-3--O--,
--CH.sub.2--NHC(O)--, --CF.sub.2CH.dbd.CH--, --CH.dbd.CHCF.sub.2--,
--CH.sub.2CH.sub.2--S--, --S--CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2--SO.sub.2--, --SO.sub.2--CH.sub.2CH.sub.2--,
--O--(CH.sub.2).sub.1-3--, --(CH.sub.2).sub.1-3--O-- and
--CH.dbd.CHCH.sub.2CH.sub.2--, and
[0204] all other variables are as originally defined.
[0205] Another particularly preferred aspect of the invention
relates to compounds represented by formula II": 3
[0206] as well as pharmaceutically acceptable salts and hydrates
thereof, wherein:
[0207] Ar.sup.1 represents phenyl, naphthyl, benzofuranyl or
methylenedioxyphenyl;
[0208] R.sup.1 represents H, OH, C.sub.1-6alkyl, C.sub.1-6alkoxy,
hydroxyC.sub.1-6alkyl, aryl, aryloxy, arylalkoxy, haloaryl,
haloheteroaryl, haloarylalkoxy, alkylaryl, haloalkylarylalkoxy,
haloarylalkoxy and haloheteroarylalkoxy;
[0209] R.sup.3 represents R.sup.4, halogen, OR.sup.4 or
SR.sup.4;
[0210] R.sup.4 represents H, lower alkyl, lower alkenyl, lower
alkynyl, CHF.sub.2 or CF.sub.3;
[0211] X represents a member selected from the group consisting
of:
[0212] --(CH.sub.2).sub.1-2--, -1,2-c-Pr--, --CH.dbd.CH--,
--CH.sub.2O--, --C+CCH.sub.2--, --C+C--, and --CH.sub.2--C+C--;
[0213] W represents a member selected from the group consisting
of:
[0214] --(CH.sub.2).sub.3-6--, --CH.sub.2CH.dbd.CH--,
--CH.dbd.CHCH.sub.2--, --CH(OH) CH.dbd.CH--, --CH.dbd.CHCH(OH)--,
--CH.sub.2-1,2-c-Pr--, -1,2-c-Pr--CH.sub.2--,
--CH.sub.2--O--CH.sub.2--, --O--(CH.sub.2).sub.1-3--O--,
--CH.sub.2--NHC(O)--, --CF.sub.2CH.dbd.CH--, --CH.dbd.CHCF.sub.2--,
--CH.sub.2CH.sub.2--S--, --S--CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2--SO.sub.2--, --SO.sub.2--CH.sub.2CH.sub.2--,
--O--(CH.sub.2).sub.1-3--, --(CH.sub.2).sub.1-3--O-- and
--CH.dbd.CHCH.sub.2CH.sub.2--, and
[0215] R.sup.12 is selected from the group consisting of: C.sub.1-6
alkyl, thienyl, phenyl, naphthyl, biphenyl, quinolinyl,
thiadiazolyl, tetrazolyl, --CH.dbd.CH-phenyl, said thienyl, phenyl,
naphthyl, biphenyl, quinolinyl, thiadiazolyl, tetrazolyl and
--CH.dbd.CH-phenyl groups being optionally substituted with
R.sup.3.
[0216] Examples of compounds within the present application are the
following:
1TABLE I (Ar.sup.1--W--Ar.sup.2-X-Q) Ex Ar.sup.1 W Ar.sup.2 X Q 1
2-(BnO)-3- (CH.sub.2).sub.3 1,2-Phe (CH.sub.2).sub.2 CO.sub.2H MePh
2 2-(BnO)-3- CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CONHSO.sub.2- MePh
2-thienyl 3 2-(BnO)-3- CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CONHSO.sub.2-2- MePh thienyl 4 2-((2-Cl-4-FPh) CH.sub.2CH.dbd.CH
1,2-Phe CH.dbd.CH CO.sub.2H CH.sub.2O)-3- CF.sub.3Ph 5
2-((2-Cl-4-FPh) CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H
CH.sub.2O)-3- CF.sub.3Ph 6 2-(BnO)Ph CH.sub.2CH.dbd.CH 1,2-Phe
CH.dbd.CH CO.sub.2Na 7 2-(BnO)Ph CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2Na 8 4-(BnO)-3,5- CH.sub.2CH.dbd.CH 1,2-Phe
CH.dbd.CH CO.sub.2Na (MeO).sub.2Ph 9 4-(BnO)-3,5- CH.dbd.CHCH.sub.2
1,2-Phe CH.dbd.CH CO.sub.2Na (MeO).sub.2Ph 10 2-(BnO)-5-
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H AcPh 11 2-(BnO)-5-
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H AcPh 12 2-(BnO)-3-
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2Na (MeO)Ph 13
2-(BnO)-3- CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2Na (MeO)Ph
14 4-(BnO)-3- CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2Na
(MeO)Ph 15 4-(BnO)-3- CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CO.sub.2Na (MeO)Ph 16 2-(BnO O)-3- CH.sub.2CH.dbd.CH 1,2-Phe
CH.sub.2 CO.sub.2Na MePh 17 2-(BnO)-3- CH.dbd.CHCH.sub.2 1,2-Phe
CH.sub.2 CO.sub.2Na MePh 18 2-(BnO)-3- CH.sub.2CH.dbd.CH 5-Cl-1,2-
CH.sub.2 CO.sub.2Na MePh Phe 19 2-(BnO)-3- CH.dbd.CHCH.sub.2
5-Cl-1,2- CH.sub.2 CO.sub.2Na MePh Phe 20 4-(BnO)-3-
(CH.sub.2).sub.3 1,2-Phe 1,2-c-Pr CO.sub.2H (MeO)Ph 21 2-(BnO)-3-
CH.dbd.CHCH.sub.2 4,5-(MeO).sub.2- CH.dbd.CH CO.sub.2H MePh 1,2-Phe
22 2-(BnO)-3- CH.sub.2CH.dbd.CH 4,5-(MeO).sub.2- CH.dbd.CH
CO.sub.2H MePh 1,2-Phe 23 3,4-(methylene CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2H dioxy)Ph 24 3,4-(methylene CH.sub.2CH.dbd.CH
1,2-Phe CH.dbd.CH CO.sub.2H dioxy)Ph 25 Ph CH.dbd.CHCH.sub.2
1,2-Phe CH.dbd.CH CO.sub.2H 26 Ph CH.sub.2CH.dbd.CH 1,2-Phe
CH.dbd.CH CO.sub.2H 27 2-(HO)-3-MePh CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2H 28 2-(BnO)-3- CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2Na MePh 29 2-(BnO)-3- CH.sub.2CH.dbd.CH 1,2-Phe
CH.dbd.CH CO.sub.2Na MePh 30 2-((7-Cl-2- CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2H quinolinyl)CH.sub.2O)- 3-MePh 31 2-((7-Cl-2-
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H
quinolinyl)CH.sub.2O)- 3-MePh 32 2-(BnO)-3- (CH.sub.2).sub.3
1,2-Phe bond CO.sub.2H MePh 33 2-(BnO)-3- CH.dbd.CHCH.sub.2 1,2-Phe
bond CO.sub.2Na MePh 34 2-(BnO)-3- CH.sub.2CH.dbd.CH 1,2-Phe bond
CO.sub.2Na MePh 35 2-(BnO)-3- (CH.sub.2).sub.3 1,2-Phe CH.dbd.CH
CO.sub.2Na MePh 36 2-(BnO)-3- (CH.sub.2).sub.3 1,2-Phe CH.dbd.CH
CO.sub.2Na (MeO)Ph 37 4-(BnO)-3- (CH.sub.2).sub.3 1,2-Phe CH.dbd.CH
CO.sub.2Na (MeO)Ph 38 4-(MeO)Ph CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH
CO.sub.2H 39 4-(MeO)Ph CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CO.sub.2H 40 3,4-(MeO).sub.2Ph CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH
CO.sub.2H 41 3,4-(MeO).sub.2Ph CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CO.sub.2H 42 2-(BnO)Ph CH(OH)CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2Na
43 2-(BnO)-3- (CH.sub.2).sub.3 1,2-Phe (CH.sub.2).sub.2
CONNaSO.sub.2- MePh 2-thienyl 44 4-(BnO)-3- CH.sub.2CH.dbd.CH
1,2-Phe CH.dbd.CH CONNaSO.sub.2- (MeO)Ph 2-thienyl 45 4-(BnO)-3-
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CONNaSO.sub.2- (MeO)Ph
2-thienyl 46 2-(BnO)-3- CH.sub.2-1,2-c-Pr 1,2-Phe CH.dbd.CH
CO.sub.2Na MePh 47 2-(BnO)-3- 1,2-c-Pr-CH.sub.2 1,2-Phe CH.dbd.CH
CO.sub.2Na MePh 48 2-(BnO)-3- CH(OH)CH.dbd.CH 1,2-Phe CH.dbd.CH
CO.sub.2Na MePh 49 2-(BnO)-3- CH.dbd.CHCH(OH) 1,2-Phe CH.dbd.CH
CO.sub.2H MePh 50 2-((2,6-Cl.sub.2Ph) CH.dbd.CHCH(OH) 1,2-Phe
CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 51 2-((2,6-Cl.sub.2Ph)
CH(OH)CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 52
2-((4-FPh) CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H
CH.sub.2O)-3-MePh 53 2-((4-FPh) CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CO.sub.2Na CH.sub.2O)-3-MePh 54 2-((3,4-F.sub.2Ph)
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 55
2-((3,4-F.sub.2Ph) CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2Na
CH.sub.2O)-3-MePh 56 2-((3,5-F.sub.2Ph) CH.sub.2CH.dbd.CH 1,2-Phe
CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 57 2-((3,5-F.sub.2Ph)
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2Na CH.sub.2O)-3-MePh 58
2-((2,6-Cl.sub.2Ph) CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H
CH.sub.2O)-3- (HOCH.sub.2)Ph 59 2-((2,6-Cl.sub.2Ph)
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H CH.sub.2O)-3-
(HOCH.sub.2)Ph 60 2-((2,6-Cl.sub.2Ph) CH.sub.2CH.dbd.CH 1,2-Phe
CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 61 2-((2,6-Cl.sub.2Ph)
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2Na CH.sub.2O)-3-MePh 62
2-((4-CF.sub.3Ph) CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H
CH.sub.2O)-3-MePh 63 2-((4-CF.sub.3Ph) CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2Na CH.sub.2O)-3-MePh 64 2-((4- CH.sub.2CH.dbd.CH
1,2-Phe CH.dbd.CH CO.sub.2H (CHF.sub.2O)Ph) CH.sub.2O)-3-MePh 65
2-((4-(CHF.sub.2O) CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2Na
Ph)CH.sub.2O)-3- MePh 66 2-((4-CF.sub.3Ph) CH.dbd.CHCH(OH) 1,2-Phe
CH.dbd.CH CO.sub.2H CH.sub.2O)-3- (HOCH.sub.2)Ph 67
2-((4-CF.sub.3Ph) CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H
CH.sub.2O)-3- (HOCH.sub.2)Ph 68 2-((4-CF.sub.3Ph) CH.dbd.CHCH(OH)
1,2-Phe CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 69 2-(PhCH.sub.2O)-3-
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H (HOCH.sub.2)Ph 70
3-(PhO)Ph CH.sub.2OCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2Na 71
2-(PhO)Ph CH.sub.2OCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2Na 72
3-(BnO)Ph CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2Na 73
3-(BnO)Ph CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2Na 74
2-(BnO)Ph O(CH.sub.2).sub.3O 1,2-Phe CH.dbd.CH CO.sub.2Na 75
2-(PhCHMeO)- CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2Na 3-MePh
76 2-(PhCHMeO)- CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H
3-MePh 77 3-(PhO)Ph CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2Na
78 3-(PhO)Ph CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2Na 79 3-Ph
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2Na benzofuran-7- yl 80
3-Ph CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2Na benzofuran-7-
yl 81 Ph CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2-
2-thienyl 82 Ph CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CONHSO.sub.2-
2-thienyl 83 4-(MeO)Ph CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CONHSO.sub.2- 2-thienyl 84 4-(MeO)Ph CH.sub.2CH.dbd.CH 1,2-Phe
CH.dbd.CH CONHSO.sub.2- 2-thienyl 85 2-(BnO)-1- CH.sub.2NHCO
1,2-Phe CH.dbd.CH CO.sub.2H naphthyl 86 2-((2-Cl-4-FPh)
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 87
2-((2-Cl-4-FPh) CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H
CH.sub.2O)-3-MePh 88 2-((2,4-F.sub.2Ph) CH.sub.2CH.dbd.CH 1,2-Phe
CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 89 2-((2,4-F.sub.2Ph)
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 90
2-((2,4,6-F.sub.3Ph) CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H
CH.sub.2O)-3-MePh 91 2-((2,4,6-F.sub.3Ph) CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2H CH.sub.2O)-3-MePh 92 2-((2,6-Cl.sub.2-4-
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H FPh)
CH.sub.2O)-3-MePh 93 2-((2,6-Cl.sub.2-4- CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2H FPh) CH.sub.2O)-3-MePh 94 2-((2,4-
CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H F.sub.2Ph)CH.sub.2O)-
3-(CHF.sub.2O)Ph 95 2-((2,4-F.sub.2Ph) CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2H CH.sub.2O)- 3-(CHF.sub.2O)Ph 96 2-((4-
CF.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CO.sub.2H FPh)CH.sub.2O)-
3-MePh 97 2-((4- CH.dbd.CHCF.sub.2 1,2-Phe CH.dbd.CH CO.sub.2H
FPh)CH.sub.2O)- 3-MePh 98 2-((4- (CH.sub.2).sub.3 1,2-Phe CH.dbd.CH
CONHSO.sub.2- FPh)CH.sub.2O)- (4-i-PrPh) 3-MePh 99 2-((4-
(CH.sub.2).sub.3 1,2-Phe CH.dbd.CH CONHSO.sub.2- FPh)CH.sub.2O)-
(4-t-BuPh) 3-MePh 100 2-((4- CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH
CONHSO.sub.2- FPh)CH.sub.2O)- (4-(MeO)Ph) 3-MePh 101 2-((4-
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2- FPh)CH.sub.2O)-
(2,3-Cl.sub.2Ph) 3-MePh 101 2-((4- CH.dbd.CHCH.sub.2 4-Cl-1,2-
CH.dbd.CH CONHSO.sub.2- FPh)CH.sub.2O)- Phe (5-Br-2- 3-MePh
(MeO)Ph) 103 2-((4- (CH.sub.2).sub.2S 3-F-1,2-Phe CH.dbd.CH
CONHSO.sub.2- FPh)CH.sub.2O)- (2,3,4-Cl.sub.3Ph) 3-MePh 104
2-((4-FPh) (CH.sub.2).sub.2S 6-CF.sub.3-1,2- CH.dbd.CH
CONHSO.sub.2- CH.sub.2O)-3-MePh Phe (5-F-2-MePh) 105 2-((4-FPh)
(CH.sub.2).sub.2S 4,5-F.sub.2-1,2- CH.dbd.CH CONHSO.sub.2-
CH.sub.2O)-3-MePh Ph (2,5-Me.sub.2Ph) 106 2-((4-FPh)
(CH.sub.2).sub.2SO.sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2-
CH.sub.2O)-3-MePh (4-CF.sub.3Ph) 107 2-((4-FPh)
(CH.sub.2).sub.2SO.sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2-
CH.sub.2O)-3-MePh 2-naphthyl 108 2-((4-FPh) CH.dbd.CHCH.sub.2
3-F-1,2-Phe CH.dbd.CH CONHSO.sub.2- CH.sub.2O)-3-MePh (3-Cl-4-FPh)
109 2-((4-FPh) SO.sub.2(CH.sub.2).sub.2 1,2-Phe CH.dbd.CH
CONHSO.sub.2- CH.sub.2O)-3-MePh (4-n-PrPh) 110 2-((4-FPh)
SO.sub.2(CH.sub.2).sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2-
CH.sub.2O)-3- (2-ClPh) (MeO)Ph 111 2-((4-FPh)
SO.sub.2(CH.sub.2).sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2-
CH.sub.2O)-3- (4-FPh) (MeO)Ph 112 2-((4-FPh) S(CH.sub.2).sub.2
1,2-Phe CH.dbd.CH CONHSO.sub.2- CH.sub.2O)-3- (2-PhPh) (MeO)Ph 113
2-((4-FPh) S(CH.sub.2).sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2-
CH.sub.2O)-3- (2-CF.sub.3Ph) (MeO)Ph 114 2-((4-FPh)
S(CH.sub.2).sub.2 4-t-Bu-1,2- CH.dbd.CH CONHSO.sub.2- CH.sub.2O)-3-
Phe (4-Cl-2,5- (MeO)Ph Me.sub.2Ph) 115 2-((4-FPh) O(CH.sub.2).sub.2
1,2-Phe CH.dbd.CH CONHSO.sub.2- CH.sub.2O)-3- (2,5-Cl.sub.2Ph)
(MeO)Ph 116 2-((4-FPh) O(CH.sub.2).sub.2 1,2-Phe CH.dbd.CH
CONHSO.sub.2- CH.sub.2O)-3- (4-Br-2- (MeO)Ph (CF.sub.3O)Ph) 117
2-((4-FPh) O(CH.sub.2).sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2-
CH.sub.2O)-3- CH.sub.2Ph (MeO)Ph 118 2-((4-FPh) (CH.sub.2).sub.2O
1,2-Phe CH.dbd.CH CONHSO.sub.2- CH.sub.2O)-3- 1-naphthyl (MeO)Ph
119 2-((4-FPh) (CH.sub.2).sub.2O 4,5-F.sub.2-1,2- CH.dbd.CH
CONHSO.sub.2- CH.sub.2O)-3- Phe (2-FPh) (MeO)Ph 120 2-((4-FPh)
(CH.sub.2).sub.2O 1,2-Phe CH.dbd.CH CONHSO.sub.2- CH.sub.2O)-3-
(2,4-Cl.sub.2Ph) (MeO)Ph 121 2-((4-FPh) (CH.sub.2).sub.3 1,2-Phe
CH.dbd.CH CONHSO.sub.2- CH.sub.2O)-3- CH.dbd.CHPh (MeO)Ph 122
2-((4- (CH.sub.2).sub.3 1,2-Phe CH.dbd.CH CONHSO.sub.2-
FPh)CH.sub.2O)-3- (3,5- (MeO)Ph (CF.sub.3).sub.2Ph) 123 2-((4-
(CH.sub.2).sub.3 1,2-Phe CH.dbd.CH CONHSO.sub.2- FPh)CH.sub.2O)Ph
(2,5-Cl.sub.2-3- thienyl) 124 2-((4-FPh) (CH.sub.2).sub.4
3-F-1,2-Phe CH.dbd.CH CONHSO.sub.2- CH.sub.2O)Ph (3-BrPh) 125
2-((4-FPh) (CH.sub.2).sub.4 3-MeO-1,2- CH.dbd.CH CONHSO.sub.2-
CH.sub.2O)Ph Phe (2-BrPh) 126 2-((4-FPh) (CH.sub.2).sub.4 1,2-Phe
CH.dbd.CH CONHSO.sub.2-(2- CH.sub.2O)Ph NO.sub.2Ph) 127 2-((4-FPh)
(CH.sub.2).sub.5 1,2-Phe (CH.sub.2).sub.2 CONHSO.sub.2-(3-
CH.sub.2O)Ph ClPh) 128 2-((4-FPh) (CH.sub.2).sub.5 1,2-Phe
(CH.sub.2).sub.2 CONHSO.sub.2-(4- CH.sub.2O)Ph (CF.sub.3O)Ph) 129
2-HOPh CH.dbd.CH(CH.sub.2).sub.2 1,2-Phe (CH.sub.2).sub.2
CONHSO.sub.2-8- quinolinyl 130 2-((4-FPh) CH.dbd.CH(CH.sub.2).sub.2
5-(CF.sub.3O)- (CH.sub.2).sub.2 CONHSO.sub.2- CH.sub.2O)Ph 1,2-Phe
(3,4-Cl.sub.2Ph) 131 4-((2,6-Cl.sub.2-4- CH.dbd.CH(CH.sub.2).sub.2
3-F-1,2-Phe (CH.sub.2).sub.2 CONHSO.sub.2-(4- FPh)CH.sub.2O)-3-
EtPh) MePh 132 2-((4-FPh) CH.sub.2CH.dbd.CH 1,2-Phe
(CH.sub.2).sub.2 CONHSO.sub.2-(4- CH.sub.2O)Ph Cl-2-NO.sub.2Ph) 133
2-((4-FPh) CH.dbd.CHCH.sub.2 4,5-F.sub.2-1,2- CH.dbd.CH
CONHSO.sub.2-(2- CH.sub.2O)Ph Phe Cl-3-Br-5- thienyl) 134
2-((4-FPh) CH.sub.2CH.dbd.CH 4,5-F.sub.2-1,2- CH.dbd.CH
CONHSO.sub.2- CH.sub.2O)Ph Phe (3,4- (MeO).sub.2Ph) 135 2-HOPh
CH.dbd.CHCH.sub.2 4,5-F.sub.2-1,2- CH.dbd.CH CONHSO.sub.2- Phe
(2,5-Cl.sub.2-3-Br- 4-thienyl) 136 4-((4- CH.sub.2CH.dbd.CH
4,5-F.sub.2-1,2- CH.dbd.CH CONHSO.sub.2-(4- FPh)CH.sub.2O)- Phe
Br-2,5-F.sub.2Ph) 3-(MeO)Ph 137 4-((4- CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CONHSO.sub.2-(5- FPh)CH.sub.2O)- (AcNH)-1,3,4- 3-(MeO)Ph
thiadiazol-2- yl) 138 4-((4-FPh) CH.sub.2CH.dbd.CH 1,2-Phe
CH.dbd.CH CONHSO.sub.2- CH.sub.2O)-3- (2,3,4,5,6- (MeO)Ph
F.sub.5Ph) 139 4-((2-Cl-4-FPh) CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
CONHSO.sub.2-(2- CH.sub.2O)-3-MePh CNPh) 140 2-((4-FPh)
CH.sub.2CH.dbd.CH 4-F-1,2-Phe CH.dbd.CH CONHSO.sub.2-(2-
CH.sub.2O)Ph Cl-6-MePh) 141 2-HOPh CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CONHSO.sub.2- (2,4,6-Me.sub.3Ph) 142 Ph CH.sub.2CH.dbd.CH
1,2-Phe CH.dbd.CH CONHSO.sub.2- (2,3-Br.sub.2-2- thienyl) 143
2-((4-FPh) CH.dbd.CHCH.sub.2 1,2-Phe CH.sub.2O CONHSO.sub.2-(4-
CH.sub.2O)Ph NO.sub.2Ph) 144 2-((4-FPh) CH.sub.2CH.dbd.CH 1,2-Phe
CH.sub.2O CONHSO.sub.2- CH.sub.2O)Ph (3,5-Cl.sub.2Ph) 145
2,4-((4-FPh) CH.dbd.CHCH.sub.2 1,2-Phe prop-1- CONHSO.sub.2-(5-
CH.sub.2O).sub.2Ph yne-1,3- Cl-2-thienyl) diyl 146
4-((2,4-F.sub.2Ph) CH.sub.2CH.dbd.CH 1,2-Phe CH.sub.2O
CONHSO.sub.2-(4- CH.sub.2O)-3- CF.sub.3Ph) (MeO)Ph 147 2-HO-3-MePh
CH.dbd.CHCH.sub.2 1,2-Phe CH.sub.2O CONHSO.sub.2- (2,4-F.sub.2Ph)
148 2-((4-FPh) CH.sub.2CH.dbd.CH 4-F-1,2-Phe 1,2-ethyne
CONHSO.sub.2-(4- CH.sub.2O)Ph diyl ClPh) 149 2-((4-FPh)
CH.dbd.CHCH.sub.2 1,2-Phe 1,2-ethyne CONHSO.sub.2-(3- CH.sub.2O)Ph
diyl CF.sub.3Ph) 150 4-HOPh CH.sub.2CH.dbd.CH 1,2-Phe 1,2-ethyne
CONHSO.sub.2-Ph diyl 151 2-((4-FPh) CH.dbd.CHCH.sub.2 1,2-Phe
prop-2- CONHSO.sub.2-(5- CH.sub.2O)Ph yne-1,3- Br-2-thienyl) diyl
152 2,4-((4-FPh) CH.sub.2CH.dbd.CH 1,2-Phe 1,2- CONHSO.sub.2-
CH.sub.2O).sub.2Ph ethynediyl Me 153 2,4-((4-FPh) CH.dbd.CHCH.sub.2
1,2-Phe 1,2-c-Pr CONHSO.sub.2- CH.sub.2O).sub.2Ph (2,5-
(MeO).sub.2Ph) 154 6-((4-FPh) CH.sub.2CH.dbd.CH 4-F-1,2-Phe
1,2-c-Pr CONHSO.sub.2-(3- CH.sub.2O)-2- MePh) naphthyl 155
2-((4-FPh) CH.dbd.CHCH.sub.2 1,2-Phe 1,2-c-Pr CONHSO.sub.2-(4-
CH.sub.2O)Ph MePh) 156 4-HO-3- CH.sub.2CH.dbd.CH 1,2-Phe 1,2-c-Pr
CONHSO.sub.2-n- (MeO)Ph Bu 157 4-((4- CH.dbd.CHCH.sub.2 1,2-Phe
1,2-c-Bu CONHSO.sub.2-(2- FPh)CH.sub.2O)- Cl-4-FPh) 1-naphthyl 158
Ph CH.sub.2CH.dbd.CH 1,2-Phe CH.dbd.CH CONHSO.sub.2- (2-MePh) 159
2-((4-FPh) CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH CONHSO.sub.2-
CH.sub.2O)Ph c-Pr 160 2,4-((4-FPh) CH.dbd.CHCH.sub.2 1,2-Phe
CH.dbd.CH CO.sub.2H CH.sub.2O).sub.2Ph 161 4-((2,4-F.sub.2Ph)
(CH.sub.2).sub.3 4-F-1,2-Phe CH.dbd.CH 1H-tetrazol- CH.sub.2O)-3-
5-yl (MeO)Ph 162 2-((4-FPh) CH.dbd.CHCH.sub.2 3-MeO- CH.dbd.CH
1H-tetrazol- CH.sub.2O)Ph 1,2-Phe 5-yl 163 2,4-((4-FPh)
CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH 1H-tetrazol- CH.sub.2O).sub.2Ph
5-yl 164 4-HO-3- CH.dbd.CHCH.sub.2 1,2-Phe 1,2-c-Pr 1H-tetrazol-
(MeO)Ph 5-yl 165 Ph CH.dbd.CHCH.sub.2 1,2-Phe (CH.sub.2).sub.2
1H-tetrazol- 5-yl 166 2-((4- CH.dbd.CHCH.sub.2 1,2-Phe CH.dbd.CH
SO.sub.3H FPh)CH.sub.2O)- 3-(MeO)Ph 167 2-((4- (CH.sub.2).sub.3
4-F-1,2-Phe (CH.sub.2).sub.2 SO.sub.3H FPh)CH.sub.2O)- 3-MePh
[0217] Optical Isomers--Diastereomers--Geometric Isomers
[0218] Some of the compounds described herein contain one or more
asymmetric centers and may thus give rise to diastereomers and
optical isomers. The present invention is meant to comprehend such
possible diastereomers as well as their racemic and resolved,
enantiomerically pure forms and pharmaceutically acceptable salts
thereof.
[0219] Some of the compounds described herein contain olefinic
double bonds, and unless specified otherwise, are meant to include
both E and Z geometric isomers. Salts
[0220] The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases including
inorganic bases and organic bases. Salts derived from inorganic
bases include aluminum, ammonium, calcium, copper, ferric, ferrous,
lithium, magnesium, manganic, manganous, potassium, sodium, zinc
salts, and the like. Particularly preferred are the ammonium,
calcium, magnesium, potassium, and sodium salts. Salts derived from
pharmaceutically acceptable organic non-toxic bases include salts
of primary, secondary, and tertiary amines, substituted amines
including naturally occurring substituted amines, cyclic amines,
and basic ion exchange resins, such as arginine, betaine, caffeine,
choline, N,N'-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine, and the like.
[0221] When the compound of the present invention is basic, salts
may be prepared from pharmaceutically acceptable non-toxic acids,
including inorganic and organic acids. Such acids include acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid, and the like. Particularly preferred are
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,
and tartaric acids.
[0222] It will be understood that in the discussion of methods of
treatment which follows, references to the compounds of Formula II
are meant to also include the pharmaceutically acceptable salts and
hydrates.
[0223] Dose Ranges
[0224] The magnitude of a prophylactic or therapeutic dose of a
compound of Formula II will, of course; vary with the nature and
the severity of the condition to be treated and with the particular
compound of Formula II and its route of administration. It will
also vary according to a variety of factors including the age,
weight, general health, sex, diet, time of administration, rate of
excretion, drug combination and response of the individual patient.
In general, the daily dose from about 0.001 mg to about 100 mg per
kg body weight of a mammal, preferably 0.01 mg to about 10 mg per
kg. On the other hand, it may be necessary to use dosages outside
these limits in some cases.
[0225] The active ingredient that may be combined with the carrier
materials to produce a single dosage form will vary depending upon
the host treated and the particular mode of administration. For
example, a formulation intended for oral administration to humans
may contain from as low as about 0.5 mg to as high as about 5 g of
active agent, compounded with an appropriate and convenient amount
of carrier material which may vary from about 5 to about 95 percent
of the total composition. Dosage units will generally contain
between from about 1 mg to about 2 g of the active ingredient,
typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600
mg, 800 mg, or 1000 mg.
[0226] Pharmaceutical Compositions
[0227] The pharmaceutical compositions of the present invention
comprise a compound of Formula II as an active ingredient or a
pharmaceutically acceptable salt or hydrate, thereof, and may also
contain a pharmaceutically acceptable carrier and optionally other
therapeutic ingredients.
[0228] For the treatment of any of the prostanoid mediated diseases
compound II may be administered orally, topically, parenterally, by
inhalation spray or rectally in dosage unit formulations containing
conventional non-toxic pharmaceutically acceptable carriers,
adjuvants and vehicles. The term parenteral as used herein includes
subcutaneous injections, intravenous, intramuscular, intrasternal
injection or infusion techniques. In addition to the treatment of
warm-blooded animals such as mice, rats, horses, cattle, sheep,
dogs, cats, etc., the compound of the invention is effective in the
treatment of humans.
[0229] The pharmaceutical compositions containing the active
ingredient may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
or syrups or elixirs. Compositions intended for oral use may be
prepared according to any method known to the art for the
manufacture of pharmaceutical compositions and such compositions
may contain one or more agents selected from the group consisting
of sweetening agents, flavouring agents, colouring agents and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets contain the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipients
which are suitable for the manufacture of tablets. These excipients
may be for example, inert diluents, such as calcium carbonate,
sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example starch, gelatin or
acacia, and lubricating agents, for example, magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate may be
employed. They may also be coated by the technique described in the
U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic
therapeutic tablets for control release.
[0230] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredients is mixed with water-miscible solvents such as propylene
glycol, PEGs and ethanol, or an oil medium, for example peanut oil,
liquid paraffin, or olive oil.
[0231] Aqueous suspensions contain the active material in admixture
with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose, hydroxypropyl
methylcellulose, sodium alginate, polyvinylpyrrolidone, gum
tragacanth and gum acacia; dispersing or wetting agents may be a
naturally-occurring phosphatide, for example lecithin, or
condensation products of an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of
ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol monooleate, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and hexitol anhydrides, for example polyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate,
one or more colouring agents, one or more flavouring agents, and
one or more sweetening agents, such as sucrose, saccharin or
aspartame.
[0232] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavouring agents may be added
to provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0233] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavouring and colouring agents, may also be
present.
[0234] The pharmaceutical compositions of the invention may also be
in the form of an oil-in-water emulsion. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and
flavouring agents.
[0235] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavouring and colouring agents. The pharmaceutical compositions
may be in the form of a sterile injectable aqueous or oleagenous
suspension. This suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a non-toxic parenterally-acceptable diluent or
solvent, for example as a solution in 1,3-butane diol. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. Cosolvents
such as ethanol, propylene glycol or polyethylene glycols may also
be used. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this purpose any
bland fixed oil may be employed including synthetic mono- or
diglycerides. In addition, fatty acids such as oleic acid find use
in the preparation of injectables.
[0236] Compound II may also be administered in the form of
suppositories for rectal administration of the drug. These
compositions can be prepared by mixing the drug with a suitable
non-irritating excipient which is solid at ambient temperatures but
liquid at the rectal temperature and will therefore melt in the
rectum to release the drug. Such materials are cocoa butter and
polyethylene glycols.
[0237] For topical use, creams, ointments, gels, solutions or
suspensions, etc., containing the compound of Formula II are
employed. (For purposes of this application, topical application
shall include mouth washes and gargles.) Topical formulations may
generally be comprised of a pharmaceutical carrier, cosolvent,
emulsifier, penetration enhancer, preservative system, and
emollient.
[0238] The composition of the present invention may also include
additional therapeutic agents. For example, conventional analgesics
such as aspirin or acetaminophen may be incorporated into the
composition. Other examples of additional therapeutic agents which
can be included are NSAIDs, such as ibuprofen or naproxen, COX-2
selective compounds, such as those which are described in the
following patents and published applications: WO96/25405, U.S. Pat.
No. 5,633,272, WO97/38986, U.S. Pat. No. 5,466,823, WO98/03484,
WO97/14691 and WO95/00501, and other compounds.
[0239] Utilities
[0240] The ability of the compounds of Formula II to interact with
prostaglandin receptors makes them useful for preventing or
reversing undesirable symptoms caused by prostaglandins in a
mammalian, especially human, subject. This mimicking or antagonism
of the actions of prostaglandins indicates that the compounds and
pharmaceutical compositions thereof are useful to treat, prevent,
or ameliorate in mammals and especially in humans: Pain, fever and
inflammation of a variety of conditions including 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 and
strains, myositis, neuralgia, synovitis, arthritis, including
rheumatoid arthritis, degenerative joint diseases (osteoarthritis),
gout and ankylosing spondylitis, bursitis, burns including
radiation and corrosive chemical injuries, sunburns, pain following
surgical and dental procedures as well as immune and autoimmune
diseases. In addition, such a compound may inhibit cellular
neoplastic transformations and metastatic tumor growth and hence
can be used in the treatment of cancer. Compounds of formula II is
also of use in the treatment and/or prevention
prostaglandin-mediated proliferation disorders such as may occur in
diabetic retinopathy and tumor angiogenesis.
[0241] Compounds of formula II inhibit prostanoid-induced smooth
muscle contraction by antagonizing contractile prostanoids or
mimicking relaxing prostanoids and hence may be use in the
treatment of dysmenorrhea, premature labor, asthma and eosinophil
related disorders. It will also be of use in the treatment of
Alzheimer's disease, the treatment of glaucoma, for the prevention
of bone loss (treatment of osteoporosis) and for the promotion of
bone formation (treatment of fractures) and other bone diseases
such as Paget's disease.
[0242] By virtue of its prostanoid or prostanoid antagonist
activity, compound II are useful as an alternative to conventional
non-steroidal anti-inflammatory drugs (NSAID'S) particularly where
such non-steroidal anti-inflammatory drugs may be contraindicated
such as in patients with peptic ulcers, gastritis, regional
enteritis, ulcerative colitis, diverticulitis or with a recurrent
history of gastrointestinal lesions; GI bleeding, coagulation
disorders including anemia such as hypoprothrombinemia, haemophilia
or other bleeding problems; kidney disease; thrombosis, occlusive
vascular diseases; those prior to surgery or taking
anti-coagulants. Compound II will also be useful as a
cytoprotective agent for patients undergoing chemotherapy.
[0243] Consequently one aspect of the invention addresses 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 withformula II in an amount
which is effective for treating or preventing said prostaglandin
mediated disease.
[0244] In another aspect of the invention, a method of treating or
preventing a prostaglandin mediated disease is described which is
further comprised of administering to said patient an effective
amount of a COX-2 selective inhibiting compound.
[0245] More particularly, a method of treating or preventing a
prostaglandin mediated disease is addressed wherein the
prostaglandin mediated disease is selected from the group
consisting of:
[0246] 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.
[0247] Further, a method of treating or preventing an E type
prostaglandin mediated disease in a mammalian patient is described
herein, 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.
[0248] More particularly, the method described with respect to
E-typ prostaglandin mediated diseases further comprises
administering a COX-2 selective inhibitor.
[0249] Examples of COX-2 selective compounds are such as those
described in the following patents and published applications:
WO96/25405, U.S. Pat. No. 5,633,272, WO97138986, U.S. Pat. No.
5,466,823, WO98/03484, WO97/14691 and WO95/00501.
METHODS OF SYNTHESIS
[0250] Compounds of the present invention can be prepared according
to the following methods. Methods A, I and J showed how to form the
linker W between Ar.sup.1 and Ar.sup.2;methods B and E-H
concentrate on linker X; method C explained how to obtain
sulfonamides and method D illustrate how to substitute Ar.sup.1.
One particular method is usually used in conjunction with other
methods to yield compounds of formula II. Reagents given below are
for illustration of the chemistry only and should not be limiting
this patent: other reagents might be as effective or better for
each reaction described.
[0251] Method A
[0252] An aryl alkene I can be coupled with an aryl bromide, iodide
or triflate II in the presence of a catalyst such as Pd(OAc).sub.2
to give the two isomers III and IV. Catalytic hydrogenation of the
double bond, using Pd/C or (Ph.sub.3P).sub.3RhCl, yield the
compound VI.
[0253] Alternatively, VI can be prepared from I via formation of
the boronate V with 9-borabicyclo[3.3.1]nonane and coupling with II
in the presence of a catalyst such as PdCl.sub.2(dppf).
Cyclopropanation of the alkenes III and IV can be performed using
conditions such as CH.sub.2N.sub.2/PdOAc.sub.2 to give VII and
VIII. The group X-Q in compounds III, IV, VI, VII and VIII can then
be transformed to another X-Q group to afford other substructures
of II. 4
[0254] Method B
[0255] The acid or esters IX can be reduced to the alcohol X using
reagents such as diisobutylaluminum hydride or sodium borohydride.
Oxidation to the aldehyde XI can be performed using MnO.sub.2 or
pyridinium chlorochromate. Wittig reaction on XI afford the
propenoate XII which can be cyclopropanated
(CH.sub.2N.sub.2/Pd(OAc).sub.2) to XIII or reduced (H.sub.2/Pd/C)
to XIV. When R.dbd.H, compounds IX, XII, XIII and XIV are
substructures of II. 5
[0256] Method C
[0257] The acid XV, which is a substructure of II, can be
transformed to the sulfonamide XVI, another substructure of II, by
treatment with a sulfonamine in the presence of a coupling reagent
such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Another
method for the preparation of XVI involves the formation of an acid
chloride or a mixed anhydride XVII and reaction with the
sulfonamine in the presence of a base such as Et.sub.3N. 6
[0258] Method D
[0259] When compound II or its precursor is substituted by an
hydroxyl group as in XVIII, it can be alkylated by a reagent
containing a leaving group XIX in the presence of a base such as
NaH or DBU to yield the ether XX. Alternatively, Mitsunobu reaction
with the alcohol derivative of XI also yield XX. The group X-Q in
XX can then be transformed to another X-Q group to afford another
example of II. 7
[0260] Method E
[0261] The aryl bromide, iodide or triflate XXI can be coupled with
an alkyne or the alkene XXIII in the presence of a catalyst such as
Pd(OAc).sub.2 (J. Org. Chem. 1979, 4078) to give the products XXII
or XXV respectively. Catalytic hydrogenation of the alkyne XXII
over Lindlar's catalyst can afford the cis alkene XXV. When
R.dbd.H, compounds XXII, XXIV and XXV are substructures of II and
they can be treated as in method B to yield other examples of II.
8
[0262] Method F
[0263] An aryl thiol, alcohol or amine XXVI can be treated with a
base and then with reagent XXVII to yield the derivative XXVIII.
The group E'--F--Q can be transformed to another E'--F--Q group
using the other methods described here and yield examples of II
possessing an heteroatom attached to Ar.sup.2 in the linker X.
9
[0264] Method G
[0265] Compounds II possessing a cyclopropane unit as an X group
XXX can be synthesized via a reaction between the alkene XXIX and a
diazoacetate in the presence of a catalyst such as rhodium acetate
dimer. 10
[0266] Method H
[0267] Compounds II possessing a double bond as part of the linker
X can be synthesized via a Wittig reaction as exemplified in the
next scheme. Phosphonium salts XXXII and XXXIV can be obtained from
the corresponding Ar--CHR.sup.9--LG by reaction with Ph.sub.3P.
11
[0268] Method I
[0269] Compounds II possessing two heteroatoms as part of the
linker W as in XL can be synthesized from a reagent containing two
leaving groups XXVII and two aromatics compounds containing an
alcohol, an amine or a thiol function E as described in the
following scheme. 12
[0270] Method J
[0271] Compounds II possessing one heteroatom as part of the linker
W as in XLV can be synthesized from a reagent containing one
leaving group XLII or XLIII and an aromatic compound containing an
alcohol, an amine or a thiol function E Q(LI or XLIV) as described
in the following two equations. 13
ASSAYS FOR DETERMINING BIOLOGICAL ACTIVITY
[0272] The compound of Formula II can be tested using the following
assays to determine their prostanoid antagonist or agonist activity
in vitro and in vivo and their selectivity. The prostaglandin
receptors investigated were DP, EP.sub.1, EP.sub.2, EP.sub.3,
EP.sub.4, FP, IP and TP.
[0273] Stable Expression of Prostanoid Receptors in the Human
Embryonic Kidney (HEK) 293(ebna) Cell Line
[0274] Prostanoid receptor cDNAs corresponding to full length
coding sequences were subcloned into the appropriate sites of
mammalian expression vectors and transfected into HEK 293(ebna)
cells. HEK 293(ebna) cells expressing the individual cDNAs were
grown under selection and individual colonies were isolated after
2-3 weeks of growth using the cloning ring method and subsequently
expanded into clonal cell lines.
[0275] Prostanoid Receptor Binding Assays
[0276] HEK 293(ebna) cells are maintained in culture, harvested and
membranes are prepared by differential centrifugation, following
lysis of the cells in the presence of protease inhibitors, for use
in receptor binding assays. Prostanoid receptor binding assays are
performed in 10 mM MES/KOH (pH 6.0) (EPs, FP and TP) or 10 mM
HEPES/KOH (pH 7.4) (DP and IP), containing 1 mM EDTA, 10 mM
divalent cation and the appropriate radioligand. The reaction is
initiated by addition of membrane protein. Ligands are added in
dimethylsulfoxide which is kept constant at 1% (v/v) in all
incubations. Non-specific binding is determined in the presence of
1 .mu.M of the corresponding non-radioactive prostanoid.
Incubations are conducted for 60 min at room temperature or
30.degree. C. and terminated by rapid filtration. Specific binding
is calculated by subtracting non specific binding from total
binding. The residual specific binding at each ligand concentration
is calculated and expressed as a function of ligand concentration
in order to construct sigmoidal concentration-response curves for
determination of ligand affinity.
[0277] Prostanoid Receptor Agonist and Antagonist Assays
[0278] Whole cell second messenger assays measuring stimulation
(EP.sub.2, EP.sub.4, DP and IP in HEK 293(ebna) cells) or
inhibition (EP.sub.3 in human erythroleukemia (HEL) cells) of
intracellular cAMP accumulation or mobilization of intracellular
calcium (EP.sub.1, FP and TP in HEK 293(ebna) cells stably
transfected with apo-aequorin) are performed to determine whether
receptor ligands are agonists or antagonists. For cAMP assays,
cells are harvested and resuspended in HBSS containing 25 mM HEPES,
pH 7.4. Incubations contain 100 FM RO-20174 (phosphodiesterase type
IV inhibitor, available from Biomol) and, in the case of the
EP.sub.3 inhibition assay only, 15 .mu.M forskolin to stimulate
cAMP production. Samples are incubated at 37 C for 10 min, the
reaction is terminated and cAMP levels are then measured. For
calcium mobilization assays, cells are charged with the co-factors
reduced glutathione and coelenterazine, harvested and resuspended
in Ham's F12 medium. Calcium mobilization is measured by monitoring
luminescence provoked by calcium binding to the intracellular
photoprotein aequorin. Ligands are added in dimethylsulfoxide which
is kept constant at 1% (v/v) in all incubations. For agonists,
second messenger responses are expressed as a function of ligand
concentration and both EC.sub.50 values and the maximum response as
compared to a prostanoid standard are calculated. For antagonists,
the ability of a ligand to inhibit an agonist response is
determined by Schild analysis and both KB and slope values are
calculated.
[0279] Rat Paw Edema Assay
[0280] The method is the same as described in Chan et al (J.
Pharmacol. Exp. Ther. 274: 1531-1537, (1995)).
[0281] LPS-Induced Pyrexia in Conscious Rats
[0282] The method is the same as described in Chan et al (J.
Pharmacol. Exp. Ther. 274: 1531-1537, (1995)).
[0283] LPS-Induced Pyrexia in Conscious Squirrel Monkeys
[0284] The method is the same as described in Chan et al (Eur. J.
Pharmacol. 327: 221-225, (1997)).
[0285] Acute Inflammatory Hyperalgesia Induced by Carrageenan in
Rats
[0286] The method is the same as described in Boyce et al
(Neuropharmacology 33: 1609-1611, (1994)).
[0287] Adjuvant-Induced Arthritis in Rats
[0288] Female Lewis rats (body weight 146-170 g) were weighed, ear
marked, and assigned to groups (a negative control group in which
arthritis was not induced, a vehicle control group, a positive
control group administered indomethacin at a total daily dose of 1
mg/kg and four groups administered with a test compound at total
daily doses of 0.10-3.0 mg/kg) such that the body weights were
equivalent within each group. Six groups of 10 rats each were
injected into a hind paw with 0.5 mg of Mycobacterium butyricum in
0.1 mL of light mineral oil (adjuvant), and a negative control
group of 10 rats was not injected with adjuvant. Body weights,
contralateral paw volumes (determined by mercury displacement
plethysmography) and lateral radiographs (obtained under Ketamine
and Xylazine anesthesia) were determined before (day-1) and 21 days
following adjuvant injection, and primary paw volumes were
determined before (day-1) and on days 4 and 21 following adjuvant
injection. The rats were anesthetized with an intramuscular
injection of 0.03-0.1 mL of a combination of Ketamine (87 mg/kg)
and Xylazine (13 mg/kg) for radiographs and injection of adjuvant.
The radiographs were made of both hind paws on day 0 and day 21
using the Faxitron (45 kVp, 30 seconds) and Kodak X-OMAT TL film,
and were developed in an automatic processor. Radiographs were
evaluated for changes in the soft and hard tissues by an
investigator who was blinded to experimental treatment. The
following radiographic changes were graded numerically according to
severity: increased soft issue volume (0-4), narrowing or widening
of joint spaces (0-5) subchondral erosion (0-3), periosteal
reaction (0-4), osteolysis (0-4) subluxation (0-3), and
degenerative joint changes (0-3). Specific criteria were used to
establish the numerical grade of severity for each radiographic
change. The maximum possible score per foot was 26. A test compound
at total daily doses of 0.1, 0.3, 1, and 3 mg/kg/day, indomethacin
at a total daily dose of 1 mg/kg/day, or vehicle (0.5% methocel in
sterile water) were administered per os b.i.d. beginning post
injection of adjuvant and continuing for 21 days. The compounds
were prepared weekly, refrigerated in the dark until used, and
vortex mixed immediately prior to administration.
EXAMPLES
[0289] The invention is further illustrated in the following
non-limiting examples in which, unless otherwise stated:
[0290] yields are given for illustration only and are not
necessarily the maximum attainable;
[0291] all the end products of the formula II were analyzed by NMR,
TLC and mass spectrometry;
[0292] intermediates were all analyzed by NMR and TLC; most
compounds were purified by flash chromatography on silica gel,
recrystallization and/or swish (suspension in a solvent followed by
filtration of the solid) with a solvent such as ether:hexane
1:1;
[0293] the course of reactions was followed by thin layer
chromatography (TLC) and reaction times are given for illustration
only;
[0294] temperatures are in degrees Celsius.
Example 1
3-(2-(3-(2-(Benzyloxy)-3-Methylphenyl)Propyl)Phenyl)Propanoic
Acid
[0295] A mixture of the products of examples 28 and 29 was
dissolved in 2 ml MeOH:EtOAc 1:1 with
tris(triphenylphosphine)rhodium(I) chloride (2 mg) and the mixture
hydrogenated under 60 psi of H.sub.2. The reaction was followed by
mass spectroscopy and, when completed, the solvent was evaporated
and the product purified by flash chromatography with EtOAc:toluene
containing 1% AcOH.
[0296] MS (APCI, neg.) 387.2 (M-1), 279.2.
Examples 2 and 3
N2-((E)-3-(2-((E)-3-(2-(Benzyloxy)-3-Methylphenyl)-1-Propenyl)Phenyl)-2-Pr-
openoyl)-2-Thiophenesulfonamide and
N2-((E)-3-(2-((E)-3-(2-(Benzyloxy)-3-M-
ethylphenyl)-2-Propenyl)Phenyl)-2-Propenoyl)-2-Thiophenesulfonamide
[0297] These acylsulfonamides were prepared from the cinnamic acids
of examples 28 and 29 following the procedure of examples 44 and
45.
[0298] MS (APCI, neg.) 528.2 (M-1).
Examples 6 and 7
Sodium
(E)-3-(2-((E)-3-(2-(Benzyloxy)Phenyl)-1-Propenyl)Phenyl)-2-Propenoa-
te and Sodium
(E)-3-(2-((E)-3-(2-(Benzyloxy)Phenyl)-2-Propenyl)Phenyl)-2-P-
ropenoate
[0299] Step 1 1-allyl-2-(benzyloxy)benzene
[0300] Sodium hydride 80% in oil (800 mg, 1.2 equiv.) was added to
a solution of 2-allylphenol (2.998 g, 22 mmol) in DMF (40 ml) at 0
C and the mixture was stirred at 0.degree. C. for 15 min. and at
r.t. for 1 h. Benzyl bromide (2.9 ml, 1.1 equiv.) was then added
and the stirring was continued for 1 h. After hydrolysis with
saturated NH.sub.4Cl, the product was extracted in EtOAc, dried
over Na.sub.2SO.sub.4, and concentrated to yield 5.01 g of an oil
(yield 100%).
[0301] .sup.1H NMR (Acetone-d.sub.6) .delta. 3.40 (2H, d),
4.95-5.08 (2H, m), 5.13 (2H, s), 6.00 (1H, m), 6.90 (1H, dd), 7.03
(1H, d), 7.18 (2H, m), 7.32 (1H, m), 7.40 (2H, dd), 7.50 (2H,
d).
[0302] Step 2
(E)-3-(2-((E)-3-(2-(benzyloxy)phenyl)-1-propenyl)phenyl)-2-p-
ropenoic acid and
(E)-3-(2-((E)-3-(2-(benzyloxy)phenyl)-2-propenyl)phenyl)-
-2-propenoic acid
[0303] A mixture containing 2-bromocinnamic acid (250 mg, 1.10
mmol), the product of step 1 (271 mg, 1.1 equiv.), Pd(OAc).sub.2 (8
mg, 0.03 equiv.), LiCl (47 mg, 1 equiv.), LiOAc (280 mg, 2.5
equiv.) and Bu.sub.4NCl (611 mg, 2 equiv.) in DMF (2 ml) was
degassed and heated to 100 C o.n.0.5 N HCl was then added and the
product was extracted in EtOAc, washed with 0.5 N HCl, dried over
Na.sub.2SO.sub.4 and concentrated to dryness. Recrystallization
from ether:hexane afforded the title product as a white solid.
Yield: 251 mg, 62%.
[0304] .sup.1H NMR (Acetone-d.sub.6) .delta. 3.68 and 3.74 (2H,
2d), 5.10 and 5.20 (2H, 2s), 6.30-6.53 (2H, m), 6.70-6.93 (2H, m),
7.03 (1H, 2d), 7.18 (1H, m), 7.25-7.43 (7H, m), 7.50 (2H, m), 7.68
and 7.77 (1H, 2d), 8.03 (11H, 2d).
[0305] Step 3
[0306] The acids of step 2 were dissolved in EtOH and 1.0 equiv. of
NaOH 1.0 N was added. The solvent was evaporated, the oil dissolved
in water and the products were freeze-dried to afford a white
solid.
[0307] MS (APCI, neg.) 369.0 (M-1)
[0308] The products of the following examples have been prepared in
a manner similar to examples 6 and 7 and are mixtures of 2
compounds each.
2 Examples Note MS (APCI, neg.).sup.c 8 & 9 429.1 10 & 11 d
411.2 12 & 13 399.1 14 & 15 399.1 16 & 17 a 371.1,
327.2 (M-CO.sub.2H) 18 & 19 a 405.2, 361.0 (M-CO.sub.2H) 21
& 22 d 443.1 23 & 24 d 307.1 25 & 26 d 1263.1, 219.1
(M-CO.sub.2H) 28 & 29 b 383.2 38 & 39 d 293.1, 234.0 40
& 41 d 323.1, 264.1 72 & 73 368.9, 233.2 a Pd coupling
(step 2) at 120.degree. C. o.n., b the two products were separated
by HPLC on a NovaPak C18 column, c M-1 d the sodium salt was not
prepared
Example 20
2-(2-(3-(4-(Benzyloxy)-3-Methoxyphenyl)Propyl)Phenyl)Cyclopropane
Carboxylic Acid
[0309] Step 1
(E)-2-(2-(3-(4-(benzyloxy)-3-methoxyphenyl)propyl)phenyl)-2--
propenoic acid
[0310] A solution of 9-borabicyclo[3.3.1]nonane 0.5 M in THF (3.8
ml, 1.5 equiv.) was added slowly to
4-allyl-1-benzyloxy-2-methoxybenzene (257 mg, 1.21 mmol, prepared
as in examples 6 and 7, step 1) and the mixture was stirred at r.t.
for 30 min. K.sub.3PO.sub.4 (384 mg), 2-bromocinnamic acid (222 mg,
978 mmol), (1,1'-bis(diphenylphosphino)ferrocene)
dichloropalladium(II) (31 mg) and DMF (4 ml) were added and the
mixture was degassed and stirred at 50.degree. C. o.n. A saturated
solution of NH.sub.4Cl was added, the solution was acidified with
AcOH and the product was extracted in EtOAc, dried over
Na.sub.2SO.sub.4 and partially purified by flash chromatography
with EtOAc:toluene:AcOH 5:95:1.
[0311] Step 2 Methyl
2-(2-(3-(4-(benzyloxy)-3-methoxyphenyl)propyl)phenyl)-
cyclopropane-carboxylate
[0312] The acid of step 1 was treated with diazomethane in ether at
reflux. The solvent was removed and the ester was purified by flash
chromatography with EtOAc:toluene 2.5:97.5.
[0313] Step 3
[0314] The ester of step 2 was hydrolyzed with NaOH as in example
61, step 3. The final product was purified by HPLC with
EtOAc:toluene:AcOH 2.5:97.5:1 on a .mu.Porasil column to yield the
title cyclopropaneacetic acid.
[0315] .sup.1H NMR (acetone, d.sub.6) .delta. 1.43 (2H, m), 1.76
(1H, m), 1.93 (2H, m), 2.55 (1H, m), 2.65 (2H, t), 2.82 (2H, m),
3.80 (3H, s), 5.07 (2H, s), 6.72 (1H, d), 6.87 (1H, s), 6.91 (1H,
d), 7.03 (1H, d), 7.08-7.22 (3H, m), 7.28-7.41 (3H, m), 7.47 (2H,
d). MS (APCI, neg.) 415.1 (M-1), 324.3.
Example 27
(E)-3-(2-((E)-3-(2-Hydroxy-3-Methylphenyl)-2-Propenyl)Phenyl)-2-Propenoic
Acid
[0316] This product was obtained as a mixture with the other isomer
(E)-3-(2-((E)-3-(2-hydroxy-3-methylphenyl)-1-propenyl)phenyl)-2-propenoic
acid via a palladium coupling between 2-bromocinnamic acid and
2-alkyl-6-methylphenol as in examples 6 and 7, step 2. The title
acid was separated from the other isomer by recrystallization from
ether:hexane 1:1. Yield of pure product: 48%.
[0317] .sup.1H NMR (Acetone-d.sub.6) .delta. 2.20 (3H, s), 3.74
(2H, d), 6.34 ((1H, m), 6.44 (1H, d), 6.70 (1H, t), 6.80 (1H, d),
6.95 (1H, d), 7.22 (1H, d), 7.30 (1H, t), 7.35 (2H, m), 7.74 (1H,
d), 8.10 (1H, d).
Examples 30 and 31
(E)-3-(2-((E)-3-(2-((7-Chloro-2-Quinolinyl)Methoxy)-3-Methylphenyl)-1-Prop-
enyl)Phenyl)-2-Propenoic Acid and
(E)-3-(2-((E)-3-(2-((7-Chloro-2-Quinolin-
yl)Methoxy)-3-Methylphenyl)-2-Propenyl)Phenyl)-2-Propenoic Acid
[0318] Step 1 Methyl
(E)-3-(2-((E)-3-(2-hydroxy-3-methylphenyl)-2-propenyl-
)phenyl)-1-propenyl)phenyl)-2-propenoate and methyl
(E)-3-(2-((E)-3-(2-hydroxy-3-methylphenyl)-2-propenyl)phenyl)-2-propenyl)-
phenyl)-2-propenoate
[0319] These two products were prepared as a mixture via
esterification of the two acids in example 27 using the procedure
of example 61, step 1.
[0320] Step 2
[0321] Treatment of the two esters of step 1 with
7-chloro-2-(bromomethyl)- quinoline (obtained by bromination of
7-chloroquinaldine with N-bromosuccinimide) and hydrolysis of the
esters was performed as in example 61, steps 2 and 3.
[0322] MS (APCI, neg.) 470.0, 468.0 (M-1).
Example 32
2-(3-(2-Benzyloxy-3-Methylphenyl)Propyl)Benzoic Acid
[0323] 3-Allyl-2-(benzyloxy)toluene (prepared as in examples 6 and
7, step 1) was treated with 9-BBN and then with ethyl
2-bromobenzoate as in example 20, step 1, to give the ester of the
title compound. This ester was hydrolyzed as in example 61, step
3.
[0324] .sup.1H NMR (acetone d.sub.6) .delta. 1.95 (2H, m), 2.30
(3H, s), 2.75 (2H, m), 3.08 (2H, dd), 4.70 (2H, s), 6.92-7.12 (3H,
m), 7.24-7.53 (8H, m), 7.93 (1H, d).
Examples 33 and 34
Sodium 2-(3-(2-Benzyloxy-3-Methylphenyl)-1-Propenyl)Benzoate and
Sodium 2-(3-(2-Benzyloxy-3-Methylphenyl)-2-Propenyl)Benzoate
[0325] 3-allyl-2-(benzyloxy)toluene (prepared as in examples 6 and
7, step 1) was coupled to ethyl 2-bromobenzoate as in examples 6
and 7, step 2. The resulting ester was hydrolyzed as in example 61,
step 3.
[0326] .sup.1H NMR (acetone d.sub.6) .delta. 2.25 and 2.32 (3H,
2s), 3.64 and 3.97 (2H, 2d), 4.76 and 4.93 (2H, 2s), 6.33 and 6.50
(1H, 2td), 6.68-7.64 (12H, m), 7.90 and 7.98 (1H, 2d).
[0327] The sodium salts were prepared as in examples 6 and 7, step
3.
Example 35
Sodium
(E)-3-(2-(3-(2-Benzyloxy-3-Methylphenyl)Propyl)Phenyl)-2-Propenoate
[0328] Step 1
2-(3-(2-benzyloxy-3-methylphenyl)propyl)benzaldehyde
[0329] 3-allyl-2-(benzyloxy)toluene was treated with 9-BBN and then
with 2-bromobenzaldehyde as in example 20, step 1, to give the
title aldehyde. Yield 58%.
[0330] Step 2 Ethyl
(E)-3-(2-(3-(2-benzyloxy-3-methylphenyl)propyl)phenyl)-
-2-propenoate
[0331] To the aldehyde of step 1 (850 mg, 2.47 mmol) was added
(methoxycarbonylmethylene)triphenylphosphorane (1.24 g, 1.5 equiv.)
and the mixture was heated to 80 C in 25 ml of toluene for 10
h.
[0332] NH.sub.4Cl was added and the mixture was extracted in EtOAc,
dried over Na.sub.2SO.sub.4 and the product was purified by flash
chromatography with EtOAc:toluene 2.5:97.5. Yield: 770 mg, 78%.
[0333] Step 3
[0334] Hydrolysis of the ester was performed as in example 61, step
3.
[0335] MS (APCI, neg.) 385.1 (M-1).
[0336] The sodium salt was prepared as in examples 6 and 7, step
3.
[0337] The products of the following table were prepared in a
manner similar to example 34.
3 Example # MS (APCI, neg.) 36 401.2 (M-1), 310.0 37 401.2 (M-1),
310.0
Example 42
Sodium
(E)-3-(2-((E)-3-(2-(Benzyloxy)Phenyl)-3-Hydroxy-1-Propenyl)Phenyl)--
2-Propenoate
[0338] Step 1 1-(2-(benzyloxy)phenyl)-2-propen-1-ol
[0339] 2-(benzyloxy)benzaldehyde (5 g, 23.6 mmol) was reacted with
vinylmagnesium bromide in THF (90 ml) at 0 C. The reaction was
quenched with 2 N HCl and the product was extracted in i-PrOAc,
dried over Na.sub.2SO.sub.4 and purified by flash chromatography
with EtOAc:toluene 2.5:97.5.
[0340] Step 2
[0341] A mixture containing the allylic alcohol of step 1 (298 mg,
1.24 mmol), 2-bromocinnamic acid (299 mg, 1.06 equiv.),
Bu.sub.4NOAc (380 mg, 1 equiv.), Et.sub.3N (1.2 ml),
PdCl.sub.2(Ph.sub.3P).sub.2 (26 mg, 0.03 equiv.) and DMF (5 ml) was
degassed and heated to 100 C for 2 h. After addition of NH.sub.4Cl
and acidification with AcOH, the product was extracted in EtOAc,
dried over Na.sub.2SO.sub.4 and purified by flash chromatography
with EtOAc:toluene:AcOH 10:90:5. Yield: 239 mg, 50%.
[0342] MS (APCI, neg.) 385.1 (M-1), 235.0
[0343] The sodium salt was prepared as in examples 6 and 7, step
3.
Example 43
N2-((E)-3-(2-(3-(2-(Benzyloxy)-3-Methylphenyl)Propyl)Phenyl)-2-Propanoyl)--
2-Thiophenesulfonamide, Sodium Salt
[0344] The mixture of the two acylsulfonamides of examples 2 and 3
were reduced by catalytic hydrogenation using 10% Pd/C in EtOAc at
atmospheric pressure for 3 days. Filtration through celite and
purification by flash chromatography yielded the title
sulfonamide.
[0345] .sup.1H NMR (Acetone-d.sub.6) .delta. 1.85 (2H, m), 2.30
(3H, s), 2.60 (4H, m), 2.71 (2H, t), 2.85 (2H, t), 4.70 (2H, s),
6.92-7.13 (7H, m), 7.20 (1H, dd), 7.30-7.50 (5H, m), 7.80 (1H, d),
7.95 (1H, d). MS (APCI, neg.) 531.9 (M-1).
[0346] The sodium salt was prepared as in examples 6 and 7, step
3.
Examples 44 and 45
N2-((E)-3-(2-((E)-3-(4-(Benzyloxy)-3-Methoxyphenyl)-1-Propenyl)Phenyl)-2-P-
ropenoyl)-2-Thiophenesulfonamide and
N2-((E)-3-(2-((E)-3-(4-(Benzyloxy)-3--
Methoxyphenyl)-2-Propenyl)Phenyl)-2-Propenoyl)-2-Thiophene
Sulfonamide, Sodium Salts
[0347] The product of examples 14 and 15 (254 mg, 634 .mu.mol) was
dissolved in 6 ml CH.sub.2Cl.sub.2. DMF (10 .mu.l) and oxalyl
chloride (76 ml, 1.4 equiv.) were then added at 0 C and the
solution was stirred at r.t. for 1.5 h. The solvent was evaporated
and the resulting acid chloride was redissolved in CH.sub.2Cl.sub.2
(6 ml). At 0 C, 2-thiophenesulfonamide (124 mg, 1.2 equiv.) and
Et.sub.3N (177 .mu.l, 2 equiv.) were added and the mixture was
stirred at 0 C for 1 h. 0.5 N HCl was then added and the product
was extracted in i-PrOAc, dried over Na.sub.2SO.sub.4 and purified
by flash chromatography on silica using EtOAc:toluene:AcOH 20:80:1.
Yield: 201 mg, 58%.
[0348] MS (APCI, neg.) 544.2 (M-1).
[0349] The sodium salts were prepared as in examples 6 and 7, step
3.
Example 46 and 47
Sodium
(E)-3-(2-((2-(2-(Benzyloxy)-3-Methylphenyl)Cyclopropyl)Methyl)Pheny-
l)-2-Propenoate and Sodium
(E)-3-(2-(2-((2-(Benzyloxy)-3-Methylphenyl)Meth- yl)Cyclopropyl)
Phenyl)-2-Propenoate
[0350] Step 1 Ethyl
2-((2-(2-(benzyloxy)-3-methylphenyl)cyclopropyl)methyl- )benzoate
and ethyl 2-(2-((2-(benzyloxy)-3-methylphenyl)methyl)cyclopronyl-
)benzoate
[0351] The intermediate ester of example 33 was treated with
portions of CH.sub.2N.sub.2 solution in ether and Pd(OAc).sub.2
alternatively and at 0 C until the reaction was complete. AcOH was
added and the mixture was filtered through silica with ether and
concentrated. This product was used as such in the next step.
[0352] Step 2
2-((2-(2-(benzyloxy)-3-methylphenyl)cyclopropyl)methyl)benza-
ldehyde and
2-(2-((2-(benzyloxy)-3-methylphenyl)methyl)cyclopropyl)benzald-
ehyde
[0353] To a solution of the ester of step 1 (3.68 mmol) in THF (20
ml) was added diisobutylaluminum hydride 1.0 M in toluene (16 ml,
4.4 equiv.) at -72 C and the mixture was stirred at -40 C for 10
min. The reaction was quenched with sodium potassium tartrate 1.0 M
and was stirred at r.t. for 1.5 h. It was neutralized with AcOH and
extracted in i-PrOAc. The product was dried over Na.sub.2SO.sub.4
and concentrated.
[0354] This benzylic alcohol was oxidized with activated MnO.sub.2
(20 equiv.) in EtOAc at r.t. o.n. The mixture was then filtered
through celite, concentrated and the aldehyde was purified by flash
chromatography with toluene. Yield: 83% for steps 1 and 2.
[0355] Step 3
[0356] The aldehyde of step 2 was treated as in Example 34, steps 2
and 3, to afford the two title products. The sodium salts were
prepared as in examples 6 and 7, step 3.
[0357] MS (APCI, neg.) 397.1 (M-1).
Example 48
Sodium
(E)-3-(2-((E)-3-(2-Benzyloxy-3-Methylphenyl)-3-Hydroxy-1-Propenyl)P-
henyl)-2-Propenoate
[0358] Step 1 Methyl
(E)-3-(2-((E)-3-(2-benzyloxy-3-methylphenyl)-3-acetox-
y-1-propenyl)phenyl)-2-prolenoate and methyl
(E)-3-(2-((Ea-3-(2-benzyloxy--
3-methylphenyl)-1-acetoxy-2-propenyl)phenyl)-2-propenoate.
[0359] The two products of examples 28 and 29 were esterified with
NaH and MeI as in example 61, step 1. These esters (928 mg, 2.33
mmol) were heated to reflux in AcOH (15 ml) with SeO.sub.2 (310 mg,
1.2 equiv.) for 15 min. After neutralization wit NaHCO.sub.3, the
products were extracted in EtOAc, dried over Na.sub.2SO.sub.4 and
purified by flash chromatography with EtOAc:toluene 5:95.
[0360] Step 2 Methyl
(E)-3-(2-((E)-3-(2-benzyloxy-3-methylphenyl)-3-hydrox-
y-1-propenyl)phenyl)-2-propenoate
[0361] The product of step 1 (2.3 mmol) was treated with
1.8-diazabicyclo[5.4.0]undec-7-ene (3 drops) in MeOH (10 ml) for 2
h. After evaporation, the title product was separated from the less
polar cyclized isomer (methyl
2-(3-((E)-2-(2-(benzyloxy)-3-methylphenyl)-1-ethe-
nyl)-1,3-dihydro-1-isobenzofuranyl)acetate) by flash chromatography
with EtOAc:toluene 2.5:97.5 and 5:95.
[0362] Step 3
[0363] Hydrolysis was performed as in example 61, step 3. The
sodium salt was prepared as in examples 6 and 7, step 3. MS (APCI,
neg.) 399.1 (M-1), 249.0.
Examples 50 and 51
(E)-3-(2-((E)-3-(2-(2,6-Dichlorobenzyloxy)-3-Methylphenyl)-3-Hydroxy-1-Pro-
penyl)Phenyl)-2-Propenoic Acid and
(E)-3-(2-((E)-3-(2-(2,6-Dichlorobenzylo-
xy)-3-Methylphenyl)-1-Hydroxy-2-Propenyl)Phenyl)-2-Propenoic
Acid
[0364] Step 1
(E)-3-(2-((E)-3-(2-(2,6-dichlorobenzyloxy)-3-methylphenyl)-3-
-acetoxy-1-propenyl)phenyl)-2-propenoic acid and
(E)-3-(2-((E)-3-(2-(2,6-d-
ichlorobenzyloxy)-3-methylphenyl)-1-acetoxy-2-propenyl)phenyl)-2-propenoic
acid
[0365] The product of example 61 was treated with SeO.sub.2 in AcOH
as in example 48, step 1 to afford the two title acetates. Yield:
92%.
[0366] Step 2
[0367] The two acetates of step 1 (153 mg, 282 .mu.mol) were heated
in AcOH:H.sub.2O 1:1 (14 ml) at 105 C for 45 min. After addition of
NH.sub.4Cl, the products were extracted in EtOAc, dried over
Na.sub.2SO.sub.4 and purified by flash chromatography with
EtOAc:toluene:AcOH 10:90:1. The two products were separated by HPLC
on a NovaPak C18 cartridge using MeOH:(1:1 AcOH:AcONa 2 g/L) 7:3
and UV detection at 280 mm.
[0368] The more polar product was
(E)-3-(2-((E)-3-(2-(2,6-dichlorobenzylox-
y)-3-methylphenyl)-1-hydroxy-2-propenyl)phenyl)-2-propenoic acid.
Yield: 28 mg.
[0369] .sup.1H NMR (acetone d.sub.6) .delta. 2.10 (3H, s), 5.20
(2H, s), 5.73 (1H, d), 6.20 (1H, d), 6.47 (1H, dd), 6.97 (1H, t),
7.04 (1H, d), 7.10 (1H, d), 7.37-7.48 (6H, m), 7.63 (1H, d), 7.72
(1H, d), 8.35 (1H, d). MS (APCI, neg.) decomposition.
[0370] The less polar isomer was
(E)-3-(2-((E)-3-(2-(2,6-dichlorobenzyloxy-
)-3-methylphenyl)-3-hydroxy-1-propenyl)phenyl)-2-propenoic
acid.
[0371] Yield: 17 mg.
[0372] MS (APCI, neg.) 467.0 (M-1), 291.0.
Example 58 and 59
(E)-3-(2-((E)-3-(2-(2,6-Dichlorobenzyloxy)-3-(Hydroxymethyl)Phenyl)-1-Prop-
enyl)Phenyl)-2-Propenoic Acid and
(E)-3-(2-((E)-3-(2-(2,6-Dichlorobenzylox-
y)-3-(Hydroxymethyl)Phenyl)-2-Propenyl)Phenyl)-2-Propenoic Acid
[0373] Step 1 3-allyl-2-(2,6-dichlorobenzyloxy)benzaldehyde
[0374] 2-(allyloxy)benzaldehyde (2.00 g, 12.33 mmol) was heated in
o-dichlorobenzene (20 ml) at reflux o.n. The mixture was poured on
top of a flash chromatography column and eluted with toluene:hexane
1:1.
[0375] Yield: 1.346 g, 67%.
[0376] Step 2
[0377] The phenol of step 1 was treated with NaH and
2.6-dichlorobenzyl bromide as in examples 6 and 7, step 1, to give
the benzyl ether. Then, the aldehyde was reduced with
diisobutylaluminum hydride in THF at -10 C for 15 min. (see
examples 46 and 47, step 2). Finally, a palladium coupling with
2-bromocinnamic acid was performed as in examples 6 and 7, step 2,
to give the two title isomers.
[0378] Overall yield: 65%.
[0379] MS(APCI, neg.) 467.1 (M-1), 291.1.
Example 61
Sodium
(E)-3-(2-((E)-3-(2-(2,6-Dichlorobenzyloxy)-3-Methylphenyl)-2-Propen-
yl)Phenyl)-2-Propenoate
[0380] Step 1 Methyl
(E)-3-(2-((E)-3-(2-hydroxy-3-methylphenyl)-2-propenyl-
)phenyl)-2-propenoate
[0381] The product of example 27 (2.001 g, 6.80 mmol) was dissolved
in DMF (14 ml) and NaH 80% in oil (244 mg, 1.2 equiv.) was added at
0 C. The mixture was stirred for an hour at 0 C, then MeI (635
.mu.l, 1.5 equiv.) was added and the stirring continued for 2 h.
After hydrolysis with 0.5 N HCl, the product was extracted in EtOAc
and purified by flash chromatography on silica with EtOAc:toluene
2.5:97.5 and 5:95. Yield: 1.70 g, 81%.
[0382] Step 2 Methyl
(E)-3-(2-((E)-3-(2-(2.6-dichlorobenzyloxy)-3-methylph-
enyl)-2--propenyl)phenyl)-2-propenoate
[0383] The product of step 1 was treated with NaH and
2,6-dichlorobenzyl bromide as in examples 6 and 7, step 1, to
afford the dichlorobenzyl ether.
[0384] Step 3
[0385] The ester (1.01 g, 2.18 mmol) was hydrolyzed with NaOH 10 N
(930 .mu.l) in THF:MeOH:H.sub.2O 4:2:1 (28 ml) at r.t. o.n. The
reaction was quenched with sat. NH.sub.4Cl, acidified with acetic
acid and the product was extracted in EtOAc, concentrated and
recrystallized in 20 ml ether:hexane 1:1. Yield: 746 mg, 75%.
[0386] The sodium salt was prepared as in examples 6 and 7, step
3.
[0387] MS (APCI, neg.) 452.0, 451.0 (M-1), 275.2.
[0388] The following compounds were prepared as in example 61.
4 Example # MS(APCI, neg.).sup.a 28 383.2 53 401.1, 275.2 55 419.1,
275.2 57 419.1, 275.2 63 451.1, 275.2 65 449.1, 275.2
[0389] a) M-1.
Example 70
Sodium (E)-3-(2-(3-Phenoxybenzyloxymethyl)Phenyl)-2-Propenoate
[0390] Step 1 Ethyl (E)-3-[2-(bromomethyl)phenyl]-2-propenoate
[0391] To a suspension of ethyl (E)-3-(2-methylphenyl)-2-propenoate
(20.0 g; 105 mmol) and NBS (19.64 g; 110.3 mmol) in refluxing
CCl.sub.4 was added benzoyl peroxide (1.27 g) and the mixture was
stirred for 12 h. The solution was cooled to r.t., filtered and
concentrated. Flash chromatography with EtOAc:hexane 5:95 yielded
the title compound (14.18 g, 50%).
[0392] .sup.1H NMR (CDCl.sub.3) .delta. 1.30 (3H, t), 4.25 (2H, q),
4.60 (2H, s), 6.45 (1H, d), 7.30 (3H, m), 7.57 (1H, m) and 8.05
(1H, d).
[0393] Step 2 Ethyl
(E)-3-(2-((3-phenoxy)benzyloxy)phenyl)-2-propenoate
[0394] To a solution of 3-phenoxybenzylalcohol (545 mg; 2.72 mmol)
in DMF (5 ml) was added NaH (92 mg; 3.1 mmol; 80% dispersion in
oil) and ethyl (E)-3-(2-(bromomethyl)phenyl)-2-propenoate (810 mg;
3.0 mmol). After 6 h at r.t., 20 mg extra NaH was added. The final
mixture was stirred at r.t. for 10 h then quenched using 0.3 ml of
AcOH. The mixture was diluted with Et.sub.2O (25 ml), washed with
water (3.times.20 ml) and brine, dried over MgSO.sub.4 and
concentrated. Flash chromatography with EtOAc:toluene 5:95 afforded
the desired material.
[0395] Yield: 822 mg, 78%.
[0396] Step 3
[0397] The ester of step 2 was hydrolyzed as in example 61, step 3,
to yield the title acid. The sodium salt was prepared as in
examples 6 and 7, step 3.
[0398] MS (APCI, neg.) 359.0 (M-1).
Example 71
Sodium (E)-3-(2-(2-Phenoxybenzyloxymethyl)Phenyl) -2-Propenoate
[0399] This product was prepared as in example 70 from
2-phenoxybenzyl alcohol.
[0400] MS (APCI, neg.) 359.0 (M-1).
Example 74
Sodium
(E)-3-(2-(3-(2-Benzyloxyphenoxy)Propoxy)Phenyl)-2-Propenoate
[0401] Step 1 Methyl
(E)-3-(2-(3-bromopropoxy)-phenyl)-2-propenoate
[0402] To a solution of methyl 2-hydroxycinnamate (1.31 g; 7.33
mmol) in 50 ml acetone was added 1,3-dibromopropane (1.50 ml; 14.8
mmol) and K.sub.2CO.sub.3 (4.36 g; 13.4 mmol). The mixture was
heated to reflux for 12 h, cooled to r.t, diluted with hexane (50
ml), filtered and finally concentrated to afford the title product
(1.96 g; 50% pure), which was used as such in the next step.
[0403] Step 2
[0404] 2-Benzyloxyphenol (obtained from catechol, NaH, and benzyl
bromide as in examples 6 and 7, step 1) was treated with NaH and
the product of step 1 as in examples 6 and 7, step 1 to afford the
ester of the title product. This ester was hydrolyzed as in example
61, step 3 to yield the acid. The sodium salt was prepared as in
examples 6 and 7, step 3.
[0405] MS (APCI, neg.) 403.1 (M-1), 233.1, 207.1.
Example 75
Sodium
(E)-3-(2-((E)-3-(2-(1-Phenylethoxy)-3-Methylphenyl)-2-Propenyl)Phen-
yl)-2-Propenoate
[0406] 1-Phenylethanol was obtained by reduction of acetophenone
with NaBH.sub.4 in THF:MeOH. It was then reacted with the ester of
example 61, step 1, via a Mitsunobu reaction (DIAD, Ph.sub.3P,
THF:CH.sub.2Cl.sub.2, Synth. Commun. 1994, 24, 1049), to yield the
ester of the title compound. This ester was hydrolyzed as in
example 61, step 3, to give the title acid.
[0407] The sodium salt was prepared as in examples 6 and 7, step
3.
[0408] MS (APCI, neg.) 397.1 (M-1), 293.0, 275.3, 233.2.
Examples 77 and 78
Sodium
(E)-3-(2-((E)-3-(3-Phenoxyphenyl)-1-Propenyl)Phenyl)-2-Propenoate
and Sodium
(E)-3-(2-((E)-3-(3-Phenoxyphenyl)-2-Propenyl)Phenyl)-2-Propeno-
ate
[0409] Step 1 1-bromo-3-phenoxybenzene
[0410] To a solution of phenol (5.08 g; 54 mmol) in 30 ml dry DMF
at 0.degree. C. was added portionwise NaH (1.98 g; 66 mmol; 80%
dispersion in oil). The mixture was stirred 30 min at r.t. then
1,3-dibromobenzene (33 ml; 273 mmol) and Cu.sub.2O (3.95 g; 28
mmol) were added. The final mixture was heated to reflux for 4 h,
cooled to r.t., diluted with Et.sub.2O (200 ml), washed with water
(3.times.200 ml), NaOH (1.0 M; 2.times.100 ml) and brine, dried
over MgSO.sub.4 and concentrated. Flash chromatography with hexane
afforded the desired material.
[0411] Yield: 7.62 g, 57%.
[0412] Step 2 1-allyl-3-phenoxybenzene
[0413] A suspension of 1-bromo-3-phenoxybenzene (2.01 g; 8.08
mmol), PdCl.sub.2(PPh.sub.3).sub.2 (296 mg; 0.42 mmol), allyl
tributyltin (3.13 g; 9.46 mmol), triphenylphosphine (455 mg; 1.73
mmol) and LiCl (1.39 g; 33 mmol) in 10 ml DMF was stirred at
100.degree. C. for 3 h. After cooling to r.t the mixture was
diluted with Et.sub.2O (75 ml), washed with water (3.times.50 ml)
and brine, dried over MgSO.sub.4 and concentrated. Flash
chromatography with hexane afforded the desired material.
[0414] Yield: 1.39 g, 81%.
[0415] Step 3
[0416] Using the procedure of examples 6 and 7, steps 2 and 3, the
product of step 2 was transformed to the title compounds.
[0417] MS (APCI, neg.) 355.1 (M-1), 311.2.
Examples 79 and 80
Sodium
(E)-3-(2-((E)-3-(3-Phenylbenzo[b]furan-7-yl)-1-Propenyl)Phenyl)-2-P-
ropenoate and Sodium
(E)-3-(2-((E)-3-(3-Phenylbenzo[b]furan-7-yl)-2-Propen- yl)
Phenyl)-2-Propenoate
[0418] Step 1 2-(2-bromophenoxy)-1-phenyl-1-ethanone
[0419] To a solution of 2-bromophenol (8.71 g; 50.3 mmol) and
bromoacetophenone (10.1 g; 50.5 mmol) in 50 ml acetone was added
K.sub.2CO.sub.3 (7.02 g; 50.8 mmol). The mixture was heated to
reflux for 10 h, cooled to r.t., filtered, diluted with EtOAc (100
ml), washed with HCl (1.0 M, 2.times.100 ml) and brine, dried over
MgSO.sub.4 and concentrated. The residual solid was recrystallized
from EtOAc:hexane to afford the desired material.
[0420] Yield: 11.6 g, 79%.
[0421] Step 2 3-phenylbenzo[b]furan-7-yl-bromide
[0422] A mixture of 2-(2-bromophenoxy)-1-phenyl-1-ethanone (6.31 g)
and polyphosphoric acid (285 g) was stirred at 95.degree. C. for 6
h. The resulting solution was cooled to 50.degree. C., poured in
water (2 L), extracted with Et.sub.2O (2.times.1 L). The combined
organic extracts were washed with water (4.times.500 ml) and brine,
dried over MgSO.sub.4 and concentrated. The residual solid was
filtered on a plug of silica gel using Et.sub.2O. Recrystallization
in hot hexane yielded the title compound (4.63 g; 78%).
[0423] Step 3
[0424] Using the procedure of examples 77 and 78, steps 2 and 3,
the bromide of step 2 was transformed to the title acid. The sodium
salts were prepared as in examples 6 and 7, step 3.
[0425] MS (APCI, neg.) 379.4 (M-1), 335.1.
Examples 81 and 82
N2-((E)-3-(2-((E)-3-Phenyl-1-Propenyl)Phenyl)-2-Propenoyl)-2-Thiophenesulf-
onamide and
N2-((E)-3-(2-((E)-3-Phenyl-2-Propenyl)Phenyl)-2-Propenoyl)-2-T-
hiophenesulfonamide
[0426] These acylsulfonamides were prepared from the cinnamic acids
of examples 25 and 26 following the procedure of Synlett 1995,
1141.
[0427] MS (APCI, neg.) 408.2 (M-1).
Examples 83 and 84
N2-((E)-3-(2-((E)-3-(4-Methoxyphenyl)-1-Propenyl)Phenyl)-2-Propenoyl)-2-Th-
iophenesulfonamide and
N2-((E)-3-(2-((E)-3-(4-Methoxyphenyl)-2-Propenyl)Ph-
enyl)-2-Propenoyl)-2-Thiophenesulfonamide
[0428] These acylsulfonamides were prepared from the cinnanic acids
of examples 38 and 39 following the procedure of Synlett 1995,
1141.
[0429] MS (APCI, neg.) 438.1 (M-1), 233.2.
* * * * *